Kerry Cooper M.D. Arizona Kidney Disease and Hypertension Center April 30, 2009

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1 Kerry Cooper M.D. Arizona Kidney Disease and Hypertension Center April 30, 2009

3 DR. KERRY COOPER IS ON THE SPEAKER BUREAU OF AMGEN, ABBOTT, GENZYME, SHIRE, AND BMS DR. COOPER IS ALSO INVOLVED IN CLINICAL TRIALS SPONSORED BY AMGEN, ABBOTT, GENZYME, AND SHIRE

4 Review the differential diagnosis of proteinuric syndromes Review the pathology of primary and secondary glomerular disorders Review diagnostic tools for evaluation of proteinuria Review treatment options for proteinuric syndromes

13 Albuminuria Timed Collection (µg/min) Spot Collection (µg/mg Cr) 24-Hour Collection (mg/24 hr) Normo- <20 <30 <30 Micro Macro

15 Heavy proteinuria ( 3 gm/24 hrs) Hypoalbuminemia Edema formation Hypercholesterolemia

16 Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Mesangiocapillary glomerulonephritis

17 Infectious diseases Post-streptococcal GN Hepatitis B/Hepatitis C HIV Parasitic infections Autoimmune diseases Systemic lupus Wegener s granulomatosis Malignancy Solid tumors/membranous nephropathy Lymphoproliferative disorders/minimal change disease Drug induced Non-steroidal agents Gold/penicillamine

18 Fever Congestive heart failure Dehydration

20 Anti-nuclear antibody Complement levels Serum/urine immunoelectropheresis Hepatitis B/C serologies HIV status Anti-neutrophil cytoplasmic antibody Renal biopsy

21 Anasarca Systemic infection Hypercoagulability Deep venous thrombosis Renal vein thrombosis

22 Dyslipidemia Male Sex Hypertension Hyperinsulinemia Microalbuminuria Age> 60 years Relative Risk of Coronary Artery Disease Tuttle KR et al. Am J Kidney Dis. 1999;34:

23 Hypertension Age (men, >55 yr; women, >65 yr) Diabetes mellitus Dyslipidemia Microalbuminuria or estimated GFR <60 ml/min Family history of premature CVD (men, <55 yr; women, <65 yr) Obesity (BMI 30 kg/m 2 ) Physical inactivity Cigarette smoking

40 Diuretics/sodium restriction ACE I, ARB Glucocorticoids Immunosuppressive agents Chlorambucil Cyclophosphamide Calcineurin inhibitors Mycophenalate mofetil

44 Microalbuminuria Proteinuria CV Events Death Doubling of Serum Creatinine Levels End-Stage Renal Disease

through increasing efferent arteriolar pressure 1 Prolonged inappropriate increase in angiotensin II

45 MC GFR CL Autoregulation through feedback mechanisms normally keeps GFR and renal blood flow constant 1 EC EA EA Resistance Angiotensin II Renin JA AA Angiotensin II plays a key role in autoregulation through increasing efferent arteriolar pressure 1 Prolonged inappropriate increase in angiotensin II leads to decreased GFR and renal blood flow as well as release of various cytokines and growth factors 1,2

46 Progression to Death, Dialysis, or Transplant (%) 40 Placebo 30 Captopril

Patients (%) 20 15 Control (n=201)* Irbesartan 150 mg/d (n=195)* Irbesartan 300 mg/d (n=194)* RRR=39% P=.08 10 RRR=70% P<.001 5 0 0 3 6 12 18 22 24 Follow-up (mo) RRR, relative risk reduction.

47 Patients (%) Control (n=201)* Irbesartan 150 mg/d (n=195)* Irbesartan 300 mg/d (n=194)* RRR=39% P= RRR=70% P< Follow-up (mo) RRR, relative risk reduction. Control defined as placebo. * Adjunctive antihypertensive therapies (excluding ACE inhibitors, ARBs, and dihydropyridine CCBs) could be added to all groups to help achieve target BP levels. Adapted from Parving H-H et al. N Engl J Med. 2001;345:

48 Patients (%) P= Control (n=201) 150 mg/d (n=195) 300 mg/d (n=194) Irbesartan

49 Irbesartan (n=579) RRR=23% P=.006 Amlodipine (n=567) RRR=20% P=.02 P=NS Control (n=569) Follow-up (mo) Control defined as placebo. SeCr, serum creatinine; ESRD, end-stage renal disease; RRR, relative risk reduction. Adapted from Lewis EJ et al. N Engl J Med. 2001;345:

50 Change in UPE (%) 3 Months Years 1, Control -1% Amlodipine 10 mg/d -4% Irbesartan 300 mg/d Control -10% Amlodipine 10 mg/d -6% Irbesartan 300 mg/d % -35 P=NS P<.001 P<.001 Control defined as placebo. UPE, urinary protein excretion (g/24h). 1. Data on file, Bristol-Myers Squibb Company. 2. Lewis EJ et al. N Engl J Med. 2001;345: P=NS P<.001 P< %

51 Reduction From Baseline (%) 0 Fosinopril 20 mg/d After 6 Weeks of Therapy Irbesartan 150 mg/d Irbesartan 150 mg/d + Fosinopril 20 mg/d P=.039

52 Change in AER (%) Change in AER (%) 0 Hypertensive (n=64) Placebo Irbesartan 0 Normotensive (n=60) Placebo Irbesartan Reduction in SBP/DBP (mm Hg) Baseline: 160/96 mm Hg Baseline: 126.5/81.5 mm Hg Placebo Irbesartan Placebo Irbesartan -1.5/ / -6.5 Reduction in SBP/DBP -3/ / -1 (mm Hg)

RENAAL, IRMA-2 and IDNT. Three featured trials linking a disease spectrum IDNT RENAAL. Death IRMA 2

RENAAL, IRMA-2 and IDNT. Three featured trials linking a disease spectrum IDNT RENAAL. Death IRMA 2 Treatment of Diabetic Nephropathy and Proteinuria Background End stage renal disease is a major cause of death and disability among diabetics BP reduction is important to slow the progression of diabetic