Download Chronic Kidney Disease, stages 1-3

Editors
Althea Mahon
Karen Jenkins
Project Co-ordinator
María Cruz Casal
Chronic Kidney Disease
A Guide to Clinical Practice
This handbook is an initiative of EDTNA/ERCA
Chronic Kidney Disease (CKD) Interest Group
A limited edition will be available in the following
languages: English, Spanish, Greek, Czech,
Hebrew, Portuguese and Turkish
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First edition: July 2007
European Dialysis and Transplant Nurses Association/ European Renal Care
Association (EDTNA/ERCA)
Pilatrustrasse 35, Postfach 3052, 6002 Luzern, Switzerland
www.edtnaerca.org
ISBN: 978-84-611-8259-6
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
6
Acknowledgments
This book is an initiative of EDTNA/ERCACKD Interest Group. A
considerable contribution has been made by all Interest Group
Members: Karen Jenkins, Anastasia Liossatou, Sue Teasdale,
Tai Mooi Ho Wong and Nurit Cohen in the production of this
publication. I would like to take this opportunity to thank all of
them. A special mention goes to Althea Mahon, Immediate Past
President of EDTNA/ERCA for her support in all phases of this
project: as Author, Editor and for Proof Reading. Along with
Karen Jenkins they have assumed all of these roles in order to
complete this book, and it has been greatly appreciated.
The EDTNA/ERCA would like to thank all authors of each
chapter
Editors:
Althea Mahon, RN, BSc Nursing, MSc Nursing
Barts and The London NHS Trust, London, UK
Karen Jenkins, RN PG Dip HE. MSc Nursing
Department of Renal Medicine, East Kent Hospitals NHS Trust,
Canterbury, UK
Co-ordinator
Maria Cruz Casal RN, DUE
Laboratory of Nephrology, Hospital Universitario 12 de Octubre,
Madrid, Spain
Acknowledgments
7
Reviewers:
Annemarie Visser, BSc, Dietetics Diploma in Hospital Dietetics
Barts and The London NHS Trust, London, UK
Lesley Bennett BA, RN, RM, Renal Cert
Oxford Radcliffe NHS Trust, Churchill Hospital, Oxford, UK
Diane Green BSc (Hons), RD
Salford Royal Hospitals NHS Trust, Manchester, UK
Dr Cordelia Ashwanden, PhD, MSc, BSc (Hons),
Adult Ed. Cert, RGN
Editor of the EDTNA/ERCA Journal of Renal Care
Ray James, BSc, MSc
Sub-editor of the EDTNA/ERCA Journal of Renal Care
Translators:
Thanks to Spanish, Greek, Czech, Israeli, Portuguese and
Turkish colleagues for their collaboration in the translation of
this book.
Sponsor:
The printing of the English version of this book has been
sponsored by an education grant from Roche Products Ltd
(UK)
Finally thanks go to the EDTNA/ERCA Executive Committee for
their support of the Chronic Kidney Disease Interest Group
Maria Cruz Casal
CKD Interest Group Chair
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
10
Preface
..............................................................................................................
15
Althea Mahon, RN, BSc Nursing, MSc Nursing
Barts and The London NHS Trust, London, UK
1. Anatomy and Physiology
of the Kidney ............................................................................................ 21
Melissa Chamney, RN, BN, MN, PG Dip Academic Practice,
City University, London, UK
2. Assessment, Diagnosis and
Management of Chronic
Kidney Disease ........................................................................................ 33
Karen Jenkins, RN, PG Dip HE, MSc Nursing
Department of Renal Medicine, East Kent Hospitals NHS Trust,
Canterbury, UK
3. Diagnostic Investigations in
Chronic Kidney Disease ................................................................ 53
Tai Mooi Ho Wong, RN, RM, DUE,
Hypertension Unit, Hospital del Mar, Barcelona, Spain
María Cruz Casal, RN, DUE
Laboratory of Nephrology. Hospital Universitario 12 de Octubre,
Madrid, Spain
Table of contents
11
4. Management of Anaemia in
Chronic Kidney Disease ................................................................ 85
Anastasia Liossatou, RN, BN, MSc
Nephrology Department, General Hospital of Kefalonia, Argostoli,
Kefalonia, Greece
Karen Jenkins, RN, PG Dip HE, MSc Nursing
Department of Renal Medicine. East Kent Hospitals NHS Trust,
Canterbury, UK
5. Nutrition and Chronic
Kidney Disease ...................................................................................... 105
Nurit Cohen, RN, BN, Master of Public Health (MPH),
Nephrology Department, Soroka University Medical Center,
Beer-Sheva, Israel
Lina Schwarz, RN, BN
Nephrology Department. Soroka University Medical Center,
Beer-Sheva, Israel
Diane Green, BSc (Hons), RD
Salford Royal Hospitals NHS Trust, Manchester, UK
6. The Effect of Diabetes Mellitus
on Chronic Kidney Disease
Progression ............................................................................................... 119
Sue Teasdale, RN, MA, BSc (Hons)
Salford Royal Hospitals NHS Trust, Manchester, UK
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
12
7. Cardiovascular Risk in Chronic
Kidney Disease ...................................................................................... 135
Sue Teasdale, RN, MA, BSc (Hons)
Salford Royal Hospitals NHS Trust, Manchester, UK
8. Management of Hypertension
in Chronic Kidney Disease ...................................................... 149
María Luisa Fernandez, RN, DUE
Hypertension Unit. Hospital Universitario 12 de Octubre,
Madrid, Spain
Julián Segura
Consultant Nephrologist, Hypertension Unit.
Hospital Universitario 12 de Octubre, Madrid, Spain
9. Patient Information
...........................................................................
Althea Mahon, RN, BSc, MSc Nursing
Barts and The London NHS Trust, London, UK
165
Table of contents
13
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
16
Preface
The early detection of chronic kidney disease (CKD) is
important as it provides the best opportunity to modify the
disease and reduce the associated cardiovascular risk. CKD
affects approximately 10% of the population1,2. Slowing the
progression of the disease has a major impact on reducing the
number of patients requiring renal replacement therapy and
improving the quality of life and outcomes for patients. It is
important to remember that, of those diagnosed with CKD, only
a small minority will reach end stage renal failure. This pocket
guide focuses on CKD stages 1-3 which has become a major
health concern as a result of early detection programmes.
The US NHANES study found the prevalence of stage
3 CKD and higher (i.e. a glomerular filtration rate of
60ml/min/1.73m2)1 in US adults in the unselected adult
population was 4.7%. This has been supported by a large
survey of 112,215 people from 12 general practice surgeries
in the UK where they found the prevalence to be 4.9%3. The
prevalence of CKD amongst people with other co-morbidities
such as diabetes, hypertension, and coronary heart disease
will be considerably higher than 4.9%.
The rise in diagnosis of CKD is multifactorial and, in part, is
associated with the ageing population. In addition to people
living longer, there have been improvements in chronic
disease management. Another important factor is the rise in
the incidence of type 2 diabetes, which is expected to double
in the next 25 years4. This in turn will lead to an increased
incidence of diabetic nephropathy, with approximately 30%
progressing to Stage 5 CKD. Other factors include an increase
in CKD prevalence with age5. Men with CKD have a more
rapid decline in renal function and progression of their renal
disease than women6. Some ethnic populations have a higher
Preface
17
prevalence of CKD such as South Asians in the UK7 and AfroCaribbean’s8. People from South Asia are at higher risk of CKD
linked to diabetes as there is a higher incidence of diabetes in
this community9. Afro-Caribbean’s and Africans are at greater
risk of CKD due to their higher prevalence of hypertension10.
The reality is that the majority of the CKD population have one
or more co-morbid condition, with a known higher prevalence
in ethnic minorities and lower socio-economic groups; combine
this with the increase in childhood obesity and prevalence of
diabetes and it is clear why we have an epidemic of CKD
and that, without effective prevention and early detection
programmes, this will continue to rise. Lastly the rise may also
be due to the development of guidelines such as KDOQI11 and
also nationally agreed CKD guidelines such as the UK CKD
guidelines12, along with the implementation of a simple blood
test-based formulae (e.g. GFR) that allows for easier and
earlier diagnosis of CKD and therefore increased reporting.
Whilst acknowledging that CKD is progressive, with good
management, mainly focusing on lowering blood pressure,
maximizing lipid control, lowering salt intake, encouraging
regular exercise and weight reduction, maintaining tight
diabetic control, giving smoking cessation advice and avoiding
nephrotoxic drugs this progression can be slowed. Early
detection and management of CKD stages 1-3 can be and
should be undertaken in primary care. Healthcare professionals
have a responsibility to understand the classification system
of CKD, its assessment process and treatment. It is hoped
that this pocket guide will be a useful tool in the assessment,
diagnosis, management and treatment of the early stages of
CKD.
Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
References
1.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey A. Prevalence of
chronic kidney disease and decreased kidney function in the adult US
population: Third national health and nutrition survey. Am J Kidney
Dis, 2003; 41, (1): 1-12.
2. John R, Webb M, Young A, Stevens PE. Unreferred
chronic
kidney
disease:
a
longitudinal
study.
Am J Kidney Dis 2004; 43: 825-835.
3. de Lusignan S, Chan T, Stevens P, O’Donoghue D, Hague N, Dzregah
B et al. Identifying patients with chronic kidney disease from general
practice computer records. Fam Pract 2005; 22, (3): 234-241.
4. Atkins R. The epidemiology of chronic kidney disease. Kidney Int
2005; 67, (Supp 94): S14-S18.
5. Rodriguez-Puyol D. Aging kidney. Kidney Int 1998; 54: 2247-2265.
6. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the
progression of nondiabetic renal disease: a meta-analysis. J Am Soc
Nephrol 2000; 11(2):319-329.
7. Buck K, Feehally J. Diabetes and renal failure in Indo-Asians in the
UK: a paradigm for the study of disease susceptibility. Nephrol Dial
Transplant 1999; 23: 1555-1557.
8. United
States
Renal
Data
System.
Annual
data
report:
incidence
and
prevalence
of
ESRD
(2003).
Am J Kidney Dis 2003; 42 (Suppl 5): S37-41.
9. Lightstone L. Preventing kidney disease: the ethnic challenge. The
National Kidney Research Fund: Peterborough. 2001.
10. Raleigh VS. Diabetes and hypertension in Britain’s ethnic minorities:
implications for the future of renal services. BMJ 1997; 313:209-215.
11. National Kidney Foundation. Clinical practice guidelines
for
chronic
kidney
disease:
evaluation
classification
and stratification. Am J Kidney Dis 2002; 39 (Supp 1):
S1-266.
12. Chronic Kidney Disease in Adults: UK CKD Guidelines for Identification,
Management and Referral of adults (2005). Available from:
http//www.renal.org/CKDguide/ckd.html
Preface
19
21
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
22
Learning Outcomes
•
•
•
Review knowledge and understanding of the normal
anatomy and physiology of the kidney
An understanding of the pathophysiology of chronic
kidney disease (CKD) and the most common causes
of CKD
Knowledge of the signs and symptoms of CKD
Introduction:
The kidneys perform a number of important regulatory, excretory
and hormonal functions that will be discussed in this chapter.
The most significant role of the kidneys is to appropriately
filter waste products from the blood excreting them in the urine.
The kidneys process the blood to form urine, which serves
several important functions.
• Waste products from cell activity are excreted
• Fluid that accumulates in the body from ingestion of food
and water is removed
• The concentration of many substances within the body is
maintained within limits
The kidneys typically produce 180L of filtrate from the blood
per day; however the vast majority of the filtered fluid is
reabsorbed into the bloodstream. Approximately 2 litres of
fluid is finally excreted as urine. The remaining 178 litres of
Anatomy and Physiology of the Kidney
fluid are reabsorbed back into the blood stream so that normal
metabolite concentration and homeostasis are maintained1.
Large molecules such as red blood cells and protein are
retained within the blood and smaller molecules enter the
filtrate. Only excess fluid and metabolic waste and toxic
products are removed from the body. Kidneys play a crucial
role in maintaining water and electrolyte balance. Kidneys also
regulate acid base balance within a narrow range2.
The purpose of this chapter is to identify the main parts of the
kidney and describe their basic function.
Normal Anatomy and Physiology
The kidneys lie on either side of the spine, just below the ribs
at the back of the body and each kidney is approximately
10 - 15 cms in length and shaped like a bean, this is
proportional to the size of the individual. The right kidney is
slightly lower than the left kidney due to the existence of the
liver on that side3. Approximately 20% of cardiac output passes
through the kidneys per minute. Under normal physiological
conditions this blood flow is autoregulated, ensuring
acceptable Glomerular Filtration Rate (GFR), ultrafiltration,
selective secretion and excretion of substances which
contribute to the production of urine and elimination of
metabolic waste products4. A high rate of blood flow and
normal blood pressure within the kidneys is essential for the
formation of urine2. The kidneys receive a constant supply of
blood which needs to be filtered in order to remove the excess
water and waste. In this manner the kidneys also regulate the
amount of various substances in the blood stream, so that
homeostasis is maintained.
So how does it all work?
The functional unit of the kidney is called the nephron and is
able to create urine by itself. Therefore it is not necessary to
23
Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
describe the entire kidney, but merely the operation of one
nephron to explain the function of the kidney5. Each kidney
contains approximately one million nephrons, each one of
which has it’s own glomerulus. Inflammation, damage and
destruction of the glomerulus will adversely affect it’s capacity
to filter blood and this in turn will reduce the scope of the
nephron to process the filtrate and produce urine. Since
the glomeruli filter waste products and water from the blood
any glomerular damage will adverely affect the person’s
homeostasis. The kidney also contains a system of collecting
ducts that carry urine through the renal pyramids into the
calyces, in the renal pelvis to the ureter. The systemic blood
pressure determines if blood enters the glomerulus from the
afferent arteriole. Holes in the capillary lining allow small
particles to pass into the renal tubule and larger proteins
are retained as they cannot pass through the glomerular
filtration barrier8.
Glomerular filtration is the process by which filtrate is
produced and it is the first phase in urine production. The
filtrate produced consists of virtually all blood components
except larger molecules such as protein and red blood cells.
However, many of the smaller substances that pass freely
through the glomerulus are vital for normal body function.
A process called tubular reabsorption is the second phase
which selects certain substances from the filtrate and returns
them to the blood via the peritubular capillaries, thus avoiding
loss into the urine. Tubular secretion is the third phase where
substances which are not filtered are secreted into the tubule
and excreted. By the time the final excretory product (urine)
drains from the collecting duct into the renal pelvis it is greatly
reduced in volume. The urine removes toxic waste products
from the body as well as excess salt and waterr4.
The glomerulus is a high pressure capillary bed which
causes fluid to be filtered out of the blood. By contrast the
peritubular capillary bed has low pressure which allows fluid
Anatomy and Physiology of the Kidney
Diagram 1: The Nephron.
Proximal
tubule
Bowman's
capsule
25
Peritubular
capillary network
Distal
tubule
Collecting
tubule
Glomerulus
Artery
Efferent arteriole
Afferent arteriole
Juxtaglomerular
apparatus
Collecting
duct
Vein
Loop of
Henle
Vasa
recta
to be reabsorbed back into the blood from the tubules. As
solutes are transported out of the proximal tubules in particular
by the reassertion process, an osmotic gradient is established
causing water to be absorbed. Consequently over 65% of the
glomerular filtrate is reabsorbed before entering the Loop of
Henle. Progressively lower fractions of water are reabsorbed
as the filtrate passes through the tubular system. By varying
the rate of reabsorption, large and small volumes of urine can
be generated allowing extracellular fluid volume in the body to
be maintained which in turn is of importance in the control of
blood pressure9. In addition to water, a number of substances
of nutritional importance are reabsorbed such as glucose,
proteins and amino acids. The vasa recta are involved in the
very important task of concentrating the urine. Without the
ability of the kidneys to concentrate urine, a great deal more
water would be needed to remove solutes from the blood3.
Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
This would require very regular drinking and result in a high
urine output.
The glomerular capillaries have very high permeability, 100
to 500 times greater than the permeability of capillaries in
other body tissues. When blood enters the glomerulus large
quantities of fluid are filtered from the blood forming the
glomerular filtrate which then enters the Bowman’s capsule.
Although the glomerular membrane is highly permeable,
it is also selective, depending on the molecular size of a
given substance. The permeability to large molecules such
as proteins is very low and thus these are confined to the
blood. For all practical purposes the glomerular filtrate has
virtually the same composition as blood plasma (containing
all dissolved solutes) with the exception of proteins. The rate
at which filtrate is generated is called the glomerular filtration
rate (GFR).
It is important that the GFR is tightly controlled. Any disparity
would otherwise upset the fine balance between filtration and
reabsorption, which controls the volume of urine produced.
An increase in GFR would cause the filtrate to pass more
rapidly through the tubules at a rate exceeding reabsorption.
Similarly if the GFR decreases, all fluid entering the tubules
would be reabsorbed and there would be no urine output.
A mechanism called auto regulation ensures that the GFR
is tightly controlled. This is achieved by vasodilation of the
afferent arteriole and vasoconstriction of the efferent arteriole.
Although the GFR is maintained relatively constant, extremes
of mean arterial pressure ultimately cause some effect in urine
output. High arterial pressure leads to increase urine output
whereas at pressures below 50 mmHg urine output virtually
ceases. This link between arterial pressure and urine output
is called pressure diuresis.
A person’s bladder can hold on average 400 mls of urine
before they will feel the need to urinate and most people pass
two litres of urine per day. The kidneys are able to vary this
Anatomy and Physiology of the Kidney
output of urine between 400 - 1500 mls to maintain a
constant fluid volume3. Usually when these processes fail
urine production may cease altogether severely limiting the
removal of waste products and excess water from the body.
Some aspects of renal function are assessed by measuring
the concentrations of metabolites such as urea and creatinine,
both of which are excreted by the kidney. The glomerular
filtration rate (GFR) is also a measure of renal function and
will be discussed further in the CKD chapter.
Functions of the Kidney
As discussed above, the functions of the kidney include the
production of urine via filtration of the blood, reabsorption
of necessary electrolytes and excretion of waste products.
This way the kidneys control homeostasis and fluid
balance as well as acid-base and electrolyte balance.
Table 1: The functions of the kidney3
Excretory
• Excretion off metabolic waste products, e.g. urea and
creatinine
Regulatory
Regulation of:
• Body water volume
• Body fluid osmolality
• Electrolyte balance
• Acid-base balance
• Blood pressure
Metabolic
• Activation of vitamin D
• Production of Renin
• Production of Erythropoietin
(From Thomas, N (2002) Renal Nursing (2nd Ed), Bailliere Tindall, London, with permission
of Elsevier Publications).
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Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
They also control hormonal functions of renin production to
control blood pressure, erythropoietin production to stimulate
red cell production, and synthesis of vitamin D to assist with
intestinal absorption of calcium.
A number of hormones influence renal function and the
regulation of various substances:
• The Renin Angiotensin Aldosterone System maintains
blood pressure
• Aldosterone contributes to the control of sodium and
potassium by stimulating sodium re-absorption in the
distal tubules and collecting ducts
• Anti-Diuretic Hormone increases the absorption of water
• Erythropoietin is produced primarily by the kidneys and
is essential for haemoglobin production
• Vitamin D and Vitamin D3 are essential to form active
Vitamin D to maintain calcium balance
• Parathyroid Hormone is released by the parathyroid
glands to maintain calcium and phosphate levels
• Calcitonin affects plasma Ca+ levels
What happens in Chronic Kidney Disease
CKD is a progression from health to illness which results in a
permanent failure of the excretory, regulatory and hormonal
(metabolic) functions of the kidney. CKD can be a slowly
progressive disease over many months or years which
results from the gradual loss of nephrons. The function may
be stable for prolonged periods of time and can be managed
with conservative management strategies. CKD is often
asymptomatic in the early stages and is often not diagnosed
until sufficient impairment exists to retain uraemic toxins in
the blood. Unfortunately the damage caused by CKD is
irreversible and so unless the patient is managed appropriately,
particularly at the early stages, it can then be impossible to
delay or even stop their CKD progressing to later stages of
established renal failure where the person will require Renal
Replacement Therapy (RRT) of some form to maintain life.
Anatomy and Physiology of the Kidney
Renal Problems:
There are many presentations of CKD; it is not a disease itself
but the result of a number of disease processes which may
affect renal function such as:
• Glomerular diseases (Glomerulonephritis)
• Cystic diseases (Adult Polycystic Disease)
• Systemic diseases (Multiple Myeloma)
• Vascular diseases (Hypertension)
• Obstructive disorders (Renal Stones)
• Drug related reactions (Paracetamol, NSAIDS)
Diabetes is the fastest growing risk for renal failure in the
western world and hypertension is the second leading cause
of CKD. People with a family history of renal failure or a person’s
age are factors that cannot be controlled, but other factors
such as controlling blood glucose levels and blood pressure
can help renal function to be maintained for longer. The
KDOQI guidelines 200310 recommend a target blood pressure
should be <130 / 80 mmHg for patients with CKD, regardless
of the degree of proteinuria.
Signs and Symptoms of CKD:
In the early stages of CKD the remaining healthy nephrons
compensate for the destroyed nephrons by increasing in size
and working harder. Over time their ability to adapt to the loss
of nephrons fails and it is then that the signs and symptoms of
CKD start to become evident. Most substances are eliminated
from the body as they are produced, primarily by way of the
kidneys. When these cannot be removed from the body due to
renal failure this will account for some of the disordered body
functions11.
Since patients with CKD stages 1 to 3 rarely have symptoms
they may be unaware that they have a problem with their
kidneys and are often diagnosed after blood tests are
29
Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
performed for other reasons. Waste products build up at
later stages of CKD, which can cause symptoms such as
nausea, vomiting, itchy skin, shortness of breath, oedema
and symptoms of anaemia and renal bone disease. These
symptoms affect people differently, but their overall quality
of life is diminished and appropriate treatment is needed to
assist them. People who have diabetes and/or hypertension
usually have their kidney function checked annually. This
type of screening can often identify early changes in kidney
function.
Summary
CKD is a common problem and improved detection and
classification using standardized criteria is needed to
improve patient outcomes12. Understanding of the anatomy
and physiology of the workings of the kidneys are important
to be aware of if we are to make progress and advances in
this specialism.
References
1.
2.
3.
4.
5.
6.
7.
8.
Al-Khader A and Al-Jondeby M. Handbook for Dialysis Nurses
(2nd Ed). Al Sayyari: Saudi Arabia, 2006.
Thibodeau G and Patton K. The Human Body in Health & Disease
(4th Ed). Elsevier Mosby: Missouri, 2005.
Thomas N. Renal Nursing (2nd Ed). Bailliere Tindall: London, 2002.
Montague S, Watson R and Herbert R. Physiology for Nursing
Practice (3rd Ed). Elsevier: Edinburgh, 2005.
Guyton A. Human Physiology and Mechanisms of disease (5th Ed).
W.B. Saunders Company: Philadelphia, 1992.
Ind D. Nephrology Nursing Practice Student Notes. The Queen
Elizabeth Hospital: Adelaide, 2004.
Stein A and Wild J. Kidney Dialysis and Transplants. Class
Publishing: London. 2004.
