1. Section 4: Managing progression of CKD

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

3. 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

4. Hypertension and Progression

5. 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:

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

7. 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:
*RRR = relative risk reduction
Adapted from Parving H-H, et al. N Engl J Med 2001;345:

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

10. 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;
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 ( date last accessed 30/04/08)
UACR
Adapted from Hallan et al. Archives Internal Medicine ;22;
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
( date last accessed 30/04/08)

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

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

13. 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:

14. Proteinuria and Progression of CKD: REIN Study

16. 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: