Background It is controversial whether proteinuria is a valid surrogate endpoint for randomized trials in chronic kidney disease. Study Design Meta-analysis of individual patient level data. Setting & Population Individual patient data on 9008 patients from 32 randomized trials evaluating five intervention types. Selection Criteria for Studies Randomized controlled trials of kidney disease progression until 2007 with measurements of proteinuria both at baseline and during the first year of follow-up, with at least one further year of follow-up for the clinical outcome. Predictor Early change in proteinuria. Outcomes Doubling of serum creatinine, end stage renal disease or death. Results Early decline in proteinuria was associated with a lower risk of the clinical outcome (pooled HR, 0.74 per 50% reduction in proteinuria); this association was stronger at higher levels of baseline proteinuria. Pooled estimates for the proportion of treatment effect on the clinical outcome explained by early decline in proteinuria ranged from −7.0% (95% CI, −40.6% to 26.7%) to 43.9% (95% CI, 25.3% to 62.6%) across five intervention types. The direction of the pooled treatment effects on early change in proteinuria agreed with the direction of the treatment effect on the clinical outcome for all 5 intervention types, with the magnitudes of the pooled treatment effects on the two endpoints agreeing for 4 of the 5 intervention types. The pooled treatment effects on both endpoints were simultaneously stronger at higher levels of proteinuria. However, statistical power was insufficient to determine if differences in treatment effects on the clinical outcome corresponded to differences in treatment effects on proteinuria between individual studies. Limitations Limited variety of interventions tested and low statistical power for many chronic kidney disease clinical trials. Conclusions These results provide new evidence supporting the use of an early reduction in proteinuria as a surrogate endpoint, but do not provide sufficient evidence to establish its validity in all settings.

. Longitudinal study of urinary excretion of phosphate, calcium, and uric acid in mutant NHERF-1 null mice. Am J Physiol Renal Physiol 290: F838 -F843, 2006. First published October 25, 2005 doi:10.1152/ajprenal.00374.2005.-NHERF-1 binds numerous renal protein targets, including the proximal tubule transporters Na ϩ /H ϩ exchanger 3 (NHE3) and Na ϩ -phosphate cotransporter 2a (Npt2a). Young NHERF-1 Ϫ/Ϫ male mice display defective targeting of Npt2a to apical membranes in the renal proximal tubule and manifest hypophosphatemia and increased urinary excretion of phosphate. The present studies describe the changes in the urinary excretion of phosphate, calcium, uric acid, and sodium in male and female wild-type and NHERF-1 null mice over a time period from 12 to 54 wk of age. Young male and female NHERF-1 Ϫ/Ϫ mice demonstrated increased urinary excretion of phosphate and urine phosphate/creatinine ratios. There was an age-related decline in the phosphate/ creatinine ratio in mutant mice such that there were no differences between wild-type and NHERF-1 Ϫ/Ϫ by 24 to 30 wk of age despite the continued presence of hypophosphatemia. Male and female NHERF-1 null mice also demonstrate increased urine calcium/creatinine and uric acid/creatinine ratios compared with wild-type controls. These studies indicate defects in the renal tubule transport of phosphate, calcium, and uric acid in NHERF-1 Ϫ/Ϫ male and female mice that could account for the increased deposition of calcium in the papilla of null mice. bone density and mineralization; hypophosphatemia; electrolyte excretion INACTIVATION OF THE GENE encoding the sodium-phosphate cotransporter 2a (Npt2a, NaPi IIa) results in increased urinary excretion of phosphate and calcium and a striking bone phenotype characterized by decreased bone density and mineralization (2). Interestingly, by mechanisms not well understood, the changes in bone resolve as the animals age. It has not been established, however, whether the changes in mineral excretion persist. Like the Npt2a null mouse, targeted gene deletion of the sodium-hydrogen exchanger regulator factor-1 (NHERF-1) results in animals with increased urinary excretion of phosphate and calcium (14). The present experiments were undertaken to determine whether there were age-related changes in the urinary excretion of phosphate, calcium, uric acid, and sodium in NHERF-1 Ϫ/Ϫ male and female animals. The results indicate that young male and female NHERF-1 null mice have increased urinary excretion of phosphate but that there is an age-related partial correction in the defect in phosphate transport. Both male and female NHERF-1 null mice also have increased urinary excretion of calcium and uric acid but, in contrast to the defect in phosphate excretion, the abnormalities persist throughout the period of observation up to 1 yr of age. The transient as well as the persistent changes in urinary mineral and electrolyte excretion in these mice predict urine prone to the formation of calcium and/or uric acid stones. Analysis of the mutant m...

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Background Nephrotic syndrome is defined as urine total protein >3.5 g/d or total protein-creatinine ratio of >3.5 g/g, low serum albumin, high serum cholesterol, and peripheral edema. These threshold levels have not been rigorously evaluated in diabetic kidney disease or using urine albumin, the preferred measure of proteinuria in diabetes. Study Design Diagnostic test study Setting and Participants Adults with type 2 diabetes, hypertension and urine total protein >0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial. Index Test Baseline measures of proteinuria (total protein, albumin, and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures. Reference Test Other signs and symptoms of nephrotic syndrome at baseline (serum albumin <3.5g/dl, serum total cholesterol >260mg/dl or use of a statin, edema or use of a loop diuretic); progression of chronic kidney disease during follow up (doubling of baseline serum creatinine or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests. Results Among 1608 participants, total urine protein of 3.5 g/d was equivalent to urine albumin of 2.2 (95% confidence interval 1.4–3.5) g/d. Of 1467 participants, 641 (44%) had urine total protein ≥3.5 g/d at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline and 385 (26%) had progression of kidney disease over a mean follow-up interval of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. The threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes. Limitations Study population limits generalizability; inability to adjust for several variables known to affect serum albumin; lack of spot urine samples Conclusions The historical definition for nephrotic-range proteinuria appears reasonable in diabetic kidney disease. The equivalent thresholds for nephrotic-range albuminuria and albumin-creatinine ratio are 2.2 g/d and 2.2 g/g, respectively.

There are a relatively small number of RCTs designed to rigorously test therapies for kidney disease progression. Current analyses of change in proteinuria as a predictor of CKD progression are heterogeneous and incomplete, indicating further evaluation in a pooled individual patient-level database is necessary to advance knowledge in this field.