Chronic Kidney Disease (CKD): An Update for the Primary Physician

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Chronic Kidney Disease (CKD)An Update for the
Primary Physician

• Joshua Augustine, M.D.
• Wade Park Veterans Administration Hospital
• 1/28/14

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Quiz Questions

• 1.Name the two formulas that are best at
  estimating glomerular filtration rate (GFR) in
  patients with CKD.
• 2.At what stage of CKD should all patients be
  referred to a nephrologist?
• 3.Name three situations that may warrant a
  nephrology referral at lower stages of CKD

3
Chronic Kidney Disease Definition

• Kidney damage for 3 months, as defined by
  structural or functional abnormalities
• Pathological abnormalities
• Markers of kidney damage by blood, urine, or
  imaging tests
• GFR lt 60 ml/min/1.73 m2 for gt 3 months, with or
  without kidney damage

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Risk Factors for CKD

• Diabetes
• Hypertension
• Autoimmune diseases
• Systemic infections
• Exposure to drugs associated with acute decline
  in kidney function
• NSAIDs
• Contrast agents

• Recovery from acute kidney failure
• Age gt 60 years
• Family history of kidney disease
• Reduced kidney mass
• Smoking

National Kidney Foundation. Am J Kidney Dis.
200239(suppl 1)S17-S31. Pinto-Sietsma SJ, et
al. Ann Intern Med. 2000133585-591.
5
Etiology of Chronic Kidney Disease

• Diabetic glomerulosclerosis
• Type I or II 33
• Glomerular disease (primary or secondary)
  19
• Vascular disease and hypertension
• Including sickle cell and HUS 21
• Tubulointersitial disease
• Pyelonephritis, analgesic, allergic 4
• Cystic disease
• Polycystic, medullary cystic 6

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Chronic Kidney Disease Stages
Stage 1 Normal GFR GFR gt90 mL/min/1.73 m2
with other evidence of chronic kidney
damage Stage 2 Mild impairment GFR 60-89
mL/min/1.73 m2 with other evidence of chronic
kidney damage Stage 3 Moderate impairment
GFR 30-59 mL/min/1.73 m2 Stage 4 Severe
impairment GFR 15-29 mL/min/1.73 m2 Stage 5
Established renal failure GFR lt 15 mL/min/1.73
m2 or on dialysis Other evidence may be
one of the following Persistent
microalbuminuria/proteinuria Persistent
hematuria from a renal origin Structural
abnormalities of the kidneys demonstrated on
ultrasound or other radiological tests
Biopsy-proven inflammation or fibrosis
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Prevalence of CKD in NHANES 1999-2004
participants
Demographic Stage I Stage 2 Stage 3 Stage 4/5
All 5.7 5.4 5.4 0.4
Age 20-39 5.9 2.2 0.3 0.1
Age 40-59 5.8 4.4 2.1 0.2
Age 60 5.0 12.8 20.3 1.3
Black race 9.4 4.8 4.7 1.1
Diabetic 19.5 11.4 8.2 1.0
Cardiovasc Dz 4.5 10.8 10.5 2.4
National Health and Nutrition Examination
Survey, n12,785 age 20 y/o
By MDRD formula, USRDS 2010
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Kidney Disease in African Americans

• African Americans make up about 12 of the
  population but account for 32 of people with
  kidney failure
• Among new patients whose kidney failure was
  caused by high blood pressure, more than half
  (51) are African American
• Among new patients whose kidney failure was
  caused by diabetes, almost 1/3 (31) are African
  American
• African-American men ages 20-29 and 30-39 are 10
  x and 14 x more likely to develop kidney failure
  due to high blood pressure than Caucasian men in
  the same age group

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Progressive CKD is Associated with Cardiovascular
Risk
10
Current CKD Outcomes Death vs. ESRD
n 40,250
D diabetes ND no diabetes
Adapted from US Renal Data System. USRDS 2002
Annual Data Report Atlas of End-Stage Renal
Disease in the United States. National
Institutes of Health. 2002. Available at
www.usrds.org/atlas.htm.
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But ESRD is More Common than Death in Blacks with
Hypertensive Kidney Disease
AASK Trial, 1/3 of patients were lt 50 y/o at
enrollment J Am Soc Nephrol 21 1361-9, 2010
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Kidney Disease Improving Global Outcomes (KDIGO)
(Kidney Int 2013)

• New CKD guidelines from 2013
• New staging concept GFR and albuminuria
  categories
• GFR categories add G3a for GFR 45-59, G3b for
  GFR 30-44
• Albuminuria categories

Category AER (24 hr) mg/mmol mg/g Terms
A1 lt30 lt3 lt30 Normal
A2 30-300 3-30 30-300 Moderate
A3 gt300 gt30 gt300 Severe
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Estimating renal function

