Glomerular and tubulointerstitial foscarnet nephropathy of kidney allograft with emphasis on ultrastructural findings: A case report.

INTRODUCTION: Foscarnet (trisodium phosphonoformate hexahydrate) is standard treatment for ganciclovir-resistant cytomegalovirus (CMV) infections. In the kidney, foscarnet-induced injury may be attributed to reversible tubulointerstitial lesions, but foscarnet crystals have also been observed within glomerular capillaries, suggesting that foscarnet can lead to glomerular lesions such as crescentic glomerulonephritis. We present biopsy and autopsy findings of foscarnet induced nephropathy in a transplanted kidney, with a particular emphasis on the histopathology and electron micrographic peculiarities of drug crystal deposits. CASE PRESENTATION: A 72-year-old Caucasian male patient with a deceased donor kidney was treated with several foscarnet applications due to ganciclovir-resistant CMV infection. Transplant kidney biopsy revealed massive glomerular crystalline precipitates, resulting in crescentic glomerulonephritis and tubular damage. The last foscarnet application was complicated with several infections and kidney graft failure. Autopsy revealed multi-organ damage due to foscarnet crystal precipitations associated with systemic CMV and fungal infection. On autopsy of kidney specimens, we succeeded in preserving the rectangular flat plate-like foscarnet crystals in stacks detected by transmission electron microscopy (TEM) after 100% alcohol fixation. The chemical composition of the crystals was confirmed by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. CONCLUSION: Transplant kidney biopsy remains the gold standard in distinguishing between foscarnet crystalline glomerular and/or tubulointerstitial lesions, and various forms of rejection and other causes of impaired renal function in transplant kidney.

Rituximab for the treatment of membranous nephropathy: a single-center experience.

BACKGROUND: Treatment of idiopathic membranous nephropathy with rituximab was introduced more than a decade ago following experimental data that suggested involvement of B-cell-mediated reactions in its pathogenesis. It was a logical step towards a more selective therapy with less severe side effects as compared to the recommended first-line immunosuppressive therapy with corticosteroids and different immunosuppressant drugs. METHODS: We retrospectively analyzed the anonymous data of patients who were treated with rituximab for idiopathic membranous nephropathy at our institution from January 2006 to July 2016. Daily proteinuria and serum creatinine were analyzed 3, 6, 9, and 12 months after rituximab application. The patients were divided into 4 groups according to proteinuria. We separately analyzed remission rates in the whole group and in groups with different quantity of daily proteinuria. Other history data and laboratory parameters were also compared within different groups of patients. RESULTS: The study involved 29 rituximab treatments in 26 patients: 7 (26.9%) female and 19 (73.1%) male patients. In 16 out of 29 treatment cases (55.1%), patients had been previously treated with cyclophosphamide and steroids, or cyclosporine with low dose of steroids, or both. In 72.4% of patients, antiphospholipase A2 receptor antibodies were present. In 2 cases of treatment (6.9%), patients received rituximab 375 mg/m2 of body surface area in 3 and 4 weekly doses, respectively. In all other cases, repeated rituximab applications were given as needed according to the levels of circulating CD-20 B-cells. The total remission rate in our cohort of patients was 37.9% (11 out of 29 cases). The average serum creatinine in the group of patients who achieved remission was significantly lower than in the group without remission (86.5 vs. 155.5 µmol/L, p = 0.003). There was no difference in the duration of the disease prior to treatment with rituximab between the groups (53.6 and 56.4 months, respectively). The remission rate was highest in the group with daily proteinuria less than 4 g per day (83.3%). There were no remissions in the group of patients with daily proteinuria more than 12 g per day. CONCLUSION: The remission rate after rituximab treatment in our cohort of patients with idiopathic membranous nephropathy was lower than in other studies. The reason for this is possibly the application of a single dose of rituximab in the majority of patients, which might have been insufficient in patients with higher proteinuria.
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Treatment of antibody-mediated rejection of kidney grafts with bortezomib and/or rituximab compared to standard regimen: experience of Slovene National Center.

