Local miscommunications between glomerular cells as potential therapeutic targets for crescentic glomerulonephritides.

Necrotizing and crescentic rapidly progressive glomerulonephritis or crescentic glomerulonephritis is one of the severest forms of acquired glomerular diseases with significant mortality. Risk of end-stage renal failure at 5 years is near 30%, with a number of patients developing chronic kidney disease. Currently, autoimmune crescentic glomerulonephritides are treated with broad-spectrum immunosuppression inducing remission of the injury in the majority of patients. However, treatment is associated with significant side effects and by the time remission is achieved the majority of patients have developed renal tissue damage and significant impairment of their kidney function with a steep slope of deterioration within the first weeks following initiation of immunosuppression. It is therefore important to develop complementary strategies that would be immediately active on the common process of destructive epithelial processes. We have worked to identify the major cellular pathways contributing to glomerular destruction in this context by a systematic comparison of patient tissues and experimental models. Our studies demonstrate the pivotal role of local intra- and intercellular communications in orchestrating the global glomerular tolerance to a severe rapidly progressive glomerulonephritis model with excellent anatomoclinical correlative expressions in kidney biopsies of individuals diagnosed with crescentic glomerulonephritis, irrespectively of the causal immune disorder. We hope that such approaches deciphering mechanisms of cellular adaptation that underlie kidney damage control in response to vasculitides, integrating both stress and damage responses, will delineate novel complementary therapies.

Association of kidney function, vitamin D deficiency, and circulating markers of mineral and bone disorders in CKD.

BACKGROUND: Vitamin D (25 hydroxyvitamin D [25(OH)D]) deficiency is common in patients with chronic kidney disease (CKD). Neither the relation of this deficiency to the decrease in glomerular filtration rate (GFR) nor the effects on CKD mineral and bone disorders (MBD) are clearly established. STUDY DESIGN: Cross-sectional analysis of baseline data from a prospective cohort, the NephroTest Study. SETTING & PARTICIPANTS: 1,026 adult patients with all-stage CKD not on dialysis therapy or receiving vitamin D supplementation. PREDICTORS: For part 1, measured GFR (mGFR) using (51)Cr-EDTA renal clearance; for part 2, 25(OH)D deficiency at <15 ng/mL. OUTCOMES & MEASUREMENTS: For part 1, 25(OH)D deficiency and several circulating MBD markers; for part 2, circulating MBD markers. RESULTS: For part 1, the prevalence of 25(OH)D deficiency was associated inversely with mGFR, ranging from 28%-51% for mGFR ≥60-<15 mL/min/1.73 m(2). It was higher in patients of African origin; those with obesity, diabetes, hypertension, macroalbuminuria, and hypoalbuminemia; and during winter. After adjusting for these factors, ORs for 25(OH)D deficiency increased from 1.4 (95% CI, 0.9-2.3) to 1.4 (95% CI, 0.9-2.1), 1.7 (95% CI, 1.1-2.7), and 1.9 (95% CI, 1.1-3.6) as mGFR decreased from 45-59 to 30-44, 15-29, and <15 (reference, ≥60) mL/min/1.73 m(2) (P for trend = 0.02). For part 2, 25(OH)D deficiency was associated with higher age-, sex-, and mGFR-adjusted ORs of ionized calcium level <1.10 mmol/L (2.6; 95% CI, 1.2-5.9), 1,25 dihydroxyvitamin D concentration <16.7 pg/mL (1.8; 95% CI, 1.3-2.4), hyperparathyroidism (1.8; 95% CI, 1.3-2.4), and serum C-terminal cross-linked collagen type I telopeptides concentration >1,000 pg/mL (1.6; 95% CI, 1.0-2.6). It was not associated with hyperphosphatemia (phosphate >1.38 mmol/L). LIMITATIONS: Cross-sectional analysis of the data prevents causal inferences. CONCLUSIONS: 25(OH)D deficiency is related independently to impaired mGFR. Both mGFR decrease and 25(OH)D deficiency are associated with abnormal levels of circulating MBD biomarkers.

Oxalate nephropathy associated with chronic pancreatitis.

BACKGROUND AND OBJECTIVES: Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis-associated AON followed in four French renal units. RESULTS: Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. CONCLUSION: AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented.