Blog entry by Meguid El Nahas

Anyone in the world

Prof Macaulay Onuigbo wrote:

Microalbuminuria in current nephrology literature revisited

There is significant evidence in the literature of temporal disassociations between measured kidney function and measured albumin creatinine ratios (ACR) in studied diabetic and non-diabetic CKD patients:

i. Tsalamandris et al. reported that of 40 patients with diabetes, followed over a period of 8-14 years, 15 developed progressive increase in albumin excretion rate (AER) with no decline in GFR, 13 had progressive increase in AER in association with decreasing GFR, and 12 (8 type 2) had decreasing GFR values without a significant increase in AER [1].

ii. In the DCCT/EDIC study, an extended median 13-year follow up of1441 study participants also documented regression to normoalbuminuria after more than a decade of persistent microalbuminuria, mostly without RAAS inhibitor use, and generally in the setting of excellent control of glycemia and blood pressure [2].

iii. In the ONTARGET trial, despite superior proteinuria reduction by combination RAAS blockade with an ACEI and an ARB, the combination group still fared worse than the monotherapy groups with regards to renal outcomes [3].

iv. Our experiences in the last ten years at the Mayo Clinic Health System, Eau Claire, in Northwestern Wisconsin, USA, have demonstrated similar patterns of variability of measured proteinuria by urinary albumin creatinine ratios among type II diabetic CKD patients, on and off the influence of concomitant angiotensin blockade [4-6]. Moreover, while we observed a tendency to increased proteinuria in our CKD patients following discontinuation of ACE inhibitors and/or ARBs, this was often in the face of improved kidney function [4-6].

v. El Nahas et al. from Sheffield, the United Kingdom, who reported on the results of discontinuation of ACE inhibitors and/or ARBs in 52 older CKD patients (21 females and 31 males, mean age 73 years) with advanced CKD (stages 4 and 5), showed sustained improved kidney function but no change in proteinuria following discontinuation of angiotensin blockade [7]. Baseline urine protein:creatinine ratio (PCR) was 77 ± 20 mg/mmol, and compared to end PCR values of 121.6 ± 33.6 mg/mmol, was not statistically significant [7].

From the foregoing, we have therefore been repeatedly called for more caution in the interpretation of degrees of proteinuria as a definitive and proven renal surrogate, more so when it is used in combination surrogate renal endpoints for study endpoints [8-10]. Indeed, Mann et al, the investigators of the ONTARGET trial, in a post hoc analysis concluded that the ONTARGET data suggest that proteinuria reduction by itself cannot be taken as a definitive marker of improved renal function [11].
We agree with El Nahas on a need to re-evaluate some of the current paradigms of CKD care especially as it relates to albuminuria as a renal surrogate [12]. Again, as El Nahas had acknowledged above, a focus on overt and progressive albuminuria is more apt and appropriate.

1. Tsalamandris C, Allen TJ, Gilbert RE, et al. Progressive decline in renal function in diabetic patients with and without albuminuria. Diabetes 1994; 43: 649-655.pmid:8168641.
2. de Boer IH, Rue TC, Cleary PA; et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011; 171(5): 412-420.
3. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547–59.
4. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008; 40:233–9.
5. Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008; 30:73–80.
6. Onuigbo MA, Achebe NJ. Late Onset Renal Failure From Angiotensin Blockade (LORFFAB) – The Results of a Mayo Clinic Health System Angiotensin Inhibition Withdrawal Study: A Clarion Call For More Preventative Nephrology, Also Called Renoprevention. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 75-90.
7. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2010 Dec;25(12):3977-82. doi: 10.1093/ndt/gfp511. Epub 2009 Oct 10.
8. Onuigbo MA. Relation between kidney function, proteinuria, and adverse outcomes – A critical look at the application of medical statistics in the Nephrology literature. QJM 2010 Jul; 103(7): 537-8. Epub 2010 Apr 11.
9. Onuigbo M, Onuigbo N. Aliskiren in Type 2 Diabetes and Cardiorenal End Points. N Engl J Med. 2013 Mar 14;368(11):1064-5. doi: 10.1056/NEJMc1300257#SA1. (
10. Onuigbo MA. The Abuse of Renal Surrogates and Combination Renal Endpoints in Nephrology RCTs. In: Macaulay Amechi Chuka Onuigbo, Editor. ACE inhibitors: medical uses, mechanisms of action, potential adverse effects and related topics. Volume 1. New York, NY. NOVA Publishers, 2013: 35-40.
11. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008; 372(9638): 547-553.
12. Onuigbo MA. Angiotensin Blockers and Renoprotection in Diabetic Chronic Kidney Disease is a Failed Paradigm? – A Revisionist View of Renoprotection in Diabetic Chronic Kidney Disease and A Novel Classification Scheme for Renoprotective Agents. In Atta ur Rahman (Editor): eBook “Frontiers in Clinical Drug Research: Diabetes and Obesity, Vol. 1”, 2014, In Print.

[ Modified: Thursday, 1 January 1970, 1:00 AM ]