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Renal Update for Internists:
Controversies and Conundrums
Paul Segal DO
Assistant Professor of Medicine
Johns Hopkins
ACP Meeting 2015
Objectives
• After viewing this presentation, the clinician will understand
 The staging system of Chronic Kidney Disease (CKD)
•
•
•
•
•
•
•
•
The strengths and weaknesses of GFR equations
The clinical associations with various CKD stages
CKD progression
When to refer and when to dialyze
The role of metabolic acidosis in CKD progression
The controversy surrounding sodium restriction
The Interaction of Physical Activity and CKD
Blood Pressure Targets in CKD
Conceptual Model of CKD
Prevalence of CKD
NHANES III : prevalence of
CKD ↑ 15.9% (1988-2004)
Stage 1
~ 5.9 million
Stage 2
~ 5.3 million
Stage 3
Stage 4
~ 7.6 million
~ 350- 400,000
Stage 5
~350, 000
Coresh, Am J Kidney Disease 2003;41:1-12.
One in 10 American Adults
• Prevalence is projected
to increase to 14.4% in
2020
Prevalence of CKD
• Grams et al (AJKD 2013): lifetime risk of reaching a GFR < 60 mL/min/1.73 m2 from birth = 59%
(Stage 3A) [33.6% (Stage 3B), and 11.5% (Stage 4)]
• Lifetime risk of: developing diabetes (33-39%), ischemic heart disease (32-49%), and invasive cancer (38-45%)
• Most patients with CKD have co-morbid illnesses
• 50% have 3 or more chronic diseases
• 20% have 5 or more chronic diseases
• The mean number of chronic conditions per individual increased from 1.88 (65-69-year age group) to 2.71 (80-84year age group)
CKD Patients Are More Likely
to Die Than Progress to ESRD
Percentage Who Remained Event-Free vs. Death vs.
Developed ESRD During 5-Year Follow-Up
100%
% of Patients
15%
16%
7%
10%
80%
28%
60%
75%
63%
64%
20%
Disenrolled
Event-free
RRT
Died
N = 27,998
40%
1%
20%
0%
10%
Stage 1
eGFR ≥90
(-) Proteinuria
20%
24%
Stage 2
Stage 3
eGFR 60-89
(+) Proteinuria
eGFR 30-59
Totals Stage 2-4
46%
3.1% RRT
24.9 % Die
Stage 4
eGFR 15-29
Keith D, et al, Arch Int Med 2004;164:659-663
2002;13:620A.
Why Do We Use a Glomerular Filtration Rate (GFR)
Equation?
• Creatinine is an imprecise value and
affected by many influences:
Increase
• High protein
mealin SCr from 1.0- - > 2.0
mg/dL, ~ 50% ↓ CrCl
• Medications:
• Cimetidine, trimethoprim, fibrates
•
•
•
•
•
Hemolysis
Hyperglycemia
Edematous states
Hydration
Age, race and gender
SCr = 1.2
mg/dL
Adapted from
Shemesh, KI, 1985
Staging of CKD
No “micro” albuminuria
NKF
KDIGO
GFR Estimating Equations
MDRD
CKD-EPI (Chronic Kidney Disease-
(Modification of Diet in Renal Disease)
Epidemiology Collaboration)
• Developed in a cohort of 1628 people
with CKD (mean GFR ~ 38
mL/min/1.73m²)
• Predominantly White Participants
• Mean age 50.6 ± 12.7 yrs
• Limited data in DM and Transplant Pts
• Tends to UNDERESTIMATE GFR in the
Healthy population (higher level of
GFR)
• Developed in a cohort of 8254 people
• Whites and Blacks
• Both + and – CKD, Diabetics and
Solid Organ Transplants
• High and Low risk groups
• Wide range in GFR (2 -198
mL/min/1.73m2) and age (18-97 yrs)
• More accurate in people with higher
levels of GFR (reduces
misclassification)
CKD Stage and Progression
Stage 3B
A Go et al, NEJM 2004;351: 1296-13305
What is a Disease?
A pathological condition characterized by an
identifiable group of signs or symptoms or
A condition that impairs normal functioning
or
Illness or sickness often characterized by
typical patient problems (symptoms) and
physical findings (signs).
Does a Change in eGFR with Aging Constitute Disease?
• Baltimore Longitudinal Study of the Aging
(Lindeman et al, JAGS 1985;33:278-285)
• “Normal” group: Average loss of 0.75
mL/min/year
• ~35% of individuals experience no decline with
age
• Higher BP and Heart Disease  greater rate of
decline of renal function
• NHANES III
• 38% of pts > 70 yrs without DM or HTN had a
MDRD eGFR < 60 mL/min/1.73 m2
• 0.7% between age 20-39 yrs had eGFR < 60
mL/min/1.73 m2
• Octabaix Study (European Journal of IM
2012;23(6):534)
• 321 individuals, community-dwelling 85 yr olds
• > 50% had an eGFR < 60 mL/min/1.73 m2
Hoerger TJ et al, AJKD 2014.
When NOT to Diagnose CKD (NICE Guidelines 2014)
• Do not diagnose CKD in people with:
• An eGFR creatinine of 45-59 mL/min/1.73 m2 (Stage 3A) and
• An eGFRcystatinC of > 60 mL/min/1.73 m2 and
• No other marker of kidney disease
Creatinine
Cystatin C
Small molecule, 113 Da
Non-glycosolated protein, 13kD
Breakdown product of creatine/muscle
metabolism
Cysteine protease inhibitor, made by all
nucleated cells
Filtered, secreted (↑ as GFR ↓) and
excreted (extra-renal elimination)
Filtered, reabsorbed and catabolized
(proximal tubule)
Colorimetric and enzymatic assays,
widely standardized
Immunoassays, becoming standardized
Multiple alterations (muscle mass, drugs,
interferents)
Alterations: obesity, thyroid disease,
steroids and HIV
“Tried and true”, GFR estimation
“New kid”, GFR estimation and prognostic
marker: CVD, all-cause mortality, DM,
unsuccessful aging
Comparison of GFR Equations
“ Moving from strictly
creatinine-based GFR
equations (MDRD and CKDEPI) to cystatin-C based or
combined equations will
decrease the prevalence of
CKD, Stage 3 by ~ 50%”
MDRD
CKD-EPI mix
CKD-EPI
CKD-EPI Cys
Delanaye P et al. BMC Nephrology 2013;14:57.
What do we know about CKD Progression?
• Stage 3B is more likely to progress to Stage 4 and 5 than Stage
3A
• Predictors: degree of albuminuria
microscopic hematuria
Stage 3 subgroup
2 x ↑ risk for
disease progression
• ≤ 45 mL/min/1.73 m2 = clinically significant breakpoint
• GFR trajectory may be an important predictor of progression
Ann
O’Hare
> 3 mL/min/1.73
m2/year requires
CLOSER follow-up
and identification of
potentially reversible
factors
When to Refer?
• KDIGO 2012 Guidelines
• Abrupt or sustained fall in eGFR (↓ GFR of ≥ 25%, change in GFR category or
sustained ↓ in GFR of ≥ 15 mL/min/1.73 m2 within 12 months)
• eGFR < 30 mL/min/1.73m2 ± Diabetes
• Urinary RBC casts or RBC > 20/hpf (microscopic hematuria without an
anatomic cause)
• Refractory HTN (≥ 3 drugs)
• Significant albuminuria:
• ACR ≥ 300mg/gm or AER ≥ 300mg/24 hrs
• PCR ≥ 500mg/gm or PER ≥ 500mg/24 hrs
• NICE 2014 Guidelines
• Take into account the individual’s wishes and co-morbidities
• Rare or genetic renal disease
When Should Dialysis Be Initiated?
• In the US, dialysis is typically
initiated at an eGFR > 10
mL/min/1.73 m2
• No survival benefit
• Reasons to start early
eGFR 10-14 mL/min/1.73 m2
eGFR 5-7 mL/min/1.73 m2
• Fluid overload/Heart Failure
• Hyperkalemia
• Uremic Symptoms (weight loss,
weakness, appetite issues)
• Non-adherence
Susantitaphong P et al, AJKD 2012;59(6):829-840
Metabolic Acidosis in CKD
• Occurs 2nd to western diet (sulfur containing amino
acids)
• Maintained until GFR < 40-50 mL/min
• Dangers:
• Protein energy wasting (muscle weakness)
• Impairment in myocardial function and glucose
homeostasis
• Uremic osteodystrophy (bone loss 2nd to ↑ bone
resorption)
• Chronic inflammation
• In observational studies, metabolic acidosis - - > faster
progression of CKD
•
•
•
•
Direct toxicity
Tubulointerstitial damage
Activation of the RAAS
~ 1.47 ± 0.19 mL/min/year reduction in eGFR decline
Treatment of Metabolic Acidosis
Chen and Abramowitz. AJKD 2014;63():311-317
Some Helpful Tips
• Baking soda is cheap (1/2
teaspoon = 26.8 mEq of
bicarbonate)
• If PO4 binder is used,
choose: calcium acetate
or sevelamer carbonate
• Surprisingly, LESS sodium
retention with NaHCO3versus NaCL
• Target bicarbonate 22-24
mEq/L
Sodium Restriction: Benefits and Controversies
• Benefits
• Reduction in SBP (~ 10 mmHg)
• Helpful in resistant HTN
• Reduction in proteinuria (≥ 300 mg/day)
• Especially if > 1 gram/day
• Control of sodium excess improves the response to
RAAS blockade in CKD -- > ↓ proteinuria
• Reduction in progression of CKD
• Decrease in mortality (all-cause, ~ 28%)
• Risks
McMahon EJ
et al. JASN
2013;24:209
6-2103.
• ↑ in plasma renin, aldosterone, adrenaline and
cholesterol
• ↑ risk of progression to ESRD
• ↑ NT-proBNP
• May be augmented by very low sodium diets (< 1.5
grams/day)
• Safe suggestion: 2300 mg/day ≈ 1 teaspoonful
salt/day
Crash Test Dummies Gain Weight to Save Lives!