Steggall M. in Brooker C and Waugh A. Foundations of Nursing
Practice, Fundamentals of Holistic Care. Mosby Elsevier:
Philadelphia. 2007.
Anatomy and Physiology of the Kidney
Seeley R, Stephens T and Tate P. Anatomy and Physiology (7th Ed).
McGraw Hill: New York, 2006.
10. US National Kidney Foundation. Kidney Disease Outcomes Quality
Initiative (KDOQI), www.kdoqi.org, accessed 15th March 2007.
11. Vander A. Renal Physiology (3rd Ed). McGraw Hill: New York. 1985.
12. Coresh J, Astor B, Greene T, Eknoyan G, Levy A. Prevalence of
chronic kidney disease and decreased kidney function in the adult
US population: third national health and nutrition examination survey,
Am J of Kidney Dis 2003; 41 (1): 1-12.
9.
31
33
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Learning Outcomes
34
•
•
•
•
To gain knowledge and understanding of the risk
factors and prevalence of Chronic Kidney Disease
(CKD)
To understand how kidney function is measured
To gain knowledge and understanding of the
classification of CKD
To gain insight into the referral process and
management of CKD
Introduction
Chronic kidney disease (CKD) is now recognised as a
major health problem. Studies carried out both in the
United States1 and the United Kingdom2 to investigate the
prevalence, progression and referral rates of CKD in the
general adult population, have shown that older age, diabetes
and hypertension are strongly associated with moderate or
severely decreased renal function. The growing prevalence
of CKD means that measures need to be taken to accurately
measure kidney function, stage of kidney disease, devise
referral criteria and develop clear management plans.
Epidemiology of CKD
The number of patients with chronic kidney disease (CKD),
and the subsequent need for renal replacement therapy (RRT),
has reached epidemic proportion and is anticipated to rise
further. CKD affects approximately 10% of the population
Assessment, Diagnosis and Management of CKD
worldwide1 and it is estimated that over 1.1 million patients
with end stage renal disease (ESRD) currently require
maintenance dialysis. A figure which is increasing at a rate
of 7% per year3. If the trend continues, by 2010 the number
will exceed 2 million4. This figure excludes third world
countries, where there is less availability of, and access to,
dialysis services, and is, therefore, an underestimate of the
true demand. In the UK the incidence of ESRD has doubled
over the last ten years and has now reached 101 patients
per million of population (pmp)5. This is below the European
and USA averages of approximately 135 and 336 pmp
respectively6. Studies such as the NHANES (National Health
and Nutrition Examination Survey) which provided data on
the adult unselected population estimated that 4.7% of US
adults had CKD stage 3 or higher (defined as estimated
glomerular filtration rate (eGFR) <60ml/min/1.73m2). They
also estimated that up to 11% of the general population
(19.2 million) has some degree of CKD1.
Risk Factors of CKD
Risk factors for CKD include:
• Diabetes
• Cardiovascular disease
• Smoking
• Obesity
• Sedentary lifestyle
• Low socio-economic status
UK studies have shown a higher incidence of CKD in deprived
areas7,8 consistent with both USA and Swedish studies9. Obesity
has become a global issue in developed countries adding to the
population of people with chronic disease. Those with diabetes
and hypertension are at greatest risk and have a higher rate
of renal problems than those in the normal population10. The
reality is that the majority of the CKD population have one or
35
Chronic Kidney Disease:
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A Guide to Clinical Practice (Stages 1-3)
more co-morbid conditions with a known higher prevalence
in ethnic minorities and lower socio-economic groups. This
along with the increase in childhood obesity and prevalence of
diabetes make it clear why there is becoming an epidemic of
CKD and that, without effective prevention and early detection
of CKD this will continue to rise.
Measurement of kidney function
Traditionally kidney function has been determined by
measuring serum creatinine alone. However, serum creatinine
alone is not an accurate index of the level of kidney function as
there is not a direct relationship between glomerular filtration
rate (GFR) and serum creatinine. By the time the creatinine
becomes elevated, there may already be a 50% reduction in
kidney function.
The use of the serum level of creatinine as an index of
Glomerular Filtration Rate (GFR) to measure kidney function
rests on three important assumptions:
• Creatinine is an ideal filtration marker whose clearance
approximates GFR
• Creatinine excretion rate is constant among individuals
and over time
• Measurement of serum creatinine is accurate and
reproducible across clinical laboratories
Although the serum creatinine concentration can provide a
rough index of the level of GFR, none of these assumptions
is strictly true, and numerous factors can lead to errors in
estimation of the level of GFR from the serum creatinine
concentration alone.
Factors other than the level of GFR can also influence
creatinine secretion include11:
• Kidney disease
• Reduced muscle mass
Assessment, Diagnosis and Management of CKD
•
•
•
•
Malnutrition
Ingestion of cooked meat
Trimethoprim; Cimetidine
Ketoacidosis
37
Creatinine is mainly derived from the metabolism of creatine in
muscle, and its generation is proportional to the total muscle
mass. As a result, mean creatinine generation is higher in
men than in women, in younger than in older individuals, and
in blacks than in whites. This leads to differences in serum
creatinine concentration according to age, gender, and race,
even after adjusting for GFR12.
In addition, measurement of creatinine clearance is not
easy. Urinary clearance measurements require timed urine
collections, which are difficult to obtain and often involve errors
in collection. Furthermore, day-to-day variation in creatinine
excretion exists, making estimation of GFR, even from a valid
24-hour urine collection, imprecise.
Therefore it is recommended that kidney function should be
assessed by an estimation of glomerular filtration rate (eGFR)
not creatinine alone. To do this there are specific formulae
available. The most widely used are:
• Modification of Diet in Renal Disease (MDRD)
• Cockcroft Gault
Equations estimating GFR based on serum creatinine are
more accurate and precise than estimates of GFR from
measurement of serum creatinine alone. Studies have
documented that creatinine production varies substantially
across sex, age, and ethnicity12.
Equations have the advantage of providing an estimate of GFR
which empirically combine all of these average effects while
allowing for the marked differences in creatinine production
between individuals13.
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Modification of Diet in Renal Disease (MDRD)
38
The four-variable Modification of Diet in Renal Disease
(MDRD) formula is used to estimate GFR in mls per minute11.
The formula requires the gender, age, serum creatinine
and ethnicity (black/non-black) of the patient. Assumption
of Caucasian ethnicity can be made when using MDRD if
ethnicity is unknown.
MDRD calculation:
The 4-variable Modification of Diet in Renal Disease (MDRD)
equation:
GFR (ml/min/1.73 m2) = 186 x {[Serum Creatinine mol/l/88.4]
-1.154} x {age (years) -0.203} x 0.742 if female and x 1.21 if
African American.
Cockcroft Gault (1976) calculation14
The formula takes into consideration: weight, gender
serum creatinine and age. However this technique tends to
underestimate creatinine clearance in obese patients and
overestimates it in patients who may be on a low protein diet.
Cockcroft Gault equation
In men:
(140-age) x weight in kg
Creatinine clearance = -------------------------------------------------· 1
72 x serum creatinine
In women:
(140-age) x weight in kg
Creatinine clearance = ------------------------------------------------- · 0.85
72 x serum creatinine
Assessment, Diagnosis and Management of CKD
The eGFR can be related to percentage of kidney function.
For example, an eGFR 20mls/min/1.73m2 = 20% kidney
function. A normal eGFR is considered to be more than
90mls/min/1.73m2.
How often should eGFR be measured?
eGFR should be measured at initial assessment and then at
least annually in all adult patients with:
1. Previously diagnosed CKD including:
• Identified renal pathology (e.g. polycystic kidney, biopsy
proven glomerular nephritis, reflux nephropathy)
• Persistent proteinuria
• Urologically unexplained haematuria
2. Conditions associated with a high risk of silent
development of obstructive kidney disease:
• Bladder voiding dysfunction (outflow obstruction,
neurogenic bladder)
• Urinary diversion surgery
• Urinary stone disease (more than one episode/year)
3. Conditions associated with a high risk of silent
development of parenchymal kidney disease:
• Hypertension, diabetes mellitus, heart failure
• Atherosclerotic coronary, cerebral, or peripheral
vascular disease
4. Conditions requiring long-term treatment with
potentially nephrotoxic drugs
• For example: ACE inhibitors (ACEI) Angiotensin
Receptor Blockers (ARB’s), Non steroidal anti-
39
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
inflammatory Drugs (NSAIDs), Lithium, Mesalazine,
Cyclosporin, Tacrolimus
40
5. Multi-system diseases that may involve the kidney
• For example systemic lupus erythematosus (SLE),
vasculitis, myeloma, rheumatoid arthritis
In summary, a normal range for serum creatinine
should no longer be given and management of the
patient needs to be based on eGFR. Until laboratories
are able to report eGFR MDRD and Cockcroft Gault
calculators can be downloaded from www.renal.org or
www.nephron.com.
Should you rely on eGFR for acute renal failure patients?
No, the eGFR is not appropriate for a patient with acute
renal failure, as it relies on a stable serum creatinine for its
predictive accuracy. eGFR cannot be used in children.
Staging of kidney disease
The presence of chronic kidney disease should be
established, based on presence of kidney damage and
level of kidney function (glomerular filtration rate - GFR),
irrespective of diagnosis.
Among patients with chronic kidney disease, the stage
of disease should be assigned based on the level of
kidney function, irrespective of diagnosis, according to the
K/DOQI CKD classification13 (Table 1).
Assessment, Diagnosis and Management of CKD
Table 1: Classification of CKD
Stage
Description
eGFR
(ml/min/1.73m²)
1
Kidney Damage with
Normal or n eGFR
t90
2
Kidney Damage with
mild p eGFR
60-89
3
Moderate p eGFR
30-59
4
Severe p eGFR
15-29
5
Kidney Failure
< 15 (or dialysis)
Definition of Chronic Kidney Disease
CKD is defined as either evidence of kidney damage or an
eGFR <60ml/min/1.73m2 for 3 months.
Kidney damage is defined as pathological abnormalities or
markers of damage including abnormal blood or urine tests
or imaging studies13,15.
K/DOQI suggests that:
• All individuals with eGFR <60 ml/min/1.73 m2 for 3
months are classified as having chronic kidney disease,
irrespective of the presence or absence of kidney
damage. The rationale for including these individuals
is that reduction in kidney function to this level or
lower represents loss of half or more of the adult level
of normal kidney function
• All individuals with kidney damage are classified as
having chronic kidney disease, irrespective of the level
of eGFR. The rationale for including individuals with
eGFR 60 ml/min/1.73 m2 is that eGFR may be
sustained at normal or increased levels despite
substantial kidney damage and that patients with kidney
41
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
damage are at increased risk of the two major outcomes
of chronic kidney disease: loss of kidney function and
development of cardiovascular disease
42
Other markers of kidney damage:
• Persistent microalbuminuria (measured by an albumin
creatinine ratio)
• Persistent proteinuria (after exclusion of other causes
e.g. urological)
• Persistent haematuria
• Structural abnormalities of the kidney
• Biopsy proven chronic glomerulonephritis
Patients found to have eGFR 60-89ml/min/1.73m2 without one
of these markers should not be considered to have CKD or
be subject to further investigation. Rate of change of eGFR
is important when considering disease progression and need
for referral. eGFR is considered stable if there is
<2ml/min/1.73m2 fall over 6 months or more.
Referral criteria
The changes in reporting of kidney function are already
having an effect on the number of referrals to nephrologists.
To provide guidance for referral the UK renal association
have drafted a set of referral guidelines which are available
from www.renal.org. Of course referral criteria may differ
amongst European countries and guidelines relevant to the
local area of practice should be considered. Table 2 shows UK
recommendations15 for referral as an example.
Assessment, Diagnosis and Management of CKD
Table 2: UK Recommendations
Estimated GFR
<15ml/min/1.73m2
Referral criteria
Immediate referral
Exceptions may include: patients in
whom CKD supervenes as part of
another terminal illness; patients in whom
further investigation and treatment is
inappropriate; those who have stable
function and appropriate investigations
and management interventions have
been performed and have an agreed care
pathway
15-29 ml/min/1.73m2
Urgent referral - routine if known to be stable
30-59 ml/min/1.73m2
Routine referral if:
Progressive fall in eGFR/increase in
creatinine, microscopic haematuria
Urinary PCR >45mg/mmol
Unexplained anaemia (Hb,11g/dl)
abnormal calcium, phosphate, or
potassium
Uncontrolled BP >150/90 on 3 agents
60-89 ml/min/1.73m2
Referral not required
Immediate referral for
• Malignant hypertension
• Hyperkalaemia (potassium >7.0mmol/L)
Renal problems
irrespective of eGFR
Urgent referral for:
• Proteinuria with oedema and low
serum albumin (Nephrotic syndrome)
Routine referral for:
• Dipstick proteinuria and urine PCR
>100mg/mmol
• Dipstick proteinuria and microscopic
haematuria
• Macroscopic haematuria but urological
tests negative
43
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Management of CKD
44
The KDOQI guidelines13,16 suggest that patients with chronic
kidney disease should be evaluated to determine:
• Diagnosis (Type of kidney disease)
• Co-morbid conditions
• Severity assessed by level of kidney function
• Complications related to level of kidney function
e.g. anaemia
• Risk for loss of kidney function
• Risk for cardiovascular disease
Treatment of CKD should include:
• Specific therapy, based on diagnosis
• Evaluation and management of co-morbid conditions
• Slowing the loss of kidney function
• Prevention and treatment of cardiovascular disease
• Prevention and treatment of complications of decreased
kidney function
• Preparation
for
kidney
failure
and
renal
replacement therapy
• Replacement of kidney function by dialysis and
transplantation, if signs and symptoms of uraemia are
present
A clinical action plan should be developed for each patient,
based on the stage of disease as defined by the K/DOQI CKD
classification13 (Table 3).
Provision should be made for the implementation of care plans
for all adult patients with CKD irrespective of age and should
be shared between primary, secondary and tertiary care.
The progression of CKD can be slowed down by focusing on:
• Blood pressure control
• Lipid control
Assessment, Diagnosis and Management of CKD
•
•
•
•
Glycaemic control
Healthy living - exercise
Smoking cessation
Avoiding nephrotoxic drugs
Both the UKPDS17 and DCCT18 study groups have shown
that good glycaemic control can decrease macrovascular
disease in type I and type II diabetes as well as slowing the
progression from albuminuria to microalbuminuria.
Table 3: K/DOQI CKD classification13
Description
eGFR
(ml/min/1.73m2)
Action
Diagnosis and treatment
Treatment of co-morbid
conditions
Slowing progression
Cardiovascular risk reduction
1
Kidney damage
with normal or
GFR
90
2
Kidney damage
with mild GFR
60-89
Estimating process
3
Moderate GFR
30-59
Evaluate and treat
complications
4
Severe GFR
15-29
Preparation for kidney
replacement therapy
5
Kidney failure
< 15
Replacement therapy or
(or dialysis) conservative management
45
Chronic Kidney Disease:
46
A Guide to Clinical Practice (Stages 1-3)
The use of angiotensin-converting enzyme (ACE inhibitors)
or angiotensin receptor blockers (ARBs) are effective at
reducing progression when there is concurrent proteinuria.
Target blood pressure may vary across Europe but in
the UK, one study19 showed that maintaining a blood
pressure below 130/75 mmHg, correlated to a reduction in
the progression of renal disease in people with type 2
diabetics with albuminuria.
It is essential that robust mechanisms are put in place in
both primary and secondary care for the early detection and
management of CKD. Education is of great importance for
both health care professionals and patients.
There are many challenges ahead for educating patients
about CKD. Perhaps the most important issue is how to avoid
labeling of patients and how to reduce anxiety when patients
are first told that they have kidney disease. Prevention of
kidney disease is crucial - but essentially the management
is the same for renal disease, diabetes and cardiovascular
disease - the priority is reducing cardiovascular risk.
The latest initiative in Europe is the forming of the
European Kidney Health Alliance (EKHA) which is
aims to raise the awareness of CKD on a European
Union level. There are four major stakeholders, ISN,
ERA-EDTA, EDTNA/ERCA and CEAPIR representing the
multidisciplinary team and patients.
Summary
Strategies for the management of people with chronic kidney
disease need to be in place to aid the prevention and help
slow down the progression of the disease. The International
Society of Nephrology (ISN) has for some time had a focus on
prevention and the COMGAN group believe in improving global
outcomes of kidney disease20. The new initiative by the Kidney
Disease: Improving Global Outcomes (KDIGO) group aims to
Assessment, Diagnosis and Management of CKD
develop a global approach to managing the CKD epidemic.
Their mission statement is “Improve the care and outcomes
of kidney disease patients worldwide through promoting
coordination, collaboration and integration of initiatives to
develop and implement clinical practice guidelines”. KDIGO
and the ISN are now working together on developing a CKD
strategy21.
Nephrology services need to adapt to cope with the increase
in the number of referrals which have been evident since
the introduction of eGFR reporting. Renal disease is a
chronic disease and as such needs a multi-disciplinary
approach in order to manage not only the renal disease but
also its cardiac and diabetic complications. This will involve
the education and training of general practitioners who are
the main contact point for many patients in the community
so that they feel confident in managing CKD stages1, 2 & 3
(without risk factors) in the community and thereby reduce
the burden of referrals to the nephrology units. Developing
guidelines is pivotal in addressing the current problem;
however the key to success lies in the implementation
process. Nurses are in a good position to take on this role
as there are clear guidelines available for managing CKD.
For example in the UK, the Renal Association in collaboration
with the Royal College of Physicians and General
Practitioners have provided a comprehensive document
to support both nephrology units and community services.
Many UK units have adapted these guidelines to meet the
local community needs and demands. The introduction
of such guidelines is also supported by renal teams
providing education to community physicians and nurses,
advising them when and how refer patients with CKD. Joint
working with renal units, community health care providers,
specialist service providers and patient groups is raising the
awareness of CKD and removing barriers which have
previously stood in the way of providing holistic patient care.
47
Chronic Kidney Disease:
48
A Guide to Clinical Practice (Stages 1-3)
Within Europe there are differences in roles and responsibilities
of nurses as was seen in the data from the European Network
of Renal Care Associations (ENRCA) project. This group in
2004 is made up of 10 National Associations (UK, Spain,
Israel, Croatia, Slovenia, Turkey, Greece, Belgium (Flanders),
Italy, Portugal and Cyprus) and the EDTNA/ERCA. They
surveyed 10% of renal units in each country to identify the task
portfolio and responsibilities of nurses and allied healthcare
professionals. They found that, for instance, the UK and Israel
had many nurse-led services in place whilst pre-dialysis care
was not usually performed by nurses in Spain. What will
become evident is how CKD is managed in the future within
these countries. Although many roles and responsibilities
have been physician-led in the past, this is an ideal
opportunity for nurses to review their way of thinking
throughout Europe and diversify the skills of healthcare
professionals.
Management of CKD requires a collaborative approach and
there is a need to be creative to enable patients to receive a
seamless journey of care.
Frequently asked Questions
1. Why is serum creatinine alone not a good
measurement of kidney function?
A: Serum creatinine is affected by the level of GFR
and by factors independent of GFR, including age,
gender, race, body size, diet, certain drugs, and
laboratory analytical methods
2. What is GFR?
A: GFR is glomerular filtration rate
3. What is a normal GFR?
A: More than 90 mls/min
Assessment, Diagnosis and Management of CKD
4. How can I calculate eGFR?
A: Laboratory measurement or download a calculator
from www.renal.orgg/ or www.nephron.co
p
m
5. How does eGFR relate to kidney function?
A: It corresponds with percentage of kidney function i.e.
eGFR 20mls/min = 20% kidney function
6. What is staging of CKD?
A: It is defined by the eGFR e.g. Stage 3 kidney disease
refers to an eGFR between 30-59 mls/min
7. At what stage should a patient be referred to a
Nephrologist?
A: This will depend on local guidelines but generally at
stages 3-5
8. Where should patients referred to a Nephrologist be
managed?
A: This will depend on the individual health care
system, but often it shared by the family doctor and
Nephrologist
References
1.
2.
3.
4.
5.
Coresh J, Astor BC, Greene T, Eknoyan G, Levey A. Prevalence of
chronic kidney disease and decreased kidney function in the adult
US population: Third national health and nutrition examination survey.
Am J Kidney Dis 2003; 41, (1): 1-12.
John R, M Webb, Young A, Stevens PE. Unreferred chronic kidney
disease: A longitudinal study. Am J Kidney Dis 2004; 43; (5):
825-835.
Lysaght MJ. Maintenance dialysis population dynamics: current trends
and long-term implications. J Am Soc Nephrol 2002; 13: 37-40.
Xue J, Ma J et al. A forecast of the number of patients with
end-stage renal disease in the United States to the year 2010.
J Am Soc Nephrol 2001; 12:2753-2758.
The Renal Association. UK Renal Registry. The sixth annual report
2004. Available at www.renalreg.com/home.htm
49
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6.
7.
50
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
A Guide to Clinical Practice (Stages 1-3)
Anandarajah S, Tai T, de Lusignan S, Stevens P, O’Donoghue D,
Walker M, Hilton S. The validity of searching routinely collected
general practice computer data to identify patients with chronic kidney
disease (CKD) : a manual review of 500 medical records. Nephrol
Dial Transplant 2005; 20, (10) :2089-2096.
Roderick P et al. What determines geographical variation rates
of acceptance onto renal replacement therapy in England?
J Health Serv Res Policy 1999; 4, (3): 139-146.
Drey N. The epidemiology of diagnosed chronic renal failure in
Southampton in South West Hampshire Health Authority. PhD
Thesis Southampton: University of Southampton, 2000.
Young EW, Mauger EA, Jiang KH, Port FK and Wolfe RA.
Socioeconomic status and end-stage renal disease in the United
States. Kidney Int 1994; 45, (3): 907-911.
Kissmeyer L, Kong C, Cohen J, Unwin RJ, Woolfson RG and Neld
GH. Community Nephrology : audit of screening for renal insufficiency
in a high risk population. Nephrol Dial Transplant 1999; 14:
2150-2155.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N and Roth D. more
accurate method to estimate glomerular filtration rate from serum
creatinine: a new prediction equation. Modification of Diet in Renal
Disease Study Group Ann Intern Med 1999;130 (6):461-79.
Perrone RD, Madias NE and Levey AS. Serum creatinine as an index
of renal function: New insights into old concepts. Clin Chem 1992;
38:1993-1953.
National Kidney Foundation. K/DOQI clinical practice guidelines for
chronic kidney disease: evaluation, classification, and stratification.
Am J Kidney Dis 2002; 39 (Suppl 2):S1–246.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from
serum creatinine. Nephron 1976; 16: 31-41.
Chronic Kidney Disease in Adults: UK CKD Guidelines for Identification,
Management and Referral of Adults. 2005. Available from:
http//.www.renal.org/CKDguide/ckd.html
Levey AS, Coresh J, Balk E et al. National Kidney Foundation Practice
Guidelines for chronic kidney disease: evaluation, classification and
stratification. Ann Intern Med 2003;139: 137–147.
UK Prospective Diabetes Study Group. Intensive blood –glucose
control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998; 352 :837-853.
The DCCT Research Group. The effect of intensive treatment
of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus.
New Engl J Med 1993; 329: 977-986.
