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This review aims to assist in the categorization of inherited, developmental, and acquired cystic disease of the kidney as well as to provide a pertinent, up-to-date bibliography. The conditions included are autosomal-dominant polycystic kidney disease, autosomal-recessive polycystic kidney disease, unilateral renal cystic disease (localized cystic disease), renal simple cysts, multicystic dysplastic kidney, pluricystic kidney of the multiple malformation syndromes, juvenile nephronophthisis and medullary cystic disease, medullary sponge kidney, primary glomerulocystic kidney disease, and glomerulocystic kidney associated with several systemic disorders mainly of genetic or chromosomal etiology, cystic kidney in tuberous sclerosis, and in von Hippel-Lindau syndrome, cystic nephroma, cystic variant of congenital mesoblastic nephroma, mixed epithelial stromal tumor of the kidney, renal lymphangioma, pyelocalyceal cyst, peripylic cyst and perinephric pseudocyst, acquired renal cystic disease of long-term dialysis, and cystic renal cell carcinoma and sarcoma. Whereas the gross and histologic appearance of some of these conditions may be diagnostic, clinical and sometimes molecular studies may be necessary to define other types.

In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease.We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic90 mm Hg; n=169) or intensified (systolic/diastolic130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat.Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99).In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

Anderson-Fabry disease (AFD) is a rare X-linked lipid storage disorder due to a deficient lysosomal a-galactosidase A (a-Gal) activity. In males with the classic form of the disease the enzymatic defect leads to progressive accumulation of glycosphingolipids (GL) in different organs, mainly in the kidney, heart, and brain, causing severe multisystem failure. AFD is usually mild in heterozygous females, but severe cerebrovascular, renal, and cardiac manifestations have been rarely described. The aim of this study is to describe renal involvement of mild symptomatic female carriers by ultrastructural analysis focusing to microvascular lesions, considered to be one of the major causes of systemic disease in AFD. Resin-embedded renal biopsies from 2 sisters with isolated mild proteinuria and belonging to a family group with AFD were observed by light and electron microscopy. In spite of the mild clinical symptoms, diffuse GL storages were demonstrated in all types of glomerular cells and in interstitial endothelial cells. Moreover, platelets were frequently observed in glomerular vassels, a feature coherent with a possible role of prothrombotic state, and platelet activation, in early glomerular lesions.

Anderson-Fabry disease (AFd) is a rare, inherited, x-linked disease characterized by the deficiency of the lysosomal enzymatic alpha-galactosidase A activity (alpha-Gal-A). The enzyme defect leads to progressive accumulation of glycosphingolipids (GL) in all kinds of cells, tissues, organs, and body fluids. The clinical manifestations are very protean, the residual activity of alpha-Gal-A and/or different gene mutations might explain different phenotypes, but as yet these concepts have not been proven. Usually, patients with AFd show 3 clinical phases, more evident in men than in heterozygous women. The first phase (childhood and adolescence) is characterized by myalgia, arthralgia, acroparesthesia, fever, cutaneous angiokeratomas, and corneal opacities. The second phase is characterized mainly by renal involvement. In the third phase, severe renal impairment and involvement of cerebrovascular and cardiovascular systems are present. The progression to end-stage renal disease (ESRD) is common in hemizygous males (3rd-5th decade of life); usually, death occurs because of cerebral and/or cardiovascular complications in patients undergoing chronic dialysis therapies. The survival of patients with AFd in dialysis is better than in diabetic patients, but it clearly is decreased compared with uremic patients with other nephropathies, despite a lower mean age of uremia (50 versus 60 y). The outcome of kidney transplantation is similar to that found in other patients with ESRD, despite controversial issues published in the past. The use of a kidney donor with normal alpha-Gal-A activity in the control of the metabolic systemic disease is unproven. The recurrence of GL deposits in the kidney graft has been documented rarely. The definitive treatment for AFd is enzyme replacement therapy with purified alpha-Gal-A produced by a genetically engineered human cell line or Chinese hamster oocytes: relatively short-term studies have shown a significant treatment effect on clinical outcome measures.

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 (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. © 1998 Wiley-Liss, Inc.

