1. Chronic Kidney Disease (CKD): An Update for the Primary Physician
Joshua Augustine, M.D.
Wade Park Veterans Administration Hospital
1/28/14

2. 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 < 60 ml/min/1.73 m2 for > 3 months, with or without kidney damage

4. 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 > 60 years
Family history of kidney disease
Reduced kidney mass
Smoking
Risk factors for CKD include the following:
Diabetes
Hypertension
Autoimmune diseases
Systemic infections
Exposure to drugs associated with acute decline in kidney function
Recovery from kidney failure
Age >60 years
Family history of kidney disease
Reduced kidney mass (includes kidney donors and transplant recipients)1,2
Smoking3.
National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S17-S31.
Bolton WK, Kliger AS. Am J Kidney Dis. 2000;36(suppl 3):S4-S12.
Pinto-Sietsma SJ, et al. Ann Intern Med. 2000;133:
National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S17-S31.
Pinto-Sietsma SJ, et al. Ann Intern Med. 2000;133:

5. Etiology of Chronic Kidney Disease
Diabetic glomerulosclerosis
Type I or II %
Glomerular disease (primary or secondary) %
Vascular disease and hypertension
Including sickle cell and HUS 21%
Tubulointersitial disease
Pyelonephritis, analgesic, allergic %
Cystic disease
Polycystic, medullary cystic %

6. Chronic Kidney Disease Stages
Stage 1: Normal GFR; GFR >90 mL/min/1.73 m2 with other evidence of chronic kidney damage*
Stage 2: Mild impairment; GFR mL/min/1.73 m2 with other evidence of chronic kidney damage*
Stage 3: Moderate impairment; GFR mL/min/1.73 m2
Stage 4: Severe impairment: GFR mL/min/1.73 m2
Stage 5: Established renal failure: GFR < 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

7. Prevalence of CKD in NHANES* 1999-2004 participants
Demographic
Stage I
Stage 2
Stage 3
Stage 4/5
All
5.7
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, n=12,785 age ≥ 20 y/o
By MDRD formula, USRDS 2010

8. 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 and 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

9. Progressive CKD is Associated with Cardiovascular Risk
A cardiovascular event was defined as hospitalization for coronary disease, heart failure, stroke, or peripheral arterial disease

10. Current CKD Outcomes: Death vs. ESRD
The impact of CKD on morbidity, mortality, and health-care resources is considerable. Data from the USRDS indicate that patients with CKD are far more likely to die from complications of their disease than to survive long enough to reach ESRD.1 This slide shows the likelihood of death or progression to ESRD among general Medicare patients for the years 1996–1997 combined who were continuously enrolled in Medicare part A and part B and alive on December 31, A total of 40,250 patients with CKD were included in this analysis. Patients who were enrolled in an HMO or already in ESRD were excluded from these numbers.1
Expected lifetimes for patients after they begin dialysis are only 16% to 37% as long as those of the US population when matched for age, gender, and race.2
Obrador and colleagues suggest that improving the care of patients in the early stages of kidney disease, particularly by aggressively treating anemia, could significantly improve patients’ physical function, cardiac function, and QOL. Should RRT later be required for these patients, they will enter that stage with better opportunities for survival.2 This might alleviate some of the social and economic burdens of the disease.
In 1994, although patients with ESRD constituted only six out of every 1,000 patients in the Medicare population, they accounted for 5.1% of all program expenditures.3
US Renal Data System. USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. National Institutes of Health Available at:
Obrador GT, et al. J Am Soc Nephrol. 1999;10:
National Institutes of Health. Healthy People Available at: Accessed 08/27/02.
Death
ESRD
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 Available at:

11. AASK Trial, 1/3 of patients were < 50 y/o at enrollment
But ESRD is More Common than Death in Blacks with Hypertensive Kidney Disease
African American individuals with hypertensive nephrosclerosis (diastolic BP ≥95 mmHg with a GFR 20 to 65 ml/min per 1.73 m2). Participants with a history of a CVD event within 6 months, New York Heart Association class 3 or 4 heart failure, diabetes, malignant or accelerated hypertension within 6 months of enrollment, UP/Cr >2.5, or evidence of renal disease other than hypertensive nephrosclerosis were excluded at trial baseline.
AASK Trial, 1/3 of patients were < 50 y/o at enrollment
J Am Soc Nephrol 21: , 2010

12. 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
<30
<3
Normal A2
30-300
3-30
Moderate A3
>300
>30
Severe

15. Estimating renal function
Abbreviated MDRD equation =
CKD-EPI equation =
186 x (SCr) x (Age) x (0.742 if female) x (1.210 if Black)

16. Estimated GFR Google: “MDRD Calculator”
Save to your favorites!
More recent CKD EPI equation is less likely to underestimate GFR in patients with higher GFR