Assessment, Diagnosis and Management of CKD
19. McIntosh A, Hutchinson A, Marshall S, Barnes S, Brown V, Hooper S
et al. Clinical Guidelines and Evidence Review for Type 2 Diabetes.
Renal Disease: Prevention and Early Management. Sheffield:
ScHARR, University of Sheffield, 2002. http://www.nice.org.uk
20. Kam-Tao Li P, Weening J, Dirks J et al. A report with consensus
statements of the International Society of Nephrology 2004 Consensus
Workshop on Prevention of Progression of Renal Disease, Hong
Kong, June 29, 2004. Kidney Int 2005; 67 (Supp 94): S2-S7. 2005.
21. Eknoyan G, Lameire N, Barsoum R, Eckardt K, Levin A et al. The
burden of kidney disease: Improving global outcomes. Kidney Int
2004; 66: 1310-1314.
51
53
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Learning Outcomes
•
54
•
To demonstrate an understanding of the different
types of diagnostic investigations including urine,
blood, imaging and renal biopsy tests
To interpret results within the clinical setting
Introduction
Routine
clinical
assessment
involves
undertaking
in-depth physical examination, social, medical and medication
histories. Diagnostic investigations play an important role in
the assessment of the cause and severity of kidney disease.
Chronic Kidney Disease (CKD) is characterised by the
gradual and progressive loss of functioning nephrons and, as
discussed in chapter 1, has various causes. Damage to the
kidneys is usually irreversible and is often insidious in nature,
taking place over many years depending on the aetiology. In
most cases there are no signs or symptoms in the early stages
of CKD. However, with the introduction of routine estimated
glomerular function rate (eGFR) measurement, CKD is often
uncovered as an incidental finding during routine blood tests.
Blood Tests
The normal function of the kidneys is to excrete waste products
which are a by-product of metabolism and there are various
blood tests that can yield a wealth of information. The following
table provides a guide to the normal range, an explanation
about the test and how to interpret the results1,2,3,4. The normal
range for tests will vary in different countries and hospitals.
Explanation and
Interpretation of Result
Other causes of elevated creatinine:
• Ageing process as the kidney function declines by 10% per decade
from the age of 40
• High meat content diets
• People with a large muscle mass
Creatinine Creatinine is not a good marker of CKD as a 50% loss of kidney function
occurs before any evidence of an elevated creatinine is seen
Some causes of non-kidney related high urea levels:
• High protein diet and/or strenuous exercise
• Certain drugs (e.g. corticosteroids, tetracycline)
• Gastrointestinal tract haemorrhage
• Prolonged malnutrition and/or dehydration
Increased blood urea may indicate kidney damage. Normally, urea rises in
Urea
conjunction with creatinine levels in CKD, but at times levels may remain
nitrogen within normal limits when the creatinine levels are high. A significant
(BUN) elevated urea in a previously healthy person can occur in acute renal
failure due to severe infection or major crush injuries
Fasting
Used to detect undiagnosed diabetes or assess diabetes control
glucose
Blood
Test
Slight variation is
expected between
male and female
0,6 - 1.2 mg/dl
(50 - 110 mol/L)
Adult:
8-18 mg/dl
(2.5-6.4 mmol/L)
Adult:
70-110 mg/dl
(3.9-5.5 mmol/L)
Normal
Range
Diagnostic Investigations in CKD
55
Explanation and
Interpretation of Result
Hyponatremia
yp
can occur in:
• Cases of excess body fluid
• Burns
• Vomiting, and diarrhoea
• Nephritis
• Diabetic acidosis
Hypokalaemia
yp
may occur in:
• Persistent vomiting and diarrhoea
• Renal tubular acidosis
• Diuretic treatment
• Excess insulin (causes an increase uptake of potassium)
Sodium Hypernatremia
yp
can occur in:
• Reduced fluid intake and dehydration
• Diabetes insipidus
• Metabolic acidosis
• Excessive infusion of isotonic fluids in renal impairment
Potassium Hyperkalaemia
yp
, may occur in:
• Kidney disease
• Burns
• Insulin deficiency
• Post-traumatic conditions (surgical and accidental)
• Disseminated intravascular coagulation (DIC)
• Diabetes mellitus
• Side effect of some medications e.g. ACE inhibitors
Blood
Test
135 - 145 mEq/L
(135 - 145 mmol/L)
3.5 - 5.0 mEq/L
(3.5 - 5.0 mmol/L)
Normal
Range
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
56
Hypoproteinaemia
yp p
related with low albumin levels of <35 g/l may be seen
in patients who are malnourished and in nephrotic syndrome where large
amount of protein leaks into the urine. It is also present in liver disease,
burns and haemorrhage
Hyperproteinaemia
yp p
with a low albumin/globulin ratio may suggest an
autoimmune disease (e.g. SLE, shock, long-term infection or multiple
myeloma)
Total
Hyperproteinaemia
yp p
with a normal albumin/globulin ratio may occur in
proteins hypovolaemia
Uric acid Elevated uric acid may be seen in:
• Gout
• Arthritis
• Kidney disease
• Certain diuretics
• Acute shock and pre-eclampsia
Bicarbonate Buffers are chemical substances that keep the pH of blood within a normal
range. Bicarbonate is the most important buffer in the blood
6.0 - 8.0 g/dl
(60 - 80 g/L)
2.0 - 7.0 mg/dl
(120 - 420 mol/L)
Slight variation is
expected between
male and female
22 - 30 mEq/L
(22 - 30 mmol/L)
Arterial pH The pH is measured via arterial blood and is a measure of the number of 7.35 - 7.45 pH units
hydrogen ions and indicates the acidity or alkalinity of the blood
Diagnostic Investigations in CKD
57
Explanation and
Interpretation of Result
58
Other conditions associated with elevated levels are seen in young
children experiencing rapid growth, in pregnancy, liver and intestinal
ulcerative disease
Alkaline Levels are raised when bone disease develops in CKD. It varies with age
phosphatase and gender
Hypophosphataemia
yp p
p
occurs in renal tubular disease resulting in
osteomalacia
Phosphorous Hyperphosphataemia
yp p
p
can be seen in conjunction with hypocalcaemia in
various types of renal failure
Hypocalcaemia
yp
may occur in certain metabolic disorders (e.g. deficient
parathyroid hormone) and may be due to phosphate retention in chronic
renal failure
Hypercalcaemia
yp
may indicate hyperparathyroidism, or may be due to
Total
calcium diuretics (thiazides). Its high level can result in renal calculi and renal
tubular disease
Hypoalbuminaemia
yp
is frequent in renal patients with poor dietary intake,
on peritoneal dialysis due to protein loss in dialysate. It is a common
feature in nephrotic syndrome
Albumin Hyperalbuminaemia
yp
may be associated with hypovolaemia
Blood
Test
30 - 120 (37ºC)
Units/L
2.4 - 4.1 mg/dl
(0.8 - 1.4 mmol/L)
8.8 - 10.3 mg/dl
2.20 - 2.58 mmol/L
4.0 - 6.0 g/dl
40 - 60 g/L
Normal
Range
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
The presence of CRP usually indicates acute inflammation. Positive results Normal value is <
5mg/L
may also occur in late pregnancy or with the use of oral contraceptives
Serum The five protein groups move at different speeds in an electrical field and Normal pattern
electro- this test measures the rate of movement. It is most commonly used to
phoresis detect multiple myeloma
CRP
Triglycerides:
<150 mg/dl
(desirable)
HDL: >60 mg/dl
(desirable)
Lipids and Dyslipidaemia is common in CKD, especially in patients with nephrotic Total cholesterol:
triglycerides syndrome or a kidney transplant. The 3 major types of cholesterol are Low
< 200 mg/dl
Density Lipoprotein (LDL), High Density Lipoprotein (HDL) and Very Low
(desirable)
Density Lipoprotein (VLDL)
Elevated levels (except HDL) are associated with cardiovascular events, LDL: <130 mg/dl
(desirable)
a major cause of morbidity and mortality
Parathyroid PTH is produced in the parathyroid gland and regulates extracellular Varies according to
hormone calcium
assay method
(PTH)
It rises progressively with declining kidney function
Diagnostic Investigations in CKD
59
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Full Blood Count (FBC) / Complete Blood Count (CBC)
Leukocytosis, (high WBC count) 4,500 - 10,000 / mm3
count /
is associated with:
White blood
• Leukaemia
cell count
• Infectious diseases
(WBC)
• Inflammatory disease (allergy
or rheumatoid arthritis)
Leukopenia (low WBC count) can
be due to:
60
• Systemic lupus
erythematosus
• Bone marrow failure
• Liver and spleen diseases
Haemoglobin The RBCs should be normocytic
(Hb)
(normal shape) and normochromic
(normal colour). However in
iron deficiency anaemia they
are microcytic (small) and
hypochromic (pale)
See chapter
management
4
on
Male:
14.5 - 16.0 g/dl
Female:
13.0 - 15.5 g/dl
Hb level in CKD7
should be > 11 g/dl in
anaemia
all patients
Haematocrit The haematocrit will be low in
(HCT)
renal anaemia, in conjunction with
a low haemoglobin level
Male:
39 - 49 %
Female:
33 - 43 %
In renal failure, levels should be
maintained above 100 ng/mL see Chapter 4
18 - 300 ng/mL
(18 - 300 g/L)
Vitamin B12 Its deficiency causes macrocytic
anaemia
150 - 1000 ng/L
Ferritin
Diagnostic Investigations in CKD
Coagulation screenings
Bleeding
time
Prolongation occurs in patients
with
vascular
abnormalities,
thrombocytopenia
and
thromboasthenia
3 - 6 minutes
(Ivy method)
61
Activated
Partial
Thrombo
Plastin Time
(APTT)
A prolonged APTT occurs in a
variety
of
disorders
(e.g.
liver
cirrhosis,
disseminated
intravascular coagulation (DIC).
22 - 37 seconds
(Values vary
between labs.)
Patient on anticoagulant therapy
may have an APTT time of 1.5 to
2.5 times control values
Platelet
Use to check for any clotting
count /
abnormality
thrombocyte
count
130,000 400,000/mm3
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Serology
Auto
antibodies eg
antinuclear
antibodies:
ANA/ANCA
Anti-GBM
The measurement of abnormal
antinuclear antibodies amount and
pattern provides a diagnosis for
certain diseases
Negative is
normal
Positive anti-nuclear antibodies
are seen in systemic lupus
erythromatosus or scleroderma
Positive anti-neutrophil cytoplasmic
antibodies (ANCA): seen in systemic
and renal vasculitis
62
Positive anti-glomerular basement
membrane
(Anti-GBM):
very
suggestive
of
Goodpasture’s
syndrome
HBsAg, HIV
HCV
Immunoglobulins
Routine performed as part of renal
screening
Negative is
normal
IgG 5.5 These are commonly referred to as
16.5 g/L
antibodies and IgG, IgM and IgA
are measured to identify certain IgA 0.8 - 4 g/L
autoimmune diseases and allergies IgM 0.4 - 2 g/L
e.g. IgA nephropathy, Multiple
myeloma etc
Urine Tests
Urinalysis plays an essential part in the assessment of any
patient with CKD. The assessment should include observation
of the physical appearance of the urine together with dipstick
testing and further laboratory analysis. Dipstick tests have
mostly replaced cumbersome laboratory testing for routine
rapid clinical work, however, machines are also available to
Diagnostic Investigations in CKD
perform urinalysis with good reliability. A laboratory microscopy,
culture and sensitivity (MC&S) test can identify and detect the
presence of any cells, casts, crystals or bacteria in the urine.
Why is urinalysis important?
• To aid in the diagnosis of kidney disease
• To screen a population for asymptomatic kidney
disease
• To monitor the progression of disease
• To monitor the effectiveness or complications of therapy
• To detect diabetes, urine infection and other urinary tract
problems such as calculi or cancers5
When undertaking a urine assessment it is important to
observe the appearance, smell and to undertake a dipstick
urinalysis. In some situations it may be necessary to measure
the volume of urine produced over a 24 hour period. The
following provides a brief overview of normal and abnormal
findings when undertaking a urinalysis.
Observational Assessment
Odour: Abnormal odour occurs most often due to
incorrect handling and storage or if there is an infection.
However, eating certain foods can also cause an abnormal
and distinctive odour e.g. asparagus. In the presence of
excess ketones in the blood (ketotic state), the urine will
have a distinctive sweet or fruity smell (although a sizeable
percentage of the population is unable to detect this smell).
This is especially important in the diagnosis of patients with
diabetic ketoacidosis, a life threatening condition.
Colour: Urine normally appears pale to dark yellow depending
on its concentration, however it can appear darker if left to
stand for too long.
63
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Table 1: Urine colour6,7
Colour
Pale
64
•
•
•
•
Causes
High fluid intake
Polyuria (renal tubules cannot reabsorb fluid)
Diabetes insipidus
Diabetes mellitus
Turbid/cloudy
• Bacterial infection/pus
• Crystallization of salts e.g. calcium, urate
and oxalate
Red or dark
urine.
Blood in
the urine
(haematuria)
- vary from
smoky to tea
colour and vary
in strength e.g.
bright or dark
• Urinary tract infections
• Trauma to the kidney
• Internal damage to the glomeruli in the
kidney
• Smoky: Can indicate bleeding from the
kidney
• Eating beetroot or other vegetable dyes.
• Porphyria
• Menstruation
• Medications e.g. rifampicin
Foam or froth
Normal urine
will foam slightly
when stored in
a container and
shaken
• Heavy proteinuria (lots of white foam when
container shaken)
Diagnostic Investigations in CKD
Volume::The normal amount of urine collected within a 24
hour period of time can range from 500mls/day to 1500mls/
day. Abnormal amounts are as follows:
Anuria:
Oliguria:
Polyuria:
failure or inability of the kidneys to
produce urine: <50-100 ml per day
where <400 ml of urine is produced
per day
is a condition of excessive production of
urine >2.5L/day
Dipstick/Urinalysis
Dipstick tests provide a cheap and simple way to assess
various substances in the urine. They are only reliable when
the manufacturer’s instructions are followed e.g. length of time
dipping in urine, leaving to stand before reading the result,
keeping the lid on when not in use. Inaccuracies may also be
caused by patient factors such as:
• Menstruation e.g. positive result for blood
• Medications, such as diuretics or high doses of vitamin
C (ascorbic acid) taken with certain antibiotics (such as
tetracycline)
• Some antibiotics, such as erythromycin and trimethoprim.
Radiological contrast material6,7
Normal urine is made up of 95% water and 5% solids,
mainly urea and sodium chloride. It is slightly acidic,
with a pH of 6.0 and the normal specific gravity is
1.010-1.030 g/ml.
65
Glucose
Measures solute load in the
urine. Is a useful indicator of
renal concentrating ability
Specific Gravity (SG) (g/ml)
A positive result is indicative of hyperglycaemia or a low renal glucose
threshold
May be unrealiable if:
• Water and electrolyte imbalance is present
• Low protein diets
• Chronic liver disease
• Pregnancy
>1.030 (no proteinuria or glycosuria) - radiographic contrast
>1.020 Usually in volume depletion
1.000 - 1005 (fixed SG) - occurs in diabetic insipidus
• Alkaline pH
pH > 7 = commonly found in vegetarians
pH> 8 = renal tubular acidosis or urine infection
Influenced by diet, recent eating, bacterial infection and storage
time.
• Acidic pH
pH< 5 = risk of uric acid stones
pH
(acidity or alkalinity of the urine)
The normal range is 4.5 - 8.0
dependent on diet
Interpretation
66
Substance
Table 2: Dipstick test6,7
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Protein
• Normal urine should not contain more than a trace of protein. It
is possible for levels of proteinuria up to 150 mg/24 hour before
any protein shows up on a dipstick
• Persistent small increases in protein or albumin in the urine are
an early sign of kidney injury and often precede any detectable
change in the serum creatinine concentration or eGFR
• Persistently high levels of protein damage the kidney and
contribute to progressive loss of kidney function; this is
particularly evident in patients with proteinuria levels greater
than 1gm/day
• High levels of proteinuria are always important; however
intermittent low levels of proteinuria may not be as significant.
Some examples of causes of intermittent proteinuria are:
• Dehydration
• Emotional stress
• Fever
• Heat injury
• Inflammatory process
• Intense activity
• Most acute illnesses
• Orthostatic (postural) disorder
Diagnostic Investigations in CKD
67
The presence of nitrites usually indicates an infection.
The presence of ketones may be seen in hyperemesis of pregnancy,
starvation or ketoacidosis
Urine does not normally contain any bilirubin, only small amount as
urobilinogen. It appears in the presence of liver disease or bile duct
obstruction
• A positive test indicates haematuria, haemoglobinuria or
myoglobinuria
• False positive readings may be due to contamination with
menstrual blood
• Haematuria is defined as >3 RBC/hpf of centrifuged sediment
under microscope
• False positives can be increased by dehydration which
concentrates the number of RBCs produced and exercise
• False negatives may occur if the urine is left to stand for several
hours prior to microscopy as during this time the red blood cells
may lyse
Nitrites
Ketones
Bilirubin
Blood
Interpretation
68
Substance
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Microalbumin
Microalbuminuria may indicate the following:
• sub-clinical cardiovascular disease
• vascular endothelial dysfunction
• prognostic marker for kidney disease:
- in diabetes mellitus
- in hypertension8,9
• The presence of small amounts of albumin is of importance as
a predictor of kidney damage and is the first indicator of kidney
disease in diabetics
• Microalbuminuria is defined as persistent albumin/creatinine
ratios >2.5mg/mmol (male) or >3.5mg/mmol (female) on 2-3
occasions or urinary albumin excretion of
20-200 g/min
• Testing should be avoided during acute illness or menstruation
to reduce the incidence of false readings8,9
Diagnostic Investigations in CKD
69
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Other specific urine tests
Osmolality: normal range 500-800 mosmolkg1.
This provides an indication of the kidneys’ ability to concentrate
and dilute the urine and provides a more accurate assessment
of renal tubular concentrating ability than the specific gravity.
A urine osmolality test should preferably be done on an early
morning urine sample as water depletion during the night
should concentrate the urine.
70
Protein/Creatinine Ratio (PCR)
Assessment of urinary protein can be carried out on a single,
preferably early morning, urine sample. Several studies have
shown that, as patients find the accurate provision of a 24-hour
urine collection very difficult, the PCR to be more accurate than
the “gold standard” of the 24-hour urine protein measurement.
The PCR will not detect microalbuminuria. A PCR >100 mg/
mmol (1g/day) requires specialist renal management and
these patients should be referred to a nephrologist. Likewise if
the PCR is >45 mg/mmol but the patient also has microscopic
haematuria they should also be referred10.
It is important to note that in nephrotic syndrome, heavy
proteinuria is a main clinical feature with proteinuria
>3.5 g/day (150 mg/24 hr). Other features are:
• Peripheral oedema, especially around the eyes, feet, and
hands
• Hypoalbuminaemia: low levels of protein in the blood
<30 g/l
• Hypercholesterolemia, specifically elevated low density
lipoproteins
• Coagulation abnormalities
Bence-Jones Protein analysis
This is ideally tested on an early morning urine sample. A
positive result may indicate the presence of multiple myeloma
Diagnostic Investigations in CKD
in 70-80% of cases and is a useful diagnostic tool. It can also
be seen in amyloidosis, Waldenstrom’s macroglobulinaemia,
cryoglobulinaemia and chronic lymphocytic leukaemia6.
Myoglobin levels
This is ideally tested on an early morning urine sample.
Myoglobin in the urine is found in conditions such as
rhabdomyolysis, the breakdown of muscle tissue usually due
to a crush injury or trauma to the area, seizures or severe
exercise. The myoglobin is released from the muscle tissue
into the bloodstream and is nephrotoxic as when it is filtered
by the kidneys it causes blockages in the renal tubules and
leads to acute tubular necrosis6.
Urinary Catecholamines
Urinary catecholamines such as adrenaline or noradrenaline
or their metabolites such as vanylmandelic acid (VMA) can
be tested for in a 24-urine sample. A level twice the upper
limit of normal is virtually diagnostic of phaeochromocytoma,
however several 24-hour samples may be needed if there is
clinical suspicion of this tumour as levels fluctuate greatly.
Hypertension may cause mildly elevated results. When
collecting the samples it is necessary to keep the container
refrigerated. Certain foods including coffee, tea, bananas,
chocolate, cocoa, citrus fruits, and vanilla can increase urinary
catecholamine and these should be avoided for several days
prior to the test. Centrally acting sympathomimetic drugs such
as methyl dopa will also affect the results as may acute stress
and vigorous exercise8.
Microscopy, Culture and Sensitivity
Microscopy of the centrifuged urinary sediment will show up
bacteria, blood cells, casts and crystals. Urinary culture will
71
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
identify bacterial and fungal urinary infection which can then
be tested for sensitivity to various antibiotic and antifungal
agents.
72
Bacteria: Bacterial urinary tract infections are common.
Predisposing factors include:
• Gender - women have a shorter urethra and are more
susceptible to urinary tract infections (UTI)
• Sexually active women
• Pregnancy
• Incomplete emptying of the bladder
• Immunosuppression
e.g. HIV patients, transplant patients
• Diabetes mellitus
• Vesico-ureteral reflux
• Urethral catheterisation
A significant finding is bacteria >100 000 / ml. If multiple
organisms are seen, then a contaminated sample is likely.
Table 3: Most common causes of UTIs11
Bacteria
Normally present in
Escherichia coli (E. Coli)
GI tract, faeces
Staphylococcus
epidermis (S. epidermis)
Skin, external genital tract
Proteus species
GI tract, faeces, hospital environment
Klebsiella species
GI tract, faeces, external genital tract
Pseudomonas
aeruginosa
GI tract, faeces (rare), hospital
environment
Diagnostic Investigations in CKD
Blood cells (erythrocytes)
When intact, they are biconcave disks with smooth
appearance. Abnormal is to find >3 per high power field. When
the erythrocytes are distorted, irregular or misshaped, they are
know as dysmorphic blood cells and usually suggest glomerular
disease, especially when accompanied by proteinuria and
blood casts. Red blood cells may be seen in the following:
• Acute tubular necrosis
• Upper and lower urinary tract infections
• Nephrotoxicity
• Tumours
• Kidney trauma
• Renal calculi
• Renal infarcts
• Physical stress
Other causes not kidney related are:
• Trauma from urinary catherization
• Menstruation
• Excessive exercise can cause microscopic haemeturia
and is common, it is advisable to re-test in 48-72 hrs
White cells (leukocytes)
These are disks with granular cytoplasm and nucleus.
Pathological findings are indicated if white cells are >5 per
high power field. The presence of increased white cells in the
urine is termed pyuria and indicates inflammation or infection
of the urinary tract. The presence of eosinophils may indicate
an allergic interstitial nephritis. White cells can be presents as
a result of a contaminant from the vagina or urethral meatus.
73
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Epithelial cells
These cells line all of the urinary and genital tracts. The
presence of squamous epithelial cells implies contamination,
transitional epithelial cells are normal.
74
Renal Epithelial cells
They are the most clinically important of the epithelial cells that
may be found in urine and result from a variety of disorders,
especially acute tubular necrosis, viral infections involving the
kidney and in renal transplant rejection.
Casts
The discovery of casts in the urine sediment is the result of
solidification of protein within the lumen of the kidneys tubules.
