EMBRANOUS glomerulonephritis, a major cause of the nephrotic syndrome and chronic renal insufficiency, is associated with a wide spectrum of infections, cancers, autoimmune diseases, and drugs. The condition is characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, but the target antigens have not been identified. Major contributions to our current understanding of the disease come from Heymann's nephritis, a rat model of membranous glomerulonephritis induced by immunization with an antigenic fraction of the renal brush border. 1 Studies of this experimental rat model led to the identification of megalin, a unique constitutive antigen expressed on the podocyte. 2,3 Although megalin has been found in human proximal tubules, it has not been found in human glomeruli or in immune deposits in patients with membranous glomerulonephritis. 4 Dipeptidyl-peptidase IV and neutral endopeptidase are two other antigens shared by the brush border and podocytes that are involved in the formation of immune deposits in animal models; these two proteins are expressed on the human podocyte. 5,6 In this article, we report that anti-neutral endopeptidase antibodies produced by a pregnant woman were transferred to her fetus, in which a severe form of membranous glomerulonephritis developed prenatally. The mother had a deficiency of neutral endopeptidase and probably had become immunized against the antigen at the time of or after an earlier miscarriage. CASE REPORTA male infant born at 38 weeks of gestation (birth weight, 3260 g; length, 50 cm) presented with oligoanuria (urine vol-M ume, 10 ml per 24 hours), massive proteinuria (Table 1), and respiratory distress on the first day of life. His parents were unrelated, healthy persons without a family history of renal or autoimmune disease. The mother, who was 24 years old, had had a miscarriage at 14 weeks of gestation 2 months before she became pregnant with this child. Her blood pressure, findings on urinalysis, and serum creatinine concentration were normal throughout and after the pregnancy, and she took no medications. However, antenatal ultrasonography showed oligohydramnios and enlarged fetal kidneys from the 34th week of gestation. The mother's level of antineutrophil cytoplasmic antibodies, antinuclear antibodies, anti-DNA antibodies, and complement were normal.Mechanical ventilation for hypoxemia was necessary from birth to 10 days. The infant's serum creatinine concentration was 1.9 mg per deciliter (170 µmol per liter) on day 2 and peaked at 2.7 mg per deciliter (240 µmol per liter) on day 4. Diuresis increased after the administration of intravenous furosemide. The serum creatinine concentration subsequently decreased, and nephrotic-range proteinuria developed (Table 1), as did hypoalbuminemia (1.9 g per deciliter on day 7). Calcium-channel blockers and beta-blockers were needed for blood-pressure control from day 5 until 6 weeks after birth. Urinary protein excretion progressively decreased to 4.2 mg per milligram of cr...

Gitelman's syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCC). Because 18 to 40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements may account for unidentified mutations. Here, we directly sequenced genomic DNA from a large cohort of 448 unrelated patients suspected of having GS. We found 172 distinct mutations, of which 100 were unreported previously. In 315 patients (70%), we identified two mutations; in 81 patients (18%), we identified one; and in 52 patients (12%), we did not detect a mutation. In 88 patients, we performed a search for large rearrangements by multiplex ligationdependent probe amplification (MLPA) and found nine deletions and two duplications in 24 of the 51 heterozygous patients. A second technique confirmed each rearrangement. Based on the breakpoints of seven deletions, nonallelic homologous recombination by Alu sequences and nonhomologous end-joining probably favor these intragenic deletions. In summary, missense mutations account for approximately 59% of the mutations in Gitelman's syndrome, and there is a predisposition to large rearrangements (6% of our cases) caused by the presence of repeated sequences within the SLC12A3 gene.

