Download Chronic Kidney Disease

Renal Pathophysiology: Chronic Kidney Disease (Doshi)
DEFINITION OF CHRONIC KIDNEY DISEASE:

Criteria:
Kidney damage for ≥3 MONTHS, as defined by structural or functional abnormalities of the kidney, WITH OR
WITHOUT a decreased GFR, manifested by:
o Pathological abnormalities, OR
o Markers of kidney damage

Abnormalities in the composition of blood or urine

Abnormalities in imaging tests
GFR <60ml/min for ≥3 MONTHS, WITH OR WITHOUT kidney damage
KIDNEY FUNCTION:

Functions of the Kidney:
Filters blood:
o 150-180 L/day (100mL/min= GFR)
o Only 1-2% of that filtered blood is made into urine (1-2L)
Maintains salt and water balance
Removes waste products
Other functions:
o Involved in ability to procreate
o Maintains healthy hear
o Maintains RBC count
o Maintains healthy bones

Renal Reserve:
Patients with 25% loss of kidney function NO ABNORMALITIES/SYMPTOMS
o Example: kidney donors (remaining kidney increases work)
Patients with 50-75% loss of kidney function  LAB ABNORMALITIES BUT NO SYMPTOMS
Patients with 90% loss of kidney function LAB ABNORMALITIES AND SYMPTOMS (FATAL)
*OVERALL POINT: patient can lose more than 50% of kidney function and NEVER KNOW*
RECOGNIZING KIDNEY FAILURE:

Biochemical Markers:
Blood Urea Nitrogen (BUN): product of protein catabolism
o Factors Affecting BUN Levels:

Protein intake (diet)

Liver function (urea cycle is in the liver; liver disease may decrease BUN production)

Protein catabolism (increased catabolism during infection increased BUN)

Urine flow rate (decreased flow rate increased re-absorption)
o Overall: not really commonly used alone as a marker for kidney disease because of all these other
factors that can determine BUN levels
Serum Creatinine:
o Basics:

Most commonly used biochemical marker of kidney disease

Comes from muscle breakdown
o Kidney Handling of Cr:

None of the Cr that is filtered is reabsorbed (all goes into urine)

5-10% of Cr excreted in urine is from secretion by the tubules (not filtration)
 As a result, when being used to estimate GFR, it overestimates by ~10%
o Caveats to Using SCr:

Need to account for:
 Age (with increased age, less muscle mass less Cr made)
 Size (changes in muscle mass falsely imply changes in kidney function)
 Drugs (drugs that inhibit Cr secretion increase serum creatinine)
o Example: cimetidine
o Relationship of Creatinine and Renal Function:

Small changes in SCr levels represent LARGE changes in GFR (exponential relationship)
 Example: if SCr doubles from 2-4mg/dl, GFR decreases by half (60-30ml/min)

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

GFR:
Basics:
o
o
o
Important to note that SCr is not a very sensitive marker in patients with renal failure
 Not sensitive for very low GFRs with very high SCr
GFR is the sum of the filtration rates of ALL FUNCTIONING NEPHRONS
Normal value is ~120-130ml/min
Varies based on variety of factors (age, race, gender)

Men > Women

Blacks > Whites
o Estimation of GFR occurs via:

24 hour urine collection

Equations
Urine Creatinine Excretion (24 Hour Urine Collection):
o In steady state, we are assuming that amount Cr filtered = amount Cr excreted in the urine

Recall: some Cr is excreted, overestimates GFR by ~10%

Amount Filtered= GFR x SCr

Amount Excreted= UCr x V
o Therefore:

Amount filtered= Amount excreted

GFR x SCr = UCr x V

GFR= (UCr x V)/SCr
Cockroft Gault:
o See previous lectures
o Used to dose drugs*
MDRD:
o See previous lectures
Spectrum for Kidney Disease:
Normal Kidney Function  Chronic Kidney Disease  End Stage Kidney Disease
o Normal= 100% function
o CKD= kidney function decreased by 10-90%
o End Stage Kidney Disease= kidney function <10% (NOT COMPATIBLE WITH LIFE)

Requires dialysis*
Stages of CKD:
Stage
Description
GFR (ml/min)
Complications
1
Kidney damage with NORMAL GFR
≥90
Patient at risk for CKD
Albuminuria
2
Kidney damage with mild decrease in GFR
60-89
Hypertension
3
Mild kidney disease
30-59
Nocturia
Mild ↑BUN, Cr
Mild ↓ Ca+
Onset of anemia
4
Moderate kidney disease
15-29
Fatigue
Anorexia
*SYMPTOMS*
Neuropathy
Moderate anemia
Hyperphosphatemia
Hyperkalemia
Dyslipidemia
LVH
5
Kidney failure
<15
Azotemia
Uremia
*SYMPTOMS*
Malnutrition
Severe anemia
Secondary hyperparathyroidism
Metabolic acidosis
CAUSES OF CHRONIC KIDNEY DISEASE:

