A new model of diabetic nephropathy in type 1 diabetes emerged from our studies of Joslin Clinic patients. The dominant feature is progressive renal decline, not albuminuria. This decline is a ...unidirectional process commencing while patients have normal renal function and, in the majority, progressing steadily (linearly) to end-stage renal disease (ESRD). While an individual’s rate of renal decline is constant, the estimated glomerular filtration rate (eGFR) slope varies widely among individuals from –72 to –3.0 ml/min/year. Kidney Disease: Improving Global Outcomes guidelines define rapid progression as rate of eGFR declines > 5 ml/min/year, a value exceeded by 80% of patients in Joslin’s type 1 diabetes ESRD cohort. The extraordinary range of slopes within the rapid progression category prompted us to partition it into “very fast,” “fast” and “moderate” decline. We showed, for the first time, that very fast and fast decline from normal eGFR to ESRD within 2 to 10 years constitutes 50% of the Joslin cohort. In this review we present data about frequency of fast decliners in both diabetes types, survey some mechanisms underlying fast renal decline, discuss methods of identifying patients at risk and comment on the need for effective therapeutic interventions. Whether the initiating mechanism of fast renal decline affects glomerulus, tubule, interstitium or vasculature is unknown. Since no animal model mimics progressive renal decline, studies in humans are needed. Prospective studies searching for markers predictive of the rate of renal decline yield findings that may make detection of fast decliners feasible. Identifying such patients will be the foundation for developing effective individualized methods to prevent or delay onset of ESRD in diabetes.
OBJECTIVE Progressive decrease in the glomerular filtration rate (GFR), or renal decline, in type 1 diabetes (T1D) is observed in patients with macroalbuminuria. However, it is unknown whether this ...decline begins during microalbuminuria (MA) or normoalbuminuria (NA). RESEARCH DESIGN AND METHODS The study group (second Joslin Kidney Study) comprises patients with T1D and NA (n = 286) or MA (n = 248) who were followed for 4-10 years (median 8 years). Serial measurements (median 6, range 3-16) of serum creatinine and cystatin C were used jointly to estimate GFR (eGFRcr-cys) and assess its trajectories during follow-up. RESULTS Renal decline (progressive eGFRcr-cys loss of at least 3.3% per year) occurred in 10% of the NA and 35% of the MA (P < 0.001). In both groups, the strongest determinants of renal decline were baseline serum concentrations of uric acid (P < 0.001) and tumor necrosis factor receptor 1 or 2 (TNFR-1 or -2, P < 0.001). Other significant risk factors included baseline HbA1c, age/diabetes duration, and systolic blood pressure. Relative impacts of these determinants were similar in NA and MA. Renal decline was not associated with sex or baseline serum concentration of TNF-α, IL-6, IL-8, IP-10, MCP-1, VCAM, ICAM, Fas, or FasL. CONCLUSIONS Renal decline in T1D begins during NA and it is determined by multiple factors, similar to MA. Thus, this early decline is the primary disease process leading to impaired renal function in T1D. Changes in albumin excretion rate, such as the onset of MA or its progression to macroalbuminuria, are either caused by or develop in parallel to the early renal decline.
Levels of proinflammatory cytokines associate with risk for developing type 2 diabetes but whether chronic inflammation contributes to the development of diabetic complications, such as ESRD, is ...unknown. In the 1990s, we recruited 410 patients with type 2 diabetes for studies of diabetic nephropathy and recorded their characteristics at enrollment. During 12 years of follow-up, 59 patients developed ESRD (17 per 1000 patient-years) and 84 patients died without ESRD (24 per 1000 patient-years). Plasma markers of systemic inflammation, endothelial dysfunction, and the TNF pathway were measured in the study entry samples. Of the examined markers, only TNF receptors 1 and 2 (TNFR1 and TNFR2) associated with risk for ESRD. These two markers were highly correlated, but ESRD associated more strongly with TNFR1. The cumulative incidence of ESRD for patients in the highest TNFR1 quartile was 54% after 12 years but only 3% for the other quartiles (P<0.001). In Cox proportional hazard analyses, TNFR1 predicted risk for ESRD even after adjustment for clinical covariates such as urinary albumin excretion. Plasma concentration of TNFR1 outperformed all tested clinical variables with regard to predicting ESRD. Concentrations of TNFRs moderately associated with death unrelated to ESRD. In conclusion, elevated concentrations of circulating TNFRs in patients with type 2 diabetes at baseline are very strong predictors of the subsequent progression to ESRD in subjects with and without proteinuria.
We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We ...obtained further support for 4q27 (IL2-IL21, P = 1.9 x 10(-8)) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 x 10(-12)), 10p15 (PRKCQ, P = 3.7 x 10(-9)), 15q24 (CTSH, P = 3.2 x 10(-15)) and 22q13 (C1QTNF6, P = 2.0 x 10(-8)).