Background and objectives: Sickle cell anemia-associated nephropathy is a growing matter of concern because renal failure affects most aging sickle cell anemia patients. Glomerular damage is a common feature revealed by a microalbuminuria or a macroalbuminuria. Although glomerular hyperfiltration has been described for decades in this population, its prevalence in young adults is unknown.Design, setting, participants, & measurements: To address this issue, as well as the clinical and biologic correlates of hyperfiltration, a single-center, cross-sectional study of 280 homozygous SS disease patients was performed.Results: The prevalence of hyperfiltration assessed by Modification of Diet in Renal Disease estimated GFR was 51%. Among patients with hyperfiltration, 49% had hyperfiltration alone, whereas 36% and 15% had an associated microalbuminuria or macroalbuminuria, respectively. Estimated GFR sensitivity and specificity for hyperfiltration were 94% and 63%, respectively, in a selected subgroup of 48 patients (measured GFR was assessed by urinary 51 Cr EDTA clearance). In patients with no albuminuria, hyperfiltration status was significantly associated with a young age (years), the absence of alpha thalassemia, a lower hemoglobin level (g/dl), and a lower fetal hemoglobin. The role of chronic hemolysis was further strengthened by multivariate analysis showing a correlation between estimated GFR and a low plasma fetal hemoglobin level, a young age, and a high reticulocyte count (r 2 ‫؍‬ 0.54). Conclusions: Together, the data suggest that the pathophysiology of hyperfiltration would rather be attributable to the hemolysis-associated vasculopathy rather than a viscosity-vaso-occlusive process.

Abstract-In hypertension, angiotensin (Ang) II is a critical mediator of cardiovascular remodeling, whose prominent features include myocardial and vascular media hypertrophy, perivascular inflammation, and fibrosis. The signaling pathways responsible for these alterations are not completely understood. Here, we investigated the importance of calpains, calcium-dependent cysteine proteases. We generated transgenic mice constitutively expressing high levels of calpastatin, a calpain-specific inhibitor. Chronic infusion of Ang II led to similar increases in systolic blood pressure in wild-type and transgenic mice. In contrast, compared with wild-type mice, transgenic mice displayed a marked blunting of Ang II-induced hypertrophy of left ventricle. Ang II-dependent vascular remodeling, ie, media hypertrophy and perivascular inflammation and fibrosis, was also limited in both large arteries (aorta) and small kidney arteries from transgenic mice as compared with wild type. In vitro experiments using vascular smooth muscle cells showed that calpastatin transgene expression blunted calpain activation by Ang II through epidermal growth factor receptor transactivation. In vivo and in vitro models of inflammation showed that impaired recruitment of mononuclear cells in transgenic mice was attributable to a decrease in both the release of and the chemotactic response to monocyte chemoattractant protein-1. Finally, results from collagen synthesis assay and zymography suggested that limited fibrogenesis was attributable to a decrease in collagen deposition rather than an increase in collagen degradation.

Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2–5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8±14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m 2 . Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. In regression analyses adjusted on classical cardiovascular and renal risk factors, aortic stiffness remained significantly associated with all-cause mortality (for 1 SD, Cox model–derived relative risk [95% CI], 1.48 [1.09–2.02]) and with fatal and nonfatal cardiovascular events (for 1 SD, Fine and Gray competing risks model–derived relative risk [95% CI], 1.35 [1.05–1.75]). Net reclassification improvement index was significant (29.0% [2.3–42.0%]). Carotid internal diameter was also independently associated with all-cause mortality. This study shows that increased aortic stiffness and carotid internal diameter are independent predictors of mortality in patients with stages 2 to 5 chronic kidney disease and that aortic stiffness improves the prediction of the risk.

Background: There is strong biologic plausibility to support change in albuminuria as a surrogate endpoint for progression of chronic kidney disease (CKD), but empirical evidence to supports its validity in epidemiologic studies is lacking. Methods: We analyzed 28 cohorts including 693,816 individuals (80% with diabetes) and 7,461 end-stage kidney disease (ESKD) events, defined as initiation of kidney replacement therapy. Percent change in albuminuria was quantified during a baseline period of 1, 2 and 3 years using linear regression. Associations with subsequent ESKD were quantified using Cox regression in Coresh et al.

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