The Conservative Management of Chronic Kidney Disease

Panduranga S Rao MD DNB MSAssociate Professor,

Division of NephrologyDepartment of Medicine

University of Michigan

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Definition of Chronic Kidney Disease

• Kidney damage for >3 months with or without decreased glomerular filtration rate as manifest by:

Markers of kidney damage including abnormalities in the composition of blood or urine or imaging

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What is the extent of the problem?

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Table 1 Stages of Chronic Kidney Disease and Prevalence in Adults.

Abboud H, Henrich WL. N Engl J Med 2010;362:56-65.

So why worry?

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CKD- a risk factor for cardiovascular disease

Estimated GFR

Relative Risk of death (any cause)

Relative Risk of cvevent

>60 1 (Ref) 1 (Ref)

30-44 1.8 2.0

15-29 3.2 2.8

<15 5.9 3.4

Go et al NEJM 2004 6

Cost of CKD

• $22 K PPPY for 65 years and older; $16K for Age 50-64• 18% of total Medicare expenditures

U.S. Renal Data System, USRDS 2013 Annual Data Report

The progressive nature of chronic kidney disease

Remuzzi JCI 2006

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ATTEMPTS AT SLOWING THE PROGRESSION OF KIDNEY DISEASE IS A WORTHY GOAL

Prevention is key, but failing that…….

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Slowing progression-implications

Snyder S American Family Physician 200510

What does CKD progress?

…and how is it relevant in day to day practice?

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HYPERFILTRATION

• When the nephron numbers are reduced, the remaining nephrons ‘hyperfilter.’

• An important mediator is Angiotensin 2.

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Angiotensin 2 and intraglomerularpressure

• Angiotensin 2 causes downstream vessel to constrict.

• This increases intra-glomerular pressure

• Although this increases filtration, over long term causes damage to the glomerulus.

Johnson Freewebs.com 13

Losartan effect on renal outcomes in type 2 DM with nephropathy

Brenner BM NEJM 2001 14

Captopril in diabetic nephropathy due to type 1 diabetes

Lewis NEJM 1993

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Effect of ACE on renal function

Bakris et al Arch Int Med 2000 16

Risk factors for hyperkalemia on ACE/ARB

Bakris et al Arch Int Med 2005

Management

• Review diet, if persisting problem get dietary input

• Beware of salt substitute!• Review drugs ( look for NASIDS)• Diuretics

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A LOT OF k!

Can 1+ 1=3?

If ACE works well and ARB works well, would ACE+ ARB work even

better?

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Combined blockade (ACE&ARB) and renal outcomes (ONTARGET)

Mann Lancet 2008 20

(Dialysis,death or doubling)

VA NEPHRON D Study

21Fried et al NEJM Nov 2013 Hyper K 6.3 vs.2.6

ARF 12.2 vs.6.7

Role of proteinuria

Why is control important?

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Intraglomerular pressure and proteinuria

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Angiotensin 2 and intraglomerularpressure

• Angiotensin 2 causes downstream vessel to constrict.

• This increases intra-glomerular pressure

• The increased intra-glomerular pressure provides a greater gradient for the escape of protein.

Johnson Freewebs.com 24

Proteinuria as a risk factor for progression

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Role of proteinuria in progression

Zandi-Nejad KI 200426

Beneficial effect of ACE on proteinurickidney disease

Maschio et al NEJM 199627

Supramaximal Candesartan and Proteinuria

Burgess JASN 2009 28

Insult to injury (or injury to insult?)

Blood pressure control and progression of kidney disease

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Blood Pressure control and progression

NKF.ORG 30

Hypertension

• Unclear whether <130/80 slows progression of CKD compared with < 140/90 – Especially in patients with protein < 300 mg/day

• SPRINT: RCT comparing <120 vs. <140 in delaying progression of CKD in patients age > 50 years.

Metabolic Complications

Other issues

• Lipids• Control of diabetes • Salt and water retention• Obesity• Smoking

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ANEMIA MANAGEMENT IN CKDWITH EPO

Too much of a good thing?

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If a little is good, is more better?

35Singh AK NEJM 2006

(13.5)

(11.3)

RCT,125 vs. 97 events (death, MI,Stroke, CHF), HR 1.34 (1.03-1.74)

CHOIR-correction of Hb and outcomes in renal insufficiency)

EPO in diabetic CKD

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• 4038 diabetic CKD• Randomized• Darbe Vs Placebo• Target Hb 13 g• NO difference in:• Death/CV events• Death/renal events

Pfeffer et al NEJM 2009

101 VS 53 STROKES

Use of oral Sodium Bicarbonate to slow progression

Yaqoob JASN 200937

Phosphorous and CKD

38Kestenbaum et al JASN 2005

Serum phosphorous and mortality in CKD

39Kestenbaum et al JASN 2005

RR=1.23 (1.12-1.36)

The trade off to maintain phosphorous levels

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PTH

CALCIUM

PHOSPHOROUS

FGF 23 and LVH in CKD. (Faul et al JCI 2011)

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FGF 23 and LVH in CKD. (Faul et al JCI 2011)

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Control of phosphorous

• Diet ( protein is the most important source). Watch out for processed food, cola products

Phosphorous binders (with food!)• Aluminum hydroxide• Ca carbonate or acetate• Sevelamer carbonate• Lanthanum

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CONTROL OF AN IMPORTANT CV RISK FACTOR-LIPIDS

If statins are is good for everybody, is it good for everybody with Chronic Kidney Disease?

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0 1 2 3 4 5 Years of follow-up

0

5

10

15

20

25

Prop

ortio

n su

fferin

g ev

ent (

%) Risk ratio 0.83 (0.74 – 0.94)

Logrank 2P=0.0022 Placebo

Eze/simv

SHARP: Major Atherosclerotic Events

Study of heart and renal event protectionMajor event-stroke, MI, Revascularization

Smoking cessation and improvement of urine albumin excretion

Phisitkul Am J Med Sc 2007

Salt

• Volume management critical• Likely contributes to high CV morbidity• Edema and high blood pressure dictates need

for salt restriction• Emphasize of avoiding processed foods.• Remember it is the salt which is the culprit,

not the water!

Sodium

• Low sodium diet– Reduces blood pressure by 10 mmHg – Also reduces proteinuria– More effective than ACE plus ARB

Slagman et al. BMJ 343:d4366, 2011

Sodium

– 2.8 g Na in Low Sodium Diet vs. 5.5 g Na in HSD

– Despite similar BP, HSD had blunted antiproteinuricresponse to ACE

Vegter et al. J Am Soc Nephrol 23: 165-173, 2012

Low sodium diet reduces progression to ESRD

Protein Intake

• Quantity– Low protein diet may slow progression of CKD– 0.7 g/kg/day: 86 kg = 60 grams = 2 oz!

• Source– Vegetable sources of protein

• Decreased production of uremic toxins: p-cresyl sulfate and indoxyl sulfate (implicated in progression)

• Low in phosphorus• Lower endogenous acid production

Obesity

Kramer et al. NephSAP 14(4): 283-293, 2015

Effect of Weight Loss

• Decreased albuminuria• Improved GFR• No study has

demonstrated slowed progression of CKD

0

10

20

30

40

50

60

70

Pr-Surgery 6 mo. Post 12 mo. Post

GFR

(ml/m

in) a

nd B

MI (

kg/m

2 )

Change in GFR with Weight Loss

GFR BMI

Navaneethan, et al. Surgery for Obesity and Related Diseases 5 (2009) 662– 665

Uric Acid

• Elevated uric acid levels are associated with CKD, hypertension, and CV disease

• Hyperuricemia associated with increased mortality and higher cardiovascular events

• Not clear that elevated uric acid leads to CKD progression. Proposed mechanisms: – hypertension with activation of RAS– increased glomerular hydrostatic pressure– fibrosis

Uric Acid

20

25

30

35

40

Baseline 6 month 12 month 24 month

GFR

(ml/

min

)

ControlAllopurinol

N=113

• Allopurinol 100 mg daily slowed progression of CKD, reduced CRP, and decreased CV events– Similar BP between groups

Goicoechea et al. CJASN 5: 1388-1393, 2010

Nocturnal Hypoxemia

• Sleep Disordered Breathing: up to 65% in CKD vs. 20% in general population– OSA vs. CSA

• Nocturnal Hypoxemia– Oxidative stress, sympathetic and RAS activation– Endothelial dysfunction → CV disease– Tubulointerstitial disease → ESRD

Sakaguchi et al. Clin J Am Soc Nephrol 8: 1502–1507, 2013

Nocturnal Hypoxemia

• Nocturnal Hypoxemia associated with accelerated decline in GFR– 161 patients followed for

1 year– Avg BMI 22; Avg GFR 30

ml/min– 10% of participants had

mod/severe hypoxemia

0

2

4

6

8

10

GFR

(ml/

min

/yr)

Dec

line

Sakaguchi et al. Clin J Am Soc Nephrol 8: 1502–1507, 2013

Medication Dosing in CKD• Avoid

– Meperidine• Increased risk of seizures

– Thiazide diuretics• GFR < 30 Ineffective

– Metformin• If GFR < 30

– Alendronate• GFR <30: reduce dose/avoid

– Mylanta/Maalox• Mg / Al

– NSAIDS

• Decrease dose/frequency– Digoxin– Cephalexin– Amoxicillin– Ciprofloxacin/Levofloxacin– Fluconazole– Acyclovir/Valacyclovir– Gabapentin– Ranitidine– Allopurinol– Sitagliptan (Januvia)– Glyburide → Glipizide

Photomicrographs of Renal-Biopsy Specimens Obtained before and after Pancreas Transplantation from a 33-Year-Old Woman with Type 1 Diabetes of 17 Years' Duration at the Time

of Transplantation (Periodic Acid–Schiff, ×120).

Fioretto P et al. N Engl J Med 1998;339:69-75.

Slowing Progression in ADPKD-Tolvaptan study- (Torres et al NEJM 2012)

Summary• Chronic kidney disease is common.• Many of the CKD progresses over time• Blood pressure control, angiotensin blockade, and

control of proteinuria slows progression• Renal anemia treatment with EPO needs a careful

approach.• Control phosphorous• Always be vigilant of drugs (both OTC and prescribed)

which could make CKD more difficult to manage.• Good medical management of risk factors like lipids,

obesity, salt intake and smoking reduce morbidity

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