Section 4: Managing progression of CKD

The downward spiral RENAL FUNCTION Glomerulosclerosis Intraglomerular hypertension Reduction in number of functioning glomeruli Increased blood flow to remaining nephrons

Renal disease: dilated afferent arteriole allows transmission of high systemic pressure leading to glomeular capillary hypertension MAP Anti-hypertensives reduce MAP GCP ACEI/ARBs dilate the efferent arteriole – the downstream pressure valve – thus controlling glomerular capillary hypertension

Hypertension and Progression

Blood Pressure and Progression of CKD AIPRD Study Meta-analysis of 11 RCTs of ACEIs 1860 patients with non-diabetic kidney disease RR Systolic BP (mmHg) Jafar et al Ann Intern Med 2003;139:244-252

Number of Medications to reach target blood pressure Bakris et al AJKD 2001

IRMA 2 - primary endpoint 70% RRR* Irbesartan 300 mg vs Placebo, p < 0.001 Incidence of diabetic nephropathy (%) 5 10 15 20 3 6 12 18 24 201 195 194 Placebo Irbesartan 150 mg Irbesartan 300 mg 164 167 180 154 161 172 139 148 159 36 45 49 No. at Risk 129 142 150 Months of Follow-up 22 IRMA-2 evaluated the renoprotective effect of irbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were enrolled in this double-blind, placebo-controlled study. Patients were randomised to an irbesartan 150mg group, an irbesartan 300mg group or a control group (placebo in addition to other non-excluded antihypertensive therapies), and were followed for 2 years. The primary outcome was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was greater than 200 μg per minute and at least 30 percent higher than the base-line level. The trial found that 5.2% in the 300 mg irbesartan and 9.7% in the 150 mg irbesartan group reached the primary end point compared to 14.9% in the placebo group (14.9 percent). Overall, the study concluded that treatment with irbesartan significantly reduces the risk of progression to clinical albuminuria. The renoprotection offered by irbesartan is independent of its blood-pressure–lowering effect in hypertensive patients with type 2 diabetes and microalbuminuria. From this study it has been calculated that treating ten patients with hypertension, type 2 diabetes and microalbuminuria with irbesartan 300mg for two years would prevent one from developing overt nephropathy. Parving H-H et al. N Engl J Med 2001;345:870-878 *RRR = relative risk reduction Adapted from Parving H-H, et al. N Engl J Med 2001;345:870-878

AIPRI: Reduction of Risk with ACE-I Creatinine Clearance Proteinuria Maschio G, et al. N Engl J Med. 1996;334(15):939-945.

Adjusted incidence rate ratios (IRR) Cardiovascular mortality risk in the general population Impact of microalbuminuria *P<0.05 †P<0.01 ‡P<0.001 ‡ Adjusted incidence rate ratios (IRR) Category of eGFR, mL/min/1.73 m2 Corresponding CKD stage 1 & 22 22 3a3 3b3 & 42 ‡ ‡ † * * This slide shows the cardiovascular mortality risk associated with eGFR in patients with optimal levels of UACR and microalbuminuria. In this study ‘optimal UACR’ was defined as <5 mg/g in men and < 7 mg/g in women. The slide shows GFR and the corresponding CKD stages. These have been correlated using K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease2 for CKD stages 1, 2 and 4 and the Edinburgh Consensus Conference3 for CKD stages 3a and 3b. Hallan et. al. determined UACR by measuring 3 urine samples in 9,709 participants of the second Nord-Trøndelag Health Study (HUNT II), a Norwegian community-based health study, followed for 8.3 years. Subjects with an optimal UACR and an eGFR of 75 mL/min/1.73 m2 or higher comprised the reference group. Lower eGFR categories were associated with increased relative risk within every ACR category. Likewise, increasing ACR categories were associated with increased mortality within every eGFR category. Subjects with microalbuminuria and an eGFR lower than 45 mL/min/1.73m2 had 12 times higher cardiovascular mortality risk compared with the reference category of subjects with an eGFR higher than 75 mL/min/1.73m2 and “optimal” ACR. These results emphasise the need to recognise microalbuminuria as a risk factor for CV events and the importance of multiplicative risk factors. Hallan et al. Archives Internal Medicine (2007) 167;22;2490-2496 K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease Am J Kidney Dis 2002; 39 (2 Suppl 1):S1-246 Edinburgh Consensus Conference on Early Chronic Kidney Disease, February 2007 (http://www.rcpe.ac.uk/Whats_New/consensus-statements/final-early-chronic-kidney-disease.pdf; date last accessed 30/04/08) UACR Adapted from Hallan et al. Archives Internal Medicine 2007 167;22;2490-2496 K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease Am J Kidney Dis 2002; 39 (2 Suppl 1):S1-246 Edinburgh Consensus Conference on Early Chronic Kidney Disease, February 2007 (http://www.rcpe.ac.uk/Whats_New/consensus-statements/final-early-chronic-kidney-disease.pdf; date last accessed 30/04/08)

Urine Protein Excretion and CKD Progression AIPRD study group RR 4685 records with non-diabetic kidney disease Meta-analysis of 11 RCTs of ACEIs Urine protein excretion (g/day) Jafar et al 2003

Proteinuria and ESRF Proteinuria Screened ESRF 86,253 185 10,000 38 4007 55 1072 76 357 55 Iseki et al KI 2003

Urine Protein Excretion and Progression of CKD AIPRD Study Group 4685 records with non-diabetic kidney disease Meta-analysis of 11 RCTs of ACEIs RR Urine protein excretion (g/day) Jafar et al, Ann Intern Med 2003;139:244-252

Proteinuria and Progression of CKD: REIN Study

Optimal Management Saves Patients from Dialysis Renoprotective strategies that decrease the rate of GFR decline also delay ESRD Slowing of GFR decline Years delay for GFR 60 (Stage 3) Years delay for GFR 30 (Stage 4) 30 % 2.94 1.24 20 % 1.72 0.72 10 % 0.98 0.32 Comparison is with expected rate of GFR decline (7.56 mL/min/1.73m2) Adapted from Trivedi et al. Am J Kidney Dis 2002; 17:371-375