BACKGROUND: The aim of our study was to determine outcomes of standard treatment of antibody-mediated rejection (ABMR) of kidney grafts as compared to the addition of bortezomib or rituximab. METHODS: The cohort of this retrospective study included patients treated for ABMR of kidney grafts at our national center in the period of 2005 - 2017, divided into two groups: standard (ST) group treated standardly with plasmapheresis or immunoadsorption, intravenous immunoglobulins, and corticosteroids, and BR group treated with the addition of bortezomib and/or rituximab. Patient and graft survival at 2 years was analyzed by Kaplan-Meier method, and predictors of graft survival were analyzed by Cox regression. RESULTS: There were 78 patients with ABMR (48 in the ST group, 30 in the BR group), 41 (53%) were men, mean age 49.5 ± 13.8 years. In ST and BR, respectively, mean serum creatinine was 267 ± 164 and 208 ± 112 µmol/L (p = 0.088), donor-specific antibodies (DSA) were positive in 75% and 97% (p = 0.022), and ABMR was acute in 50% and 33% (p = 0.149). Patient survival at 2 years was 89% in the ST and 100% in the BR group (p = 0.125). Cumulative proportion of kidney graft survival at 1 and 2 years was 67% and 53% in the ST group and 73% and 48% in the BR group, respectively, (p = 0.641). Chronic ABMR (HR 5.22, p = 0.004) was significant, while dialysis dependency at biopsy (HR 3.28, p = 0.072), serum creatinine at kidney biopsy (HR 1.003, p = 0.082), and presence of DQ-DSA (HR 3.37, p = 0.062) were borderline significant predictors of worse graft outcome. Infections were relatively common in both groups, with a trend towards more rehospitalizations due to infections in the first 6 months after treatment in the BR group (p = 0.066). In 5 patients (17%), treatment with bortezomib was discontinued prematurely due to cytopenia. CONCLUSIONS: Bortezomib or rituximab, added to standard treatment, did not significantly improve kidney graft survival and was also not associated with significant side effects, except cytopenia in some cases. Treatment of acute ABMR resulted in better graft survival than chronic ABMR.
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Tubular urinary indexes reliably distinguish between primary tubulointerstitial and primary glomerular diseases in patients referred for kidney biopsy.

AIMS: Kidney biopsy remains the gold standard for accurately diagnosing renal diseases. Urinalysis and assessment of renal function are the cornerstones for assessment of patients prior to biopsy. There is significant overlap in the results of routine urine parameters (proteinuria, erythrocyturia, leukocyturia) among different kidney diseases, which hinders the possibility of adequately estimating disease etiology prior to the biopsy. The aim of our study was to assess whether diverse markers of glomerular and tubular proteinuria - urinary albumin, IgG, α-1-microglobulin (α-1-m) and N-acetyl-ß-D-glucosaminidase (NAG) - are capable of distinguishing between patients with primary tubulointerstitial (TID) and primary glomerular disease (GLOM). METHODS: Our study is a retrospective, single-center, consecutive case series of patients referred for kidney biopsy. We analyzed routine urinalysis results performed on a second morning urine sample immediately prior to the biopsy. RESULTS: Patients with TID had significantly higher values of α-1-m and NAG, with lower values of albumin and IgG in the urine compared to patients with GLOM. Three tubular urinary indexes had high sensitivity and specificity for distinguishing TID from GLOM: NAG/albumin, α-1-m/proteinuria, and α-1-m/albumin, with the highest values in the latter index (96.6% and 98.2%, respectively, cut-off point ≥ 0.33). CONCLUSIONS: Prior to kidney biopsy, tubular urinary indexes may present a valuable tool in distinguishing patients with TID from patients with GLOM.
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Increase in spot urine protein excretion is associated with late kidney graft rejection and predicts rejection phenotype.