Cells 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 [alpha (III)]3 and collagen IV. However, part of the collagen components remained unidentified in spite of the fact that they exhibited a typical M(r) of alpha 1(I) and alpha 2(I) in the presence of urea. Immunoprecipitation with monospecific antibodies and Northern blotting with specific probes failed to recognize alpha 1(I) and alpha 2(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 cytogenetic mechanisms in vivo.

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.

Abnormalities of tubular membrane structure and composition have been proposed as the primary defect in nephronophthisis (NEF). In order to characterize the protein composition of tubular cells in NEF, in vitro methods were developed to culture and propagate tubular cells obtained from biopsy fragments. Accordingly, microdissected cortical slices (1 x 3 mm) were first digested with collagenase and DNAse and then grown in RPMI medium supplemented with 10% NU serum and conditioned serum deriving from 3T3 cultures. At confluence, cultured cells from NEF showed characteristics which were typical of normal tubules, i.e. presence of cytokeratin and positivity for succinic dehydrogenase and alkaline phosphatase stainings, and presented no morphological alterations compared to cultured cells from normal tubular epithelium. Moreover, no difference was observed for fibronectin, collagen IV and laminin stains. Analysis by two-dimensional electrophoresis of cellular extracts revealed several changes in protein composition of NEF, the main one being the decrease in NEF cells of a polypeptide with a molecular weight of 120 kD and a pI of 4.8; this polypeptide was a constant finding in normal kidneys. These observations demonstrated that human tubular epithelial cells can be successfully cultured from very small biopsy fragments, which represents a new approach to the study of molecular disorders involving tubular cells in inherited disease. Cultured cells from NEF maintain the same morphological, immunological and cytochemical characteristics as normal tubular cells, but present a few alterations in polypeptide composition which may have pathogenetic relevance. A more careful analysis of these alterations is needed to define the molecular disorder(s) involving the tubule in NEF.

Key words: Fabry disease; glomerular proteinuria; lipid involvement, and the third phase involves vascular,storage diseases; hereditary kidney diseases; glyco- cardiac, and cerebral disease and renal functionalsphingolipids; alpha-galactosidase A; angiokeratomas; deterioration.acroparaesthesias; corneal opacities Death occurs around the fifth decade from renal,cardiac, and cerebral complications. Nevertheless, clin-ical evidence supports phenotypic heterogeneity ofFabry’s disease, and genetic heterogeneity has been

Anderson-Fabry disease is a rare inborn X-linked glycosphingolipid storage disorder in which the deficient activity of the enzyme alfa-galactosidase A (alfa-gal A) leads to the progressive tissular accumulation of lipidic molecules which, in turn, cause a protean pattern of multi-organ disfunction. Enzyme replacement therapy has recently become available and has proved to be effective in controlling the disorder. We present and discuss the case of a family with this disease, with special attention to the variability of clinical features and the difficulty of a correct diagnosis.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.

Objective— To better understand the role of lecithin:cholesterol acyltransferase (LCAT) in lipoprotein metabolism through the genetic and biochemical characterization of families carrying mutations in the LCAT gene. Methods and Results— Thirteen families carrying 17 different mutations in the LCAT gene were identified by Lipid Clinics and Departments of Nephrology throughout Italy. DNA analysis of 82 family members identified 15 carriers of 2 mutant LCAT alleles, 11 with familial LCAT deficiency (FLD) and 4 with fish-eye disease (FED). Forty-four individuals carried 1 mutant LCAT allele, and 23 had a normal genotype. Plasma unesterified cholesterol, unesterified/total cholesterol ratio, triglycerides, very-low-density lipoprotein cholesterol, and pre-β high-density lipoprotein (LDL) were elevated, and high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, apolipoprotein A-II, apolipoprotein B, LpA-I, LpA-I:A-II, cholesterol esterification rate, LCAT activity and concentration, and LDL and HDL 3 particle size were reduced in a gene–dose-dependent manner in carriers of mutant LCAT alleles. No differences were found in the lipid/lipoprotein profile of FLD and FED cases, except for higher plasma unesterified cholesterol and unesterified/total cholesterol ratio in the former. Conclusion— In a large series of subjects carrying mutations in the LCAT gene, the inheritance of a mutated LCAT genotype causes a gene–dose-dependent alteration in the plasma lipid/lipoprotein profile, which is remarkably similar between subjects classified as FLD or FED.

