Renoprotection: clues from knockout models of rare diseases.

Glomerulopathies due to defective known genes are partially or completely reversed at 24 months without becoming a central source of information in the field clear change in creatinine clearance. Other reports deof mechanisms of progression of renal disease. Among scribed no effects of ACE inhibitor in few sporadic cases. hereditary diseases, Alport syndrome of glomerulopathy In this issue of Kidney International, Gross et al [3] and hearing loss has long been the best recognized one compared the effects of ramipril given since early stage and yet the disease remains a major challenge for both versus more advanced disease on renal structure and basic and clinical scientists. Mutations of the gene encodfunction in homozygous 3(IV) chain (COL4A3) knocking for the 5 chain of type IV collagen are the molecular out mice, a model for autosomal-recessive Alport synbasis in the classic form, inherited in an X-linked domidrome. The ACE inhibitor given to mice since 4 weeks nant pattern (85% of cases). Genetic and phenotypic of life markedly delayed the onset of proteinuria, proheterogeneity, however, is large and other patients have gressive renal damage, and uremia. Remarkably, the autosomal-recessive or, most rarely, autosomal forms treatment also prolonged their lifespan by several weeks, resulting from mutations of 3 or 4(IV) collagen chain up to 150 days on average instead of 71 days if continued genes. The target organs reflect the sites where these until death. Ramipril showed no apparent protective efcollagen chains are normally highly expressed and assemfect against the ultrastrucural changes of the glomerular bled into functional networks. Thus, the abnormal 5 basement membrane. Conversely, drug treatment exchain appears to prevent incorporation of 3 or 4 chains erted antifibrotic effects attributable to inhibition of exinto the triple helical collagen monomers of the glomerucess transforming growth factor (TGF) production. lar membrane. Common to different Alport forms are the ACE inhibitor beginning at 7 weeks of age, when the typical splitting of the glomerular basement membrane, animals were already heavily proteinuric, had no effect persistent hematuria, and variable degrees of proteinon renal damage and survival. The main findings in the uria. End-stage renal failure almost inevitably develops paper by Gross et al [3] that the prolonged treatment in male patients, as well as in patients with autosomalwith the ACE inhibitor, and, to a lesser extent, a treatrecessive Alport syndrome in the long term. Despite adment given for a shorter period postponed the onset of vances in defining the molecular lesion, mechanisms unuremia and prolonged life revives hopes that patients derlying the progressive injury in Alport syndrome have with Alport syndrome may have their kidney function remained obscure. Furthermore, there is no accepted preserved to a significant extent. It was already known treatment that may delay the time of dialysis or a kidney that the ACE inhibitor could have beneficial effects transplant. Cyclosporine treatment given for 7 to 10 years against proteinuria, renal function deterioration, and to eight patients with Alport syndrome (on the theosurvival in Samoyed dogs, a model of X-linked hereditary retical basis of a favorable hemodynamic action) reduced nephropathy closely mimicking human Alport syndrome proteinuria and was associated with no aggravation of [4]. However, factor(s) that may be affected by ACE lesions present at the first biopsy [1]. Angiotensin I-coninhibitor therapy have remained elusive. In the study by verting enzyme (ACE) inhibitors have been attempted Gross et al [3], a role for increased glomerular capillary recently and few preliminary results are published. Propressure could not be formally excluded and the experiesmans, Knockaert, and Trouet [2] administered enalamental protocol lacked a group of mice treated with pril at a starting dose of 0.1 mg/kg body weight per day other antihypertensive drugs to achieve comparable levto five children with the classical form and two siblings els of blood pressure. Nevertheless, hypertension usually with the autosomal-recessive form. Overall, proteinuria occurs late and does not seem to play a primary pathoand protein/creatinine ratio decreased at 6 months and genic role. On the other hand, the reduction of proteinreached nadirs at 18 months (approximately one fifth uria has been established as an important strategy to and one tenth from the baseline levels of 40 mg/kg/day retard or prevent the loss of renal function in progressive and 2.5). This effect, which was observed in five patients, nephropathy. In this respect, the effect of ACE inhibitor in the COL4A3 knockout mouse, as well as in the dog model, was no exception. The knockout mice studied by