Causes of CKD:
Diabetes (42%)*
Hypertension (29%)*
Other/Unknown Etiology (20%)
Glomerulonephritis (7%)
Cystic Kidney Disease (2%)

Risk Factors:
Race: much more prevalent in blacks than whites

Progression to Chronic Kidney Disease:
Initial kidney insult  decreased number of nephrons  increased single nephron GFR by 2-3x to adapt
o Does so by increasing capillary flow and pressure
Increase in capillary flow and pressure hyperfiltration and glomerular injury
o Eventually, glomerular sclerosis results
Glomerular sclerosis further decrease in nephron numbers exacerbates above cycle*

Adaptation in CKD:
Initial Nephron Loss (>75% remaining): complete adaptation/compensation by increasing SNGFR
Loss of 25-75% of Nephrons: partial adaptation/compensation (SNGFR no longer increasing)
Loss of >75% of Nephrons (<25% remaining): inadequate adaptation
BIOCHEMICAL DERANGEMENTS IN CKD:

Salt and Water Overload:
In CKD, patients have a limited reserve in how much H2O/Na the kidney can get rid of or conserve
Need to keep strict daily intake of H2O and Na, otherwise  EDEMA

Acid Base Abnormalities:
Basics:
o Normal acid production is 12,000meq/day
o 60meq excreted per day in the urine (non-volatile acids)
o Bicarbonate acts as a major buffer (generate by the kidney)
Summary of Acid Base Derangements:
o Metabolic Acidosis:

Early CKD (Stages III and IV)- Non Gap Acidosis:
 Decreased NH4 excretion due to decreased renal mass and decreased NH4
production (lack of NH4; can’t get rid of HCl)
 GI HCO3 loss

Advanced CKD (Stage V)- Gap Acidosis (+ still have NGA mixed):
 AG elevated due to retention of anions (phosphate, sulfate, urate, hippurate)
 Bicarbonate concentration stabilizes around 12-20meq/L
o Will not drop below 10meq/L
o Due to various body buffers (ie. bone) that prevent progressive fall in
plasma HCO3
o Metabolic Alkalosis: (not discussed)*

Acid loss (ie. N/V due to UREMIA)

HCO3 gain (ingestion)
o Mixed Metabolic and Respiratory: rarely (not discussed)*

Potassium Balance:
Basics:
o Take in 60-100meq/day in the diet
o Body maintains normal levels via a variety of mechanisms:

Uptake by muscles (via insulin)

Secretion by collecting tubule

Secretion by the gut
Maintenance of K Balance in CKD:
o In chronic kidney disease, hyperkalemia usually does not ensue unless GFR <20m/lmin*

Why?
 Increased uptake by muscle
 Increased secretion by gut (aldosterone also works here)*
 Increased single nephron K+ secretion (increased aldosterone production)
-


Causes of Hyperkalemia Early in CKD (GFR not yet <20ml/min):
o Diabetics:

Hyporeninoremic hypoaldosteronism
 Decreased renin release or production
 Decreased response to minerlacorticoids
o Pre-Renal States:

Decreased Na delivery to the distal nephron decreased reabsorption Na AND decreased
secretion/excretion of K
o Drugs:

Aldosterone can be altered
 ACEI/ARB (block ang II, which stimulates aldosterone release)
 Spironolactone (aldosterone antagonist)
 Heparin

Altered Na channels (prevent Na reabsorption and K secretion)
 Triamterene/Amiloride (ENaC blockers; can’t reabsorb Na)
 Pentamidine

Altered K distribution across cells (prevent K from entering cells- ie. muscle cells)
 Non-selective B blockers
 Digitalis
 NSAIDs
o Dietary:

Potassium rich foods (spinach, cantaloupe, lima beans, bananas, milk, orange juice)
Hyperkalemia Late in CKD:
o Metabolic acidosis causes H+ to enter cells and K+ to exit
o Decreased sensitivity to insulin decreased influx into muscles
o Decreased nephron mass less K+ filtered and secreted
Secondary Hyperparathyroidism:
Mechanism:
o Hyperphosphatemia in CKD due to decreased GFR less filtered

Binds Ca hypocalcemia  INCREASED PTH
o Decreased active vitamin D (due to kidney disease)