At the time of cast formation, any material present within the
tubule e.g. cells, fat, or bacteria is trapped within the cast
matrix7,11.
Type
Cause
Hyaline casts
also known as
Tamm-Horsfall
proteins
These come from the renal tubules and are the
least important of casts. They may be seen without
significant proteinuria. They are often found in
people who undertake strenuous exercise, fever
and the use of diuretics. Large numbers are
related with moderate or severe renal disease and
may be seen in pyelonephritis
Granular or
cellular
May be seen in renal parenchymal disease.
Their quantification and progression are of great
importance in diagnosis
Red Blood
Cells
Indicates bleeding of renal origin often
glomerulonephritis. However are also seen in
patients who participate in contact sports
Leukocyte
Their finding indicates inflammation/ infection. May
be indicative of interstitial nephritis, pyelonephritis
or glomerulonephritis
Diagnostic Investigations in CKD
Crystals
It is important to interpret the presence of crystals in conjunction
with urinary pH and concentration.
Abnormal forms may indicate metabolic disorders, such as
the presence of cystine crystals in the urine of people with
cystinuria, an inherited metabolic condition. In acidic uric the
presence of uric acid crystals and elevated serum uric acid
may be associated with gout. Triple phosphate crystals are
associated with an alkaline pH and infection.
Culture
Microoganisms are identified after culturing the urine for 24/48
hours. A gram stain will determine the exact organisim and also
which antibiotics the organism is sensitive and resistent to.
Cytology
A cytology exam of urine is used to detect cancer and
inflammatory diseases of the urinary tract. Collection of a
“clean-catch” (midstream) urine sample is required.
Kidney Function Tests
In healthy individuals, from 40 years of age
onwards, GFR diminishes at about 10 ml/
min per decade
• eGFR should not be used as a marker
of kidney function in acute renal
failure patients
Estimated
Glomerular Non-renal causes of increased eGFR:
• High protein diet
filtration
• Diurnal variation
rate
• Pregnancy
(eGFR)
(GFR) /
Non-renal causes of decreased eGFR:
• Low protein diet
• Liver disease
• Ageing
See Chapter 2 for eGFR calculation and
classifications of CKD
70 125 ml/min
75
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Imaging Tests
They are diagnostic methods in medicine that use certain
techniques to produce internal images of the body. The
techniques employed are:
76
•
•
•
•
X-rays
Sound waves
Magnetic fields
Radioactive particles
These techniques work on the principle that rays, sound waves
and particles interact differently with various types of tissues.
They are detected and converted into images after passing
through body tissues. Contrast agents are sometimes used
in conjunction with X-ray tests to enhance better images. In
nephrology practice, imaging tests are employed according
to their specific capability to detect structural or functional
problems. However, when there is renal damage, caution is
taken in choosing the type of imaging test to confirm diagnosis.
This is because the contrast agent used in some of these
tests may further worsen the already impaired renal function.
Caution should be taken in all investigations involving x-rays
and contrast media if a woman is possibly pregnant and all
patients should be asked if they suffer from any allergies (e.g.
iodine) or asthma.
Precautions
Plain abdominal x-rays can show the contour • All women should be asked if they are
of kidneys, ureters and bladder (KUB). It is pregnant or could be pregnant
useful in the initial assessment of the size,
shape, position and the presence of one or
two kidneys. Likewise, of any abnormalities,
especially kidney calculi
Indications
Intravenous A contrast medium (usually iodine based) is • Check for allergies to contrast agent,
pyelography injected into the vein and enters the blood as there is a potential for an allergic
(IVP) /
stream. It collects in the kidneys and the anaphylactic reaction
urinary tract outlining the whole urinary • Caution is taken in women who may
Intravenous collecting system. X-ray films are then taken
urography at intervals and the progress of the contrast be pregnant; they must notify the
radiologist
(IVU)
dye is observed. Used to study the kidneys
•
Contrast
media is nephrotoxic. In those
(calyces and pelvis), the ureters and urinary
with known CKD, kidney function should
bladder
be checked post procedure. Acute renal
failure may result after the procedure. If
possible patients should increase oral
fluid intake and urinary output should be
monitored
X-ray /
radiograph
Test
Description and Objective of Use: ImagingTests6,8,12,13
Diagnostic Investigations in CKD
77
• Contrast media is nephrotoxic. In those
with known CKD, kidney function should
be checked post procedure. Acute renal
failure may result after the procedure. If
possible patients should increase oral
fluid intake and urinary output should be
monitored
Retrograde A cystoscope is inserted into the urethra • The patient needs to be nil by mouth
pyelography and a small ureteric catheter is passed in a for 6 hours (check local policy) as it is
retrograde manner into the kidney. Contrast usually done under general anaesthetic
media is then injected through the catheter in an operating theatre. Written consent
into the pelvis of the kidneys and ureter. is required
X-rays are then taken. Used to outline calculi,
calyceal defects and tumours in the ureter or • After the procedure, patients should
be advised to check their urine for
renal pelvis
signs of any blood (haematuria), and
It can also be done after an IVP or notify if they have a fever or pain. If not
ultrasound to define deformities such as contraindicated, the patient should be
encouraged to drink plenty of water to
hydronephrosis
avoid urinary infection. Prophylactic
antibiotic may be ordered
Indications
Precautions
• Follow local policies for fasting and
Useful to detect:
bowel preparation. Usually includes
• renal calculi
a mild laxative to be taken the night
• enlarged prostate
• tumours in the kidney, ureters or urinary before the test to clear the bowel which
will allow for adequate visibility of the
bladder
urinary system
78
Test
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Abdominal
Ultrasound
scan /
sonography
Aids in the diagnosis of kidney disease by
defining the kidneys size, echogenicity,
presence or absence of hydronephrosis,
lesions and cysts. It is also used to guide the
operator in renal biopsy
None
Renal arterio- Angiogram involves the injection of contrast • Prior to the test, anticoagulant therapy
graphy/ renal medium into a blood vessel to carry out X- should be withheld according to medical
angiogram ray examination. Useful in diagnosing renal instruction
artery stenosis, tumours and injuries of • Written consent is necessary. Patient
vessels
should be informed of any restricted
activity after the procedure and to
report of any haematoma at the site of
puncture or any haematuria
• Contrast media is nephrotoxic. In those
with known CKD, kidney function should
be checked post procedure. Acute renal
failure may result after the procedure. If
possible patients should increase oral
fluid intake and urinary output should be
monitored
Diagnostic Investigations in CKD
79
Renogram: a renal scintigraphy in which
dynamic and rapid serial imaging is done
following the intravenous injection of an
isotope (e.g. 99MTc-MAG3, an ideal radioisotope
due to its filtration by glomeruli and
elimination exclusively by tubular secretion).
It is used to evaluate renal function, e.g. in the of
transplanted kidneys
• Renogram
• Renal Scan Renal Scan: a renal scintigraphy in which two
to four hours prior to the test, a small amount
of radioisotope (e.g. 99MTc-DMSA) is injected
intravenously. Various static images are then
taken. It is often used to evaluate renal cortical
lesions
Produces cross-sectional images of the body. None if non-toxic contrast media used
Gadolinium, a non-nephrotoxic contrast
agent, may be used intravenously. MRI gives
very clear and detailed images of soft-tissue
structures. Hence, it is useful in revealing
mass lesions, renal vein thrombosis, etc
Magnetic
Resonance
Image (MRI)
scan
None
Indications
Precautions
Shows in detail the renal anatomy and its • If contrast media used, those with known
adjacent structures. The use of contrast CKD, kidney function should be checked
enhances the visibility of the renal cortex post procedure. Acute renal failure may
from the medulla. It is the test of choice in result after the procedure. If possible
patients should increase oral fluid intake
the study of renal mass and renal trauma
and urinary output should be monitored
80
Test
Computed
Tomography
(CT) scan /
computed axial
tomography
(CAT) scan
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Contraindicated:
• Single kidney (except transplanted)
• Gross obesity
• Uncontrolled hypertension
• Severe anaemia
• Uncontrolled coagulopathy
• Kidney with hydronephrosis or cysts
• Reduced size kidney (< 9 cm)
Percutaneous An invasive procedure by which a special • Prior to the procedure, patient should
renal biopsy needle is introduced into the lower pole of have his/her blood coagulation checked
the kidney (preferably the left as it is more • Written consent needed
easily accessible and not near the liver) to
obtain a piece of tissue specimen for study. • Patient should be informed of 24h
It is used to establish diagnosis, to orientate complete bed-rest after native biopsy
or according to unit policy and observe
treatment regime and to classify prognosis
puncture site for signs of bleeding and
check urine for signs of haematuria
Indicated in CKD:
• Conserved kidney size (> 9 cm)
• Proteinuria
• Microscopic haematuria
Renal Biopsy
Diagnostic Investigations in CKD
81
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
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1.
2.
3.
4.
82
5.
6.
7.
8.
9.
10.
11.
12.
13.
Mahon, A. Investigations in Renal Failure. EDTNA ERCA J. 2004
Jan-Mar; 30(1): 4-8.
Laposata M. SI Unit Conversion Guide. The New England Journal of
Medicine. NEJM Books: Boston. 1992.
http://www.nlm.nih.gov/medlineplus/encyclopedia.html
Locatelli F et al. Revised European Best Practice Guidelines for
the Management of Anemia in Patients with Chronic Renal Failure.
Nephrol Dial Transplant 2004; 19 (suppl 2): 1-47.
Munson K and Jorgenson Linne J. Urinalysis and Body Fluids.
A color Text and Atlas. Chapters 2, 3, 4. Elsevier: Toronto. 1995.
Thomas, N Renal Nursing (2nd Edition). BaillièreTindall: Edinburgh.
2002.
French TW and Blue JT. Urine Sediment Atlas. Cornell University:
New York. 1997.
Fairley KF, Johnson R and Feehally J. Comprehensive Clinical
Nephrology. Mosby: London. 2001.
Brenner B. Benner and Rector’s The Kidney 2 Vol Set (7th Edition).
W.B. Saunders Company: Ontario. 2004.
CKD guideline Guidelines for Chronic Kidney Disease:
Identification, management and referral. http://www.renal.org/
JSCRenalDisease/JSCRenalDisease.html
Higgins C. Understanding laboratory investigation. Blackwell
Science: Oxford. 2000.
Brenner, B. Rector, F. The Kidney, Fourth Edition Volume1. W.B.
Saunders Company: Ontario. 1991.
http://www.radiologyinfo.org/index
Further Reading
Sociedad Española de Nefrología. Diagnóstico Sindrómico y Exploraciones
Diagnósticas 1998. Harcourt Brace de España: S.A.
Pattison J.et al. A Colour handbook of Renal Medicine 2004. Manson
Publishing Ltd: London.
Steddon S, Ashman N, Chesser A & Cunningham J. Oxford Handbook of
Nephrology and Hypertension 2006. Oxford University Press: Oxford.
Diagnostic Investigations in CKD
83
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Chronic Kidney Disease:
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Learning Outcomes
•
•
•
86
•
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To gain insight into the prevalence of anaemia in
Chronic Kidney Disease (CKD)
To develop an understanding of the causes, signs
and symptoms of anaemia in CKD patients
To understand which CKD patients to screen for
anaemia
To review the current anaemia guidelines
To understand the current recommended
management strategies for anaemia management
in CKD patients
To reflect on the benefits of correcting anaemia in
CKD patients
Definition of Anaemia in CKD
The World Health Organisation defines anaemia as
haemoglobin (Hb) level of less than 11g/dl in pregnant
women and children aged 6 months to 5yrs, less than 12g/dl
for non pregnant women and less than 13g/dl for men1.
Management of anaemia should be considered in chronic
kidney disease (CKD) when the Hb level is less than or equal
to 11 g/dl. An estimated glomerular filtration rate (eGFR) of
less than 60ml/min/1.73m² should trigger investigation into
whether anaemia is due to CKD. When the eGFR is greater
than or equal to 60ml/min/1.73m2 the anaemia is more likely
to be related to other causes2.
Management of Anaemia in CKD
Anaemia of Chronic Kidney Disease (ACKD)
Many conditions are associated with ACKD, mainly because
many chronic, systemic conditions lead to abnormalities in
haemopoiesis (production of red blood cells)3. Anaemia in
patients with CKD may develop in response to a wide variety
of causes as systemic diseases have different effects on the
kidney and the bone marrow.
Causes of ACKD
1.Reduced Erythropoietin Production
Anaemia in CKD is normally normochromic and normocytic.
Erythropoietin deficiency is the primary cause of anaemia
associated with CKD. Erythropoietin is predominantly
produced by peri-tubular cells in the kidney and is the
hormone responsible for maintaining the proliferation and
differentiation of erythroid progenitor cells in the bone
marrow. Loss of peri-tubular cells leads to an inappropriately
low level of circulating erythropoietin. The production of
inflammatory cytokines (common in CKD) such as interleukin
1 and Tubular Necrosis Factor (TNF alpha) can inhibit the
maturation of the progenitor cells4 and lead to the reduction
in production of erythropoietin.
2.Haemolysis
The reason for impaired red blood cell survival (haemolysis)
in CKD is not well understood although it is thought that
uraemia plays a central role. In this situation a Coombs test
is useful to look at the survival of the red cells. Normal red
blood cell survival is 120 days in patients with CKD it may
be reduced to 90 days.
3.Iron Deficiency2
Iron has an essential role in supporting erythropoiesis with
65% of the iron stored in the body used to form haemoglobin.
Iron deficiency should be considered in people with stage 3
and 4 CKD if the ferritin level is less than 100g/l.
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Chronic Kidney Disease:
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Measurements of Iron Status
Serum Ferritin: This refers to the amount of iron stored
in the body. The body requires 150mg of iron to raise the
haemoglobin by 1g/dl. As red cell production increases
iron stores are depleted. Iron stores need to be adequate
otherwise red blood cell survival is reduced.
88
Serum ferritin is commonly used as a standard marker
for measuring iron deficiency. However it can be
falsely raised in cases of infection and inflammatory
conditions. It is useful to measure the C reactive protein
(CRP) at the same time as the ferritin. If the CRP is also
raised then this will indicate that there is an infection or
inflammatory condition and that the raised ferritin is not
a true indication of the iron status at that time.
% Transferrin Saturation (%Tsats): This is the body’s
transport system for iron. This needs to be >20% to
be effective; however this is not a very reliable tool as
%Tsats constantly alter. More than one measurement
is required to ascertain an average reading.
% Hypochromic Red Cells: This is defined as an
individual cell with a haemoglobin concentration <10%.
Normally 2.5% of red blood cells are hypochromic.
If iron stores are insufficient and/or mobilisation of
iron is inadequate the amount of hypochromic red blood
cells increase in number and when they are greater than
10%, iron supplementation is required5.
Definition of Iron Deficiency
Absolute Iron Deficiency: Iron stores are inadequate
to support the erythropoietic needs of the bone
marrow, defined by a low serum ferritin level less
than 100g/L.
Functional Iron Deficiency: Iron stores are adequate
but cannot supply bone marrow quickly enough with the
Management of Anaemia in CKD
iron required to support demands of erythropoiesis when
stimulated acutely. This is defined by normal or high
serum ferritin, % transferrin saturation less than 20% or %
hypochromic red cells greater than 10%.
4.Vitamin B12 and Folate Deficiency
Vitamin B12, also called cobalamin, is required to maintain
healthy nerve cells, red blood cells and DNA. Vitamin
B12 is bound to protein in food. Hydrochloric acid in the
stomach releases B12 from the protein during digestion.
Once released, B12 combines with a substance
called intrinsic factor (IF) before it is absorbed into the
bloodstream. Vitamin B12 deficiency is defined when B12
levels are less than 160ng/l.
Pernicious anemia is a form of anaemia that occurs
when there is an absence of intrinsic factor. Absence of
intrinsic factor prevents normal absorption of B12 and
results in pernicious anemia. Treatment for pernicious
anaemia is by an initial treatment course of intramuscular
hydroxycobalamin injections, 1mg three times a week,
for two weeks followed by three monthly maintenance
injection of 1mg which will continue indefinitely6.
Folate and folic acid are forms of a water-soluble B vitamin.
Folate is essential for the production and maintenance of
new red blood cells. Folate is also needed to make DNA
and RNA. Those with renal disease should have a serum
folate level > 20g/l. Supplementation with folic acid 5mg
once a day should be given if the serum folate level is
<20g/l.
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Causes of Anaemia Other than CKD
Not all types of anaemia in patients with CKD will be ‘renal
anaemia’ and causes of anaemia other than CKD should
be actively investigated and excluded before a diagnosis of
anaemia associated with CKD is made2.
Table 1: Other causes of anaemia
90
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•
•
•
•
•
•
Chronic blood loss
Hypothyroidism
Chronic infection or inflammation
Hyperparathyroidism
Aluminium toxicity
Bone marrow infiltration
Pure red cell aplasia
Malignancy
Table 2: Screening for anaemia of CKD
Investigations should be performed when Hb<12g/dl (men) or
11g/dl for women and should include the following tests:
• Haemoglobin
• Red cell folate concentration
• Serum B12
• Serum ferritin
• Serum % transferrin saturation
• % Hypochromic red cells
• Tests for haemolysis (Haptoglobin, lactate dehydrogenase,
Coomb’s test)
• Reticulocyte count
• C-Reactive protein (CRP)
• Assessment of occult gastrointestinal blood loss
• Nutritional status of the patient
The above tests will exclude causes for anaemia other than
CKD, especially bone marrow suppression and haemolysis. It
is important to screen for other causes of anaemia in order to
reach the correct diagnosis. Haematological abnormalities need
to be clearly recognised and appropriate treatment given.
Management of Anaemia in CKD
Table 3: Signs and Symptoms of ACKD
•
•
•
•
•
•
•
•
•
Dizziness or light headedness
Fatigue and weakness
Headache
Irritability
Less endurance in exercise
Shortness of breath, especially with exercise
Pale skin and eyes
Rapid heartbeat
Reduced cognitive function
91
Signs & Symptoms of Anaemia of CKD
The anaemia of chronic disease (ACD) may occur insidiously
and is easy to overlook amid the general malaise related to
the disease itself. Many of the signs and symptoms can be
considered to be due to the effects of chronic disease but are
in fact also signs and symptoms of anaemia7.
The prevalence of anaemia in patients with CKD
The importance of anaemia in CKD has been increasingly
recognised since the introduction of erythropoietin
(EPO) therapy in the late 1980s. However, until recently
it has not been fully appreciated that anaemia begins
to develop early in the course of CKD. NHANES III
study found lower levels of kidney function to be associated
with lower haemoglobin levels and a higher prevalence and
severity of anaemia8.
In the UK one study showed the population prevalence
of stage 3-5 CKD in this study was estimated to be 4.9%.
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Table 4: Stages of CKD and prevalence of anaemia
Stage
eGFR
of CKD (ml/min/1.73m2)
Median Hb
in men
(g/dl) %
Median Hb
in women
(g/dl) %
Prevalence of
anaemia* %
2
60
14.9
13.5
1
3
30
13.8
12.2
9
4
15
12.0
10.3
33
*Hb<12g/dl in men, Hb <11g/dl in women.
92
In those patients with stage 3-5 CKD the prevalence
anaemia,
defined
as
a
haemoglobin
level
of
<12g/dl in men and post-menopausal women and 11g/dl in
premenopausal women, was 12.0%, with a haemoglobin level
<11g/dl in 3.8%9.
Anaemia in Diabetes and CKD
Those with CKD stage 3 and diabetes have a greater incidence
of anaemia, 22% compared to 7.9% in non-diabetics10.
Anaemia occurs early in the course of diabetic kidney
disease and is associated with inappropriately low
erythropoietin concentrations11. A comparison of those with
Type 2 diabetes and CKD and those with non-diabetic CKD,
showed that those with Type 2 diabetes were significantly
more anaemic12.
Similar findings have also been
demonstrated in people with Type 1 diabetes and CKD
compared with those without diabetes.
Cross-sectional surveys of patients with diabetes, have also
demonstrated that at all levels of eGFR, anaemia was more
prevalent in those with diabetes compared with the general
population13,14. With increasing albuminuria, the prevalence of
anaemia was higher at each level of renal function, and that
Management of Anaemia in CKD
levels of erythropoietin were inappropriately low in those with
anaemia15.
Cardiovascular Effects of Anaemia.
Possible adverse effects of anaemia in patients with CKD
include reduced oxygen utilization, increased cardiac output
and left ventricular hypertrophy (cardiac dilatation) ± increased
wall thickness. In a study of 318 non-dialysis patients a mean
decrease in Hb of 0.5 g/dl from baseline of 12.8 ± 1.9 g/dl was
found to be one of three factors that was associated with left
ventricular hypertrophy (LVH)16.
Whether early anaemia treatment prevents development of
LVH, reduces cardiovascular mortality and morbidity, delays
progression of CKD and reduces stroke and heart failure
related hospitalisations, is clearly still open to question.
However, there are currently three large studies seeking to
answer these questions. The Correction of Haemoglobin
and Outcomes in Renal Insufficiency (CHOIR)17 study, the
CREATE18 trial (Cardiovascular Risk reduction by Early
Anaemia Treatment with epoetin beta) and the TREAT19 (Trial
to Reduce Cardiovascular Events with Aranesp Therapy)
study should help to determine the optimal management of
pre-dialysis renal anaemia.
Guidelines for Management of Anaemia
When should Anaemia of CKD be treated?
There are many anaemia guidelines and standards and
each country may use country specific. The Kidney Disease
Outcomes Quality Initiative guidelines of the National Kidney
Foundation (NKF K/DOQI)20 define anaemia in CKD as
a haemoglobin concentration of less than 11 g/dL in premenopausal females and pre-pubertal patients, and less
than 12 g/dL in adult males and postmenopausal females.
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
The Revised European Best Practice Guidelines (EBPG)5
define anaemia as an Hb fall below the mean Hb level of the
population mean -2 Standard Deviation (SD) (i.e. <95%), as
follows:
• <11.5 g/dl in adult female patients
• <13.5 g/dl in adult male patients
• <12.0 g/dl in adult male patients aged over 70
The UK NICE guidelines suggest a trigger for treatment when
Hb 11g/dl.
94
Target or aspirational ranges of haemoglobin levels also vary
with each guideline.
Having so many sets of guidelines and haemoglobin ranges
can be confusing. However, it is important to have an agreed
set of evidence based guidelines to use in your unit when
managing anaemia of CKD.
Table 5 - Target haemoglobin levels for treatment of ACKD using available guidelines
Target H
i
aemia Ma ageme t
D
e ised
D
g dL
ideli es
D
e ised
g dL
g dL
er limit
ot de i ed
g dL
er limit
i di id alised
ca tio
g dL
ith mai te a ce
g dL
D
g dL D
g dL o D
g dL D
g dL o D
M
g dL
D
g dL
a ada
g dL
Management of Anaemia in CKD
Treatment of Renal Anaemia Associated with CKD
Managing Iron deficiency
The correction of iron deficiency anaemia is essential
before considering the use of any erythropoiesis stimulating
agents (ESA). In people with functional iron deficiency, iron
supplements should be given concurrently when initiating
ESA therapy as adequate iron stores are necessary to allow
an optimal response to ESA therapy2. ESA therapy should not
be initiated in the presence of absolute iron deficiency without
also managing the iron deficiency. Treatment with intravenous
iron may, by itself, correct anaemia amongst some patients
with CKD.
Oral iron
Oral Iron can be poorly absorbed and the absorption can be
inhibited by other drugs such as calcium based phosphate
binders and aluminum and by taking it with food and tea.
Vitamin C however assists absorption and taking iron
supplements with a glass of orange juice may help. However
with many renal patients having to cope with dietary changes
and restrictions, this may not always be possible.
The side effects of oral iron such as constipation, diarrhoea
and flatulence can often prevent it being taken regularly.
However, oral iron is used in practice mainly for non-dialysis
and peritoneal dialysis patients where the practicalities of
administering intravenous iron are limiting.
Intravenous Iron
Intravenous iron is currently available as two preparations in
the UK: Iron Dextran (Cosmoferr®) Iron Sucrose (Venoferr®).
Iron Dextran (Cosmoferr®)6
A complex of ferric hydroxide with dextrans containing 5%
(50mg/ml) of iron.
Dose: by intravenous slow infusion (up to 4hours) calculated
according to bodyweight and iron deficit (not recommended
in a child under 14 years).
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Cautions: facilities for cardiopulmonary resuscitation
must be at hand; increased risk of allergic
reaction in immune or inflammatory conditions;
hepatic impairment; renal impairment; oral iron not to be
given until 5 days after last injection; pregnancy.
Contra-indications: history of allergic disorders including
asthma and eczema; infection; active rheumatoid arthritis.
Side-effects: nausea, dyspepsia, diarrhoea, chest pains,
hypotension, dyspnoea, arthralgia, myalgia, pruritis,
urticaria, rash, fever, shivering, flushing, headache; rarely
anaphylactic reactions; injection site reactions including
phlebitis reported.
96
There are concerns regarding risk of anaphylaxis with Iron
Dextran. Dextran antibodies can exist but this is unknown
until Iron Dextran is given to the patient and within seconds
an anaphylactic reaction may occur. This means that this
drug must be given in an environment where there are full
resuscitation facilities available.
The advantage of Iron Dextran is that it can be given as a single
dose infusion which is advantageous if the patient has to travel
long distances for treatment. It cannot be given undiluted as
a bolus dose.
Iron Sucrose (Venoferr®)6
A complex of ferric hydroxide with sucrose containing 2%
(20mg/ml) of iron.
Dose: by slow intravenous injection (over 5-10 minutes) or
by intravenous infusion, calculated according to body-weight
and iron deficit, consult product literature (not recommended
in children).
Cautions: oral iron therapy should not be given until 5 days
after last injection; facilities for cardiopulmonary resuscitation
must be at hand; pregnancy.
Management of Anaemia in CKD
Contraindications: history of allergic disorders including
asthma, eczema and anaphylaxis; liver disease; infection.
Side-effects: nausea, vomiting, taste disturbances,
headache, hypotension; less frequently paraesthesia,
abdominal disorders, myalgia, fever, flushing, urticaria,
peripheral oedema; rarely anaphylactoid reactions; injection
site reactions including phlebitis have been reported.
Venoferr® can be safely given to patients across all modalities
either as an infusion, or undiluted as a bolus dose via a
butterfly needle. It is the most commonly used intravenous
iron supplementation in renal medicine.
Haemodialysis patients are able to receive intravenous iron
during dialysis without it being removed by dialysis. Therefore
all haemodialysis patients who require iron supplementation
can have intravenous iron rather than oral iron. The amount
given will vary from unit to unit but a standard dose would be
100mg every fortnight as a maintenance dose. Or if the patient
required a course of iron 1g it would be given over a 5-10 week
period depending on the unit protocol.
Peritoneal and non-dialysis patients may receive
intravenous iron when their serum ferritin is <100g/dl,
% Tsats<20% or %hypochromic Red Cells >10%.
Patients who are intolerant of oral iron may be given
maintenance intravenous iron every 6-8 weeks to maintain
their serum ferritin >100g/l.
In countries where the above preparations are not
available Ferrous Gluconate may be used. Further
information regarding this product should be sought
from the pharmaceutical provider.
Monitoring Iron Stores
All patients who are receiving erythropoiesis stimulating
agents (ESAs) require iron supplementation to support the
demands made on the iron stores. Regular monitoring of iron
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
stores is essential during treatment. In CKD patients with a
stable haemoglobin level not being treated with ESAs, iron
stores should be measured every three to six months5. Patients
who are being treated with ESAs should have their iron status
checked every 4 weeks during the correction phase (three
months) and thereafter every three months5. Patients who are
receiving regular intravenous iron therapy should have their iron
status checked every three months and the intravenous therapy
discontinued for at least a week prior to performing the tests5.
98
Iron toxicity needs to be avoided and if the serum ferritin
is persistently above 500g/l, and/or >40% Tsats greater
than 40% iron supplementation should be withheld for
up to three months as long as there are no signs of functional
iron deficiency. Iron status should be measured monthly in
these situations.
Erythropoiesis Stimulating Agents (ESAs)
Treatment with ESAs should be offered to people with
anaemia of CKD who are likely to benefit in terms of quality
of life and physical function2. The choice of ESA should
be discussed with the person with anaemia of CKD when
initiating treatment and at subsequent review, taking into
consideration the patient’s dialysis status, the route of
administration and the local availability of ESAs. There is no
evidence to distinguish between ESAs in terms of efficacy2.
There are several commercial Erythropoiesis Stimulating
Agents (ESAs) available. Those currently licensed for use in
CKD are:
• Epoetin alfa
• Epoetin beta
• Darbepoetin alfa
• Epoetin delta
They all work in a similar way by continually stimulating the
bone marrow to produce red blood cells.
Management of Anaemia in CKD
Route of Administration
The stage of CKD, treatment setting and patient choice should
determine the route of ESA administration and type of ESA
used. Convenience favours subcutaneous (SC) administration
in non dialysis and peritoneal dialysis patients and intravenous
(IV) administration in haemodialysis patients. However some
preparations require higher doses when given intravenously
and this needs to be considered.
Frequency of administration
The CKD stage, treatment setting, efficacy considerations, and
type of ESA should determine the frequency of administration.
Convenience favours less frequent administration, particularly
in non haemodialysis patients.
Dosing
The initial ESA dose and ESA dose adjustments should be
determined by the patient’s Hb level, the target Hb level, the
observed rate of increase in Hb level, and clinical circumstances.
ESA doses should be decreased, but not necessarily withheld,
when a downward adjustment of Hb level is needed. Scheduled
ESA doses that have been missed should be replaced at the
earliest possible opportunity. ESA administration in ESAdependent patients should continue during hospitalisation.
Hypertension, vascular access occlusion, inadequate dialysis,
history of seizures, or compromised nutritional status are not
usually contraindications to ESA therapy.
Managing Non-Response to ESAs
The patient with anaemia and CKD should undergo evaluation
for specific causes of non response whenever the Hb level is
inappropriately low for the ESA dose administered.
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Table 6 Screening for non-response
100
The following also need to be considered:
• Chronic blood loss (e.g. from gastrointestinal or genitourinary
tracts)
• Iron deficiency
• Folate / Vitamin B12 deficiency
• Reticulocyte count
• Infection/inflammation
• Tuberculosis, systemic lupus erythematosus (SLE)
• Chronically rejecting transplants
• Hyperparathyroidism / osteitis fibrosa
• Aluminium/chloramine toxicity
• Haemoglobinopathies (alpha, beta thalassaemia, sickle cell
anaemia)
• Multiple myeloma, myelofibrosis, myelodysplasia
• Malignancy
• Malnutrition
• Drugs interaction such as high dose ACE inhibitors
• Inadequate dialysis
• Antibodies to Epoetin - red cell aplasia
A process of elimination will determine the cause of nonresponse to treatment. However if none of the above are
lacking and have all been fully investigated then a bone
marrow aspiration may be necessary to rule out any other
haematological cause of anaemia or non-response to
treatment.
The Benefits of Treating ACKD
Untreated anaemia has a number of adverse consequences
both for the patient as well as for the healthcare system ranging
from effects on quality of life, cognitive function and libido through
to increased mortality and morbidity with its associated costs.
Management of Anaemia in CKD
The major risk is cardiovascular disease (CVD), with one of the
earliest manifestations of left ventricular hypertrophy (LVH).
Anaemia has both direct and indirect effects on left ventricular
function and growth. Age, hypertension, and the level of Hb
are independent predictors for the presence of LVH. A number
of other studies have shown that anaemia predicts increased
left ventricular mass, left ventricular dilatation, heart failure
and death, and that anaemia is associated with increased
hospitalisation rates and increased mortality21,22. Anaemia is
also a potent risk marker for poor outcome amongst patients
with acute myocardial infarction.
The patients who are most likely to gain the greatest long-term
benefit from correction of anaemia in CKD are those who are
approaching dialysis. Early intervention to correct anaemia
has the potential to impact on the progression of chronic
kidney disease and effect patient morbidity, hospitalisation
rates, quality of life and mortality.
Managing ACKD
People offered ESA therapy and their primary care physicians
should be given information about why ESA therapy is
required, how it works and what benefits and side effects may
be experienced. When managing the treatment of people with
anaemia of CKD, there should be agreed protocols defining
roles and responsibilities of healthcare professionals.
People with anaemia of CKD should have access to
a designated contact person or persons who have
principal responsibility for their anaemia management and
who have skills in the following activities2:
• Monitoring and managing a caseload of patients in line
with locally agreed protocols
• Providing information, education and support to empower
patients and their families and carers to participate in
their care
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Chronic Kidney Disease:
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• Co-ordinating an anaemia service for people with CKD,
working between secondary and primary care and
providing a single point of contact, to ensure patients
receive a seamless service of the highest standard
• Prescribing medicines related to anaemia management
and monitoring their effectiveness
In the UK ACKD is predominantly managed by nurses23, often
with the help of electronic algorithms. Nurses across Europe
are now increasingly taking on this role.
References
102
1.
2.
3.
4.
5.
6.
7.
8.
9.
World Health Organization. Iron Deficiency Anaemia, Assessment,
Prevention and Control: a guide for programme managers.
2001.
National Collaborating Centre for Chronic Conditions. Anaemia
management in chronic kidney disease: national clinical guideline
for management in adults and children. Royal College of Physicians:
London. 2006.
Spivak JL. The blood in systemic disorders. Lancet 2000; 355:
1707-12.
Peirera BJG, Sundaram S, Barrett TW, Butt NK, Porat R and King AJ.
Cytokine production by human peripheral blood mononuclear cells
stimulated by a Pseudomonas aeruginosa culture filtrate: Role of
plasma and polymyxin B. International Journal of Artificial Organs
1996; 19;(5):276-283.
Revised European Best Practice Guidelines for Management of
anaemia in patients with chronic renal failure. Nephrol Dial Transplant
2004; 19 ;(suppl 2) S1-S47.
British National Formulary. March 2007.
Jenkins K. Anaemia in CKD Chapter 3 in Thomas N, editor.
Advanced Renal Nursing. Blackwell Publishing: London. 2005.
Coresh J, Astor BC, Greene T et al. Prevalence of chronic
kidney disease and decreased kidney function in the adult US
population: Third National Health and Nutrition Examination Survey.
Am J of Kidney Dis 2003; 41(1):112.
De Lusignan S, Stevens PE, O’Donoghue D et al. Identifying patients
with chronic kidney disease from general practice computer records.
Family Practice 2005;22(3):234–241.
Management of Anaemia in CKD
10. El Achkar TM, Ohmit SE, McCullough PA et al. Higher prevalence
of anemia with diabetes mellitus in moderate kidney insufficiency:
The Kidney Early Evaluation Program. Kidney Int 2005; 67(4):
1483–1488.
11. Bosman DR, Winkler AS, Marsden JT et al. Anemia with erythropoietin
eficiency occurs early in diabetic nephropathy. Diabetes Care
2001;24(3):495– 499.
12. Ishimura E, Nishizawa Y, Okuno S et al. Diabetes mellitus increases
the severity of anemia in non-dialysed patients with renal failure.
Journal of Nephrology1998; 11(2):83–86.
13. Thomas MC, MacIsaac RJ, Tsalamandris C et al. Unrecognized
anemia in patients with diabetes: a cross-sectional survey.
Diabetes Care 2003;26(4):1164–1169.
14. Thomas MC, MacIsaac RJ, Tsalamandris C et al. The burden of
anaemia in Type 2 diabetes and the role of nephropathy: a crosssectional audit. Neph Dialysis Transplant 2004;19(7):1792–1797.
15. Thomas MC, Cooper ME, Tsalamandris C et al. Anemia with impaired
erythropoietin response in diabetic patients. Archives of Internal
Medicine 2005;165(4):466–469.
16. Levin A, Thompson CR, Ethier J et al. Left ventricular mass index
increase in early renal disease: impact of decline in hemoglobin.
Am J of Kidney Dis 1999; 34(1):125–134.
17. Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin
alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–98.
18. Macdougall IC. CREATE: New strategies for early anaemia
management in renal insufficiency. Nephrol Dial Transplant
2003;18: Suppl 2.
19. Mix TCH, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P,
Levey AS et al. Trial to Reduce Cardiovascular Events with Aranesp
Therapy (TREAT): Evolving the management of cardiovascular risk
in patients with chronic kidney disease. American Heart Journal
2005;149 (3): 408-413.
20. NKF-KDOQI Clinical Practice Guidelines and Clinical Practice
Recommendations for Anemia in Chronic Kidney Disease.
Am J Kidney Dis 2006; 47:S1-S146.
21. Jones M, Schenkel B, Just J. Epoetin alfa’s effect on left ventricular
hypertrophy and subsequent mortality. International Journal of
Cardiology 2005;100 (2):253–265.
22. Weiner DE, Tighiouart H, Vlagopoulos PT et al. Effects of anemia
and left ventricular hypertrophy on cardiovascular disease in patients
with chronic kidney disease. Journal of The American Society of
Nephrology 2005;16 (6):1803–1810.
23. Bennett L. The anaemia research nurse in effective multidisciplinary
management of patients on erythropoietin. EDTNA/ERCA Journal
1998; 24(3):38–39.
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Chronic Kidney Disease:
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Learning Outcomes
•
•
•
•
To gain knowledge and understand the role of diet
in the treatment of patients with Chronic Kidney
Disease (CKD) stages 1-3
To explain the role of diet in hypertension
management
To gain knowledge in the dietary management of
hyperlipidaemia
To understand the measures that should be taken
to slow down the progression of CKD
106
Introduction
Nutritional therapy is one of the cornerstones of treatment for
patients with CKD stages 1-3. Early CKD is very common,
but the majority of patients with early CKD do not progress to
end stage renal disease (ESRD), but do have an increased
risks of cardiovascular disease. Optimal management of the
risk factors for cardiovascular disease also reduces the risk of
progression from early CKD to ESRD.
The Aims of Nutritional Therapy
• To prevent progression from early CKD to ESRD
• To reduce the risk factors for cardiovascular disease
Nutrition and Chronic Kidney Disease (Stages 1-3)
Diet Therapy for CKD Stages 1 - 2
Recent research shows that 0.9% of the general population
have CKD1. Those aged 75 years 50%, have CKD caused
by the normal ageing of their kidneys. This can increase the
chances of high blood pressure, heart disease or stroke.
Although age is a non-modifiable risk factor, the time it takes
to reach stage 4 and 5 CKD provides an opportunities to slow
the progression of CKD, treat underlying co-morbidities, and
to prevent the systemic complications that develop in the
course of gradual loss of kidney function1, 2. A common factor
associated with this is hypertension, which contributes to the
progression of CKD and is a major risk factor for cardiovascular
disease3.
Hypertension
Hypertension management should focus on weight reduction
and reducing sodium intake. Other variables include alcohol,
potassium, calcium and a low fat diet that needs to includes fruit
and vegetables (5-9 portions daily) and low fat dairy produce
(2-4 servings daily) which will be rich in potassium, magnesium,
calcium and will modestly reduce blood pressure4.
It is helpful to consider sodium and fluid together as they are
closely linked in the management of blood pressure. The
body’s sodium and fluid status is the main determinant of
blood pressure. Dietary restrictions should be implemented if
patients are hypertensive to an intake of <100mmols sodium
(6g salt) per day. A study by Law et al (1991)5 demonstrated
that in people aged 50-59 years, a reduction in daily sodium
intake of 50mmol (about 3g of salt), attainable by moderate
dietary salt reduction, after a few weeks, lowered systolic
blood pressure by an average of 5mmHg, and by 7mmHg in
those with high blood pressure (>170 mmHg); diastolic blood
pressure would be lowered by about half as much5. The DASH
study also demonstrated that a moderate sodium restriction
107
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
showed a reduction in blood pressure of 5mmHg for systolic
and 2mmHg for diastolic blood pressure in hypertensive
individuals and the lower the sodium intake the greater the
lowering of blood pressure6.
Most of the sodium people consume is from the salt added
to processed foods such as breakfast cereals, bread and
tinned foods. The majority of manufactured foods now provide
nutritional labelling information with include data of the sodium
content. Educational information needs to be provided to
patients as 1.25g salt (0.5g sodium) or more per 100g is a lot
of salt whereas, 0.25g salt (0.1g sodium) or less per 100g is
a little salt. In order to reduce a person’s sodium intake you
need to provide advice on a reduction of salt added during
cooking and at the table before food is eaten, avoiding food
which is high in salt such as manufactured food, ready made
meals, smoked or cured foods.
108
Lipids
CKD patients are at a high risk for atherosclerotic cardiovascular
disease. Hyperlipidaemia is common in patients with CKD,
particularly those with nephrotic syndrome. In addition to
accelerating the development of systemic atherosclerosis,
experimental studies suggest that high lipid levels also may
promote progression of renal disease7. Furthermore, the
beneficial effect of lipid lowering is similar to that of lowering
the blood pressure in at least some models of chronic renal
disease8. The amount and type of fat are prescribed on
an individual basis and depend on factors such as serum
lipid levels, protein intake and body weight9. In addition to
dietary changes, statins are prescribed for treating high LDL
cholesterol (low-density lipoprotein) and reducing the levels
to <100mg/dL (<2.59mmol/L)10. Dietary restrictions include a
diet containing <10% of energy intake derived from saturated
fatty acids (SFA). Some individuals (i.e. people with LDL
cholesterol > 100mg/dl) may benefit from lowering SFA intake
Nutrition and Chronic Kidney Disease (Stages 1-3)
to <7% of energy intake. Dietary cholesterol intake should be
less than <300mg/day. Practically this means a reduction in
saturated dietary fat such as butter, ghee, cakes, biscuits and
instead using monounsaturated fats such as olive oil9. The
intake of trans-unsaturated fatty acids should be minimized.
Recommendations also include two to three servings of fish
per week to provide dietary n-3 polyunsaturated fatty acids
(n-3 PUFA)11.
Diabetes
In people with diabetes, excessive consumption of protein
may be harmful. Experts recommend that people with diabetic
nephropathy consume the recommended dietary allowance
for protein, but avoid high-protein diets. For those with greatly
reduced kidney function, a diet containing reduced amounts
of protein may help delay the onset of kidney failure12. Anyone
following a reduced-protein diet should work with a dietitian
to ensure adequate nutrition. Antihypertensive drugs and
low-protein diets can slow kidney disease when significant
nephropathy is present. Intensive management of blood
glucose is important for people with type 1 and type 2 diabetes,
especially for those in early stages of diabetic nephropathy13.
Intensive management is a treatment regimen that aims
to keep blood glucose levels close to normal. The regimen
includes testing blood glucose frequently, administering insulin
frequently throughout the day on the basis of food intake
and physical activity, following a diet and activity plan, and
consulting a health care team frequently.
Diet Therapy for CKD Stage 3
As patients progress to CKD stage 3, dietary advice depends
on many factors including existing co-morbidities, medications,
blood biochemistry, nutritional status, weight and usual dietary
intake. Lifestyle advice as in stages 1-2 will form the main
basis of diet therapy; however additional advice on protein,
109
Chronic Kidney Disease:
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phosphate, potassium, vitamins and minerals might also be
provided dependent on the individual requirements of the
patient.
Protein Intake
Control of protein intake may delay the progression of CKD and
improve the effects of excessive accumulation of nitrogenous
waste14. A re-analysis of The Modification of Diet in Renal
Disease (MDRD) demonstrated that a 0.2g/kg a day reduction
in protein intake correlated with a 1.15ml/min/year reduction
in the rate of decline in glomerular filtration rate (GFR). This
decline has been shown to correlate with a 41% prolongation
of renal survival15.
110
A Cochrane systematic review further demonstrates the
benefits of decreasing protein intake in the diet on delaying
the progression of CKD12. Unfortunately, the evidence
is not conclusive and opinions are divided and further
research is required in the future. Currently, there are variant
recommendations of dietary protein intake for CKD patients
(Table 1)
Table 1: Current recommendations of dietary protein intake for CKD patients
Glomerular
Filtration Rate
(GFR)
Recommended protein
intake
(g/kg ideal body weight)
Professional
organisation
> 30 ml / min
0.75 g / kg
K/DOQI
< 30 ml / min
0.6 g / kg
K/DOQI
20 - 30 ml / min
0.6 - 1.0 g / kg
EDTNA / ERCA
Although the benefit of protein restriction may be sufficient to
delay renal replacement therapy for several years, there is a
large cost in terms both of effort on the part of the healthcare
team and patient, and of the relatively poor palatability of more
severe protein restriction. Only highly compliant patients are
Nutrition and Chronic Kidney Disease (Stages 1-3)
likely to comply with this regimen over a prolonged period16. At
present, optimal dietary treatment of non-diabetic patients with
CKD is uncertain. A reasonable regimen consists of rigorous
blood pressure control and the intake of approximately 0.8 to
1.0g/kg of high biologic value protein per day, with the lower
value used in patients with progressive disease. It is possible,
although not proven, that vegetable proteins and egg whites
are a safer sources of protein, since they are less likely to
increase glomerular filtration16.
Low-protein diets reduce the generation of nitrogenous
wastes and inorganic ions, which cause many of the clinical
and metabolic disturbances characteristic of uraemia such as
hyperphosphataemia, metabolic acidosis, hyperkalaemia, and
other electrolyte disorders16.
Nephrotic syndrome comprises of a group of symptoms
including proteinuria (exceeding 3.5 grams per day), low blood
protein levels, hypercholesterolemia, and oedema caused by
various disorders that damage the kidneys, particularly the
basement membrane of the glomerulus. It can both decrease
protein excretion and diminish hepatic albumin synthesis;
the net result is usually no change in the plasma albumin
concentration16.
9, 17
Recommended nutritional management
g
:
• Treatment of hypertension - low salt diet, (NKF K/DOQI:
1 - 2 g sodium/day)
• Protein intake of 0.8 - 1.0 g protein / kg ideal body
weight
• Adequate energy intake
• Treat hyperlipidaemia:
- manipulate fat intake
- lipid-lowering drugs
• Maintain fluid balance
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Renal Bone Disease and Nutritional Interventions
Hyperphosphataemia
A tendency toward phosphate retention begins early in CKD,
due to the reduction in the filtered phosphate load. Although
this problem is initially mild with hyperphosphataemia being a
relatively late event, phosphate retention is intimately related
secondary
to
the
common
development
of
hyperparathyroidism. High circulating levels of parathyroid
hormone play an important role in the development
of renal osteodystrophy and possibly in other uraemic
complications18.
