[Controversial issues in the Giornale Italiano di Nefrologia: how to treat patients with focal segmental glomerular sclerosis]. / Le contoversie del Giornale Italiano di Nefrologia: come trattare i pazienti con glomerulosclerosi focale segmentaria?

Primary focal segmental glomerular sclerosis (FSGS) commonly presents with nephrotic syndrome. Spontaneous remission is rare and persistent nephrotic syndrome is a marker of poor prognosis. For this reason, obtaining remission using drugs with minimal side effects is desirable. The treatment of FSGS, however, represents a challenge. Not only is there a lack of prospective controlled trials, but FSGS is a syndrome of unknown pathophysiology, generally treated with drugs having a mechanism of action that is poorly understood in this setting, the use of which has often drawn criticism because it is based on empirical assumptions rather than pathogenetic evidence. At present, corticosteroids are the standard first-line approach in patients with idiopathic FSGS. Cytotoxic agents and cyclosporin A constitute a good therapeutic option for steroid-dependent patients or frequent relapsers. Mycophenolate mofetil, rituximab and plasmapheresis should be used as rescue treatment because further studies are required to determine their safety and efficacy. Clearly, real progress in FSGS treatment can only be obtained by research focused on the pathophysiology of this disease, so that a therapeutic approach can be defined that is based on reason rather than chance.

[Nephrotic proteinuria with type 2 diabetes mellitus and autoimmune thyroiditis]. / Proteinuria nefrosica in paziente con diabete mellito di tipo II e tiroidite autoimmune.

This study reports on a 67-year-old man, suffering from type 2 diabetes mellitus for 11 years along with arterial hypertension and autoimmune thyroiditis, in whom nephrotic proteinuria was detected together with a mild reduction in GFR. No autoantibodies or monoclonal proteins were detected in blood and urine. Renal biopsy material examined by light microscopy, immunofluorescence and electron microscopy showed AL amyloidosis. This case underlines the role of renal biopsy in patients with type 2 diabetes mellitus, in whom renal diseases other than diabetic nephropathy may occur frequently.

[Thin glomerular basement membrane disease]. / La nefropatia a membrane basali sottili.

Thin glomerular basement membrane disease (TBMD) is a hereditary nephropathy characterized by thinning of the glomerular basement membrane evinced by electron microscopy and, clinically, by isolated hematuria without extrarenal manifestations. Familial aggregation is found in 50-60% of cases, with autosomal dominant transmission. TBMD is considered to belong to the type IV collagen spectrum of diseases, since heterozygous mutations of the COL4A3 or COL4A4 gene have been detected in more than 30% of patients. The disease is found in 1-2% of biopsies, but the prevalence in the general population may be higher. The differential diagnosis with Alport's syndrome may be difficult and requires accurate family investigations, immunohistochemical evaluation of type IV collagen alpha chains in renal tissue and, if appropriate, genetic studies. Progression towards chronic renal failure, although rare, has been reported in some patients, and may be related to the phenotypical variability of COL4A3/COL4A4 mutations, to a missed Alport syndrome, or to superimposed glomerular disease. Patients suffering from TBMD and affected relatives should be periodically examined for signs of disease progression and informed about the possibility of transmitting the autosomal recessive form of Alport's syndrome.

Peritoneal leiomyosarcoma in a kidney transplant patient: a case report.

Sarcomas are rare neoplasms, accounting for a 1.7% incidence among all transplanted patients presenting with de novo malignancies. Our present report focused on a 46-year-old woman who received immunosuppressive therapy based on cyclosporine and steroids for renal transplantation. Eight years after transplantations, she suffered lower abdominal pain and a mass involving peritoneal soft tissues was located near the right iliac vessels. Upon radical tumor excision, the histological examination revealed a high-grade leiomyosarcoma. Immunosuppression was reduced and cyclosporine switched to rapamycin. After 30 days, a computed tomography scan revealed two small pulmonary metastases, so the patient received adriamycin. Six months after the diagnosis, there was no intra-abdominal relapse and the pulmonary metastasis remain stable. The function of the transplanted kidney was normal and the patient was listed for laparoscopic pulmonary resection. Sarcomas in solid organ transplant patients appear to have aggressive features with 62% being high grade and 40% metastatic at the time of primary diagnosis with a recurrence rate of 30% and a 5-year survival rate of 25%. Patients diagnosed with sarcoma should be treated with multimodality therapy. After aggressive surgery whenever possible, a combination of a traditional cytotoxic drug and a "signal" blocking agent like rapamycin may increase selectivity toward tumor cells.

