High risk of ESRD in type 1 diabetes: new strategies are needed to retard progressive renal function decline

Abstract

Care of patients with type 1 diabetes (T1D) has changed during the past 30 years. Tools to control hyperglycemia have improved and it was shown that improvement in glycemic control diminished the risk of late diabetic complications, including nephropathy. Moreover, in patients with impaired renal function, aggressive treatment of hypertension and renoprotective blockade of the renin-angiotensin system were shown to postpone end-stage renal disease (ESRD), albeit for a short while. Despite these achievements, the incidence of ESRD caused by T1D in the US population has not decreased but rather has increased over the past 20 years, although it now occurs at slightly older ages. This state of affairs is a call to action. This should begin with adopting a new model of diabetic nephropathy in human beings. In that model, instead of microalbuminuria or proteinuria, the focus should be on diagnosis and treatment of progressive renal function decline that leads to ESRD. Such a model has received significant support in clinical and epidemiologic studies. Investigation of mechanisms of such progressive renal function decline should help in the identification of new therapeutic targets and the development of new interventions. To evaluate these interventions, accurate diagnostic algorithms are needed so T1D patients will be stratified according to time to onset to ESRD. Consistent with concepts of personalized medicine, the new interventions should be tailored to and evaluated in patients predicted to have rapid, moderate, or even slow progression to ESRD.

Figure 1

Number of incident cases of ESRD in the US Caucasian population attributed to T1D according to calendar time and age at ESRD onset. Arrows indicate publication of the DCCT and the Collaborative Study. Because data on the number of patients with T1D duration >15 years (and therefore at risk of ESRD) in the US population are not available, an incidence rate was not computed. (Reproduce from ref. #24)

Figure 2

Cumulative risk of ESRD according to follow-up time and cohort and according to calendar time of entry into follow-up in the Joslin cohort (Data adapted from ref. #24) and in the FinnDiane cohort (data adapted from ref. #25).

Figure 3. Trajectories of renal function changes in patients with T1D and new onset microalbuminuria who were followed for 12 years

MA onset – 2 year interval during which multiple determinations of ACR became elevated; E – date when ESRD was diagnosed; eGFRcyst – glomerular filtration rate estimated from serial measurements of serum cystatin C. At the end of follow-up numbers of patients with various categories of AER are reported: NA – normoalbuminuria, MA - microalbuminuria, Prot – proteinuria. Panel A shows patients with early progressive renal function decline (decliners). eGFRcyst slopes in these patients were faster than −3.3% ml/min/year. Panel B shows patients with stable renal function (non-decliners). eGFRcyst slopes of these patients were slower than −3.3% per/min/year. Figure adapted from reference # and supplemented with unpublished data about patients who developed ESRD.

Figure 4. Examples of trajectories of changes in renal function in patients with T1D and proteinuria

Upper row: For the patient in Panel 4A, eGFR loss was 52.5 ml/min/year and renal function progressed from normal to ESRD within 2 years. For the patient in Panel 4B, eGFR loss was 20 ml/min/year and renal function progressed from normal to ESRD within 6 years. For the patient in panel 4C, eGFR loss was 4ml/min/year, and renal functiont is estimated to progress from normal to ESRD within 20 years. Lower row: The eGFR loss in this patient represents the median of the distribution of eGFR loss in a large cohort of patients with proteinuria who entered observation with normal renal function and were followed for 5–18 years (Adapted from reference # 29)

Figure 5

New model of progressive diabetic nephropathy in T1D. Urinary albumin excretion increases in progressively smaller subsets and also regresses, while progressive renal function decline develops early in a subset of microalbuminurics and proteinurics and almost always progresses to ESRD.

Figure 6

Cumulative risk of CKD≥3 in patients with T1D during 12 years of follow-up according to quartile (Q1–Q4) of circulating TNFR2 at baseline. (Figure reprinted from ref. # 34)