Microalbuminuria and the Risk for Early Progressive Renal Function Decline in Type 1 Diabetes

Perkins, Bruce A.; Ficociello, Linda H.; Ostrander, Betsy; Silva, Kristen H.; Weinberg, Janice; Warram, James H.; Królewski, Andrzej S.

doi:10.1681/asn.2006080872

Cited by 328 publications

(332 citation statements)

References 52 publications

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“…In Pima Indians with type 2 diabetes, RFD occurs frequently before the onset of macroalbuminuria, as it does in type 1 diabetes (3)(4)(5). Progression to ESRD, however, is strongly dependent on progression to macroalbuminuria.…”

Section: Discussionmentioning

confidence: 99%

“…Such a decline can occur at any level of albuminuria, but typically appears shortly after the onset of microalbuminuria (4,5). This early renal function decline (RFD) was defined arbitrarily as a decline in the GFR .3.3%/yr, a threshold corresponding to the 97.5 percentile of the distribution of the decline in creatinine clearance in nondiabetic normotensive Caucasians in the Baltimore Longitudinal Study on Aging (6).…”

Section: Introductionmentioning

confidence: 99%

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Early Renal Function Decline in Type 2 Diabetes

Pavkov

Knowler

Lemley

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Early decline in GFR may reflect progressive kidney disease in type 1 diabetes, but its predictive value in type 2 diabetes is uncertain.Design, setting, participants, & measurements In this longitudinal study, GFR was measured serially over approximately 4.0 years in 195 Pima Indians with type 2 diabetes. Renal function decline (RFD) was defined during this initial period by an average GFR loss $3.3%/yr, as defined previously in type 1 diabetes. Subsequently, participants were followed for up to 17.8 years to ESRD onset, death, or December 31, 2010, whichever came first.Results RFD prevalence during the initial period was 32% in 68 participants with normal baseline albuminuria (albumin/creatinine ratio [ACR] , 30 mg/g), 42% in 88 with microalbuminuria (ACR 30 to ,300 mg/g), and 74% in 39 with macroalbuminuria (ACR $300 mg/g; P,0.001). The cumulative incidence of ESRD 10 years after the initial period was 41% in those with RFD and 15% in those without (P,0.001); 41 of the 49 ESRD cases (83.7%) occurred in participants who had or developed macroalbuminuria during the initial period. When adjusted for age, sex, diabetes duration, and hemoglobin A1c, the ESRD hazard rate was 4.78 times (95% confidence interval, 2.39-9.58) as high in those with RFD as in those without; further adjustment for albuminuria attenuated this association (hazard ratio, 1.79; 95% confidence interval, 0.82-3.91).Conclusions In type 2 diabetes, loss of GFR often occurs before the onset of macroalbuminuria, but a decline predictive of ESRD is strongly dependent on progression to macroalbuminuria.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early Renal Function Decline in Type 2 Diabetes

Pavkov

Knowler

Lemley

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…The most profound effect of the combination therapy is the complete prevention of albuminuria in the diabetic mice without a significant change of the blood glucose. Microalbuminuria is a major risk factor for progressive renal function decline in diabetic nephropathy (41) and is thought to be the first step in an inevitable progression to proteinuria and renal failure (42,43). Thus, reduction of albuminuria is a major target for renoprotective therapy in both type 1 and type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Zhang

Ning

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

261

225

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The renin-angiotensin system (RAS) plays a critical role in the development of diabetic nephropathy, and blockade of the RAS is currently used for treatment of diabetic nephropathy. One major problem for the current RAS inhibitors is the compensatory renin increase, which reduces the efficacy of RAS inhibition. We albuminuria ͉ glomerulosclerosis ͉ renin-angiotensin system D iabetic nephropathy is the most common renal complication that often leads to end-stage kidney disease and high mortality (1). Previous studies have suggested the renin-angiotensin system (RAS) as a major mediator of progressive renal injury in diabetic nephropathy. Drugs targeting the RAS including angiotensin (Ang)-converting enzyme inhibitors (ACEIs) and Ang II type 1 receptor blockers (ARBs) have been shown to reduce the progression of glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria (2-6). The systemic components of the RAS are actually down-regulated in diabetic mellitus (7), whereas renal interstitial Ang II levels are estimated to be 1,000-fold higher than in the plasma (8); therefore, intrarenal RAS is thought to play the major damaging role. In fact, all components of the RAS are present within the kidney (9). Cells in the kidney are able to synthesize renin, prorenin/renin receptor (10), angiotensinogen, and Ang II receptors independent of the systemic RAS (11), making the kidney capable of maintaining a high level of intrarenal Ang II. Intrarenal renin and angiotensinogen levels are induced in diabetic animals (12, 13), and high glucose has been shown to stimulate renin and Ang II synthesis in mesangial cells and podocytes (14-16). Intrarenal Ang II exerts multiple effects on the kidney that promote the progression of renal injury; these include an increase in glomerular capillary pressure, induction of profibrotic and proinflammatory cytokine production, promotion of immune cell infiltration, stimulation of cell proliferation and hypertrophy, up-regulation of extracellular matrix (ECM) synthesis, and damaging of podocytes (17)(18)(19) (21), and null mutant mice lacking the vitamin D receptor (VDR) gene develop hyperreninemia, high blood pressure, and cardiac hypertrophy (22)(23)(24). Our recent studies showed that in diabetic state VDR-null mice developed more severe nephropathy than wild-type mice (25), suggesting that vitamin D plays a protective role against hyperglycemia-induced renal injury by regulation of the RAS. However, whether vitamin D or vitamin D analogs have therapeutic effects in intervention or prevention of diabetic nephropathy remains to be tested.Although RAS inhibitors, including ACEIs and ARBs, are widely used in the therapy of renal and cardiovascular diseases, the major problem of these drugs is the compensatory renin rise due to the disruption of the feedback inhibition of renin production (26). The increase in renin activity stimulates the conversion of Ang I and ultimately Ang II, which largely limits the efficacy of RAS inhibition (27,28). The increased renin can also act through the...

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“…DK41526) (20). Details of the selection criteria, methods, and follow-up have been previously published (20)(21)(22)24), with an abbreviated description provided here. From January 1991 to April 1992, a 50% sample of patients with type 1 diabetes at the Joslin Diabetes Center, aged 15-44 years, were screened for albuminuria using the urinary albumin excretion rate (AER).…”

Section: Selection Of Study Participantsmentioning

confidence: 99%

“…Although it was not the primary objective, baseline HRV data were measured in a subset of patients who have had subsequent long-term follow-up for renal outcome measures; this cohort design provides a unique opportunity to reconcile the relationship between HRV and future DN risk. In the current study, we aimed to determine the relationship between cardiac autonomic neuropathy and early progressive renal decline (EPRD), including the development of early GFR loss (22) and advanced CKD (23), among nonmacroalbuminuric patients with type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

Orlov

Cherney

Pop‐Busui

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes.Design, setting, participants, & measurements A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) ,20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C ,23.3%/year) and incident advanced CKD (stage $3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] ,60 ml/min per 1.73 m 2 ). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards.Results Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P,0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P,0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002).Conclusions Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.

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Microalbuminuria and the Risk for Early Progressive Renal Function Decline in Type 1 Diabetes

Cited by 328 publications

References 52 publications

Early Renal Function Decline in Type 2 Diabetes

Early Renal Function Decline in Type 2 Diabetes

Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: Blockade of compensatory renin increase

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

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