112
Phosphate
The K/DOQI practice guidelines made the following
recommendations for the goal serum phosphate at different
levels of CKD19.
• At an estimated GFR between 15 and 59 ml/min/
1.73m2 (stage 3 and 4 CKD), the serum phosphate
should be between 2.7 and 4.6 mg/dl (0.87 and
1.49 mmol/L)
• The calcium phosphate product (corrected calcium x
phosphate) should be maintained below <55 mg²/dl²,
(<4.4 mmol²/L²) in patients with stage 3 to 5 CKD
Potassium
Hyperkalaemia in CKD stages 1-3 is rare, however patients
with CKD should be monitored on a regular basis to avoid
hyper or hypokalaemia. In CKD stages 1-3 non-dietary reasons
could be the cause of a hyperkalaemic episode and should
be considered, this include blood transfusions, anaesthetics,
insulin insufficiency, acidosis and medication20. Drugs that can
cause hyperkalaemia include angiotensin-converting enzyme
inhibitors (ACEI), angiotensin receptive blockers (ARB),
beta-blockers, potassium-sparing diuretics (spironolactone),
non-steroidal anti-inflammatory drugs and ciclosporine.
Nutrition and Chronic Kidney Disease (Stages 1-3)
Vitamins and minerals
Vitamin and mineral requirements are not well defined in CKD,
but non-dialysed patients treated with a controlled-protein diet
may need some vitamin supplements. Vitamin preparations
should contain the daily recommended intake of water-soluble
vitamins, including folate2. The normal dietary intake of Vitamin
C is 60mg/day and should not exceed 100mg/day because
it plays a role in the formation of oxalosis2,18. Fat-soluble
vitamins and especially vitamin A, should be avoided as renal
function decreases as this is raised in renal failure2, 20. Routine
supplementation of water-soluble vitamins will most likely
outweigh the risk of deficiency, especially in those patients
who are unable to manage an adequate dietary intake18.
Mineral supplementation, including trace elements, is not
recommended in this patient population. Iron supplementation
should be individualized and iron levels monitored closely2.
It is important to avoid prescribing iron supplementation
with phosphate binders to prevent drug interaction20. Zinc
supplementation is only indicated once zinc deficiency has
been established20.
Summary
r off Diet and Lifestyle Advice
Improving diet and lifestyle is a critical component for reducing
cardiovascular disease risk factors.
The current recommendations are:
• to balance calorie intake and physical activity to achieve
and maintain a healthy body weight (BMI 20-25)
• to eat a diet rich in vegetables and fruit
• choose wholegrain, high fibre foods such as whole grain
cereals and wholemeal bread
• to include oily fish in the diet two or three times a week
such as mackerel, sardines, salmon or fresh tuna
• limit saturated fat to <7% of the total calorie intake and
cholesterol to <300mg/day by choosing lean meats
113
Chronic Kidney Disease:
•
•
•
•
A Guide to Clinical Practice (Stages 1-3)
and low fat dairy products and minimizing the intake of
hydrogenated fats (found in biscuits, crisps)
to minimize the intake of food and drinks with added
sugars
to prepare food with little or no salt
to consume alcohol in moderation
to ensure good blood glucose control if the person suffers
from diabetes
Appendix I
Nutrition recommendation for CKD patient without dialysis
114
Recommendations20
American Dietetic
Association14
Protein
0.6-1.0 g/kg IBW/day
(high biologic
value >50%)*
0.75 g / kg / day
Energy
30-35 kcal/kg IBW/day
Based on energy
expenditure
Carbohydrates
50%-60% of total calories
50-60 % of total
calories
Total Lipids
30%-40% of total calories
25-35 % of total
calories
Saturated
Lipids
7%-10% of total calories
<7 % of total calories
Polyunsaturated
Lipids
7%-10% of total calories
Up to 10 % of total
calories
Monounsaturated
Lipids
10%-20% of total calories
Up to 20 % of total
calories
Nutrition and Chronic Kidney Disease (Stages 1-3)
Sodium
1800 - 2500 mg/day
(80 - 100 mmol sodium or
5 - 6 g salt per day)*
Varies 1 - 4 g / day
to no added salt,
depending on
co-morbidities
Potassium
1.0 mmol/kg IBW with K+
>5.5 mmol/l*
Usually no restriction
unless serum levels
are raised
Phosphorus
600 - 1000 mg/day
(19 - 31 mmol/l)*
Monitor and restrict if
> 4.6 mg/dl
(>1.49 mmol/L)
Calcium
1000 - 1500 mg/day
1200 - 1500 mg /
day, maintain serum
level at lower end
Fluids
Urine volume 24-hours
+ 750 ml
No restriction
Magnesium
DRI, no supplement
No supplement
Iron
DRI, individualized
supplementation if
indicated
Individualize from
stages 3 - 5
Zinc
DRI, supplement if
deficiency confirmed
Individualize from
stages 3 - 5
* EDTNA/ERCA 2001
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Chronic Kidney Disease:
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Appendix 2
Vitamins - diet may be supplemented with these quantities
116
Vitamins
Quantity
Thiamine
1.5 mg / day21
Riboflavin
1.8 mg / day21
Pantothenic Acid
5 mg / day21
Niacin
20 mg / day21
Pyridoxine
5 mg / day21
Vitamin B12
3 g / day20,21, Daily Recommended Intake (DRI)
Vitamin C
60 - 100mg/day3 (DRI)
Folic Acid
1 mg / day21
Vitamin A
No supplement2,20, 21
Vitamin D
Individualize from stages 3 - 52 ,20, 21
Vitamin E
15 IU / day21
Vitamin K
No supplement2 ,20, 21
References
1.
2.
3.
4.
Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal
disease: a new paradigm. Am J Kidney Dis 2000; 35 (4 Suppl 1):
S117-31.
Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of
cardiovascular disease in chronic renal disease: What do we know?
What do we need to learn? Where do we go from here? National
Kidney Foundation Task Force on Cardiovascular Disease. Am J
Kidney Dis 1998; 32 (5): 853-906.
Bakris GL, Williams M, Dworkin L, et al. Preserving renal function
in adults with hypertension and diabetes: a consensus approach.
National Kidney Foundation Hypertension and Diabetes Executive
Committees Working Group. Am J Kidney Dis 2000; 36 (3): 646-61.
Karppanen H, Karppanen P, Mervaala E. Why and how to implement
sodium, potassium, calcium and magnesium changes in food items
and diet? J Hum Hypertens 2005; 19 Suppl 3: S10-9.
Nutrition and Chronic Kidney Disease (Stages 1-3)
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Law MR, Frost CD, Wald NJ. By how much does dietary salt reduction
lower blood pressure? III--Analysis of data from trials of salt reduction.
BMJ 1991; 6;302(6780):819-24.
Sacks et al. DASH trial. N Engl J Med 2001; 344: 3-10.
Fried L, Orchard T, Kasiske B. Effect of lipid reduction on the progression
of renal disease: A meta-analysis. Kidney Int 2001; 59: 260-269.
Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker
G. The effects of dietary protein restriction and blood-pressure control on
the progression of chronic renal disease. Modification of Diet in Renal
Disease Study Group. N Engl J Med. 1994; Mar 31;330 (13): 877-84.
McCann L, editor. Pocket Guide to Nutrition Assessment of the
Patient with Chronic Kidney Disease 3rd ed. National Kidney
Foundation: New York. 2002.
NKF-K/DOQI Clinical Practice Guidelines for Management of
Dyslipidemias in Patients with Kidney Disease. Am J Kidney Dis
2003; 41 (4 Suppl 3): I-IV, S1-91.
Calder PC. N-3 fatty acids and cardiovascular disease: evidence
explained and mechanisms explored. Clinical Science 2004; 107: 1-11.
Fouque D, Laville M, Boissel JP. Low protein diets for chronic
kidney disease in non diabetic adults. The Cochrane Database
of Systematic Reviews 2006, Issue 2. Art. No.: CD001892. DOI:
10.1002/14651858.CD1892.pub2. 2006.
Diabetes Control and Complication Trail Research Group (DCTT).
The effect of intensive therapy on the development and progression of
diabetic nephropathy in the Diabetes and Complication Trial. Kidney
Int 1995; 47 (6); 1703-20.
Byham-Gray L, Wiesen K, editors. A Clinical Guide to Nutrition Care
in Kidney Disease.1st ed. Faulhaber Publisher: Chicago. 2004.
Levey AS, Adler S, Caggiuka AW et al. Effects of dietary protein
restriction on the progression of advanced renal disease in the
Modification of diet in Renal Disease study. Am J Kidney Dis 1996;
27:652 - 663.
Rose BD. Protein restriction and progression of chronic kidney
disease. Up-To-Date; 8/2006: 14.3.
NKF-K/DOQI Clinical practice guidelines for nutrition in CRF. Am J
Kidney Dis 2000; 35 (6), suppl 2: S9, S56-63.
Cronin RE, Treatment of hyperphosphatemia in chronic renal failure.
Up-To-Date; 08/2006: 14.3.
NKF-K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease
in Chronic Kidney Disease. Am J Kidney Dis 2003; (4) Suppl 3: S1-201.
Jacobs C. Costs and benefits of improving renal failure treatment
– where do we go? Nephr Dial Transpl 2006; 21: 2049 – 2052.
Kopple JD, Massry SG. Nutritional Management of Renal Disease.
1st ed. Williams and Wilkins: Baltimore. 1997.
117
11 9
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Learning Outcomes
•
•
•
To gain knowledge and understanding about
diabetes mellitus and the effect on kidney function
To explain the effects of Chronic Kidney Disease
(CKD) on diabetes control
To gain an understanding of the treatment of
diabetes
Introduction
120
Diabetes mellitus is the leading cause of end stage renal failure
within the western world and the number of people developing
diabetes is increasing rapidly. The world wide number of
diabetes cases reached 171 million in the year 2000 and this is
predicted to rise to over 300 million by 2030, with a prevalence
globally of 4.4% in all age groups1. Reasons for this rapid
rise include an ageing population, unhealthy diets, sedentary
lifestyles and the increase in obesity.
The World Health Organisation states that the number of
deaths attributed annually to diabetes is around 3.2 million,
with diabetes being the major causes of premature illness and
death in most countries, mainly through the increased risk of
cardiovascular disease (CVD)2. Diabetes is among the leading
causes of CKD, but its frequency varies between populations.
According to the European Dialysis and Transplant Registry
2004 the percentage of people with diabetes as the leading
cause of CKD ranges from 4.6% in Finland to 45.2% in
Austria3.
The Effect of Diabetes Mellitus on Progression CKD
What is Diabetes mellitus?
Diabetes Mellitus is a condition that results in chronic high
blood sugar levels (hyperglycaemia) due to insulin deficiency,
insulin resistance or a combination of these two factors.
Type
yp 1 Diabetes - usually occurs in children or young adults,
but can occur at any age and accounts for approximately 510% of all cases of diabetes2. It results from destruction of
the cells that produce insulin, mainly by the autoimmune
destruction of the pancreatic beta cells. People with type 1
diabetes are dependent on insulin injections to survive as they
do not produce any of their own insulin.
Type
yp 2 Diabetes - accounts for the majority of cases of
diabetes (90-95%) and results from a combination of insulin
deficiency and insulin resistance. The level of hyperglycaemia
is usually less severe and can be managed initially with a
combination of lifestyle change and oral medication. As the
disease progresses however the need for insulin injections
to manage blood sugar levels becomes more likely. Lifestyle
factors such as obesity and a sedentary lifestyle contribute to
the increased risk of developing type 2 diabetes as do genetic
factors and ethnicity.
In the presence of typical symptoms of diabetes - weight
loss, polyuria, polydipsia, blurred vision and glycosuria - a
single fasting plasma glucose level of >7.0mmol1 or a random
plasma glucose of >11.1mmol1 is diagnostic. In the absence
of symptoms two such values are needed. A formal glucose
Table 1: Diagnosis of Diabetes
Diabetes
Fasting plasma glucose
> 7.0mmmol/l (126mg/dl)
or
or
2hr plasma glucose after a 75g oral > 11.1mmol/l (200mg/dl)
glucose load
121
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
tolerance test can be ordered where a fasting glucose level
is taken then the patient is given 75g of glucose and, 2 hours
later, a further glucose level taken. Blood sugar monitoring
(BM) tests can not be used for diagnosis2.
How does Diabetes Affect Renal Function?
Although people with diabetes can develop any type of kidney
disease, the reason for the high risk of CKD in diabetes is
related to the risk of developing diabetic nephropathy. This
is a condition characterised by glomerular hyperfunction and
hypertrophy, followed by microalbuminuria and then finally
progressive decline in renal function to end stage disease.
The exact cause of this is not completely understood but
hyperglycaemia plays a role in damaging the microcirculation
within the kidney. Hypertension which is highly prevalent
particularly in type 2 diabetes also plays a key part.
122
Can Diabetic Nephropathy
p p y be Prevented? - Not all patients
with diabetes will develop diabetic nephropathy. The prevalence
is estimated to be 25-30% in type 2 diabetes, and among
white patients with type 1 diabetes of 15-30 years’ duration,
in the United Kingdom, fewer than 20% will have established
nephropathy4. The prevalence of nephropathy is higher among
patients of Asian or African-Caribbean origin. Genetic factors,
ethnicity, age and gender are all factors that can not be altered.
However the risk of developing nephropathy can be reduced
by controlling modifiable risk factors such as glycaemic control
and blood pressure.
The Diabetes Control and Complications Study demonstrated
the benefits of achieving good diabetes control in reducing the
risk of developing diabetic nephropathy. Patients with type 1
diabetes assigned to intensive insulin treatment who achieved
a mean HbA1c of 7.2% (compared with 9.1% in the control
group) delayed the onset of microvascular complications
The Effect of Diabetes Mellitus on Progression CKD
such as diabetic nephropathy and also had a slower rate of
progression of microvascular damage once established5.
The United Kingdom Prospective Diabetes (UKPDS) study
reported similar findings in a large randomised control study of
people with type 2 diabetes. A 1% reduction in HbA1c result
was associated with a 37% reduction in the risk of developing
microvascular complications and a 21% reduction in risk of
any morbidity end point or death related to diabetes6.
There was no specific threshold found in either of these studies
to indicate a level above which patients were at greater risk;
any improvement in HbA1c is beneficial in reducing the risk of
complications and the nearer normal the HbA1c concentration
the better. The European Association for Study of Diabetes
(EASD) recommend a target HbA1c of 6.5% or below7.
How does CKD affect diabetes control?
Once CKD is established diabetes becomes difficult to control.
Advancing CKD is associated with an increase in insulin
resistance, this can result in more insulin being required or
a conversion from tablets to insulin. However as the disease
progresses to end stage renal failure there is a reduction in
insulin degradation resulting in a marked reduction in insulin
requirements or even cessation of insulin / tablets in type 2
diabetes.
Potential problems in achieving good diabetic control in CKD:
• Risk of severe hypoglycaemia with aggressive
control, particularly if dietary intake is unpredictable
• Lack of symptoms of hypo- or hyper-glycaemia
• Potential for inaccuracy of blood test results
• Presence of other diabetes related complications e.g.
neuropathy or retinopathy
• Effect of impaired renal function on treatments used to
control hyperglycemia
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Measuring Level of Diabetes Control
HbA1c - diabetes control can be assessed by serial
measurement of HbA1c levels. This gives an assessment
of glycaemic control for the previous 3months (assuming a
normal red blood cell life).
High urea levels may interfere with some of the methods used
to measure HbA1c, it is important check with the laboratory
which assay they use and whether or not results will be
affected by urea levels.
Home Blood Glucose Monitoring
g - patient self monitoring via
home blood glucose meters is useful to determine the optimum
insulin regime and monitor the effect on a daily basis of changes
in treatment. Hydration levels, uric acid and the maltose used
in some peritoneal dialysis fluids, will affect some test strips.
It is essential to check with the manufacturers any potential
interference that may lead to inaccurate results before using
home blood glucose results to change treatment.
Managing the Patient With Diabetes
124
All patients with diabetes should be seen at least annually by a
family doctor or hospital consultant so that their condition can
be monitored and any complications detected early. They may
be seen more often by diabetes nurses and diabetes educators
to ensure that they have the right skills and knowledge to be
able to self manage their diabetes where this is appropriate.
Care of the person with diabetes should include8,9:
• Providing education to ensure self caring e.g. how to
blood glucose monitor and how to adjust insulin if blood
sugars are not controlled
• Assessing cardiovascular risk factors with the aim to
reduce cardiovascular risk e.g. smoking cessation;
consider aspirin and statins if appropriate; target BP
(<130/80mmHg), total cholesterol (<4mmol/l) and HbA1c
(<6.5%)
The Effect of Diabetes Mellitus on Progression CKD
• Annual screening for complications including eyes, feet
and urine test for microalbuminuria/ proteinuria
• Support with lifestyle changes such as increasing physical
activity and reducing weight and choosing a healthy diet
• Consider use of an angiotensin converting enzyme (ACE)
inhibitor or angiotensin 2 antagonist if microproteinuria or
overt proteinuria present
• Refer to a nephrologists when CKD stage 3-4, or sooner
if there is a rapid deterioration in renal function which
may suggest a non-diabetes related kidney disease
Treatments Used to Achieve Good Diabetes Control
Lifestyle
y Changes
g
• A healthy balanced diet low in refined sugars is
recommended in diabetes. When CKD is present
particularly in advanced stages dietary restrictions are
complex and advice from a dietician should be sort to
enable the person to combine the various aspects of the
dietary recommendations
• Exercise is an important aspect to maintain ideal weight
and help control blood glucose levels
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Chronic Kidney Disease:
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Pharmacology
Table 2: Oral Hypoglycaemic agents used in type 2 diabetes
Agents
Sulphonylurea- act
on the pancreas
to increase insulin
secretion. Only
effective if patient still
produces some of
their own insulin
e.g. Glicalzide,
Glipizide, Glyburide,
Glimepiride
Alpha- Glucosidase
126
Side Effects
Cautions in CKD
Usually mild
and infrequent
may cause
gastrointestinal
side effects nausea, vomiting
diarrhoea or
constipation
Risk of hypoglycaemia
Accumulation of drug if
renal function impaired,
reduce dose or avoid
using once patient
reaches end stage
renal failure
Hypoglycaemia,
weight gain
Frequently cause Not recommended in
CKD due to increased
gastro-intestinal
Inhibitors - delays
side
effects
levels of the drug
digestion and
if
kidney function
absorption of starch
e.g
fl
atulence
impaired
and sucrose
and abdominal
e.g. Acarbose
bloating, diarrhoea
Meglitinides- stimulate Gastrointestinal
Caution advised
insulin secretion
due to the risk of
side effects,
hypoglycaemia
rarely
e.g Repaglinide,
hypoglycaemia
Nateglinide
Biguanides- suppress Gastrointestinal
Excreted mainly
unchanged in the urine
side effects
hepatic glucose
such as nausea, thus if renal function is
production and
increase insulin
impaired accumulation
vomiting,
sensitivity in
diarrhoea,
of the drug occurs.
peripheral tissue
Should not be used if
flatulence,
creatinine clearance is
metallic
taste
e.g. Metformin
reduced due to risk of
lactic acidosis. Caution
needed once GFR is
<50ml
The Effect of Diabetes Mellitus on Progression CKD
Thiazolidinediones
- increase insulin
sensitivity
e.g. Rosiglitazone,
Pioglitazone
Gastrointestinal
side effects,
weight gain,
headache
anaemia,
oedema, rare
reports of liver
toxicity
Metabolised by the
liver thus not affected
by dialysis and
accumulation does
not occur in CKD.
However associated
with heart failure and
oedema and should be
avoided in advanced
CKD, especially if there
is pre-existing heart
failure
Insulin
Table 3: Insulin used in type 1 diabetes and in some patients with type 2 diabetes
Insulin
Type
Examples
Onset
of
action
Peak
action
Duration of
action
Rapid Acting
Aspart
Lispro
Gluilisine
5-10 mins
must be
injected with
food
30-90
mins
Up to
4 hours
Actrapid
Humulin S
Hypurin
Neutral
30 mins
Inject
20-30mins
before food
1-2
hours
Up to
6-7
hours
Insulatard
Humulin I
Intermediate
Insuman
Acting
basal Hypurin
Isophane
60
mins
3-6
hours
18-24
hours
Long acting
Analogues
1.5-2
hours
Minimal
peak
18- 24
hours
Short Acting
Detemir
Glargine
127
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Insulin Regimes
Examples
Subcutaneous insulin injections
One or two injections per day of a basal
insulin (eg Glargine, Detemir, Isophane
Basal Bolus Regime insulin ) with meal time injections of a short
acting insulin (eg Aspart, Lispro,Glulisine,
Soluble insulin)
Twice daily Mixed
insulin
One injection of a mixture of basal and
short acting insulin given with breakfast and
evening meal
Basal Insulin only
One or two injections per day of basal
insulin (eg Glargine, Detemir, Isophane
insulin) given at breakfast, evening meal or
pre bed. Usually given in combination with
oral diabetes medication
Injections of short acting insulin given with
each meal (eg Aspart, Lispro,Glulisine,
Meal time only insulin Soluble insulin). Usually given in
combination with oral diabetes medication
and not suitable for use in type 1 diabetes
128
Continuous Subcutaneous Insulin via a pump
Short acting insulin (eg Aspart, Lispro,Glulisine, Soluble insulin)
administered subcutaneously via a small portable electronic pump
device Pumps are an advantage in allowing fine adjustment to be
made to insulin doses but they are expensive and there is potentially
an increased risk of diabetic ketoacidosis developing
Inhaled Insulin
Relatively new to the market, inhaled insulin is short acting and is
given at meal times via an inhalation device directly into the lungs.
Must be used in conjunction with a subcutaneous basal insulin
injection in type 1 diabetes. Contraindicated in smokers and those
with respiratory diseases e.g. asthma
The Effect of Diabetes Mellitus on Progression CKD
KDOQI guidelines 2005 suggest that newer insulin regimes
and insulin preparations should be used to maintain good
glycaemic control in CKD. Insulin analogues are associated
with reduced risk of hypoglycaemia and increased predictability
in their actions, thus helping to maintain better control8.
How to decide which insulin regime is best
The choice of insulin regime often depends on a number of
factors: the type of diabetes, the patients personal preference,
the risk of hypoglycaemia, eating habits and persons lifestyle.
If someone is active and has an erratic lifestyle a basal bolus
regime is usually preferable to give more flexibility. If someone
is less active and needs help with their injections then a once
daily or twice daily regime would be more suitable.
Cautions for Insulin Use in CKD
The kidneys play an important role in metabolising insulin,
however there is little change in the metabolic clearance rate
in CKD until there has been a substantial reduction in GFR.
At this point there is a dramatic reduction in insulin clearance
increasing the risk of severe hypoglycaemia occurring if insulin
doses are not adjusted.
The effect on individual patients will vary depending on factors
such as dietary intake, presence of other diabetes complications
and the types of treatments they are prescribed. An integrated
multidisciplinary approach is required to minimise problems
and maintain adequate diabetes control.
