Prediction of ESRD in pauci-immune necrotizing glomerulonephritis: quantitative histomorphometric assessment and serum creatinine.

BACKGROUND: Clinical and pathologic features that predict outcome have important potential application in patients with pauci-immune necrotizing glomerulonephritis (usually antineutrophil cytoplasmic antibody-associated vasculitis). This study examines the predictive value of simple quantitative renal histologic measurements in a large cohort with extended follow-up. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 390 consecutive patients with pauci-immune necrotizing glomerulonephritis at a single hospital (1983-2002); 90 patients underwent repeated kidney biopsy during follow-up. PREDICTORS: Age and serum creatinine concentration at biopsy, antineutrophil cytoplasmic antibody specificity, percentage of normal glomeruli, percentage of glomeruli with active lesions, and index of chronic damage (quantitative measurement of established cortical damage) in the initial kidney biopsy for all patients. The same factors were assessed in both biopsy specimens for patients undergoing an additional biopsy. OUTCOMES & MEASUREMENTS: End-stage renal disease and patient survival. RESULTS: Mortality at 1 and 5 years was 23% and 40%, respectively: standardized mortality ratio, 4.74 (95% CI, 3.62-6.32). End-stage renal disease was reached by 14% and 18% at 1 and 5 years, respectively. In multivariable analysis, serum creatinine level at biopsy and percentage of normal glomeruli in the initial biopsy specimen were the best predictors of kidney survival. C Statistics were 0.80 for creatinine level alone and 0.83 for creatinine level with normal glomeruli. In patients undergoing an additional biopsy, rapid progression in the index of chronic damage and serum creatinine level at the second biopsy were associated with kidney survival in multivariable analysis. LIMITATIONS: Retrospective analysis. External validity of the index of chronic damage requires further assessment. Selection bias may influence repeated biopsy analyses. CONCLUSIONS: Serum creatinine level at biopsy best predicts kidney survival in patients with pauci-immune necrotizing glomerulonephritis overall.

The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease.

To assess the relationship between interstitial capillary density and interstitial macrophages we prospectively measured these factors in situ in 110 patients with chronic kidney disease. Macrophage numbers and urinary MCP-1/CCL2 levels significantly correlated inversely with capillary density which itself significantly correlated inversely with chronic damage and predicted disease progression. In 54 patients with less than 20% chronic damage, there was a significant correlation between the urinary albumin to creatinine ratio and MCP-1/CCL2, and MCP-1/CCL2 and macrophages but not between MCP-1/CCL2 and capillary density. Conversely, in 56 patients with over 20% chronic damage there was no correlation between MCP-1/CCL2 and macrophages but there were significant inverse correlations between capillary density and both macrophages and chronic damage. The expression of VEGF mRNA significantly correlated with macrophage infiltration, capillary density and chronic scarring. In an ischemic-hypertensive subgroup there was upregulation of the hypoxia marker carbonic anhydrase IX and with over 20% chronic damage an increased macrophage to CCR2 ratio. Our study shows that proteinuria and MCP-1/CCL2 are important for macrophage recruitment in early disease. As renal scarring evolves, alternative pathways relating to progressive tissue ischemia secondary to obliteration of the interstitial capillary bed predominate.

Reflux nephropathy in transplants.

Reflux nephropathy, renal scarring after urine infection, typically occurs in infancy. Although vesicoureteric reflux occurs commonly in kidney allografts, grafts have not previously been regarded as likely to be affected by reflux nephropathy, perhaps because older kidneys are considered to have matured out of the risk. Evidence that adult pigs remain at risk of reflux nephropathy challenges that assumption. We therefore reviewed the pathological findings in allograft nephrectomy specimens to look for evidence of reflux nephropathy, and sought evidence of focal transplant renal scarring in paediatric recipients who had a urine infection and vesicoureteric reflux. Consecutive allograft nephrectomy specimens (146) that had been removed between 1990 and 1999 were examined for evidence of reflux nephropathy, and relevant case notes were reviewed. Also, children with a renal transplant who had a urine infection were investigated for focal scarring by dimercaptosuccinic acid (DMSA) scanning and for reflux with a cystogram. Four transplanted kidneys from adult donors that were removed from adult recipients had developed changes consistent with reflux nephropathy. Of these, 3 also had definite evidence and 1 probable evidence of a glomerulopathy associated with hyperfiltration due to reduced renal mass. All 4 patients had had recurrent urine infection and the 2 assessed had had vesicoureteric reflux. Two children with renal transplants that also had urine infections and vesicoureteric reflux to their graft were shown to have sustained focal damage on DMSA scan, confirmed as reflux nephropathy scarring on biopsy in 1 case. The grafts were aged 14.4 years and over 16 years at the time of scarring. Reflux nephropathy can occur in previously healthy adult human kidneys after transplantation. Previous studies of the effect of vesicoureteric reflux on renal allografts were not designed to assess the possibility of mild or focal scarring.