AIMS: A noninvasive test that foretells kidney graft rejection before loss of kidney function would be desirable. We hypothesized that an increase in estimated protein excretion rate (ePER) from spot urine samples is associated with graft rejection and predicts rejection phenotype. METHODS: 151 patients who had undergone first-indication kidney biopsy due to graft dysfunction beyond 3 months after transplant were identified from a national cohort of 616 transplant recipients between 2000 and 2012 (25%). ePER were calculated from spot urine protein-to-creatinine ratios at baseline, 3 months before biopsy (ePER-3m), and at the time of biopsy (ePERbiopsy) and were correlated with histologic biopsy findings. RESULTS: Levels of ePER 3 months before biopsy and at the time of biopsy were greater in 32 patients with antibody-mediated rejection (ABMR) than in 77 patients with T-cell-mediated rejection (TCMR) and 42 patients with other findings (median ePER-3m 912 vs. 320 vs. 232 mg/day/1.73m2; and median ePERbiopsy 1,672 vs. 356 vs. 268 mg/day/1.73m2; p < 0.001). Receiver operator characteristics (ROC) analyses demonstrated that ePER-3m and ePERbiopsy had good diagnostic accuracy to discriminate between biopsy specimens showing ABMR vs. those showing TCMR or other histologic findings (area under the ROC curve 0.84, 95% CI 0.75 - 0.93 and 0.89, 95% CI 0.82 - 0.97, respectively; p < 0.001). CONCLUSIONS: An increase in ePER before kidney graft dysfunction appears to be associated with graft rejection and predicts ABMR phenotype.
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Outcome of polyomavirus nephropathy in renal transplant patients: a single-center experience.

BACKGROUND: Reduction of immunosuppression is a common therapeutic strategy in patients with polyomavirus nephropathy (PVN) but may be associated with acute rejection. This study aimed to evaluate the morphology of PVN in renal biopsies after reduction of immunosuppression. METHODS: Eight of 241 patients who received a kidney transplant between January 2012 and December 2015 presented with BK viremia and biopsy-proven PVN. Morphological evaluation according to Banff criteria and correlation with viremia and kidney function after immunosuppression reduction was performed. RESULTS: PVN grades A and B were diagnosed on average 4.7 months post-transplant in 1 and 7 patients, respectively. Indication biopsies after immunosuppression reduction showed an increase in tubulitis and interstitial inflammation score compared to those at the time of the PVN diagnosis. Surveillance biopsies 1 year after transplantation revealed resolution of interstitial inflammation and tubulitis accompanied by clearance of BK viremia in 4 patients (50%), including 1 patient with rejection. One patient showed residual interstitial inflammation after viral clearance. In these patients, renal function returned to baseline. One patient with persisting low BK virus (BKV) in serum and kidney showed a decrease of tubulointerstitial inflammation but scarring was seen. Rejection occurred in 3 patients (38%). CONCLUSION: PVN-associated interstitial inflammation and tubulitis cannot be differentiated morphologically from T-cell-mediated tubulointerstitial rejection. Significant interstitial inflammation and tubulitis in PVN under low-dose immunosuppression might represent immune reconstitution injury, which is reduced after successful BKV clearance from the serum and kidney. Concomitant rejection in PVN patients on low immunosuppression might be efficiently treated with transient pulse immunosuppressive therapy.
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Severe active C3 glomerulonephritis triggered by immune complexes and inactivated after eculizumab therapy.

BACKGROUND: Understanding the role of alternative complement pathway dysregulation in membranoproliferative glomerulonephritis (MPGN) has led to a dramatic shift in its classification into two subgroups: immune complex-mediated MPGN and complement-mediated MPGN, consisting of dense deposit disease and C3 glomerulonephritis (C3GN). A limited number of C3GN cases have been published to date with not yet conclusive results since the novel therapeutic approach with eculizumab was introduced. CASE PRESENTATION: We report the clinical follow-up of a 16-year-old patient in whom a diagnosis of C3GN was confirmed by immunofluorescence and electron microscopy in second and third kidney biopsies, while the first biopsy revealed idiopathic immune complex-mediated MPGN type III, Anders and Strife variant, which failed to improve after several attempts at conventional immunosuppression therapy. Although applied late in an already fairly advanced stage of the severe active form of MPGN, the efficacy of eculizumab on C3GN was evidenced clinically and pathohistologically. Its beneficial influence on pathomorphogenesis was demonstrated by a unique follow-up in the last three biopsies, despite the recent observation, confirmed in this study, of eculizumab binding within the kidney tissue. CONCLUSIONS: Clinicians and pathologists should be aware that, in some patients, an underlying genetic or acquired complement alternative pathway abnormality can be masked by an initial immune complex-mediated mechanism, which subsequently triggers an unbalanced excessive continual driving of complement terminal pathway activation and the development of C3GN. In such a patient, supplementary steroids in addition to eculizumab appear necessary to achieve an adequate response.