Table 4: Recommendations for adjusting insulin with decline in renal function10
No dose adjustment required
GFR 10-50ml/min
Reduce to 75% of baseline dose
GFR <10ml/min
Reduce by as much as 50%
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Side Effects of Insulin
Insulin has few side effects, occasionally people may develop
sensitivity to insulin resulting in redness and inflammation
at the injection site but this is rare. The main concern when
someone takes insulin is the risk of hypoglycaemia (blood
sugars <4mmol/s) resulting in symptoms of sweating, pallor,
dizziness, shaking, confusion and possible collapse.
Action to take if hypoglycaemia occurs:
• If conscious give patient a sugary drink, 3 glucose tablets
or Glucogel
• Follow this with a carbohydrate based snack e.g. bread,
biscuits
• If unconscious do not give anything by mouth use
intramuscular Glucagon or intravenous dextrose
Another side effect of insulin is possible problems with injection
sites with skin/ fat atrophy or hypertrophy occurring. This can
be prevented by advising people to regularly change their
injection sites.
130
What to do if patient is unwell
If the patient is unwell it is important to do the following:
• Not to stop the insulin or tablets, they may even need
to be increased as hyperglycaemia is common in the
presence of illness
• Increase blood glucose monitoring
• Ensure hydration, maintaining fluid balance
• Refer to a medic if vomiting to prevent ketoacidosis
Other Complications of Diabetes
The person with diabetes who develops CKD is likely to have
also developed a number of other complications related to
The Effect of Diabetes Mellitus on Progression CKD
their diabetes. This is due to the fact that the vascular damage
that is occurring within the kidney also occurs in other areas.
These complications include:
• Peripheral neuropathy and peripheral vascular disease
resulting in high risk of foot ulceration and amputation
• Autonomic neuropathy resulting in postural hypotension
or gastric disturbances e.g. gastroparesis
• Cardiovascular Disease e.g. angina, stroke, myocardial
infarction or heart failure
• Retinopathy resulting in visual impairment and possible
blindness
• Sexual dysfunction e.g. erectile dysfunction in men
The risk of these complications occurring can be reduced
through tight control of blood pressure, cholesterol and blood
sugar levels.
Key Points Summary
• Diabetes is the leading cause of end stage renal disease
in the western world
• The number of people developing diabetes is increasing
rapidly world wide
• The risk of developing diabetic kidney disease can be
reduced through good diabetes control (HbA1c <6.5%)
• Once CKD is established diabetes becomes difficult to
control and careful adjustment of treatment is needed to
avoid problems
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Frequently asked Questions
1 What is Diabetes Mellitus?
Diabetes is a condition that results in chronic high blood
sugar levels and is the result of insulin deficiency, insulin
resistance or a combination of these two factors.
2 What is the difference between type 1 and type 2
diabetes?
Type 1 diabetes is caused by an auto immune response
in which the body destroys the cells that make insulin.
The person with type 1 diabetes is dependent on insulin
injections to survive as they do not make any of their own.
In type 2 diabetes the person still produces some insulin but
not enough or may be insulin resistant and can be treated
with diet, tablets but some patients will need insulin.
3 Why do a lot of patients with diabetes have CKD?
Diabetic nephropathy which results in microalbuminuria
then progressive decline in renal function is caused by
high blood sugar levels. People with diabetes are also
more likely to have high blood pressure which contributes
to CKD.
132
4 Can diabetic nephropathy be prevented?
Yes, good diabetes control and tight control of blood
pressure reduces the risk of diabetic nephropathy
5 How does CKD affect diabetes control?
A person with CKD is likely to have difficulty in managing
blood sugar levels and may be at risk of severe
hypoglycaemia due to poor clearance of medication
6 Are diabetes treatments safe to use in CKD?
Many of the oral medications used to treat diabetes become
contra-indicated in advanced CKD or should be used with
caution. Insulin can be used safely in all stages of CKD and
is not affected by dialysis. However significant reductions
in dose may be needed once GFR falls below 20.
The Effect of Diabetes Mellitus on Progression CKD
References
1.
Wild S, Roglic G, Green A et al. Global Prevalence of Diabetes.
Diabetes Care 2004; 27, (5): 1047-1053.
2. World Health Organisation, Facts and Figures, 2007.
http://www.who.int/diabetes/facts/world_figures/en
3. ERA-EDTA. European Dialysis and Transplantation Registry,
2004. http://www.era-edta-reg.org/index.jsp
4. Harvey JN, Rizvi K, Craney L, Messenger J, Shah R, Meadows PA.
Population-based survey and analysis of trends in the prevalence of
diabetic nephropathy in Type 1 diabetes. Diabetes Medicine 2001;
18: 998-1002.
5. DCCT. Diabetes Control and Complications Trial Research Group –
The effect of intensive treatment of diabetes on the development and
progression of long term complications in insulin-dependant diabetes
mellitus. N Engl Med 1993; 329:304.
6. Stratton I, Adler A, Neil A et al. Association of glycemia with
macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ 2000; 321:
405-412.
7. EASD. Guidelines on Diabetes, pre diabetes and cardiovascular
disease. EASD 2007. http://www.easd.org/
8. National Kidney Foundation. K/DOQI Clinical Practice Guidelines
for Cardiovascular Disease in Dialysis Patients. NKF 2005.
http://www.kidney.org/professionals/KDOQI/guidelines_cvd/guide11.htm
9. British Cardiac Society, British Hypertension Society, Diabetes
UK, HEART UK, Primary Care Cardiovascular Society, The Stroke
Association – JBS2: Joint British Society Guidelines on Prevention
of Cardiovascular Disease in Clinical Practice. BMJ 2005; 91,
(suppl v).
10. Snyder RW and Berns JS. Use of insulin and oral hypoglycaemic
medications in patients with diabetes mellitus and advanced kidney
disease. Semin Dial 2004;17: 365.
133
135
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Learning Outcomes
•
•
To gain knowledge and understanding of the
Cardiovascular (CV) risk associated with Chronic
Kidney Disease (CKD)
To evaluate and understand how CV risk can be
reduced in patients with CKD
Introduction
136
Cardiovascular disease (CVD) occurs as a result of disease
processes affecting the heart and blood vessels with the
underlying cause being atherosclerosis. This results in
cardiovascular (CV) events such as myocardial infarction,
stroke, and heart failure. CVD is the leading cause of
death in end stage kidney disease1. The risk of developing
cardiovascular disease is multifactorial and the increased risk
starts early in the course of chronic kidney disease (CKD).
When cardiovascular events occur morbidity and mortality
is higher amongst patients with CKD and the implications
of CV disease are for many far greater than the risk of the
progression to end stage renal failure. If the burden of CV
risk in CKD is to be reduced, all patients with CKD need to
be offered preventative advice and treatments to reduce this
risk.
What is the risk of CV disease in CKD?
It is well recognised that patients with end stage renal failure
have much higher CV mortality and morbidity rates than
patients without renal failure. The death rate is 5-90 times
Cardiovascular Risk in CKD
greater in dialysis patients than the general population, the
difference being greatest in the younger age group1. However
what may not be well recognised is the fact that this increased
CV risk starts early in the course of CKD.
A study of more than 1.1 million adults from the Kaiser
Permanente Renal Registry in San Francisco, found that when
kidney function measured as estimated glomerular function
(eGFR) dropped, the risk of death and cardiovascular events
such as heart disease and stroke, increased. Compared with
patients whose eGFR was at least 60ml/min/1.73m2:
• The increased risk of death ranged from 17% in those
with eGFR 45-59ml/min/1.73m2 to 600% in those with
eGFR <15ml/min/1.73m2
• The increased risk of cardiovascular disease (CVD)
events ranged from 43% in those whith eGFR
45-59ml/min/1.73m2 to 343% in those whith eGFR
<15ml/min/1.73m2
The KDOQI3 Guidelines state that: patients with chronic kidney
disease, irrespective of diagnosis, are at increased risk of CVD,
including coronary heart disease, cerebrovascular disease,
peripheral vascular disease, and heart failure. Both “traditional”
and “chronic kidney disease related (non-traditional)” CVD risk
factors may contribute to this increased risk.
• All patients with chronic kidney disease should be
considered in the “highest risk” group for cardiovascular
disease, irrespective of levels of traditional CVD risk
factors3
Traditional Risk Factors for CV Disease
Non Modifiable CVD Risk Factors
• Age > 55yrs for men, age >65yrs women
• Family history of early CV death
• Ethnicity
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Modifiable CVD risk factors
The Interheart study identified that there were nine potentially
modifiable risk factors for developing cardiovascular disease,
which are as follows4:
• Smoking
• Dyslipidaemia
• Hypertension
• Diabetes
• Abdominal obesity
• Psychosocial factors
• Lack of daily consumption of fruit and vegetables
• Regular excessive alcohol intake
• Lack of regular physical activity
Smoking.- Smoking is a major contributory factor to CV risk,
cardiac events fall 50% in people who stop smoking and the
risk of CVD, including acute myocardial infarction, stroke
and peripheral vascular disease, also decreases significantly
over the first two years after stopping smoking5. The CV risks
relating to smoking are no different in patients with CKD to that
of the general population however the consequences may be
far greater including a more rapid progression of CKD.
138
Dyslipidaemia.- In worldwide studies, 46% of coronary heart
disease deaths are attributable to raised cholesterol levels
and cardiovascular risk increases directly in relation to the
concentration of total cholesterol6. In the presence of CKD,
triglyceride clearance may be impaired leading to raised serum
triglycerides and HDL cholesterol, which is cardio protective,
is decreased.
Hypertension.- Hypertension leads to left ventricular
hypertrophy and is a major risk factor for CV disease. The
risk for both coronary heart disease and stroke increases
progressively with every increment in blood pressure above
110/75mmHg7. High blood pressure can be both a cause of
CKD and a consequence of it. The prevalence of hypertension
Cardiovascular Risk in CKD
among patients with CKD reported in previous studies has
ranged from 60 to 100%, depending on the study population,
the cause and the level of renal dysfunction8.
Diabetes.- Diabetes is now well recognised as a major CV
risk factor with up to 75% of people with diabetes dying from
CV disease. The relationship between blood sugar levels
and CV risk is continuous with every 1% rise in HbA1c level
associated with 14% more deaths9. If diabetes and CKD are
present together the patient is considered to be very high risk
of a CV event. In 5 years 32% of patients with type 2 diabetes
who develop microalbuminuria are dead with cardiovascular
disease accounting for 53% of these deaths10.
Weight control.- Excess body weight is associated with
high blood pressure, raised cholesterol and type 2 diabetes,
contributing to morbidity and mortality from heart disease and
stroke11. Obesity also plays an important role in progression of
kidney disease.
CKD Related CV Risk Factors
Intensive treatment of conventional CV risk factors has
not resulted in improved outcomes in CKD patients12. This
implies that other CV risks factors exist that are specific to
CKD patients, these are discussed below:
Vascular Calcification.- CKD patients have excessive
vascular calcification. Significant coronary calcification has
been observed in end stage renal failure patients as early as
in their 30’s and this has been noted to progressively increase
overtime13. Vascular calcification leads to increased stiffness
in arterial walls, reduced vascular compliance and increased
systolic blood pressure, this puts stress on the heart and
eventually leads to CV morbidity and mortality.
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Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Calcium and Phosphorus Metabolism.- CKD is associated
with changes in mineral metabolism. Abnormal calcium and
phosphorous metabolism are independent predictors of death
in ESRD due to vascular calcification13.
Inflammation.- Inflammation which is common in the uraemic
state is linked to high CV mortality. Also atherosclerosis which
is common in CKD patients represents an inflammatory state
which leads to worsening anaemia14.
Anaemia.- The available evidence, consisting of large
database analysis and population studies, clearly show that
low haemoglobin (Hb) levels are associated with higher rates of
hospitalisations, cardiovascular disease, cognitive impairment,
and other adverse patient outcomes, including mortality15.
When anaemia is present the workload on the heart increases
which can lead to left ventricular hypertrophy, increasing the
risk of death from heart failure or ischaemic heart disease.
How can CV risk be reduced?
140
CV risk reduction can be achieved through lifestyle and risk
factor intervention, appropriate drug therapies to lower blood
pressure, modify lipids and reduce glycaemia, as well as
the use of anti-thrombotic medication. As most patients with
CKD have multiple risk factors for CVD a multi-disciplinary,
coordinated approach will be necessary. The data available
to support CV risk reduction is not specific to reducing risk
in CKD however evidence from general population studies
supports the following key interventions:
The key lifestyle interventions to reduce CV risk are:
• To stop smoking.- cardiac events fall 50% in people
who stop smoking and the risk of CVD also decreases
significantly over the first two years after stopping
smoking5
• Make healthier food choices.- nutritional intake is an
important part of reducing CV risk through reductions in
Cardiovascular Risk in CKD
for example salt, fat and alcohol intake. However due
to the complexity of dietary restrictions in CKD a full
nutritional assessment with a dietitian will be necessary
to help people to make healthier choices that not only
reduce traditional CV risk but also take into account CKD
specific risk factors such as anaemia and bone disease
rather than bone metabolism
• Increase aerobic activity.- regular moderate physical
activity can reduce overall CV risk. For example, brisk
walking for half an hour per day reduces relative CHD
risk by 20%16. The goal for all people with CKD should be
30 mins of exercise most days of the week, however for
those not currently active low levels are recommended
initially with a gradual increase
• Optimise weight and weight distribution (e.g. reducing
central obesity) Reducing weight to a body mass index
(BMI) of 25 is preferable, however, a reduction of 5-10%
of initial body weight is still associated with significant
health benefits including improved blood pressure, lipid
and glucose metabolism17
Table 1: Key Treatment Targets3, 18
Waist
Circumference
Men < 102cm (Asian men < 90cm)
Women < 88cm (Asian women < 80cm)
Body Mass Index
< 25
Blood Pressure
< 130mmHg and < 80mmHg
(though this target may vary depending on
other clinical factors)
Lipids
LDL-C < 100mg/dl (< 2.6mmol/l)
Triglycerides < 200mg/dl (2.26mmol/l)
Glucose
Fasting 6.0mmol/l
HbA1c < 6.5%
141
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Blood Pressure.- meta-analysis and systematic reviews of
blood pressure lowering have consistently demonstrated the
benefit of blood pressure reduction in reducing CV risk, the
benefit of treatment driven by the quality of blood pressure
control19. KDOQI guidelines place all those with CKD in the
“highest risk” group for CV development and as such will
require pharmacological as well as lifestyle intervention to
lower blood pressure to <130/80mmHg3. A multi-disciplinary
approach used to deliver multiple interventions for blood
pressure and other CV risk factors has been shown to be
beneficial to help reduce CV risk20.
Lipid Lowering.- The benefit of lipid lowering in reducing
cardiovascular risk has been demonstrated in numerous
randomised control trails and is considered to be even more
beneficial in people at high CV risk. The ASCOTT-LLA and
the Heart Protection Study demonstrated that lowering
LDL-C levels by 1mmol/l in high risk patients with only
moderately raised levels reduced risk of coronary heart
disease by 25% and 36% respectively21.
NKF KDOQI guidelines recommend aggressive treatment of
raised cholesterol levels in CKD22. Lifestyle advice to reduce
total and LDL cholesterol, lower triglycerides and increase
HDL and drug therapy with statins is indicated in most high
risk people and can be used safely and effectively in CKD.
142
Antithrombotic Treatments.- anti-thrombotic treatments
have been shown to have significant positive benefits in
patients at high risk of CVD23. Low dose Aspirin is indicated
if 10 yr CV risk is >20% and blood pressure is controlled to
<150/90 mmHg24.
Targets for CKD specific CV risk factors3
• Correction of anaemia.- target Hb levels 11-12 g/dl.
(Hb<12.0 g/dl in men, Hb<11.0 g/dl in women). (See
anaemia chapter for further information). More evidence
Cardiovascular Risk in CKD
is needed as to the most appropriate Hb values to reduce
CVD risk
• Correction of serum phosphate/calcium.- target
phosphorus levels (3.5-5.5 mg/dl / 1.13-1.78 mmol/l)
• Parathyroid
Hormone
level
should
also
be
controlled to reduce CV risk with a target
PTH-150/300 pg/ml (16.5-33.0 pmol/l)
• Non-calcium based binders should be used if there is
severe vascular calcification
Key Points
• The risk of CV disease is very high in CKD
• The majority of people from CKD will die from CVD and
for many it is more important than the implications of
reaching end stage renal failure
• People with CKD will have traditional risk factors for CKD
the same as the general population but also have CKD
specific risk factors increasing the risk further
• CV risk can be reduced in CKD by addressing individual
CV risk factors
• As CV risk factors will be numerous; a coordinated multidisciplinary approach to treatment will be essential
143
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Frequently Asked Questions
What is Cardiovascular Disease?
Cardiovascular disease (CVD) occurs as a result of disease
processes affecting the heart and blood vessels with the
underlying cause being atherosclerosis. This results in CV
events such as myocardial infarction, stroke, and heart
failure.
What is the risk of CVD in CKD?
The risk of CVD starts early in the course of CKD. When
microalbuminuria is present even before eGFR starts to fall CV
risk is already increasing and the risk progresses substantially
as the person approaches end stage renal failure.
What traditional CVD risk factors affect people with
CKD?
Smoking, dyslipidaemia, hypertension, diabetes, abdominal
obesity, psychosocial factors, lack of daily consumption of
fruit and vegetables, regular excessive alcohol intake, lack of
regular physical activity.
What specific CKD related CVD risk factors are there?
Anaemia, vascular calcification, abnormal calcium and
phosphorous metabolism, inflammation.
144
How can CV risk be reduced?
A multi-disciplinary, multi-intervention approach is necessary
to help people deal with the numerous CV risk factors they are
likely to need. This will include lifestyle modification e.g. stop
smoking, reduce weight, exercise more and make healthier
food choices. Pharmacological treatment will also usually
be needed to achieve strict targets for blood pressure, lipid
and glycaemic control as well as to control anaemia and bone
metabolism problems.
Cardiovascular Risk in CKD
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
US Renal Data System USRDS Annual Data Report. National
Institutes of Health, National Institute of Diabetes and Digestive and
Kidney Diseases: Bethesda MD. 2002.
Go A, Chetow G, Fan D, McCulloch C, and Hsu C. Chronic
Kidney Disease and the risks of death, cardiovascular events and
hospitalisation. N Engl J of Med 2004; 35: 1296-1305.
NKF KDOQI Guideline 15. Association of Chronic Kidney Disease
with Cardiovascular disease. NKF 2002.
http://www.kidney.org/
professionals/kdoqi/guidelines_ckd/p7_risk_g15.htm
Yusuf S, Hawken S and Ounpuu S et al. Effect of potentially modifiable
risk factors associated with myocardial infarction in 52 countries. The
interheart study. Lancet 2004; 364, (9438): 937-52.
World Health Organisation. CVD prevention and control: missed
opportunities.
2007.
http://www.who.int/cardiovascular_diseases/
prevention_control/en/
Magnus P & Beaglehole R. The real contribution of the major risk
factors to the coronary epidemic. Arch Intern Med 2001; 161, (22):
2657.
Lloyd-Jones D, Evans & J Levy D. Hypertension in adults across the
age spectrum: current outcomes and control in the community JAMA
2005; 294:466.
Whelton PK, Perneger TV, Brancati FL & Klag MJ. Epidemiology
and prevention of blood pressure-related renal disease. J Hypertens
Suppl 1992; 10: S77–S84.
Stratton I, Adler A, Neil H, Mathews D et al -on behalf of the
UKPDS study group Association of glycaemia with macrovascular
and microvascular complications of type 2 diabetes (UKPDS 35):
prospective observational study. BMJ 2000; 321 (7258): 405-12.
Royal College of General Practitioners UK. Type 2 diabetes :Diabetic
renal disease :prevention and early management. RCGP: University
of Sheffield UK. 2002.
Field A, Coakley E, Must A et al. Impact of overweight on the risk of
developing common chronic diseases during a 10-year period. Arch
Intern Med 2001; 61(13):1581-6.
Rakhit D, Marwick T, Armstrong K et al. Effect of aggressive risk factor
modification on cardiac events and myocardial ischemia in patients
with CKD. Heart 2006; 92:1402-1408.
Goodman W, Goldein J, Kuizon B et al. Coronary artery calcification
in young adults with end stage renal failure undergoing dialysis.
N Engl J of Med 2000; 342:1478-1483
Ross R. Atherosclerosis - an inflammatory disease. N Engl J Med
1999; 340:115-126.
145
Chronic Kidney Disease:
146
A Guide to Clinical Practice (Stages 1-3)
15. Levin A and Foley RN. Cardiovascular disease in chronic renal
insufficiency. Am J Kidney Dis 2000; 36:S24-S30.
16. Tanasescu M, Leitzmann M, Rimm EB et al. Exercise type and intensity
in relation to CHD in men. JAMA 2002; 288(16): 1994–2000.
17. Department of Health. National Service Framework for Coronary
Heart Disease. Department of Health 2000.
18. British Cardiac Society, British Hypertension Society, Diabetes
UK, HEART UK, Primary Care Cardiovascular Society, The Stroke
Association. JBS2: Joint British Society Guidelines on Prevention of
Cardiovascular Disease in Clinical Practice. BMJ 2005; 91, S5.
19. Williams B, Poulter N, Brown M, Davis M, Mcinnes G, Potter J et
al. British Hypertension Society Guidelines: Guidelines for the
management of hypertension: report of the 4th working party of
the British Hypertension Society. BHS IV. Journal of Human
Hypertension 2004; 18, 139-185.
20. Gaede P, Vedel P, Larsen N et al. Multifactorial intervention and
cardiovascular disease in patients with type 2 diabetes. N Engl J Med
2003; 348:383-393.
21. Sever P, Dahlof B, Poulter N et al. Prevention of coronary and stroke
events with Atorvastatin in hypertensive patients who have average
or lower than average cholesterol concentrations, ASCOTT-LLA:
a multicentre randomised control trial. Lancet 2003; 361(9364):
1149-58.
22. NKF KDOQI. Managing Dyslipidemias in Chronic Kidney Disease
Am J of Kidney Dis 2003; April.
23. Anti-thrombotic Trialist Collaborative. Collaboration and meta analysis
of randomised trials of ant-platelet therapy for the prevention of death,
myocardial infarction and stroke in high risk people. BMJ 2002;
324:71-86.
24. Chronic Kidney Disease in Adults: UK CKD Guidelines for
Identification, Management and Referral of Adults 2005. Available from:
http//.www.renal.org/CKDguide/ckd.html.
25. Heart Protection Study Collaborative. Heart protection study of
cholesterol lowering with Simvastatin in 20,536 high risk individuals: a
randomised placebo controlled trial. Lancet 2002; 360:7-22.
Cardiovascular Risk in CKD
147
149
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Learning Outcomes
• To gain knowledge of the management of
hypertension in patients with Chronic Kidney
Disease (CKD)
• To understand the specific indications and contraindications of antihypertensive medications
• To highlight specific precautions when using
antihypertensive drugs in patients with CKD
Introduction
150
The aim of this chapter is to provide an overview of the
pharmacological management of hypertension. The
term CKD encompasses chronic renal failure of many
different origins1. Trials investigating the effect of
different therapies on the evolution of renal function have
usually included patients with primary renal diseases
and/or early or established diabetic nephropathy2.
