Systematic study of the course of renal function decline and progression to proteinuria in patients with type 1 diabetes and new onset microalbuminuria has not been reported. From the 1080 participants with normoalbuminuria enrolled in the 1st Joslin Kidney Study, we identified 109 who developed new onset microalbuminuria in the first four years of observation and followed 79 for a subsequent 12.4±1.4 years to estimate glomerular filtration rate by the four-variable MDRD formula (GFRMDRD) and the course of microalbuminuria. 12–year cumulative risk of advanced chronic kidney disease (CKD)[defined by GFRMDRD<60ml/min/1.73m2] and proteinuria were 23(29%) and 21(27%). However, concordance between these outcomes was weak. Only 12 of the 23 subjects (52%) who developed advanced CKD had progression to proteinuria. Furthermore, this progression generally did not precede but rather accompanied the development of advanced CKD. The remaining 11(48%) subjects who developed advanced CKD experienced only persistent microalbuminuria (8 subjects) or regressed to normoalbuminuria (3 subjects). In conclusion, risk of advanced CKD approaches one-third early after microalbuminuria onset and its development is not conditional on the presence of proteinuria. Contrary to the existing concept of early nephropathy in type 1 diabetes, less emphasis should be placed on the mechanisms of progression to proteinuria and more on the mechanisms initiating and promoting early renal function decline that leads to advanced CKD.

Historically, patients with type 1 diabetes and macroalbuminuria had high competing risks: cardiovascular death or renal failure. Here, we assessed these risks in patients receiving therapies implemented during the last 30 years. Between 1991 and 2004, we enrolled 423 white patients with type 1 diabetes who developed macroalbuminuria (albumin excretion rate, Ն300 g/min). With follow-up for 98% through 2008, ESRD developed in 172 patients (incidence rate, 5.8/100 person-years), and 29 died without ESRD (mortality rate, 1/100 person-years). The majority of these outcomes occurred between ages 36 and 52 years with durations of diabetes of 21 to 37 years. The 15-year cumulative risks were 52% for ESRD and 11% for pre-ESRD death. During the 15 years of follow-up, the use of renoprotective treatment increased from 56 to 82%, and BP and lipid levels improved significantly; however, the risks for both ESRD and pre-ESRD death did not change over the years analyzed. There were 70 post-ESRD deaths, and the mortality rate was very similar during the 1990s and the 2000s (11/100 person-years versus 12/100 person-years, respectively). Mortality was low in patients who received a pre-emptive kidney transplant (1/100 person-years), although these patients did not differ from dialyzed patients with regard to predialysis eGFR, sex, age at onset of ESRD, or duration of diabetes. In conclusion, despite the widespread adoption of renoprotective treatment, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD, suggesting that more effective therapies are desperately needed.

Background and objectives: The aim of our study was to examine serum markers of the TNF and Fas pathways for association with cystatin-C based estimated glomerular filtration rate (cC-GFR) in subjects with type 1 diabetes (T1DM) and no proteinuria. Results: Of these, TNF␣, sTNFRs, sFas, sICAM-1, and sIP10 were associated with cC-GFR. However, only the TNF receptors and sFas were associated with cC-GFR in multivariate analysis. Variation in the concentration of the TNF receptors had a much stronger impact on GFR than clinical covariates such as age and albumin excretion.Conclusions: Elevated concentrations of serum markers of the TNF␣ and Fas-pathways are strongly associated with decreased renal function in nonproteinuric type 1 diabetic patients. These effects are independent of those of urinary albumin excretion. Follow-up studies are needed to characterize the role of these markers in early progressive renal function decline.

Background and objectives: Early renal function decline begins before the onset of proteinuria in patients with type 1 diabetes. The association of elevated serum uric acid with advanced impaired renal function prompts an examination of its role in early renal function decline in patients before proteinuria develops.Design, setting, participants, & measurements: Patients with type 1 diabetes and normoalbuminuria or microalbuminuria were recruited to the Second Joslin Kidney Study. A medical history and measurements of BP, hemoglobin A1c, albumin excretion rate, and serum concentrations of uric acid and cystatin C were obtained. Estimated glomerular filtration rate was measured by a cystatin C-based formula.Results: We studied 364 patients with normoalbuminuria and 311 patients with microalbuminuria. Mean glomerular filtration rate in these groups was 119 and 99 ml/min, respectively. Mildly or moderately impaired renal function (<90 ml/min) was present in 10% of those with normoalbuminuria and 36% of those with microalbuminuria. In univariate and multivariate analyses, lower glomerular filtration rate was strongly and independently associated with higher serum uric acid and higher urinary albumin excretion rate, older age, and antihypertensive treatment.Conclusions: Serum uric acid concentration in the high-normal range is associated with impaired renal function in patients with type 1 diabetes. Follow-up studies are needed to confirm that this level of serum uric acid is a risk factor for early renal function decline in type 1 diabetes and to determine whether its reduction would prevent the decline.