Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

Cell Biology of the Glomerular Podocyte

The cloning of a G protein-coupled extracellular Ca(2+) (Ca(o)(2+))-sensing receptor (CaR) has elucidated the molecular basis for many of the previously recognized effects of Ca(o)(2+) on tissues that maintain systemic Ca(o)(2+) homeostasis, especially parathyroid chief cells and several cells in the kidney. The availability of the cloned CaR enabled the development of DNA and antibody probes for identifying the CaR's mRNA and protein, respectively, within these and other tissues. It also permitted the identification of human diseases resulting from inactivating or activating mutations of the CaR gene and the subsequent generation of mice with targeted disruption of the CaR gene. The characteristic alterations in parathyroid and renal function in these patients and in the mice with "knockout" of the CaR gene have provided valuable information on the CaR's physiological roles in these tissues participating in mineral ion homeostasis. Nevertheless, relatively little is known about how the CaR regulates other tissues involved in systemic Ca(o)(2+) homeostasis, particularly bone and intestine. Moreover, there is evidence that additional Ca(o)(2+) sensors may exist in bone cells that mediate some or even all of the known effects of Ca(o)(2+) on these cells. Even more remains to be learned about the CaR's function in the rapidly growing list of cells that express it but are uninvolved in systemic Ca(o)(2+) metabolism. Available data suggest that the receptor serves numerous roles outside of systemic mineral ion homeostasis, ranging from the regulation of hormonal secretion and the activities of various ion channels to the longer term control of gene expression, programmed cell death (apoptosis), and cellular proliferation. In some cases, the CaR on these "nonhomeostatic" cells responds to local changes in Ca(o)(2+) taking place within compartments of the extracellular fluid (ECF) that communicate with the outside environment (e.g., the gastrointestinal tract). In others, localized changes in Ca(o)(2+) within the ECF can originate from several mechanisms, including fluxes of calcium ions into or out of cellular or extracellular stores or across epithelium that absorb or secrete Ca(2+). In any event, the CaR and other receptors/sensors for Ca(o)(2+) and probably for other extracellular ions represent versatile regulators of numerous cellular functions and may serve as important therapeutic targets.

Extracellular Calcium Sensing and Extracellular Calcium Signaling

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

Geigy Scientific Tables

Defects in type IV collagen, a collagenous protein involved in the formation of basement membranes, have been implicated in hereditary Alport's syndrome and acquired Goodpasture's syndrome. Mutations in genes corresponding to the building blocks of type IV collagen cause Alport's syndrome, whereas autoantibodies against structures that are usually hidden in the recesses of collagen IV cause Goodpasture's syndrome.

Alport's Syndrome, Goodpasture's Syndrome, and Type IV Collagen

BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

https://www.nejm.org/doi/pdf/10.1056/NEJM199610103351505

A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

The tenth reported case of methotrexate‐induced congenital malformations is presented. The abnormalities were mainly of the skull bones. The mother was given the methotrexate as treatment for psoriasis during early pregnancy. The case is reported to emphasize the need for adequate contraceptive advice when methotrexate is used for the treatment of women who may become pregnant.

Methotrexate-induced congenital malformations

Denys-Drash syndrome (DDS) and Frasier syndrome (FS) are two related conditions caused by mutations of the Wilms tumor gene, WT1. Both syndromes are characterized by male pseudohermaphroditism, a progressive glomerulopathy, and the development of genitourinary tumors. DDS and FS have previously been distinguished by differences in nephropathy, with DDS patients demonstrating diffuse mesangial sclerosis (DMS) in contrast to focal and segmental glomerulosclerosis (FSGS) in FS patients. The clinicopathological features and genotype analysis of two patients with WT1 mutations are presented in this report. Genotype analysis of the first patient revealed a previously undescribed mutation in exon 8 of the WT1 gene. The second patient presented with a rapidly progressive nephropathy characterized histologically by DMS, but was found to have the genetic mutation seen in FS patients. A summary of all reported patients with the characteristic mutation associated with FS demonstrates the clinical overlap of this syndrome with DDS. This suggests that both these conditions should be considered as part of the spectrum of disease due to WT1 gene mutations rather than as separate diseases. Clinical classification remains important for prognosis, as the underlying renal disease appears to predict the progression of nephropathy independently of the genetic abnormality.

Clinical spectrum of Denys-Drash and Frasier syndrome.

Defects seen on early cortical scintigrams of the renal cortex in children with urinary tract infection may represent acute inflammatory change or established scar. The purpose of this study was to determine the relationship between these defects and age, sex, the presence and grade of vesicoureteral reflux, and infective organism in a cohort of children examined after their first proved urinary tract infection.We prospectively examined 193 consecutive patients less than 5 years old who were seen at the ambulatory pediatric department during a 3-year period and had a first proved urinary tract infection. Children with obstructed or solitary kidneys were excluded. All patients were imaged with scintigraphy of the renal cortex and radiographic voiding cystourethrography within 15 days of diagnosis. The association of age, sex, the presence and grade of vesicoureteral reflux, and infective organism with a defect (acute pyelonephritis or a renal scar) seen on a cortical renal scan was studied.The prevalence o...

Risk factors in the development of early renal cortical defects in children with urinary tract infection.

PURPOSE: To determine the association between vesicoureteral reflux (VUR) and the presence of acute pyelonephritis in children with urinary tract infections. MATERIALS AND METHODS: The authors studied 150 consecutive patients less than 5 years of age with their first proved urinary tract infection. All patients underwent renal cortical scintigraphy (with technetium-99m dimercaptosuccinic acid or Tc-99m gluconate) and voiding cystourethrography (VCUG) to identify the presence of cortical defects and VUR, respectively. RESULTS: Of 300 kidneys, 88 (29.3%) had a cortical defect at scintigraphy. Fifty-four of the 88 patients (61%) did not have VUR demonstrated at VCUG. Conversely, 72 of the 300 kidneys (24%) had VUR; of these, 38 (53%) had no cortical defect. The sensitivity of VCUG in helping predict a defect was 38.6%, and the specificity was 82.1%. CONCLUSION: VUR (as shown by VCUG) and renal cortical scintigraphic defects frequently occur independently of each other. Renal cortical scintigraphy may be a mo...

Harley R. Powell

Papers

A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

Methotrexate-induced congenital malformations

Clinical spectrum of Denys-Drash and Frasier syndrome.

Risk factors in the development of early renal cortical defects in children with urinary tract infection.

Vesicoureteral reflux: an accurate predictor of acute pyelonephritis in childhood urinary tract infection?