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Elevated plasma concentrations of TNF receptors 1 and 2 (TNFR1 and TNFR2) predict development of ESRD in patients with type 2 diabetes without proteinuria, suggesting these markers may contribute to ...the pathogenesis of renal decline. We investigated whether circulating markers of the TNF pathway determine GFR loss among patients with type 1 diabetes. We followed two cohorts comprising 628 patients with type 1 diabetes, normal renal function, and no proteinuria. Over 12 years, 69 patients developed estimated GFR less than 60 mL/min per 1.73 m(2) (16 per 1000 person-years). Concentrations of TNFR1 and TNFR2 were strongly associated with risk for early renal decline. Renal decline was associated only modestly with total TNFα concentration and appeared unrelated to free TNFα. The cumulative incidence of estimated GFR less than 60 mL/min per 1.73 m(2) for patients in the highest TNFR2 quartile was 60% after 12 years compared with 5%-19% in the remaining quartiles. In Cox proportional hazards analysis, patients with TNFR2 values in the highest quartile were threefold more likely to experience renal decline than patients in the other quartiles (hazard ratio, 3.0; 95% confidence interval, 1.7-5.5). The risk associated with high TNFR1 values was slightly less than that associated with high TNFR2 values. TNFR levels were unrelated to baseline free TNFα level and remained stable over long periods within an individual. In conclusion, early GFR loss in patients with type 1 diabetes without proteinuria is strongly associated with circulating TNF receptor levels but not TNFα levels (free or total).
The patterns of estimated glomerular filtration rate (eGFR) decline to end-stage renal disease (ESRD) in patients with type 1 diabetes has not been conclusively described. Decline could be linearly ...progressive to ESRD but with a variable rate. Conversely, decline may be linear but interrupted by periods of plateaus or improvements.
This observational study included 364 patients with type 1 diabetes attending the Joslin Clinic who developed ESRD between 1991 and 2013. We retrieved serum creatinine measurements from clinic visits or research examinations up to 24 years (median 6.7 years) preceding the onset of ESRD. Using serial measurements of serum creatinine to estimate renal function (eGFR), we used regression-based spline methods and a data smoothing approach to characterize individual trajectories of eGFR over time for the 257 patients with five or more data points.
The rate of eGFR decline per year ranged widely, from -72 to -2 mL/min/1.73 m
(median -8.5). The trajectories, as characterized with linear regression-based spline models, were linear or nearly so for 87% of patients, accelerating for 6%, and decelerating for 7%. Smoothed trajectories evaluated by a Bayesian approach did not significantly depart from a linear fit in 76%.
The decline of eGFR in type 1 diabetes is predominantly linear. Deviations from linearity are small, with little effect on the expected time of ESRD. A single disease process most likely underlies renal decline from its initiation and continues with the same intensity to ESRD. Linearity of renal decline suggests using slope reduction as the measure of effectiveness of interventions to postpone ESRD.
Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case–control study evaluated 40 cases ...who progressed to ESRD during 8–12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry–based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid–derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.
Progressively decreasing glomerular filtration rate (GFR), or renal decline, is seen in patients with type 1 diabetes (T1D) and normoalbuminuria or microalbuminuria. Here we examined the associations ...of kidney injury molecule-1 (KIM-1) in plasma and urine with the risk of renal decline and determine whether those associations are independent of markers of glomerular damage. The study group comprised patients with T1D from the 2nd Joslin Kidney Study of which 259 had normoalbuminuria and 203 had microalbuminuria. Serial measurements over 4 to 10 years of follow-up (median 8 years) of serum creatinine and cystatin C were used jointly to estimate eGFRcr-cys slopes and time of onset of CKD stage 3 or higher. Baseline urinary excretion of IgG2 and albumin were used as markers of glomerular damage, and urinary excretion of KIM-1 and its plasma concentration were used as markers of proximal tubular damage. All patients had normal renal function at baseline. During follow-up, renal decline (eGFRcr-cys loss 3.3% or more per year) developed in 96 patients and 62 progressed to CKD stage 3. For both outcomes, the risk rose with increasing baseline levels of plasma KIM-1. In multivariable models, elevated baseline plasma KIM-1 was strongly associated with risk of early progressive renal decline, regardless of baseline clinical characteristics, serum TNFR1 or markers of glomerular damage. Thus, damage to proximal tubules may play an independent role in the development of early progressive renal decline in non-proteinuric patients with T1D.
We sought to study new-onset microalbuminuria, its progression, and the decline of renal function in patients with type 1 diabetes. Using a cohort of 109 patients who developed new-onset ...microalbuminuria in the first 4 years following enrollment in the 1st Joslin Kidney Study, we simultaneously tracked the change in their renal function and urinary albumin excretion. Of these, 79 patients were followed for an average of 12 years after microalbuminuria onset, wherein their glomerular filtration rate was estimated by the Modification of Diet in Renal Disease Study formula and compared with their microalbuminuria and proteinuria. The concordance between these outcomes was weak. Only 12 of the 23 patients who progressed to advanced (stage 3–5) chronic kidney disease developed proteinuria, which, in general, did not precede but accompanied the progression to advanced chronic kidney disease. The remaining 11 patients who developed advanced disease had persistent microalbuminuria or returned to normal albuminuria. Thus, we found that one-third of patients with type 1 diabetes developed advanced chronic kidney disease relatively soon after the onset of microalbuminuria and this was 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 placed on mechanisms initiating and promoting the early decline of renal function that eventually progresses to advanced chronic kidney disease.
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