Background Hyperhomocysteinemia, a risk factor for atherosclerosis, is frequently detected in patients with renal failure. Vitamin B supplementation reduces but rarely normalizes homocysteine (Hcy) levels in hemodialysis patients. There are no data about the effects of vitamin B therapy on Hcy levels in patients on peritoneal dialysis (PD). Aims We performed this trial both to observe baseline plasma Hcy levels in PD patients and to assess the effects of vitamin B therapy on Hcy levels in continuous ambulatory PD patients. Methods We conducted a 6-month prospective study of the effects of vitamin B therapy on plasma Hcy levels. Biochemical analyses were obtained at baseline and after every phase of treatment with folic acid, folic acid plus vitamin B12, and folic acid plus vitamin B12 plus vitamin B6. Eighteen of the 25 enrolled patients finished the study. Results Hyperhomocysteinemia was present in 83% of PD patients. We detected a trend toward a significant inverse relationship between baseline Hcy and folate levels. There were no significant correlations between baseline Hcy and vitamin B12, peritoneal membrane permeability, dialytic efficiency, or computed peritoneal Hcy clearance. We obtained an effective decrease in mean Hcy concentration from 20 to 14.8 μmol/L after folic acid and vitamin B12 treatment. We observed a further reduction in mean Hcy level to 12.8 μmol/L using the triple therapy; 72% of patients normalized their Hcy value. Conclusions High doses of folic acid, vitamin B6, and vitamin B12 normalize Hcy values in the majority of PD patients. This treatment may be important in reducing cardiovascular morbidity and mortality.

Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome characterized by germline mutations in the VHL tumor suppressor gene located at chromosome 3p25-26 and pleomorphic clinical picture. The major clinical manifestations include retinal angiomas, central nervous system hemangioblastomas, pheopleochromocytoma, pancreatic cysts, epididymal cystoadenomas and renal lesions. Recently, we observed a 58-year-old male patient with macrohematuria and a history of nephrectomy due to renal cell carcinoma (RCC). The patient showed retinal angiomatosis, cerebellar hemangioblastomas, multiple pancreatic cysts, right kidney with polycystic features plus two RCC. The patient's offspring, two females and one male, showed VHL lesions, such as retinal angiomatosis, cerebellar hemangioblastomas and polycystic kidney disease (PKD). The affected family members were screened for mutations in the VHL gene. Data suggested the presence of a deletion encompassing exon 1 of the VHL gene. Early diagnosis of VHL disease in patients and their relatives is important for clinical and geneticreasons. VHL disease patients have an increased incidence of malignant carcinomas and the syndrome can mimic the presentation of other cystic kidney diseases. Early diagnosis and molecular genetic testing of family members is essential to improve the clinical management of patients and to allow an accurate risk assessment in asymptomatic individuals. In conclusion, nephrologists and urologists must carefully evaluate patients with PKD and RCC to confirm or exclude VHL disease, and physicians must play a crucial role in the clinical process of therapeutical decisions and choices for VHL patients.

Anderson-Fabry disease (AFd) is a rare X-linked lisosomal storage disorder of glycosphingolipid (GL) metabolism, caused by a deficiency of the activity of alpha-galactosidase A (alpha-gal A). The progressive accumulation of GL in tissues results in the clinical manifestations of the disease, that are more evident in hemizygous males, and include characteristic skin lesions (angiokeratomas), neurological symptoms (acroparesthesia), ocular features (cornea verticillata), cardiac involvement (left ventricular enlargement, conduction abnormalities), cerebrovascular manifestations (thromboses, hemorrhage, etc.), and kidney involvement with progression to end-stage renal failure (ESRF). ESRF is a common manifestation in hemizygous males (3rd-5th decade) and death occurs around the 5th decade of life because of severe cardiac and/or cerebrovascular complications. Heterozygous females have an attenuated form of this systemic disease. In the kidney, accumulation of GL occurs in the endothelial cells of every vessel, in the epithelial cells of every tubular segment, and in all kinds of glomerular cells. The broad spectrum of renal lesions is a pathophysiological continuum with progressive impairment in the renal function related to continuous intracellular deposition of GL. Electron microscopic study of renal biopsies shows typical osmiophilic inclusion bodies in the cytoplasm of all kind of renal cells, characterized by concentric lamellation of clear and dark layers (35-50 A of periodicity). ESRF is treated by dialysis and kidney transplantation: neither treatment modifies the progression of the cardiovascular and cerebrovascular lesions due to progressive GL deposition. The outcome of kidney transplantation seems to be similar to that found in other non-diabetic patients, but the survival rate on dialysis is lower than in patients with other causes of ESRF. Nowadays, treatment with enzyme replacement infusion with purified alpha-Gal A, produced by a genetically engineered human cell line or Chinese hamster ovocytes, seems to be effective and safe.

Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients. These patients frequently have hyperhomocysteinemia, a putative risk factor for cardiovascular disease. Treatment with folate, B6 and B12 partially reduces hyperhomocysteinemia. We conducted a long-term study to evaluate whether 15 mg is more effective than 5 mg oral folic acid as a daily dosage to decrease hyperhomocysteinemia, and to assess whether homocysteine-lowering treatment reduces the risk of cardiovascular disease in hemodialysis patients.In a 1-year prospective randomised trial, 81 chronic hemodialysis patients, matched for age, gender and dialytic age, were divided into three groups: 30 untreated patients, 26 patients receiving 5 mg per day, and 25 patients receiving 15 mg per day.There was a significant reduction in hyperhomocysteinemia over time in treated patients as compared to untreated, but there were no significant differences between the two treated groups. Only 12% of the treated patients reached normal total homocysteine plasma levels. We observed a trend towards a significant difference in survival rate in cardiovascular morbidity between treated and untreated patients. Furthermore, hemodialysis patients with new vascular events showed higher homocysteine levels than patients without events.High-dose folic acid treatment did not improve outcome in hyperhomocysteinemia, and 88% of treated patients maintained higher than normal homocysteine levels. There was a trend towards a decreased rate of cardiovascular events in treated participants as compared to untreated ones.

Molecular genetics has strongly influenced clinical medicine and particularly nephrology. Several gene mutations of single-gene hereditary nephropathies have been recently identified. These data are useful to develop methods of diagnosis and treatment, but also to understand the pathogenesis of these particular disorders. In this review we focused on several monogenic hereditary renal diseases inducing nephrotic syndrome and other hereditary diseases with renal involvement and progression towards end-stage renal failure.

Background: Fechtner syndrome (FTNS), also known as Alport-like syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9 , the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9 . Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting. Am J Kidney Dis 41:95-104. © 2003 by the National Kidney Foundation, Inc.

Anderson-Fabry disease (AFd) is caused by an X-linked inborn error in the glycosphingoLipid metabolic pathway due to an enzymatic defect in a lysosomal hydrolase: alpha-galactosidase A. The defect results in the progressive accumulation of neutral glycosphingolipids in most body fluids and several tissues. The clinical manifestations of AFd are related to organ damage and, obviously, are more severe in hemizygous males than in heterozygous females. In the third decade of life, the course of the disease involves severe deterioration of kidney function progressing to end-stage renal failure. All kind of cells of renal structures are filled with glycosphingolipid deposits. Electron microscopic studies document typical intracytoplasmic osmiophilic bodies with a characteristic "zebra" or "onion-skin" appearance due to concentric lamellation of alternating clear and dark layers. Clinical interest in Fabry patients is related to recent advances in treatment with an intravenous specific enzyme to modify the biochemical error of the glycosphingolipid catabolic pathway.

Fabry disease is a rare X-linked disorder, characterized by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to systemic accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in all body tissues and organs, including the kidney. Renal manifestations are less evident in female heterozygotes than in male hemizygotes, according to the Lyon hypothesis. Accumulation of Gb3 occurs mainly in the epithelial cells of Henle's loop and distal tubule, inducing early impairment in renal concentrating ability; involvement of the proximal tubule induces Fanconi syndrome. All types of glomerular cells are involved, especially podocytes, and glomerular proteinuria may occur at a young age. The evolution of renal Fabry disease is characterized by progressive deterioration of renal function to end-stage renal failure (ESRF). Ultrastructural study of kidney biopsies reveals typical bodies in the cytoplasm of all types of renal cells, characterized by concentric lamellation of clear and dark layers with a periodicity of 35-50 A. Management of progressive renal disease requires dietetic and therapeutic strategies, usually indicated in developing chronic renal failure, with dialysis and renal transplantation required for patients with ESRF. The recent development of enzyme replacement therapy, however, should make it possible to prevent or reverse the progressive renal dysfunction associated 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.