• Abbreviated MDRD equation
• CKD-EPI equation

186 x (SCr)-1.154 x (Age)-0.203 x (0.742 if
female) x (1.210 if Black)

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Estimated GFR

• Google MDRD Calculator
• http//www.nephron.com/MDRD_GFR.cgi
• Save to your favorites!
• More recent CKD EPI equation is less likely to
  underestimate GFR in patients with higher GFR

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MDRD vs. CKD-EPI EquationNHANES data 2003-2006
MDRD MDRD CKD-EPI CKD-EPI
Stage 3 CKD Stage 4/5 CKD Stage 3 CKD Stage 4/5 CKD
All Adults 7.8 0.5 6.3 0.6
Male 6 0.5 5.2 0.6
Female 9.4 0.5 7.4 0.6
White 9.2 0.5 7.4 0.6
Black 4.8 1.1 4.9 1.2
USRDS 2010
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Cystatin C

• A low molecular weight cysteine protease
  inhibitor- produced by all nucleated cells
• Filtered at the glomerulus and not reabsorbed
• However, metabolized in the tubules
• Inflammation, thyroid disease, and steroids may
  affect levels
• Less dependent on race and body mass
• Potetential uses
• Confirming stage 3a CKD (eGFR 45-59 ml/min)
• KDIGO if cystatin C formula gt 60, patient should
  not be labeled as having CKD
• Assessing for CKD in malnourished patients

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Testing for CKD and Monitoring Progression

• Regular testing of patients at risk with
• Diabetes
• Hypertension
• Family history of kidney failure
• Cardiovascular disease
• Rapid progression is considered a decline of more
  than 5 ml/min/1.73m2/yr

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Graphing glomerular filtration rate


59 y/o with autosomal dominant polycystic kidney
disease
51 y/o with severe acute and chronic interstitial
nephritis

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Screen for Proteinuria

• As part of the initial assessment of patients
  with
• Diabetes mellitus
• Newly discovered GFR lt 60 ml/min/1.73 m2
• Newly discovered hematuria
• Newly diagnosed hypertension
• Unexplained edema
• Suspected heart failure
• Suspected multisystem disease, e.g. lupus

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Screening for Proteinuria Spot Sample is
Recommended

• KDIGO recommends albumincreatinine ratio
• Better laboratory precision than
  proteincreatinine
• May also check spot total urine protein to
  creatinine ratio or 24 hr urine
• Test a.m. samples
• Avoid testing in febrile patient or after
  vigorous exercise
• Confirm with repeat testing

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Treatment of Hypertension KDIGO

• Recommended that all CKD patients with no
  proteinuria have a target BP 140/90
• Goal blood pressure for all CKD patients with any
  degree of proteinuria 130/80 (JNC8-140/90)
• ARB or ACEI first line for any diabetic with
  abnormal proteinuria, and for any CKD patient
  with albumin excretion
• ACEI/ARB combination not recommended

24
Intensive blood pressure control in non-diabetic
blacks with CKD benefit in subgroup with
proteinuria
N Engl J Med 363 918-29, 2010
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Referral to Nephrology

• All patients with GFR lt30 mL/min/1.73m2 (Stage 4)
  should be referred to a nephrologist
• Additionally refer stage 3 CKD with
• Younger Age
• Poorly controlled blood pressure
• Declining kidney function
• Hyperkalemia on acei/arb therapy
• Proteinuria

DeCoster C et al. J Nephrol 23 399-407, 2010
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Late Referral to Nephrology

• Often defined as referral at lt six months prior
  to initiation of dialysis therapy
• Historically the case for 30-50 of patients
• Typically leads to inpatient dialysis (often
  urgently) with a vascular catheter
• Associated with increased one year morbidity and
  mortality
• High rate of infection, line sepsis

Nephrol Dial Transplant 20 490-6, 2006
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Late Referral to Nephrology

• Causes
• Fulminant renal failure
• Lack of access to any medical care
• Emergency room presentation
• Patient failure to follow through with referral
• Older patient with plans for conservative
  management of uremia
• However, most older patients choose dialysis

Nephrol Dial Transplant 20 490-6, 2006
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Case 1

• 77 y/o white female with longstanding diabetes
  and 2 proteinuria, Cr 2.4
• eGFR 20 ml/min/1.73m2
• Patient states she is not interested in
  dialysis
• Who is?
• Cr appears stable, so decision made not to refer
• Three months later, patient hospitalized with
  CHFrequiring diuresis
• Cr on f/u testing is 3.3
• eGFR14 ml/min/1.73m2
• Patient agrees to dialysis if necessary

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Survival in the Elderly Dialysis vs.
Conservative Management

• UK study of 202 patients gt 70 y/o with stage 5
  CKD
• 173 chose dialysis, 29 chose conservative
  management
• Median survival 37.8 mos (range 0 to 106) for
  dialysis vs. 13.9 mos (range 2 to 44) for
  conservative management
• But dialysis patients spent more time in the
  hospital relative to days of survival and were
  more likely to die in the hospital