Minimum Amount of PA for Reduced Mortality and
Extended Life Expectancy
• Physical Activity Guidelines for Americans
Largest health gains occur within the
1st 15-29 min/day in inactive people
Minimum Amount of PA and Benefits
• 15 minutes/day or 90 minutes/week (6
days/week) of moderate-intensity
exercise)
• Reduction in all-cause mortality by
14%
• Reduction in cancer mortality by 10%
• Reduction in mortality from CVD by
20%
• 3 year longer life expectancy
Wen CP et al. Lancet 2011;378:1244-1253.
• 150 minutes/ week or more of moderateintensity aerobic PA or 75 minutes/ week of
vigorous-intensity aerobic PA or a combination
of moderate- and vigorous-intensity aerobic
activity
• Episodes of at least 10 minutes, spread
throughout the week
• For additional and more extensive health
benefits, adults should increase their aerobic
activity to 300 minutes/week of moderateintensity or 150 minutes/ week of vigorousintensity activity
• Adults should do muscle-strengthening
activities at moderate or high intensity
involving ALL muscle groups on 2 or more days
a week
• Excess sitting harms lean and obese alike
CDC Guidelines December 2011
Association of Walking with Survival and
RRT in CKD Stages 3-5
• Observational cohort, June 2003 to
May 2013, Taiwan
• Competing risks analysis
• 6363 pts with CKD, stages 3-5
Overall
Mortality
• Higher frequency of exercise and
Longer duration was associated
with: lower mortality and lower
RRT risk
• Not related to: higher renal
function, comorbidity or younger
age
Chen IR et al. CJASN 2014
RRT
BP Targets: What is the Evidence?
• JNC 8 focused on individuals and populations
• Expert-opinion based, not evidence-based
• 5 out of 17 dissenting authors published comments
in the AIM January 2014.
• ACC/AHA anticipates new guideline in 2015
• Clinical Pearls
• If SBP > 160 mmHg, consider combo therapy (CCB
plus RAAS blocker)
• Faster BP control and lower CV event rate
• Consider dosing a short to moderate-acting BP med
at night in pts with CKD
• Enalapril, Nifedipine XL or Losartan
• There is no advantage to DUAL RAAS blockade (ACE
plus ARB), and potential risks
• ↑ risk of GFR decline and hyperkalemia
• BP ↓ of 2.4 mmHg with dual versus 1.2 mmHg alone
• Reduction in albuminuria ~ 440 mg/day
A = strong, E = expert
• If you suspect white coat HTN, but continued CV
events, consider ambulatory BP monitoring
JACC 2014;64(4):394-402.
Recent HTN Trials
11,056 pts, randomized + double blinded
Secondary Endpt:
-Progression of CKD, doubling SCr , need for RRT or ESRD
Bakris GL. Lancet 2010;375:1173-1181
Obesity Paradox
Impact of Achieved BP on Mortality and ESRD
60-79
mmHg
130-139
mmHg
• Retrospective cohort study, Kaiser
Permanente Southern California
• 398,419 treated hypertensive subjects
Sim JJ et al.
JACC
2014;64(6):588
-597
• 30% (+) diabetes mellitus
• 43% (+) BMI ≥ 30 kg/m2 (obesity paradox with
lower HR)
• Mortality in 25,182 (6.3%) and ESRD in 4,957
(1.2%)
• DM population had a lower nadir at 131 and 69
mmHg
• Age ≥ 70 had a higher nadir at 140 and 70
mmHg
• U-shaped curve with incremental risk
increases in BOTH directions
What Medications to Use?
Chlorthalidone or
Indapamide
Obesity Paradox
ASH Guidelines December 2013
Importance of the Team Approach
• ~ 7.6 million people with Stage III CKD (eGFR 30-60 mL/min/1.73 m2)
~ 6891 Full-time Nephrologists ( January 2006, AAMC) but ~30% ≥ 55 years or older
~ 1100 pts with Stage III CKD per Nephrologist ( i.e. ~ 7 new patients/day/Nephrologist)
IMPOSSIBLE!
Take Home Points
• Though GFR equations continue to evolve, they are helpful in predicting CKD complications and
provide prognostication.
• CKD-EPI is the preferred equation due to less bias.
• Newer markers such as cystatin C may provide advantages over creatinine-based assays.
• eGFR ≤ 45 mL/min/1.73 m2 is an important decision point.
• Every individual likely has a unique GFR trajectory.
• The addition of proteinuria (≥ 1 gram/day) or albuminuria (≥ 300 mg/gm creatinine) worsens every stage
of GFR.
• Metabolic acidosis (serum bicarbonate < 22 mEq/L) should be treated and may slow progression in
CKD.
• The degree of salt restriction remains controversial, though moderate restriction (~ 2300 mg/day)
may assist with proteinuria reduction and augment RAAS blockade.
• Inactivity has important associations (↑ CV morbidity/mortality, ↑ risk of malignancy as well as
increases the risk of progression to RRT and death). Inactivity is more deadly than obesity.
• BP goals continue to be moving targets and hopefully further studies will elucidate the optimal
values.