Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m 2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r ‫؍‬ 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.

Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.

Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from ten kidney donors (not Americans Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study.

ResultsResponse to donor nephrectomy in healthy humans. Twenty-one subjects underwent clinical, physiological, and radiological assessments immediately before, early after (median, 0.8 years), and late after (median, 6.1 years) (hereafter, pre-donation, early post-donation, and late post-donation) living kidney donation. A morphometric evaluation of glomeruli was performed on renocortical tissue that was obtained by wedge biopsy at the time of donor nephrectomy in 19 subjects. Baseline demographic, physio-BACKGROUND. Over 5,000 living kidney donor nephrectomies are performed annually in the US. While the physiological changes that occur early after nephrectomy are well documented, less is known about the long-term glomerular dynamics in living donors. METHODS.We enrolled 21 adult living kidney donors to undergo detailed long-term clinical, physiological, and radiological evaluation pre-, early post-(median, 0.8 years), and late post-(median, 6.3 years) donation. A morphometric analysis of glomeruli obtained during nephrectomy was performed in 19 subjects.RESULTS. Donors showed parallel increases in single-kidney renal plasma flow (RPF), renocortical volume, and glomerular filtration rate (GFR) early after the procedure, and these changes were sustained through to the late post-donation period. We used mathematical modeling to estimate the glomerular ultrafiltration coefficient (K f ), which also increased early and then remained constant through the late post-donation study. Assuming that the filtration surface area (and hence, K f ) increased in proportion to renocortical volume after donation, we calculated that the 40% elevation in the single-kidney GFR observed after donation could be attributed exclusively to an increase in the K f . The prevalence of hypertension in donors increased from 14% in the early post-donation period to 57% in the late post-donation period. No subjects exhibited elevated levels of albuminuria. CONCLUSIONS.Adaptive hyperfiltration after donor nephrectomy is attributable to hyperperfusion and hypertrophy of the remaining glomeruli. Our findings point away from the development of glomerular hypertension following kidney donation.

We conclude that a reduction in overall, two-kidney Kf contributes to GFR depression in aging subjects. We infer that this is due in part to structural changes that lower SNKf, and in part to the reduction in the actual number of functioning glomeruli that has been demonstrated by others at autopsy.