Hypocalcemia INCREASED PTH
Result: overall result is a STEPWISE decline in GFR with a matching STEPWISE increase in PTH to maintain normal
phosphate and calcium levels (want to DECREASE phosphate and INCREASE Ca)
o PTH stimulates bone resorption increase Ca (and phosphate)
o PTH stimulates Ca reabsorption by the kidney increase Ca
o PTH stimulates PTH excretion by the kidney decrease PO4 (major effect)*
o PTH stimulates calcitriol synthesis increased Ca (and PO4) absorption in gut
Consequences:
o Renal Osteodystrophy:

Increased bone resorption

Relative deficiency of calcitriol defective bone mineralization
Treatment:
o Reduction in Serum Phosphorous:

Dietary restrictions
 Avoid high phosphorous foods (sesame seeds, pumpkin seeds, nuts, dairy, eggs,
chicken, red meat, salmon/canned fish)

Phosphate binders
o Vitamin D Supplementation:

Ergocalciferol

Active vitamin D (calcitriol)
Adaptation in CKD with Resultant Changes in Serum Markers:
Order of Events:
o BUN/Cr are the first markers to increase in CKD (increase prior to inadequate adaptation stage)
o PO4/Uric acid increase (decreasing GFR)
o HCO3 (retaining acids)/Na decrease
o K+ rises LATE*
SIGNS AND SYMPTOMS OF CHRONIC RENAL FAILURE:

Uremic Toxins (Uremia):
Uremic Toxins: products of protein and amino acid metabolism (small molecular weight proteins)
o Urea (>80%)
o Guanidino compounds
o Many others (phenols, indoles, polyamines etc.)

Metabolic Changes:
Hypothermia: uremic toxins reduce O2 consumption and heat production

Hormonal Changes:
Hormones DECREASED in CKD:
o Calcitriol: leads to renal osteodystrophy (osteomalacia)
o Erythropoietin: leads to anemia
o Somatomedin: decreased growth in children
o Testosterone: impotence and decreased libido
Hormones INCREASED in CKD:
o Insulin: decreased metabolism by kidney higher levels (patients may be able get off diabetes meds)
o Prolactin: lactation
o Luteinizing Hormone: gynecomastia
o Gastrin: gastritis
o Renin/Aldosterone: HTN
o Glucagon: glucose intolerance
o PTH: increased bone turnover (OFC), pruritis

Renal Osteodystrophy:
Basics:
o 30-90% of patients with renal disease have histological/radiological evidence of bone disease
o However, only 10% have clinical evidence of bone disease
Components:
o Osteitis Fibrosa Cystica: cyst formation in the bone due to increased bone resorption (PTH effects)
o Osteosclerosis: increased bone density in upper and lower margins of the vertebrae (leads to spinal
deformities such as kyphosis or scoliosis)
o Osteomalacia: failure to mineralize bone due to lack of calcitriol (children renal rickets)
o Osteoporosis: metabolic acidosis slowly leaches Ca from bone over time (elderly)

Extraosseous Calcification:
Basics: extra Ca and PO4 mobilized from bone due to PTH, and deposits in soft tissues
o In addition, Ca can be increased due to use of Ca based oral phosphate binders to lower PO4
o PO4 already high (hyperphosphatemia) combines with Ca
Result: metastatic calcifications:
o Vessels  CV mortality, ischemia (calciphylaxis- ulcers due to ischemia)
o Other sites

Hematologic Complications:
Anemia (Uremic Anemia; Normochromic, Normocytic):
o Mechanism:

Uremia leads to decrease EPO

GI bleeding tendency (due to excess gastrin)

Loss of blood during dialysis

Loss of appetite (not enough iron intake)

Increased PTH can cause marrow fibrosis decreased RBC production

Aluminum toxicity (used to be used as PO4 binder)
o Lab Characteristics:

Hct: stable between 20-35% (if no bleeding)

MCV: normal

Serum ferritin: variable (may be high if anemia of chronic disease)

Serum iron: variable

Marrow iron stores: present early on and variable

Reticulocyte index: <1.5

Blood smear: Burr cells
o Treatment: check iron levels if iron replete, give EPO (if decreased iron, give iron)
o Important Point: anemia is NOT corrected by dialysis
-



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Lymphopenia/Leukopenia
o Important Point: NOT corrected by dialysis
Bleeding Diathesis (Uremic Bleeding):
o Platelet Dysfunction: due to uremia; ABSOLUTE COUNT IS NORMAL*

Increased NO production (inhibits platelet aggregation)

