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...

COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps.

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Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

We retrospectively analyzed clinical presentation, immunopathological data and renal outcome in 13 patients with glomerulonephritis (GN) and chronic lymphocytic leukemia (CLL) or related diffuse well-differentiated lymphocytic lymphoma (WDLL) of B-cell lineage. B-cell proliferation and glomerulopathy were simultaneously diagnosed in seven of the 13 patients. Nephrotic syndrome was observed in nine patients. Serum creatinine was elevated (greater than 120 mumol/liter) in 10 patients and exceeded 400 mumol/liter in three patients. A clear cut relationship between GN and hematologic disease could be established in nine cases: five patients had MPGN caused by type I or type II cryoglobulinemia; two had MPGN or mesangial hypertrophy with circulating and deposited noncryoprecipitating monoclonal IgG K and IgM K, respectively; in the two remaining patients, monotypic IgG K glomerular deposits exhibiting fibrillary organization were observed in association with MGN or MPGN, despite the absence of circulating M-component by immunofixation. The pathophysiologic link between glomerular lesions and B-cell proliferation was further evidenced by effectiveness of specific treatment of the malignancy by chlorambucil. This drug, used in the absence of steroids, induced complete remission of nephrotic syndrome in the five patients to whom it was given. Moreover, in the five patients with creatininemia greater than 200 mumol/liter who received chemotherapy, substantial improvement in renal function was observed. These overall data demonstrate that the occurrence of GN in B-CLL and related lymphoma is not fortuitous, and testify to the paraneoplastic nature of glomerular involvement mediated by deposition and possibly processing of cryoprecipitating or noncryoprecipitating M-components.

Light-, light-and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light-and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly , and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

ABSTRACT. The A3243G mutation of the mitochondrial tRNA(Leu) gene has been recently reported in rare patients with focal and segmental glomerulosclerosis (FSGS). However, the full spectrum of systemic and kidney manifestations in adults presenting with this mutation remains poorly defined. Assessment of renal and nonrenal manifestations was performed in nine patients with A3243G mutation and prominent kidney disease diagnosed in adulthood. At first renal evaluation, median age was 35 years. Renal lesions consisted of FSGS (n = 2), tubulointerstitial nephropathy (n = 3), or bilateral enlarged cystic kidneys (n = 1). All but one patient exhibited extrarenal manifestations: deafness (8 of 9) requiring hearing aid in half the cases, diabetes mellitus (3 of 9), neuromuscular involvement (2 of 9), hypertrophic cardiomyopathy (1 of 9), and macular dystrophy (1 of 9). After a median follow-up of 5 yr, five patients progressed to end-stage renal disease between the ages of 15 and 51 years, four being successfully transplanted. Similarly, extrarenal manifestations progressed since all patients had deafness and diabetes (including three posttransplants), while half had neuromuscular, cardiac, or retinal involvement. In the adult patients with A3243G mutation and renal involvement, preexisting deafness is almost consistently found. While FSGS remains the most typical lesion, tubulointerstitial nephropathy or bilateral, enlarged cystic kidneys may also be encountered. In most cases, diabetes mellitus, macular dystrophy, hypertrophic cardiomyopathy, or neuromuscular features occur later in the course of the disease. The severity of the clinical course is heterogeneous, with end-stage renal failure being reached between the second and sixth decades. Renal transplantation may be offered to these patients, despite a high incidence of steroid-induced diabetes mellitus. E-mail: dominique.chauveau@nck.ap-hop-paris.fr