Clin J Am Soc Nephrol 41611-9, 2009
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Survival in the Elderly Dialysis vs.
Conservative Management
Clin J Am Soc Nephrol 41611-9, 2009
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Hypertension

• Can consider nephrology referral if blood
  pressure gt 150/90 despite usage of three
  antihypertensive drugs from different classes
• ACE inhibitors or ARBs are first line in any
  patient with proteinuria/albuminuria
• Diuretics key to blood pressure control
• Thiazide if eGFR gt30
• Loop diuretics for lower GFR
• May need 4-5 agents, varied timing, bedtime dosing

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Ambulatory Blood Pressure Monitoring in CKD

• VA study of 217 CKD patients stage III to V
  (pre-ESRD) with abnormal urinary protein
• Clinic BP vs. 24 hr. ambulatory monitoring
• Correlated measurements with ESRD and death
• Occurred in 34.5 over a median of 3.5 yrs
• Systolic blood pressure correlated with primary
  outcome
• But normal home BP more predictive of renal
  outcomes in patients with high clinic BP

Kidney Int. 69 1175-80, 2006
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Predictive value of ambulatory BP in patients
with high clinic BP
n95 n51
Kidney Int. 69 1175-80, 2006
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Correlation of non-dipping with ESRD
Kidney Int. 69 1175-80, 2006
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Diabetic Nephropathy

• Microalbuminuria defines the onset
• Urinary albumin excretion of 30-300 mg/day
• Spot urinary albumincreatinine ratio gt 30 mg/g
  Cr
• Persistent elevation of urinary protein in the
  absence of other kidney disease
• Consider referral when proteinuria is increasing,
  even with normal creatinine

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Natural history of diabetic nephropathy
d
Hyperfiltration
Microalbuminuria
37
Type II DM IDNT (Irbesartan in Diabetic
Nephropathy) Trial(NEJM 2001 345851-60)
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Addition of the Aldosterone Inhibitor
Spironolactone to ACE Inhibitor in Diabetic
Nephropathy
Potassium level 6 meq/L occurred in 14/27
(52) on spironolactone
J Am Soc Nephrol 20 2641-50, 2009
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Preventing hyperkalemia with angiotensin blockade

• Introduce agents at low dose
• Check labs 1 week after initiation/dose change
• If adding spironolactone or eplerenone, do not
  exceed 25 mg/day
• Avoid if GFR is lt 30 ml/min or potassium gt5.0
  mmol/L
• Diuretics can increase distal sodium delivery and
  potassium excretion
• Loop diuretics if GFR lt 30 ml/min
• Avoid volume depletion with diuretics, which may
  worsen hyperkalemia

NEJM 2004 351585-592
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Possible scenarios of change in creatinine after
angiotensin blockade
Volume depletion, CHF, NSAIDs or RAS
Stable CKD
Normal kidney function
Arch Intern Med 2000 160685-693
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Anemia Treatment in CKD-KDIGO

• Intravenous iron usage is encouraged
• With TSAT up to 30 and ferritin up to 500 ng/ml
• Avoid with acute infection
• Based on animal data demonstrating impaired
  response to infection
• Do not initiate ESA therapy unless Hb lt 10 g/dl
• Goal to avoid Hb lt 9 g/dl and Hb gt 11.5 g/dl
• Avoid escalation in resistant patients to greater
  than double the weight-based recommended dosage
• Use with great caution in patients with active
  malignancy or history of CVA

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Caveats on Treating Anemia in CKD

• TREAT trial
• Randomized 4038 patients with DM and CKD
• Mean age 68 yrs, median eGFR 33 ml/min/1.72m2
• Median follow-up 29 months
• Darbepoetin treatment
• Target Hb of 13 g/dL vs. watchful waiting and
  rescue Tx for Hb lt 9 g/dL
• Achieved Hb level 12.5 vs. 10.6 g/dL
• No difference in death, CHF, or time to ESRD

New Engl J Med 361 2019-32, 2009
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Caveats on Treating Anemia in CKD

• TREAT trial
• Slight improvement in fatigue score in treated
  group
• More transfusions in untreated group
• 24.5 vs. 14.8 (plt0.001)
• Greater stroke risk in treated group
• 5 vs. 2.6, hazards ratio 1.92 (1.38 to 2.68,
  plt0.001)
• Also greater risk of venous and arterial
  thrombosis

New Engl J Med 361 2019-32, 2009
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Lipid Lowering SHARP trial