Cryoglobulinemic glomerulonephritis is particularly frequent in type II mixed IgMk-IgG cryoglobulinemia. The typical form is a membranoproliferative glomerulonephritis with a particular monocyte infiltration. In the most severe cases, there is occlusion of the capillary lumina by the same immunoglobulin constituents of the cryoprecipitate. While it is generally accepted that the “hyaline thrombi” are endoluminal aggregates of IgG-IgM immune complexes, probably favored by high endocapillary concentration of cryoglobulins, the modality of generation has not been studied. To study the dynamic formation of such “thrombi,” we reproduced an experimental model of cryoglobulinemic glomerulonephritis in mice by injecting them twice a day for 3 days with 4 mg human IgMk-IgG cryoglobulins previously solubilized at 37 degrees C. The dynamic formation of immunodeposits was studied by immunofluorescence and electron microscopy. After 1 day, only mesangial deposits were found; after 3 days, in addition to mesangial deposition, all the capillary lumina were occluded by huge electron-dense bodies. To look for and quantify the contacts between such “thrombi” and mesangial or subendothelial deposits, we obtained serial, ultrathin, 0.5-microm sections that allowed us to reconstruct the whole glomerular tuft. Within each serial section, there was continuity between hyaline thrombi and mesangial or subendothelial deposits ranging from 80% to 85% of the capillary loops. The percentage was 100% for two adjacent serial sections. In conclusion, our data demonstrate directly for the first time that hyaline thrombi follow mesangial deposits. The high percentage of contacts between thrombi and mesangial or subendothelial deposits suggests that they result from in situ build-up of true huge endoluminal immunodeposits after saturation of the clearance capacity of the mesangium. (Am J Kidney Dis 1998 Mar;31(3):435-42)

Aspergillus fumigatus is present in the environment worldwide and it is only able to infect debilitated or immunodepressed subjects. Nosocomial outbreaks of A. fumigatus infection have been associated with hospital reconstruction. Spores are released into the environment and are inhaled by immunodepressed patients housed in nearby Medical Units. Specific clinical syndromes are allergic bronchopulmonary aspergillosis and invasive pulmonary aspergillosis with characteristic radiological features. Invasive A. fumigatus infection is commonly fatal, even if promptly diagnosed and treated. Three consecutive cases of A. fumigatus infection occurred in debilitated patients housed in our Renal Unit while building renovation near the Unit was being performed. Two of these patients died and pulmonary and diffuse aspergillosis was found on postmortem examination. The third patient, highly suspected to be infected with Aspergillus, was aggressively and successfully treated with liposomal amphotericin B. Our experience suggests that fungal infections have gained increasing prominence in clinical medicine and they must be considered in chronic debilitated patients including dialysis patients, and that liposomal amphotericin B represents an important advance in the treatment of aspergillosis.

Mutations in the COL4A5 gene, which encodes the a5 chain of type IV collagen, are found in a large fraction of patients with X-linked Alport syndrome. The recently discovered COL4A6, tightly linked and highly homologous to COL4A5, represents a second candidate gene for Alport syndrome. We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6. Nine unrelated families, accounting for 5% of the cases, were found to have a rearrangement in COL4A5. No rearrangements were found in COL4A6, with the exception of a deletion encompassing the 5' ends of both COL4A5 and COL4A6 genes in a patient with Alport syndrome and leiomyomatosis. COL4A5 rearrangements were all intragenic and included 1 duplication and 7 deletions. Polymerase chain reaction (PCR) analysis was carried out to characterize deletion and duplication boundaries and to predict the resulting protein abnormality. The two smallest deletions involved a single exon (exons 17 and 40, respectively), while the largest ones spanned exons 1 to 36. The clinical phenotype of patients in whom a rearrangement in COL4A5 was detected was severe, with progression to end-stage renal failure in juvenile age and hypoacusis occurring in most cases. These data have some important implications in the diagnosis of patients with Alport syndrome.

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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.