IgA-dominant acute poststreptococcal glomerulonephritis with concomitant rheumatic fever successfully treated with steroids: a case report.

There are only a few reports of the co-occurrence of acute poststreptococcal glomerulonephritis (APGN) and acute rheumatic fever. We report an unusual case of a 3-year-old boy with nephrotic syndrome and acute renal failure with the transitional need for peritoneal dialysis, biopsy-proven atypical IgA-dominant APGN, and concomitant acute rheumatic fever, successfully treated by steroids. Aggressive treatment with pulses of methylprednisolone proved to be successful and we recommend its use in this type of cases.

Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy.

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

Do C1q or IgM nephropathies predict disease severity in children with minimal change nephrotic syndrome?

BACKGROUND: It has been suggested that C1q and immunoglobulin M (IgM) nephropathy are variants of minimal change nephrotic syndrome (MCNS). Many researchers believe that these two conditions signify a worse prognosis for children with MCNS in comparison with immunofluorescence (IF)-negative MCNS. The aim of our study was to determine the prognostic significance of C1q nephropathy and IgM nephropathy in children with MCNS. METHODS: Fifty-five children with MCNS who had been biopsied over the course of 24 years at our institution were retrospectively categorized into three groups on the basis of IF microscopy findings: IF-negative MCNS (29/55 patients), MCNS with IgM nephropathy (19/55 patients), and MCNS with C1q nephropathy (7/55 patients). Clinical characteristics at disease presentation, clinical course, and renal outcome were compared between groups during the median follow-up period of 16.9 years (minimum 1.0, maximum 31.1 years). RESULTS: No statistically significant differences in clinical characteristics at disease presentation, clinical course, and renal outcome were found. Children with IgM nephropathy, C1q nephropathy, and IF-negative MCNS were clinically indistinguishable. CONCLUSIONS: We concluded that C1q or IgM nephropathy variants do not seem to signify a worse prognosis in children with MCNS in comparison with IF-negative MCNS.

Goodpasture's syndrome with concomitant immune complex mixed membranous and proliferative glomerulonephritis.

Classical Goodpasture's (GP) syndrome is a monophasic illness characterized by pulmonary hemorrhage and rapidly progressive glomerulonephritis with linear IgG deposition along the glomerular and distal tubular basement membrane and estructive necrotizing diffuse extracapillary crescentic glomerulonephritis. The majority of patients have circulating anti-glomerular basement membrane (GBM) antibodies, detectable with standard anti-GBM ELISA. Concurrence of GP syndrome with proliferative glomerulonephritis has only rarely been described. In this report, for the first time we describe in a 21-year-old woman GP syndrome with 50% crescentic sclerosing glomerulonephritis with linear immunofluorescence characteristic of anti-GBM pathogenesis, combined with mixed membranous and membranoproliferative glomerulonephritis with granular immunofluorescence and subepithelial, mesangial and subendothelial deposits characterizing immune complex pathogenesis. The clinical picture was also unusual for GP syndrome, manifesting a recurrent but non-progressive course, nephrotic syndrome, normal renal function and low values of anti-GBM antibodies, identified only by novel more sensitive techniques.

Urinary immunoglobulin G to albumin ratio and N-Acetyl-Beta-D-Glucosaminidase as early predictors of therapeutic response in ANCA-associated glomerulonephritis.