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

18. 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 ml/min)
KDIGO: if cystatin C formula > 60, patient should not be labeled as having CKD
Assessing for CKD in malnourished patients

19. 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

20. Graphing glomerular filtration rate
59 y/o with autosomal dominant polycystic kidney disease
51 y/o with severe acute and chronic interstitial nephritis

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

22. Screening for Proteinuria: Spot Sample is Recommended
KDIGO recommends albumin:creatinine ratio
Better laboratory precision than protein:creatinine
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

23. 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
During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group.
N Engl J Med 363: , 2010

25. Referral to Nephrology
All patients with GFR <30 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: , 2010

26. Late Referral to Nephrology
Often defined as referral at < 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

27. 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

28. 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
eGFR=14 ml/min/1.73m2
Patient agrees to dialysis if necessary

29. Survival in the Elderly: Dialysis vs. Conservative Management
UK study of 202 patients > 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 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 4:1611-9, 2009

30. Survival in the Elderly: Dialysis vs. Conservative Management
Clin J Am Soc Nephrol 4:1611-9, 2009

31. Hypertension
Can consider nephrology referral if blood pressure > 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 >30
Loop diuretics for lower GFR
May need 4-5 agents, varied timing, bedtime dosing

32. 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: , 2006

33. Predictive value of ambulatory BP in patients with high clinic BP
Kidney Int. 69: , 2006

34. Correlation of non-dipping with ESRD
Kidney Int. 69: , 2006

35. Diabetic Nephropathy “Microalbuminuria” defines the onset
Urinary albumin excretion of mg/day
Spot urinary albumin:creatinine ratio > 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

36. Natural history of diabetic nephropathy
Hyperfiltration
Microalbuminuria

37. Type II DM: IDNT (Irbesartan in Diabetic Nephropathy) Trial (NEJM 2001; 345:851-60)
1715 patients with type 2 DM, HTN, urinary protein > 900 mg/d, Cr 1-3 mg/dl
Randomized to irbesartan vs amlodipine or placebo
Significant reduction in risk of doubling creatinine in irbesartan vs placebo and vs amlodipine at mean follow-up of 2.5 years
rr = 0.71, 95% CI: 0.54 to 0.92 vs placebo
rr = 0.61, 95% CI: 0.48 to 0.79 vs amlodipine

38. Addition of the Aldosterone Inhibitor Spironolactone to ACE Inhibitor in Diabetic Nephropathy
A double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). Randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily). Blood pressure did not differ between groups.
Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. 48 wk.
**Potassium > 6 in 14/27 (52%) in spironolactone group
*Potassium level ≥ 6 meq/L occurred in 14/27 (52%) on spironolactone
J Am Soc Nephrol 20: , 2009

39. 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 < 30 ml/min or potassium >5.0 mmol/L
Diuretics can increase distal sodium delivery and potassium excretion
Loop diuretics if GFR < 30 ml/min
Avoid volume depletion with diuretics, which may worsen hyperkalemia
NEJM 2004; 351:

40. Possible scenarios of change in creatinine after angiotensin blockade
Volume depletion, CHF, NSAIDs or RAS
Stable CKD
Normal kidney function
Arch Intern Med :

41. 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 < 10 g/dl
Goal: to avoid Hb < 9 g/dl and Hb > 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

42. 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 < 9 g/dL
Achieved Hb level: 12.5 vs g/dL
No difference in death, CHF, or time to ESRD
New Engl J Med 361: , 2009

43. 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% (p<0.001)
Greater stroke risk in treated group
5% vs. 2.6%, hazards ratio 1.92 (1.38 to 2.68, p<0.001)
Also greater risk of venous and arterial thrombosis
New Engl J Med 361: , 2009

44. 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% (rr=0.83, 95% CI: 0.74 to 0.94, p=0.002)
Lancet 377: , 2011

45. SHARP Trial
Lancet 377: , 2011

46. SHARP Trial
Lancet 377: , 2011

47. 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

48. 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

49. Lifestyle and Dietary Goals
BMI kg/m2
< 2 g Sodium/day (<5 g NaCl)
Protein 0.8 gm/kg/day
Exercise: goal 30 minutes 5x/week
EtOH no more than 2/d men, 1/d women

50. Preparing for Hemodialysis Access
When GFR <45 (CKD stage 3b) the patient should be educated about saving veins in non-dominant arm (avoid needle sticks and BP checks)
When GFR <30 (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.

51. Mortality in First 90 Days of Dialysis Related to Vascular Access
Am J Kidney Dis 54: ,2009

52. 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

54. Case 3
42 y/o white male with hypertension and Cr of 1.6, eGFR of 48 ml/min/1.73m2, urinary albumin:cr 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

55. 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

56. Summary Monitor eGFR and spot protein in high risk patients
Refer all patients with CKD stage 4 or with albuminuria/proteinuria > 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

57. PCP Should be Part of the Team
One quarter of patients > 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