Adalberto Sessa

Variability of clinical phenotype in a large Alport family with Gly 1143 Ser change of collagen alpha 5(IV)-chain.

In a large Italian family with adult-onset Alport syndrome, molecular analysis of the COL4A5 gene, which encodes the alpha 5(IV)-chain of glomerular basement membrane collagen, revealed a GGC-->AGC change in exon 38, resulting in substitution of a serine for a glycine in position 1143 of the polypeptide chain, between interruptions 19 and 20 of the triple helical domain. The mutation leads to loss of a restriction site for the enzyme Msp I, and could thus be easily recognized in several female and male relatives. Among relatives of both sexes who carried the same mutation, the clinical phenotype of Alport syndrome was variable as for the onset of renal failure and the presence of associated ear and eye abnormalities.

Renal transplantation from living donor parents in two brothers with Alport syndrome. Can asymptomatic female carriers of the Alport gene be accepted as kidney donors

Renal transplantation from living donor parents was performed in two brothers with end-stage renal failure due to Alport syndrome (AS). Two years later, the patient receiving the kidney graft from the mother, obligate carrier of AS, presented persistent microhematuria and proteinuria with normal renal function. The histological study demonstrated ultrastructural glomerular lesions consistent with AS. The authors conclude that: (1) Alport patients should not be deprived of renal transplantation from living donors, since anti-GBM nephritis is a rare complication; (2) an oligosymptomatic female carrier of the Alport gene may be considered as living renal donor, although a longer follow-up is needed in order to draw definitive conclusions.

Acute Renal Failure Due to Hypersensitivity Interstitial Nephritis Induced by Warfarin Sodium

Dr. A. Volpi, Unità Operativa di Nefrologia e Dialisi, Ospedale di Vimercate, Via Cereda, 2, I-20059 Vimercate (Italy) Sir, Adverse reaction to a growing number of drugs is being recognized as a cause of acute renal failure [1]. The clinician should suspect the possibility of acute drug-induced tubulointerstitial nephritis in all cases of acute renal failure of unknown etiology. Acute drug-induced hypersensitivity reaction is a common form of tubulointerstitial nephritis with sudden deterioration of renal function and oliguria. Renal function usually returns toward baseline after withdrawal of the drug. Systemic signs and symptoms such as fever, skin rash, arthralgias, myalgias, eosinophilia and seldom lym-phoadenopathy suggest a hypersensitivity mechanism; certain observations suggest that immunologically mediated tissue damage is the consequence of cell-mediated injury [2]. We have observed a 65-year-old female who developed fever, arthralgias, gross hematuria, sterile pyuria and oliguric acute renal failure (serum creatinine rose from 1.2 to 6.8 mg/dl). She was treated for 25 days with diltiazem, nitroglycerine discs and warfarin sodium (20 mg/day) because of myocardial infarction. Renal biopsy showed a typical picture of acute tubulointerstitial nephritis, with several interstitial eosino-phils, mononuclear cells, patchy focal tubular necrosis and intratubular casts of eosinophil cells (fig. 1). The glomeruli showed mild mesangial hypercellularity with IgA and C3 mesangial deposits at immunofluorescence. Late assay of serum IgE was normal. Withdrawal of warfarin sodium and treatment with corticosteroids (1 mg/kg/day) returned renal function to the normal level in 45 days (serum creatinine 1 mg/dl). Acute renal failure due to acute drug-induced tubulointerstitial nephritis is seen more frequently in older patients and, usually, the mean latent period of treatment is 15 days (from 2 to 44 days) [2]. In the absence of other apparent causes we think that warfarin sodium hypersensitivity has likely been the

Extracellular matrix formation by epithelial cells from human polycystic kidney cysts in culture

SummaryCells from the cysts of patients with autosomal dominant polycystic kidney disease (PKD) were grown in vitro under standard conditions without the aid of collagen-pretreated surfaces, and both the synthesis and composition of the extracellular matrix were investigated. At confluence, PKD cells presented the typical features of epithelial cells, but showed a different collagen composition from fibroblasts. Compared with normal tubular epithelia (NTE), PKD monolayers produced an excess of extracellular matrix, which accounted for 30% of the total incorporation of [3H] proline, although this value was considerably lower (by a factor of 10) in the case of NTE. Immunohistochemical and electrophoretic techniques revealed a complex collagen composition in the extracellular matrix which included [α(III)]3 and collagen IV. However, part of the collagen components remained unidentified in spite of the fact that they exhibited a typical Mr of α1(I) and α2(I) in the presence of urea. Immunoprecipitation with monospecific antibodies and Northern blotting with specific probes failed to recognize α1(I) and α2(I), but demonstrated their presence in fibroblasts. Purification and cyanogen bromide digestion demonstrated a strong interhomology in fingerprint peptide composition among the uncharacterized collagens synthesized by PKD cells, thus suggesting a common identity. These observations document a markedly augmented production of extracellular matrix by PKD cultured cells in vitro, and show the presence of collagens which do not share homologies with the major collagen molecules. A better characterization of extracellular matrix composition is central to any comprehension of the cystogenetic mechanisms in vivo.