[Recurrence of glomerulonephritis in transplanted kidney]. / Recidiva della glomerulonefrite nel rene trapiantato.

Recent advances in immunosuppressive therapy have dramatically reduced the incidence of acute rejection, thus improving graft survival. As a result, the importance of recurrence of the original nephropathy as a factor affecting the long-term outcome of the graft has grown considerably The incidence of recurrence increases with the increase in graft survival and can currently be estimated between 6 and 15% 10 years after surgery, with great variability among the different histological types of nephropathy. More than 50% of patients with recurrence experience progressive deterioration of graft function, and recurrence of the nephropathy accounts for long-term graft failure in more than 15% of cases. The original disease should be duly considered in all candidates for renal transplantation to identify patients at higher risk for recurrence and to define those treatment protocols devoted to risk reduction. Finally, the risk of disease recurrence should always be included among the parameters used in evaluating a possible transplantation from living donor.

IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Thin glomerular basement membrane disease.

The term thin glomerular basement membrane disease (TBMD) refers to a condition characterised by thinning of the GBM at electron microscopy examination and, clinically, by isolated hematuria, frequently occurring in other family members, with no extra-renal manifestations. Progression towards chronic renal failure (CRF), although rare, has been reported and blood pressure is high in 30-35% of cases during follow-up. TBMD is generally considered different from Alport syndrome since immunohistological investigation does not show abnormalities of type IV collagen alpha chains in the GBM, as frequently observed in Alport patients; moreover, in familial cases, the disease is transmitted as autosomal dominant trait, rarely observed in Alport syndrome. Genetic studies suggest that TBMD is a heterogeneous disease, but some cases may be related to mutations of COL4A3/COL4A4 genes, thus belonging to the spectrum of type IV collagen diseases. TBMD may arise with other glomerular diseases, most frequently IgA nephropathy, and it remains to be established whether these cases are a casual occurrence or whether a thinner than normal GBM predisposes to immune complex deposition.

Renal transplantation in patients with microscopic polyarteritis and antimyeloperoxidase antibodies: report of three cases.

This paper reports on 3 patients on renal dialysis for crescentic glomerulonephritis associated with microscopic polyarteritis (MPA) and antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCAs). They successfully underwent renal transplantation from a cadaver donor 6-63 months after the onset of the disease, despite the persistence of antibodies at high titer. A triple immunosuppressive regimen including steroids, cyclosporin and azathioprine was used. One patient underwent transplantectomy for surgical complications 3 months later, while the serum creatinine was 2.0 mg/dl (178 mu mol/l): the remainder have a well-functioning graft after 21 and 38 months, no clinical sign of disease recurrence, and a MPO titer within the normal range. We conclude that MPA patients can undergo renal transplantation even if ANCAs persist at a high titer in the circulation.

Combined treatment in Wegener's granulomatosis with crescentic glomerulonephritis--clinical course and long-term outcome.