Current international hypertension guidelines3,4 recognise
microalbuminuria, elevation serum creatinine and a reduction
in estimated GFR (eGFR) as major cardiovascular (CV) risk
factors and further increase the risk if pre-existing CV risk
factors already exist. In fact, patients progressing to end-stage
renal disease (ESRD) are a minority in individuals developing
the different forms of CKD, and could be considered as
survivors because CV disease accounts for the death of the
great majority of patients with CKD before the development
of ESRD5,6.
Management of Hypertension in CKD
The fact that CKD and CV disease are so closely
associated
has
raised
interest
in
investigating
the evolution of renal function in trials involving
hypertensive, as well as heart failure and post-myocardial
infarction patients. This interest is fully justified by the
demonstration, in all these situations, of the predictive
capacity of renal function alterations for the development of
CV events or death. From its earliest stages, the presence
of CKD must be considered as presenting an increased
CV risk in any hypertensive patient and in any patient
presenting with established forms of cardiovascular
disease7.
Reduction of CV events in CKD population requires
the implementation of effective integral therapeutic
interventions that simultaneously protect both the kidney
and the cardiovascular system. These interventions
have to be implemented at the earliest stage possible
in CKD, the attainment of strict blood pressure (BP) control
is essential and hypertension should be treated first in any
patient with an elevated global CV risk.
Hypertensive nephropathy was very common in untreated
primary hypertension. In one study proteinuria was
present in 42% and CKD present in 18% of a series
of 500 patients followed until death8. With the advent
of antihypertensive therapy the cardiovascular and
renal prognosis of hypertensive patients improved
dramatically, and the general belief is that only a
very small percentage of patients (<2%) develop
CKD. However, some studies have indicated that the
prognosis of renal function is not so good in
hypertensive patients, and that renal insufficiency is
still prevalent in essential hypertension7.
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Mechanisms of Action
Antihypertensive Therapy
and
Renal
Effects
of
Diuretics
There are three main types of diuretics as follows:
• Loop diuretics
• Thiazides
• Distal potassium-sparing agents
Loop Diuretics
The prime action of loop diuretics occurs in the thick ascending
limb of the loop of Henle. The addition of loop diuretic
decreases the absorption of sodium. Loop diuretics can cause
hyponatraemia, hyperkalaemia, hypomagnesaemia and
metabolic alkalosis. They raise the plasma concentrations of
urate and cholesterol, and can impair carbohydrate tolerance.
Acute renal failure can develop if the diuresis or fall in blood
pressure is excessive.
Thiazides
The major site of action of thiazide diuretics is the proximal
distal convoluted tubule, where they block the coupled
reabsorption of sodium and chloride. Unlike loop diuretics,
they do not block reabsorption in the loop of Henle; therefore
thiazides do not impair the urine concentrating mechanism.
Thiazide therapy raises the serum urate concentration, and
they are contraindicated in patients with gout. Thiazides
can impair carbohydrate tolerance and increase plasma
cholesterol concentration.
152
Distal Potassium-Sparing Agents
These agents act on the principal cells in the distal convoluted
tubule and initial connecting tubule and the cortical collecting
duct, where they inhibit entry of sodium. Their main action is
to reduce the excretion of potassium; however, hyperkalaemia
is a potentially lethal complication of using these drugs.
The risk is dose-dependent and increases considerably
in patients with CKD or in those receiving potassium
Management of Hypertension in CKD
supplements. Hyperkalaemia is potentiated by other drugs
that impair potassium excretion or raise the plasma potassium,
such as angiotensin-converting enzyme (ACE) inhibitors,
non-steroidal anti-inflammatory drugs (NSAID), beta-blockers
or heparin which limits aldosterone synthesis.
-Adrenergic Antagonists
E-Adrenergic antagonists (“beta blockers”) attenuate
sympathetic stimulation through competitive antagonism
of catecholamines at E-adrenergic receptors. The initial
systemic haemodynamic effects are decreases in heart
rate (HR) and cardiac output (CO) and an increase in
total peripheral vascular resistance (TPVR) proportional
to the degree of cardiac depression. In general,
E-adrenergic antagonists have little or no clinically
important effect on glomerular filtration rate (GFR),
effective renal plasma flow (ERPF), or renal vascular
resistance (RVR). The long-term oral administration of
E-adrenergic antagonists usually has no effect on
sodium, potassium or free water excretion. This means body
fluid composition and weight are unchanged.
Central D - Adrenergic Agonists
Central D2-adrenergic agonists have a direct effect on
specific pre-synaptic and post-synaptic D2-adrenergic
receptors located at midbrain and medullary sites.
The net pharmacologic effect is a reduction in
catecholamine release and turnover. In general,
central D2-adrenergic agonists have little or no clinically
important effect on GFR or ERPF. Fractional excretion of sodium
and potassium is unchanged, and body fluid composition and
weight are not modified.
Peripheral D -Adrenergic Antagonists
D1-adrenergic antagonists induce dilation of both
resistance and capacitance vessels by selectively inhibiting
post-junctional D1-adrenergic receptors. The net physiologic
effect is a decrease in TPVR. D1-adrenergic antagonists have
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Chronic Kidney Disease:
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little or no clinically important effect on GFR or ERPF. However,
fractional sodium excretion is reduced and the extracellular
fluid compartment is expanded.
Direct-Acting Vasodilators
Direct-acting vasodilators may have an effect on both
arterial resistance and venous capacitance. The net
physiologic effect is a decrease in TPVR associated
with increases in HR and CO. Monotherapy with
Hydrallazine and minoxidil is associated with salt and
water retention and expansion of plasma and
extracellular fluid volumes. Retention of salt and water is not
related to a reduction in GFR; it may be due to a direct drug
effect on the proximal convoluted tubule.
Calcium Antagonists
The
calcium
antagonists
are
a
chemically
heterogeneous group of drugs sharing a common
antihypertensive mechanism of action: interference
with entry of calcium into smooth muscle cells of
resistance arterioles through L-type voltage-operated
channels. The net physiologic effect of calcium antagonists
is a decrease in TPVR. All of the calcium antagonists induce
an acute natriuresis and diuresis. This effect appears to be
independent to a direct drug effect on either the proximal tubule
or segments located more distally than the loop of Henle.
154
Angiotensin-Converting Enzyme Inhibitors (ACEI)
Angiotensin-converting enzyme (ACE) inhibitors lower blood
pressure by decreasing TPVR. In general, ACE inhibitors
maintain GFR, increase ERPF, and decrease RVR in patients
who have essential hypertension with normal renal function.
Urinary protein excretion is decreased. In patients with
impaired GFR, a marked improvement in renal function may
occur. The decrease in proteinuria is unrelated to changes
in systemic blood pressure, GFR, ERPF, or filtration fraction.
ACE inhibitors may produce functional renal insufficiency in
patients who have essential hypertension with severe bilateral
Management of Hypertension in CKD
hypertensive nephrosclerosis, in patients with severe bilateral
renal artery stenosis, or in patients with stenosis of the renal
artery of a solitary kidney. Finally, ACE inhibitors have been
demonstrated to reset sodium and water homeostasis, by an
initial natriuresis and water diuresis, and to spare potassium
loss. Clinically significant potassium retention may occur,
especially in the presence of renal disease, therefore concurrent
administration of potassium supplements, potassium sparing
diuretics, or drugs impairing potassium excretion should be
avoided.
Angiotensin II Receptor Blockers (ARBs)
Angiotensin II receptor blockers reduce TVPR and systemic
arterial pressure in hypertensive patients. In patients with
essential hypertension,ARBs generally have no discernible effect
on GFR as assessed by creatinine clearance. In patients with
renalimpairment and renovascular occlusivedisease, reversible
increases in serum creatinine have been reported
following commencement on ARB. Angiotensin II
receptor antagonists produce a modest natriuretic
action through blockade.
Table 1. Showing most indications and contraindications of the major classes of
antihypertensive medications4.
Contraindications
Class
Conditions
for use
Compelling
Possible
• Congestive heart
failure
• Elderly
hypertensives
Diuretics
(Thaizdies) • Isolated systolic
hypertension
• Hypertensives of
African origin
• Gout
• Pregnancy
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Chronic Kidney Disease:
Class
Diuretics
A Guide to Clinical Practice (Stages 1-3)
Conditions
for use
Compelling
Possible
• Renal insufficiency
(Loop)
• Congestive heart
failure
Diuretics
• Congestive heart
failure
(Anti• Post myocardial
aldosterone)
infarction
• Angina pectoris
• Renal failure
• Hyperkalaemia
• Asthma
• Peripheral
• Chronic
vascular disease
obstructive
• Glucose
pulmonary
intolerance
• Congestive heart
disease
failure (up-titration)
•
Athletes and
(COPD)
• Pregnancy
physically active
• A-V block
patients
• Tachyarrhythmia’s
(Grade 2 or 3)
• Post myocardial
infarction
Betablockers
• Elderly patients
• Isolated systolic
hypertension
156
Calcium
• Angina pectoris
antagonists
• Peripheral vascular
(Dihydrodisease
pyridines)
• Carotid
atherosclerosis
• Pregnancy
• Tachyarrhythmia’s
• Congestive heart
failure
Management of Hypertension in CKD
• Angina pectoris
Calcium
antagonists • Carotid
atherosclerosis
(Verapamil,
diltiazem) • Supraventricular
tachycardia
• AV block (grade
2 or 3)
• Congestive
heart failure
• Congestive heart
failure
• LV dysfunction
Angiotensinconverting
enzyme
(ACE)
inhibitors
• Post myocardial
infarction
• Pregnancy
• Non-diabetic
nephropathy
• Bilateral renal
artery stenosis
• Hyperkalaemia
• Type I diabetic
nephropathy
• Proteinuria
• Type 2 diabetic
nephropathy
Angiotensin • Diabetic
II receptor microalbuminuria
antagonists
• Proteinuria
(AT1
blockers) • Left ventricular
hypertrophy
• Pregnancy
• Hyperkalaemia
• Bilateral renal
artery stenosis
• ACE-inhibitor cough
157
• Prostatic
• Orthostatic
Alfa-blockers hyperplasia (BHP)
hypotension
• Hyperlipidaemia
• Congestive
heart failure
Chronic Kidney Disease:
A Guide to Clinical Practice (Stages 1-3)
Table 2. Describes the most common and specific side effects of antihypertensive
medications and relevant precautions that should be considered for their
administration9.
Side effects
Precautions
• Hypokalaemia
• Hyperuricaemia
• Metabolic alkalosis
• Hyponatremia
Diuretics*
• Hypernatremia
• Avoid high doses use*
• Dyslipidaemia
• Avoid potassium sparing
diuretics with renal
insufficiency
• Dehydration
• Glucose intolerance
• Erectile dysfunction
• Hyperkalaemia
(potassium sparing
diuretics)
• Bradycardia
• In patients with cardiac
failure start with a minimal
dose and they require
• Cold extremities
close clinical monitoring
Beta-blockers
• Bronchoconstriction before increasing the
dose
• Dyslipidaemia
• Fatigue
158
• Glucose intolerance • Never stop abruptly
Management of Hypertension in CKD
• Low extremities
oedema
• Headache
• Palpitations
Calcium
antagonists
• Tachycardia
• Sweating
• Face redness
• Nocturia
• Due to the bradycardic
effect, Verapamil and
Diltiazem shouldn’t be
use together with betablockers
• Constipation and
bradycardia with
Verapamil
• Cough in 5-20% of
patients
• Hyperkalaemia
• Acute decrease in
renal function
ACEI
• First dose
hypotension in
patients with
volume depletion
• Rash
• Angioedema
ARB
• Similar to ACEI
except without the
cough
• Care in patients with
intermittent claudication
as there may be possible
renal artery stenosis
present
• Monitor kidney function
prior to and post
commencement
• For volume depletion
patients the depletion
must be corrected before
treatment
• Similar to ACEI
• Give first dose at bedtime
Alfa-blockers
• First dose
hypotension
• Orthostatic
hypotension
• Check for orthostatic
hypotension prior to
commencement in elderly
patients and diabetics
patients
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Chronic Kidney Disease:
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Renal Protection
The renoprotection provided by antihypertensive agents
depends on their capacity to lower systemic blood pressure
and also on their specific effects on renal haemodynamics;
these effects can positively or negatively influence intraglomerular pressure. In hypertensive patients with CKD,
antihypertensive therapy should aim for a target of
130/80mmHg initially using an ACE inhibitors or
ARB to inhibit the renin-angiotensin system and then
adding diuretics and other agents as needed4. ACE
inhibitors, ARBs and possibly aldosterone antagonists
are indicated because they reduce proteinuria in both
diabetic and non-diabetic nephropathy. In the presence
of proteinuria higher than 1 g/day, the recommended target
for blood pressure control is 125/75 mmHg3, 4
A reduction in proteinuria to 0.5 g/day is associated with a
slower progression of both renal and cardiovascular disease.
Similarly, both ACE inhibitors and ARBs are associated
with a slower GFR decline although without a return to
normal values. There may also be an argument for using a
non-dihydropyridine (DHP) calcium channel blocker (CCB)
although DHP CCBs may increase proteinuria and even
accelerate the decline in GFR.
The possible specific adverse effects of DHP CCBs may result
in countering the benefits of better blood pressure control.
160
Precautions should be taken into consideration for the use
of concomitant treatments that can cause drug induced
hyperkalaemia in CKD patients10, especially combinations of
the following:
• ACEI and ARB
• Potassium sparing diuretics
• Potassium supplements
• Non-steroids antiinflammatory (NSAIDs) drugs
• COX-2 inhibitors
Management of Hypertension in CKD
•
•
•
•
Heparin and low molecular weight heparins
Digoxin toxicity (but not at therapeutic levels)
Ciclosporin and Tacrolimus
Beta-blockers, Trimethoprim, Ketoconazole and Pentamidine
Treatment of Hyperkalaemia
• If eGFR 60 ml/min, commence on a loop diuretics and
continue to treat with ACEI or ARB with serum potassium
5.5mmol/L
• If the potassium >5.5mmol/L correct the hyperkalaemia
with a loop diuretics and correct the metabolic acidosis, if
present, with bicarbonate
• Do not use spironolactone dosage >25mg per day if using
ACEI
• Advice on dietary restriction of potassium
• Stop NSAIDs
• Discontinue ACEI/ARB or spironolactone if potassium
continually >5.5.mmol/l
Lifestyle Changes
Along with the use of antihypertensive medication, education
on health promotion should be addressed in this group of
patients. It is important to ensure that all advice is provided
in a culturally sensitive way and various types of educational
tools are provided e.g. DVD, written information leaflets etc.
The following health advice should be given along with the
advice given for the reduction in cardiovascular risk factors10:
• Weight loss - obesity (BMI>30kg/m2)
• Healthy eating and reduction in salt intake
• Exercise
• Education in alcohol intake
• Reduction in caffeine intake
• Reduce stress
• Smoking cessation
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Chronic Kidney Disease:
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Conclusions
Individuals with CKD usually present with hypertension
and multiple other risk factors for CV disease. The
risk attributable to CKD or to the presence of the other
factors may be totally independent. An integral
CV protection programme is required in patients
presenting with CKD.
Antihypertensive and other
cardiovascular drugs, like statins or aspirin, can also
prevent further decline in renal function. It is important
to ensure a good understanding of the indications for
of
use,
contraindications
and
side
effects
antihypertensive medications, along with the benefits
that can be achieved by effective and early treatment
of hypertension.
References
1.
2.
3.
4.
5.
162
6.
7.
K/DOQI clinical practice guidelines on hypertension and
antihypertensive agents in chronic kidney disease. Am J Kidney Dis
2004; 43: S1-S290.
Casas JP, Chua W, Loukogeorgakis S, et al. Effect of inhibitors of the
renin-angiotensin system and other antihypertensive drugs on renal
outcomes: systematic review and meta-analysis. Lancet 2005; 366:
2026-2033.
Chobanian A, Bakris GL, Black HR, et al. The Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. The JNC 7 Report. JAMA 2003;
289: 2560-2572.
Guidelines Committee: 2003 European Society of HypertensionEuropean Society of Cardiology guidelines for the management of
arterial hypertension. J Hypertens 2003; 21: 1011-1053.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic
kidney disease and the risks of death, cardiovascular events, and
hospitalisation. N Engl J Med 2004; 351: 1296-1305.
Weiner DE, Tabatabai S, Tighiouart H, et al. Cardiovascular outcomes
and all-cause mortality: exploring the interaction between CKD and
cardiovascular disease. Am J Kidney Dis 2006; 48: 392-401.
Segura J, García-Donaire JA, Praga M, Ruilope LM. Chronic kidney
disease as a situation of high added risk in hypertensive patients.
J Am Soc Nephrol 2006; 17 Suppl 2: S136-140.
Management of Hypertension in CKD
8.
Perera GA. Hypertensive vascular disease: description and natural
history. J Chronic Dis 1995; 1: 33-42.
9. Manual de intervención de enfermería en Hipertensión y Riesgo
Cardiovascular. Group EHRICA.
10. Steddon S, Ashman N, Chesser A and Cunningham J. Oxford
Handbook of Nephrology and Hypertension. Oxford University
Press: Oxford 2006.
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Chronic Kidney Disease:
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Patient Information
People who are diagnosed with chronic kidney disease (CKD)
should be provided with adequate and appropriate information.
Informing and educating people to enable them to live with and
manage their chronic disease empowers them to take control
of their own health. The following are some suggestions of
the information that people with CKD stage 1-3 should receive
and also a list of useful websites.
Where are the kidneys?
Most people are born with two kidneys, however you can live
a normal life with one kidney. The kidneys are located at the
back of your body just below your rib cage and they are about
the size of your fist.
Abdominal aorta
Interior vena cava
Left kidney
Right kidney
Left ureter
Right ureter
Urinary bladder
Urethra
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NORMAL ANATOMY OF THE KIDNEYS
AND URINARY TRACT
(www.kidney.org)
Patient Information
What do the kidneys do?
They filter the blood and remove excess fluid, toxins and
waste products. They regulate susbtances in your body such
as calcium and phosphate (from cheese and milk products) for
healthly bones, potassium which regulates your heart rhythm
(from tomatoes, bananas etc) and many other substances
that you get from your food which your body needs to stay
healthy. They remove excess fluid and also help control your
blood pressure, produces a hormone called erythropoietin,
(EPO) which stimulates the bone marrow to produce healthy
red blood cells so you do not become anaemic. The waste
products from the body are removed by the kidney and leave
your body as urine.
What does the term chronic kidney disease (CKD) mean?
This term means that the kidneys have been damaged and
are not working as well as they should normally.
How common is CKD?
Around 1 in 10 people have CKD; however it is less common
in young adults. In the older person it is more common due
to the natural ageing of the kidneys. A number of diseases
can damage the kidneys such as diabetes, hypertension (high
blood pressure) and some inherited conditions. Almost all of
these will damage both your kidneys at the same time.
How do you know if you have CKD?
In most cases CKD does not cause any symptoms, and is
detected because they have a test that shows an abnormality.
These may be urine tests for blood or protein; an X-ray or scan
of the kidneys; or a blood test to measure kidney function.
Most cases are discovered by your GP/family doctor as part
of normal care.
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What are the causes CKD?
The most common causes of CKD is, diabetes, high blood
pressure and the natural agening process of the kidney. There
are other causes such as inflammation of the kidneys (e.g.
glomerulonephritis), inherited diseases (e.g. polycystic kidney
disease) and autoimmune diseases (e.g. systemic lupus
erythematosus). Only a small number of causes of CKD can
be completely cured.
Measurement of kidney function
A blood test called eGFR (estimated glomerular filtration rate)
is used to measure kidney function and is calculated from a
substance in the blood called creatinine. Creatinine is a waste
product excreted by the kidneys.
What is normal kidney function?
Normal kidney function is when the eGFR is 90 ml/min/
1.73m2 in young adults. Some people have an eGFR between
60-90 ml/min and this is considered normal kidney function
if there is no blood or protein in the urine or any disease or
identified problem with the kidney.
Over the age of 40 years the eGFR falls by 1ml/min per year
and so in the older person (over 75 years) the eGFR may be
lower (i.e. 50-60 ml/min).
What does it mean to have CKD Stage 1, 2 or 3?
Stage
g 1: It means there is mild damage to the kidney and is
not something that you should be overly concerned about. The
eGFR is >90 ml/min/1.73m2, with blood or protein in your urine
and/or some sign of kidney damage has shown up on a test.
168
Stage
g 2: It means there is mild damage to the kidney and is
not something that you should be overly concerned about. The
Patient Information
eGFR is between 60-90 ml/min/1.73m2, with blood or protein
in your urine and/or some sign of kidney damage has shown
up on a test.
Stage
g 3:It means that there is some moderate damage to the
kidney. The eGFR is between 30-59 ml/min.
What is the treatment for CKD?
It is important to treat high blood pressure. If it is above 140/85
mmHg on three consecutive occasions, you will need some
blood pressure medication. The aim is to get your blood
pressure to 130/80 mmHg or lower. It is also important to have
your cholesterol level checked and you may be advised to take
an aspirin a day. Those people with diabetes need to have
good control of their blood sugar to prevent further damage to
the kidneys.
How often will I need to have my kidney function
checked?
You may be asked to either have your kidney function checked
every six months or annually.
This will involve a blood and urine test. Your GP/family doctor
will refer you to a kidney specialist if your kidney function
declines.
What can I do to help?
Try to live a “healthy” lifestyle as you are more at risk of
getting heart disease and developing further damage to your
kidneys.
Try to do the following:
• If you are overweight, you should lose weight
• Try to exercise regularly
• Stop smoking
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• If you have diabetes, make sure you speak with your
diabetes team and you have good control of your
diabetes
• It is important to take your blood pressure medications if
you have been given them to keep your blood pressure
down and prevent further damage to your kidneys
• Reduce the amount of salt in the diet in order to help
control your blood pressure
• Eat a healthy balanced diet, lower the amount of
cholesterol in your diet
• Drink about 2 litres of fluid a day (2 litres is about 10
cups or 6 mugs). There is no benefit in drinking large
amounts of fluid, except in people who get lots of urine
infections, or in a few other special cases
• Avoid anti-inflammatory drugs (includes some that you
can buy over the counter without a prescription unless
your GP/family doctor has approves them e.g. Ibuprofen
• Consider buying an automatic blood pressure monitor to
check your blood pressure at home
• Have an annual flu vaccination, and have the pneumonia
(pneumococcal) vaccine once (talk to your GP/family
doctor about this)
• Attend for your kidney function checks when asked to by
your GP/family doctor or nurse
• If you do have a kidney disease, tell your family as
they may need to check with their GP/family doctor
that it not a disease that runs in the family
• You need to let other doctors and nurses know that
you have a problem with your kidneys e.g. if you go to
accident and emergency or have an operation or
procedure
170
Patient Information
Add your national kidney patient association details to the
leaflet so your patients can make contact with them.
Useful Patient Information Websites
Renal patient information:
www.renalpatient.org
Kidney patient guide:
www.kidneypatientguide.org.uk
National Kidney Federation:
www.kidney.org.uk
Kidney Research UK:
www.nkrf.org.uk
The National Kidney Foundation:
www.kidney.org
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