Lowering of Proteinuria in Response to Antihypertensive Therapy Predicts Improved Renal Function in Late but Not in Early Diabetic Nephropathy: A Pooled Analysis

Abstract

In late diabetic nephropathy (DN) the initial lowering of albumin excretion rate (AER) with antihypertensive therapy is proportional to the degree of subsequent preservation of glomerular filtration rate (GFR). Whether a similar relationship exists between AER and GFR in early diabetes is not known. The present analysis has compared AER and GFR responses to antihypertensive therapy in 33 published studies (77 treatment groups) of early and late DN in type 1 (T1) and type 2 (T2) diabetes, analyzed on an intention-to-treat basis. Prospective trials were included if the initial change in AER during the first year of therapy and the change in GFR during at least 2 years of follow-up could be estimated from group mean data. The initial % decreases in AER were 5.9 ± 4.3 (T1), 10.5 ± 5.4 (T2, normotensive) and 18.4 ± 6.2 (T2, hypertensive) in early DN and 7.6 ± 11.1 (T1) and 20.8 ± 5.5 (T2) in late DN. The corresponding annual % rates of decline of GFR were 2.0 ± 0.5 (T1), 1.6 ± 0.5 (T2, normotensive) and 2.1 ± 0.3 (T2, hypertensive) in early DN and 9.8 ± 1.5 (T1) and 9.2 ± 1.1 (T2) in late DN. AER and GFR responses in each treatment group were closely correlated in late nephropathy (T1, r = –0.67, p = 0.03; T2, r = 0.57, p = 0.02) but not in early nephropathy. In contrast to late DN, the initial decrease in AER with antihypertensive therapy was not shown to predict the subsequent rate of decline of GFR in early DN. It follows that assessment of renoprotection during antihypertensive therapy in early nephropathy should be based not only on albuminuria but also on the GFR response.

Blockade of Endothelial-Mesenchymal Transition by a Smad3 Inhibitor Delays the Early Development of Streptozotocin-Induced Diabetic Nephropathy

“…However, large randomized clinical trials have revealed that inhibition of the RAS fails to prevent the development of early diabetic renal disease (5,32), suggesting that additional mechanism(s) may participate in the development of diabetic renal disease. The present findings demonstrated that AGEs induced EndoMT in vitro and in vivo and that blockade of Smad3 phosphorylation by SIS3 significantly reduced EndoMT, decreased glomerulosclerosis and tubulointerstitial fibrosis, and improved renal function.…”

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

“…the inhibitors of the renin-angiotensin system used for the management of patients with DN suppress urinary albumin excretion in a relatively short term but do not prevent renal function decline and the progression to end-stage chronic kidney disease (Jerums et al, 2008). Conversely, stem cell-based intervention is known to act through multiple mechanisms, a clear advantage when facing diseases with highly complex pathophysiology, as is the case of DN.…”

Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

“…Thus, it may be misleading to extrapolate from more advanced to early DN stages and from T2DM to T1DM studies, especially given substantial differences in relationships of renal structure to albuminuria 31 and the frequent presence of hypertension, obesity and other albuminuria risk factors in T2DM 2 . Decreased progression of microalbuminuria to proteinuria in diabetic patients could result from direct effects of ACEIs on proteinuria 11,32 . Thus, despite 8 years of treatment, two months after discontinuation of ACEI albuminuria differences from placebo were no longer significant 32 , suggesting masking of progression of underlying injury.…”

“…9 Intensive multifactorial intervention in type 2 diabetic patients with microalbuminuria nearly halved progression of proteinuria but did not alter the GFR decline. 10,11 The present study asked whether the institution of RAS blockade prior to the onset of albuminuria in patients with type 1 diabetes mellitus (T1DM) could slow progression of early DN histologic lesions and was based on the concept that slowing the structural changes responsible for renal dysfunction in diabetes 2,3 would delay or prevent clinical DN.…”