Acute Glomerulonephritis in Human Brucellosis

Acute Glomerulonephritis in Human Brucellosis C. Cecilia Doregatti A. Angela Volpi L.T. Laura Torri Tarelli M. Mario Brognoli F. Ferdinando Giordano M. Mietta Meroni G. Giancarlo Orlandini A. Adalberto Sessa Servizio di Nefrologia e Dialisi, Ospedale di Leno, Leno, Italia;Servizio di Nefrologia e Dialisi, Ospedale di Vimercate, Vimercate, Italia; Istituto di Anatomia Umana Normale, Università degli Studi, Milano, Milano, Italia

Two Brothers With Idiopathic Membranous Nephropathy and Familial Sensorineural Deafness

Genetic factors could play an important role in the pathogenesis of idiopathic membranous nephropathy, and a few cases of familial membranous nephropathy have been described: an increased incidence of some HLA antigens as DR3 and others has been reported. We present two brothers with idiopathic membranous nephropathy and sensorineural deafness. HLA typing was performed in the two patients and in the members of the family, and it showed the absence of linkage of an HLA antigen with the renal disease in the family.

Renal transplantation in patients with Fabry disease.

Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of α-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of α-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10–15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids. This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.

Hypocomplementemic Type II Membranoproliferative Glomerulonephritis in a Male Patient with Familial Lecithin-Cholesterol Acyltransferase Deficiency due to Two Different Allelic Mutations

Patients with familial lecithin-cholesterol acyltransferase (LCAT) deficiency very often show progressive glomerulosclerosis with evolution to end-stage disease. High levels of an abnormal lipoprotein (lipoprotein X) cause glomerular capillary endothelial damage. The ultrastructural study of renal biopsy specimens shows characteristic glomerular deposits of membrane-like, cross-striated structures and vacuole structures. The gene encoding for LCAT has been mapped to chromosome 16q22.1, and several mutations of this gene cause LCAT deficiency which is inherited as an autosomal recessive trait and which is characterized by corneal opacities, normochromic normocytic anemia, and renal dysfunction. Herein we report clinical features and renal histological findings concerning a 24-year-old male patient with classical familial LCAT deficiency due to two different allelic mutations: a nonsense mutation inherited from the father and a missense mutation inherited from the mother. Moreover, the patient showed glomerular histological lesions and an immunofluorescent glomerular pattern typical of hypocomplementemic membranoproliferative type II glomerulonephritis (dense-deposit disease). The nature of electron-dense material that characterizes dense-deposit disease is still unkwown, but there are suggestions that some chemical modifications might occur in the renal basement membranes. Therefore, this clinical case might induce to consider possible relations between disorders of the lipoprotein metabolism and renal dense-deposit disease.

Transforming growth factor β blocks cystogenesis by MDCK epithelium in vitro by enhancing the paracellular flux: Implication of collagen V

Transforming growth factor β (TGFβ) determines a nearly complete inhibition of cystogenesis by MDCK cells grown in collagen I‐enriched matrices in vitro. In order to elucidate the mechanism implicated in this phenomenon, we performed a series of experiments aimed at discovering a relevant role of extracellular matrix. TGFβ (2 ng/ml) played a marked stimulatory effect on the expression of extracellular matrix by MDCK with a selective effect on collagen V (three to fourfold increase of protein and mRNA) and in parallel inhibited cystogenesis by 95%. Cotreatment with TGFβ and anti‐collagen V antibodies restored a normal cystogenesis. In analogy, when MDCK cells were grown in three‐dimensional matrices containing collagen I and minor (10%) amounts of collagen V, cystogenesis was once again inhibited by 95%. To characterize the molecular mechanism activated by TGFβ and collagen V, we looked at the electrophysiological characteristics of MDCK monolayers and found a drastic fall of transepithelial electrical resistance (TER) in both conditions. In parallel with the decrease in TER, TGFβ and collagen V also induced the leakage of two high molecular weight tracers, i.e., [3H]‐inulin and 150 kD FITC‐Dextran, suggesting a perturbation of the paracellular permeability. Finally, TGFβ at the relevant concentration did not stimulate apoptosis in our cellular model, as judged by propidium iodide staining and by in situ end labeling of DNA fragments. These observations suggest that TGFβ inhibits cystogenesis by MDCK cells in vitro by altering the collagenic composition of the three‐dimensional milieu where MDCK cells grow and form cysts. The molecular mechanism responsible for inhibition of cystogenesis is the increase of paracellular flux which overcomes the active transport of solutes and water inside cysts. J. Cell. Physiol. 177:214–223, 1998.

Alport syndrome with type I membranoproliferative glomerulonephritis.

Alport Syndrome with Type I Membranoproliferative Glomerulonephritis M. Meroni A. Sessa G. Battini L.T. Torri Tarelli T. Bertani A. Renieri M. Seri M. De Marchi UO Nefrologia e Dialisi, Vimercate, Istituto di Anatomia Umana Normale, Università degli Studi, Milano, Divisione di Nefrologia, Ospedali Riuniti, Bergamo, Cattedra di Genetica Medica, Dipartimento di Biologia Molecolare, Università di Siena, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Ospedale San Luigi Gonzaga, Orbassano, Italia