In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria

Abstract

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.

Figure 1. Serial Estimates of GFR_MDRD (3) in ml/min/1.73m² and of Urinary Albumin Excretion Rate (▲) in μg per minute for Three Representative Cases of End Stage Renal Disease

Panel A describes the clinical course of an individual who was followed for approximately four years before the onset of microalbuminuria. After 8.8 years from the onset of microalbuminuria, end stage renal disease occurred (indicated by “E”). Although end stage renal disease was preceded by proteinuria, the fifth estimate of GFR_MDRD indicates that renal function had already begun to decline soon after the onset of microalbuminuria. The sixth estimate of GFR_MDRD was below 60 ml/min/1.73m² despite short duration of exposure to proteinuria. Panel B describes a case that had decline in GFR_MDRD to a level near 60 ml/min/1.73m² during the course of microalbuminuria. Panel C describes another case of end stage renal disease preceded by proteinuria. However, after only very short exposure to proteinuria the GFR_MDRD had declined to a level below 60 ml/min/1.73m². Evidence that decline in GFR_MDRD had begun soon after the onset of microalbuminuria was evident for 5 of the 6 cases of end stage renal disease (as in Panels A and B). The arrows indicate the time of initiation of angiotensin converting enzyme inhibitor agents.

Figure 2. Serial Estimates of GFR_MDRD (3) in ml/min/1.73m² and of Urinary Albumin Excretion Rate (▲) in μg per minute for Three Representative Cases of Stage 3–4 Chronic Kidney Disease

Panel A shows the clinical course of GFR_MDRD for a case of stage 4 chronic kidney disease that developed proteinuria. Panel B describes the course for a subject who developed Stage 3 chronic kidney disease but who had stable levels of urinary albumin excretion rate in the microalbuminuria range without developing proteinuria. Panel C describes the course of a subject with Stage 3 chronic kidney disease despite remission of urinary albumin excretion to normoalbuminuria levels. In all of these three examples, the initiation of renal function decline clearly occurred during microalbuminuria-range albumin excretion. The arrows indicate the time of initiation of angiotensin converting enzyme inhibitor agents.