TXA2/PGI2 imbalance

Decreased GPIIb/IIIa interaction with vWF
Increased Susceptibility to Infections:
o Cause: lymphopenia and reduced lymphocyte function; also decreased chemokine activity

Other Contributors:
 Malnutrition
 Acidosis
 Hyperglycemia
 Increased osmolarity
Metabolic Complications:
Sexual dysfunsfunction/infertility
o Males:

Decreased libido/frequency of intercourse

Impotence

Gynecomastia (LH)

Impaired spermatogenesis (decreased testosterone)

Testicular atrophy

Infertility

Retrograde ejaculation
o Females:

Decreased libido/frequency of intercourse/frequency of orgasm

Galactorrhea (prolactin)

Anovulation

Cystic ovarian disease

Infertility

Amenorrhea
Impaired growth and development
Malnutrition (only one that can be improved by dialysis)
Hyperlipidemia
Hyperuricemia ( gout)
Neuromuscular Complications: major signs as physician**
Lethargy/fatigue/coma
Sleep disorders
Asterixis/myoglonic jerks/seizures
Peripheral neuropathy
Burning foot syndrome
Restless leg syndrome
Foot flap/foot drop
Dermatologic Complications:
Pallor (due to anemia)
Hyperpigmentation
Pruritis (due to Ca and PO4 deposition in the skin)
Ecchymoses/purpura (platelet dysfunction)
Uremic frost (uric acid/urea deposits as powder on the skin)
Calciphylaxis
Cardiovascular Complications:
Hypertension (80-90% of patients):
o Causes:

Salt and water retention
 Decreased filtration area Na retention increased BP glomerular HTN
 Glomerular HTN glomerular sclerosis further decrease in filtration area

Increased SS outflow

Increased RAAS


Decrease vasodepressor hormones

Increased vasoconstrictor natriuretic factors
o Result: may cause LVH
Other Complications:
o Coronary artery calcification
o Ischemic heart disease
o Pericarditis (due to uremia)
GI Complications:
Stomatitis
Halitosis
Esophagitis
N/V/D (or constipation)
Anorexia
GI bleeding
Abdominal distention
SLOWING PROGRESSION OF CKD:

Factors Causing Progressive Renal Failure:
Primary Disease: ongoing kidney injury
Hypertension: increases intra-glomerular pressure
Proteinuria: toxic to tubules and hastens tubular injury

Factors Associated with Accelerated GFR Decline:
Non-Modifiable:
o Male gender
o Older age
o Etiology of kidney disease
o African American
o Decreased baseline level of kidney function
Modifiable:
o Increased proteinuria
o Decreased serum albumin
o Increased BP
o Poor glycemic control
o Smoking

Slowing the Progression of Symptoms:
ACEIs/ARBs for Diabetics:
o Decrease BP
o Independent of decreased BP, also prevent decline to end stage kidney disease in diabetics
Other Strategies:
o Protein restriction
o Phosphorous restriction
o Hyperlipidemia control
o Control of acidosis (limit protein intake, give bicarbonate; prevent bone damage)
o Control anemia (EPO shots if iron, vitamin replete)
o Renal replacement (if indications for dialysis/transplant)
DIALYSIS:

When to Consider Dialysis:
Biochemical Markers:
o Volume overload
o Hyperkalemia
o Hyperphosphatemia
o Acidosis
o GFR <10 (non diabetics) or <12 (diabetics)
o Patient is SYMPTOMATIC (ie. anorexia, weight loss, asterixis, neuropathy, pericardial rub etc.)

Types of Dialysis:
Hemodialysis: blood flows to dialyzer and filtered blood returns to the body (3-4 hours, 3x per week)

Peritoneal Dialysis: sterile clean fluid placed in belly, toxins move into clean fluid via diffusion (drain and replace
every 4-6 hours)
Downsides of Dialysis:
Hooked to machine
Needle sticks
Infections
Travel restrictions
Dietary restrictions
Decreased quality of life
EXPESINVE ($67,000 per year)
TRANSPLANT:

Benefits:
No longer rely on machine
No needle sticks
No travel restrictions
Minimal dietary restrictions
Ability to become pregnant and bear children
Physical activity may resume
Improved quality of life
Economic benefits (after first 3 years post-transplant, $50,000 saved per year per patient)
Survival benefits over dialysis

Transplant Facts:
95,000 US patients waiting for kidney
4,000 new patients added per month
3,916 patients died in 2006 due to lack of available donors
IMPORTANT POINTS:

CKD symptoms and laboratory abnormalities occur after loss of 50% of renal function

CKD increases risk of death, CV complications and infection

Prevention is better than cure

Dialysis should be considered as a bridge to kidney transplant