This study reports on 9 patients suffering from Wegener's granulomatosis (WG) with crescentic GN and severe systemic manifestations. On admission the mean serum creatinine was 10.9 +/- 5.1 mg/dl (4-20 mg/dl); 8 patients were oliguric and required dialysis treatment. Renal biopsy showed crescents in all cases, involving 66 to 100% of glomeruli. Patients were treated with a protocol including: a plasma exchange (PE) course; methylprednisolone; cyclophosphamide; and an antithrombotic agent (defibrotide). Clinical picture and renal function progressively improved in all patients within the first 4 weeks of treatment. After 1 month serum creatinine was 2.7 +/- 0.8 mg/dl and dialysis was no longer needed in any patient. Five relapses occurred in 3 patients 12-26 months after the onset of the disease, while they were still receiving immunosuppressive treatment. At follow-up (22 to 112 months: mean 71) all patients were alive with no clinical signs of disease activity. One patient was on regular dialysis while the others had a serum creatinine of 1.2-2.8 mg/dl (mean 1.9). Our results confirm that crescentic GN associated with WG can be successfully treated even when associated with severe clinical picture and suggest that PE can contribute to control the disease without increasing immunosuppression.

Plasma exchange treatment in rapidly progressive glomerulonephritis associated with anti-neutrophil cytoplasmic autoantibodies.

This study reports on 12 patients with acute renal failure due to biopsy-proven rapidly progressive glomerulonephritis and signs of systemic disease in whom antineutrophil cytoplasmic autoantibodies (ANCA) were detected by indirect immunofluorescence (IIF) on alcohol-fixed neutrophils and assessed in serial determinations by ELISA. The diagnosis was: Wegener's granulomatosis in nine patients who showed a diffuse cytoplasmic pattern at IIF (c-ANCA), and microscopic polyarteritis in three where a perinuclear pattern (p-ANCA) was seen. All patients underwent a course of plasma exchange - PE - (3-10 sessions per patient) associated with steroids and cyclophosphamide. The ANCA titer dropped steeply during PE in all cases and was followed by disappearance of systemic symptoms and renal function improvement within four weeks. After a follow-up period of 50 +/- 31.2 months all patients were alive without signs of disease activity; ten had stable renal function, with serum creatinine 1.8 +/- 0.7 mg/dl; two had entered regular dialysis treatment after 44 and 82 months. Our results suggest that the rapid removal of ANCA by means of PE can help control disease activity and reduce the risk of death or end-stage renal disease.

Ten years experience with plasma exchange in renal transplantation.

Plasma exchange has been used in our renal transplantation programme for over ten years to treat 86 patients divided into four groups. Five patients had preformed cytotoxic antibodies before transplantation (group A); 13 sensitized patients (greater than 60% PRA) underwent prophylactic plasma exchange in the immediate post-operative period (group B); 62 patients were treated for acute vascular rejection (group C); six patients had chronic graft rejection (group D). Plasma exchange is a valid tool for the treatment of acute vascular rejection, provided that it is started before irreversible graft damage occurs: 75% rejection crises were reversed by plasma exchange and the actuarial graft survival from the rejection episode was 75% at one year, 66% at two and 50% at five years. Serum creatinine before treatment and glomerular thrombosis at graft biopsy correlated with the response to plasma exchange. In sensitized patients and in those with chronic rejection the results were disappointing and suggest that in these clinical conditions plasma exchange should be used only in selected cases.

Prevention of chronic glomerular uremia in steroid resistant glomerulonephritis. A clinical trial with a new antithrombotic agent.

To investigate the possibility of slowing down disease progression 27 patients with primary glomerular diseases unresponsive to steroids and cytotoxic drugs were treated with Defibrotide. This drug is a single stranded DNA fraction which has profibrinolytic and deaggregating properties and can promote the generation and release of prostacyclin from vascular tissue. Before treatment all patients showed proteinuria in excess of 1 g/day and 16 had a nephrotic syndrome (59%); 10 patients had serum creatinine above 1.6 mg/dl (37%) and 6 were hypertensive. After therapy a significant decrease in daily proteinuria was observed, although the reduction exceeded 50% of pre-treatment values in only 16 patients (59%). A progressive decrease in serum creatinine occurred in patients with abnormal renal function; serial measurement of renal plasma flow showed a progressive improvement with an average increase of 6 and 12%, after 1 and 3 months of treatment, respectively. These observations confirm the view that drugs improving endothelial function and renal hemodynamics can be of value in the treatment of chronic glomerular diseases and can contribute to the maintenance of renal function.