Background and objectives: Hepatocyte nuclear factor 1␤ (HNF1␤) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than ؉3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated.Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

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Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Podocytes are specialized epithelial cells covering the basement membrane of the glomerulus in the kidney. The molecular mechanisms underlying the role of podocytes in glomerular filtration are still largely unknown. We generated podocin-deficient (Nphs2 ؊/؊ ) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis. Nphs2 ؊/؊ mice developed proteinuria during the antenatal period and died a few days after birth from renal failure caused by massive mesangial sclerosis. Electron microscopy revealed the extensive fusion of podocyte foot processes and the lack of a slit diaphragm in the remaining foot process junctions. Using real-time PCR and immunolabeling, we showed that the expression of other slit diaphragm components was modified in Nphs2 ؊/؊ kidneys: the expression of the nephrin gene was downregulated, whereas that of the ZO1 and CD2AP genes appeared to be upregulated. Interestingly, the progression of the renal disease, as well as the presence or absence of renal vascular lesions, depends on the genetic background. Our data demonstrate the crucial role of podocin in the establishment of the glomerular filtration barrier and provide a suitable model for mapping and identifying modifier genes involved in glomerular diseases caused by podocyte injuries.Glomeruli are specialized structures responsible for blood filtration in the kidney and are targets of injury in a number of human diseases. Plasma ultrafiltration occurs through the glomerular filtration barrier, which is composed of highly specialized visceral epithelial cells called podocytes, a fenestrated capillary endothelium, and an intervening glomerular basement membrane (GBM) (28). Podocytes are octopus-like cells (18), comprising a cell body and cytoplasmic extensions called major processes, which divide into actin-rich foot processes interdigitating over each capillary loop and counteracting the distensive forces. Each foot process is attached to its neighbor along its length by an intercellular adherens-type junction (46), the slit diaphragm (SD), which is located just above the GBM. The recent discovery of several novel podocyte proteins and the description of their physical and functional interactions highlighted the critical role of the SD complex and of the actin cytoskeleton in the maintenance of the glomerular filtration barrier (34, 39; reviewed in references 31 and 41).Glomerular diseases are associated with leakage of proteins across the filter into the urine and with disappearance (effacement) of podocyte foot processes. Whether effacement of foot processes is the cause or consequence of the glomerular filter alterations is uncertain. However, in renal diseases progressing toward focal and segmental glomerulosclerosis (FSGS), podocytes are now thought to be the primary targets, responsible for the development of the lesion. FSGS is characterized by segmental ...