BACKGROUND: The aim of our study was to evaluate the prognostic value of glomerular and tubular proteinuria and tubular enzymuria as early indicators of therapeutic response to induction therapy with i.v. pulse cyclophosphamide (CyC) and methylprednisolone (MP) in patients with antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis. METHODS AND FINDINGS: An observational single-center study was conducted in 30 patients with ANCA-associated glomerulonephritis. Patients were divided into subgroups with good or poor response to CyC therapy according to clinical and laboratory parameters. The diagnosis of ANCA-associated glomerulonephritis was based on the Chapel-Hill disease definitions. Good response to induction therapy was significantly associated with higher absolute values of urine N-acetyl-beta-D-glucosaminidase (NAG) to creatinine ratio (above 14.83 microcat/mol) and urine immunoglobulin G (IgG) to albumin ratio (above 0.09) at the time of diagnosis, while albuminuria or proteinuria did not have any early predictive value. The remission of renal disease was anticipated as early as 3 months after introduction of induction therapy in patients with reduction of urine NAG to creatinine ratio below the baseline value and in patients with at least 24% rise in eGFR. CONCLUSIONS: Urine IgG to albumin and urine NAG to creatinine ratio are better early predictors of treatment response in patients with ANCA-associated glomerulonephritis than proteinuria or albuminuria.

Successful treatment of severe hantavirus nephritis with corticosteroids: a case report and literature review.

Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33-year-old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti-fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 µmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus.

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Acute kidney injury in immunoglobulin A nephropathy: potential role of macroscopic hematuria and acute tubulointerstitial injury.

The aim of our retrospective study was to analyze the clinical course and outcome of patients with immunoglobulin A (IgA) nephropathy who presented with macroscopic hematuria and acute kidney injury (AKI). During the period from 1990 to 2005, seven out of 584 adult patients with IgA nephropathy (1.2%) fulfilled the criteria for macroscopic hematuria-induced AKI. There was an equal gender distribution among our patients, and a rather high average age at presentation (55.7 +/- 10.9 years). Four patients who were oliguric upon admission to hospital needed hemodialysis treatment. The average serum creatinine at the time of kidney biopsy was 429.8 +/- 377 micromol/L (median value 378). The percutaneous kidney needle biopsies showed focal proliferative crescentic glomerulonephritis of subclass III, according to the Haas scheme, associated with prominent red blood cell tubular casts and acute tubulointerstitial nephritis. Four patients with the most prominent crescents and tubulointerstitial involvement were treated with methylprednisolone. All patients, treated and untreated, recovered their kidney function (the serum creatinine at a median follow-up of 15 months was 111.7 +/- 38 micromol/L). In conclusion, AKI in IgA nephropathy accompanied by macroscopic hematuria appears to have been a reversible condition in our series of patients. Regarding pathogenesis, the kidney biopsy study points to the important role of glomerular bleeding with consequent, widespread obstructive red blood cell tubular casts accompanied by tubular injury and interstitial nephritis.

Encapsulating peritoneal sclerosis in patients on peritoneal dialysis in Slovenia.

Encapsulating peritoneal sclerosis (EPS) is a rare complication in patients on peritoneal dialysis (PD), the prevalence of which increases with the time spent on PD. Various causative factors have been proposed, but the pathogenesis still remains unclear. The aim of our retrospective study was to analyze the basic clinical characteristics and outcomes of five patients diagnosed with EPS out of 423 patients treated with PD between January 1983 and December 2003. One patient was admitted due to ultrafiltration failure of the peritoneal membrane, and four patients were admitted for acute peritonitis. All of our patients presented with clinical symptoms suggestive of obstructive ileus. We confirmed the diagnosis of EPS with a computer tomography scan, a diagnostic laparotomy or laparoscopy, and a biopsy of the parietal peritoneum. We treated all of our patients with catheter removal, transferal to hemodialysis, antibiotics, complete parenteral nutrition, methylprednisolone, and tamoxifen for 6 months. One patient was treated with surgical enterolysis and died of septic complications, another patient died of sudden cardiac death during treatment. Three patients were doing well for 4-7 months after the treatment was started. The incidence of EPS was 1.2% and the mortality rate was 40%. EPS is a rare complication in longstanding PD patients in our institution. Despite treatment with hemodialysis, complete parenteral nutrition, steroids, tamoxifen and surgical intervention, the mortality rate is high and comparable to other reports.