• Study of Heart and Renal Protection
• 9270 patients 40 y/o with CKD
• SCr 1.7 mg/dl in men, 1.5 mg/dl in women
• 1/3 of patients had ESRD
• Randomized to simvastatin 20 mg/d ezetimibe 10
  mg/d vs. placebo
• F/U average 4.9 yrs
• Analyzed rate to first major atherosclerotic
  event (MI, coronary death, CVA or arterial
  revascularization)
• 11.3 vs. 13.4 (rr0.83, 95 CI 0.74 to 0.94,
  p0.002)

Lancet 377 2181-92, 2011
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SHARP Trial
Lancet 377 2181-92, 2011
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SHARP Trial
Lancet 377 2181-92, 2011
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Lipid Lowering SHARP trial

• Subgroup analysis showed statistical difference
  only in non-dialysis cohort
• No affect on mortality
• No affect of progression of CKD
• Well tolerated, no increase in myopathy or other
  s.e.s

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Monitoring Markers of Bone Mineralization When
to Refer?

• CKD stage III
• Check Serum Ca, Phos, PTH annually
• Phos goal 2.7 to 4.6 mg/dL
• PTH goal 35 to 70 pg/mL
• If high check 25 vitamin D
• Treat low 25 vitamin D with ergocalciferol
• Monitor Ca and Phos on vitamin D therapy
• Repeat PTH and 25 vitamin D in six months
• If persistent elevation in phos or PTH
• Refer to nephrology for dietician, binders or
  calcimimetic therapy

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Lifestyle and Dietary Goals

• BMI 20-25 kg/m2
• lt 2 g Sodium/day (lt5 g NaCl)
• Protein 0.8 gm/kg/day
• Exercise goal 30 minutes 5x/week
• EtOH no more than 2/d men, 1/d women

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Preparing for Hemodialysis Access

• When GFR lt45 (CKD stage 3b) the patient should be
  educated about saving veins in non-dominant arm
  (avoid needle sticks and BP checks)
• When GFR lt30 (CKD Stage 4) and patient chooses
  hemodialysis, nephrologist should refer to
  surgeon for AV fistula consultation.
• Best for AV fistula to be created 6 months to 1
  year prior to dialysis start to allow for
  maturation time
• Goal should be to avoid hemodialysis catheter
  whenever possible.

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Mortality in First 90 Days of Dialysis Related to
Vascular Access
Am J Kidney Dis 54 912-21,2009
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Coordinating Care between the PCP and the
Nephrologist

• Nephrologist needs to maintain a relationship
  with the primary physician
• Care for the CKD patient should not transfer
  entirely to the nephrologist
• Primary doctor should maintain active role in
  monitoring of CKD, treating cardiovascular risk
  and addressing other comorbidities
• The nephrologist may see patient once for
  counseling or follow annually if renal function
  is stable and CKD is stage 3 or lower

Nephrol Dial Transplant 20 490-6, 2006
53
Case 2

• 85 y/o black female with longstanding
  hypertension, serum creatinine of 1.7, eGFR 35
  ml/min/1.73m2, minimal proteinuria
• This patient could be monitored initially by the
  PCP
• Blood pressure management and cardiovascular risk
  reduction is the first goal
• May need nephrology referral for blood pressure
  management
• Discussion about end of life appropriate at this
  age
• If Cr trends up and eGFR falls below 30, referal
  to nephrologist is appropriate

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Case 3

• 42 y/o white male with hypertension and Cr of
  1.6, eGFR of 48 ml/min/1.73m2, urinary albumincr
  ratio of 3400 mg/g
• This patient is at significant risk of
  progressing to ESRD over years
• Refer to nephrologist early
• Patient would require biopsy to evaluate for
  underlying glomerular disease
• May require aggressive therapy with angiotensin
  blockade and/or immunosuppressive therapy
  depending on diagnosis

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Quiz Questions

• 1.Name the two formulas that are best at
  estimating glomerular filtration rate (GFR) in
  patients with CKD.
• 2.At what stage of CKD should all patients be
  referred to a nephrologist?
• 3.Name three situations that would warrant a
  nephrology referral at lower stages of CKD

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Summary

• Monitor eGFR and spot protein in high risk
  patients
• Refer all patients with CKD stage 4 or with
  albuminuria/proteinuria gt 600-1000 mg/g
  creatinine
• Reasonable to refer early with stage 3 CKD
  particularly with
• A younger patient
• Kidney function worsening quickly
• Urinary protein not decreasing with acei/arb
• Difficulty managing acei/arb due to rise in
  potassium serum creatinine
• Refractory hypertension

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PCP Should be Part of the Team

• One quarter of patients gt age 60 have been
  identified as having CKD stage 3
• Approximately 8 million patients
• Not enough nephrologists to staff all patients
• Most will not progress to ESRD, but require
  careful monitoring, blood pressure control, and
  cardiac risk assessment and treatment
• Older, Caucasian, diabetic more likely to die
  than progress to ESRD
• The PCP is essential in the care of CKD patients