Clinical outcome of patients with coexistent antineutrophil cytoplasmic antibodies and antibodies against glomerular basement membrane.

Antineutrophil cytoplasmic antibodies (ANCA) and antibodies against glomerular basement membrane (anti-GBM) rarely coexist. Both antibodies may be associated with rapidly progressive glomerulonephritis and pulmonary hemorrhage. We describe the clinical, serological and histological features of our patients with dual antibodies. From 1977 to 2008, 48 patients with anti-GBM antibody-associated renal disease were observed. Eight out of the 30 tested patients (26.7%), all females, had positive myeloperoxidase (MPO)-ANCA coexistent with anti-GBM antibodies. The patients' mean age was 63.4 +/- 7.8 years. Five presented with pulmonary-renal syndrome, all but one were dialysis-dependent on admission. They had constitutional symptoms and different organ involvement. The kidney biopsies revealed intense linear staining for immunoglobulin G and C3 along the glomerular and distal tubular basement membrane associated with irregular diffuse or focal extracapillary crescentic glomerulonephritis with necrosis of varying extent. Lesions of varying ages were characteristically expressed. Seven patients were treated with methylprednisolone and plasma exchange, four with cyclophosphamide, and one with intravenous immunoglobulin. After 28-74 months, there were three dialysis-dependent survivors and one patient with stable chronic renal disease. Two clinical relapses with pulmonary involvement and MPO-ANCA positivity without anti-GBM antibodies occurred in two dialysis-dependent patients. In summary, screening for ANCA and anti-GBM antibodies should be undertaken in patients with clinical signs of systemic vasculitis. In dialysis-dependent patients, the goal of treatment is to limit the damage of other involved organs and not to preserve renal function. Careful follow-up is necessary due to the relapsing nature of the ANCA component of the disease.

Microthrombotic/microangiopathic manifestations of the antiphospholipid syndrome.

The paper presents an overview of clinical manifestations and histopathologic findings in different organs in microvascular thrombotic and microangiopathic antiphospholipid syndrome (MAPS). Subsets of antiphospholipid syndrome (APS) are presented and defined. Clinico-pathologic correlations seem insufficient so far, because of a lack of detailed systematic studies of the histopathology in different organs. Based on their own autopsy and biopsy studies, the authors propose a novel categorization of histopathologic lesions that occur in patients with classic and catastrophic APS. In addition to the already accepted category of a microvascular thrombotic type of lesions, microangiopathic lesions consistent with thrombotic microangiopathy are proposed to be included in new revised classification criteria for definite APS. Microvascular thrombotic and so far underestimated microangiopathic histopathologic lesions have been shown to appear in various combinations and of different ages in patients with both classic and catastrophic APS, which fits into the concept of MAPS. These preliminary findings of our studies are also in line with the most recent hypothesis of two main mechanisms in the pathogenesis of APS, emphasizing a key role of endothelial cell affection induced by aPL on the one hand and interference with coagulation cascade on the other side.

Balkan endemic nephropathy: a still unsolved puzzle.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial renal disease, occurring in certain regions in 5 countries of the Balkan peninsula. Its etiology is largely unknown, though several hypotheses have been formulated and are discussed in this review. In several cases, etiological hypotheses (e.g., viral, ochratoxin or trace element involvement) are verified only in local endemic areas and can not be confirmed when tested elsewhere. Only certain families in the endemic areas are affected. An exposure of at least 20 years to the unknown factors in the endemic areas seems to be mandatory for the development of the disease, but a genetic predisposition to this disease also seems to be mandatory. Prominent clinical features are severely shrunken kidneys, a more severe anemia relative to the level of renal function, and a slow progression to end-stage renal failure. An international approach to solving the etiological and pathogenetic enigma of BEN is needed in the coming years. It is also time to reevaluate other chronic, slowly progressive tubulointerstitial nephropathies diagnosed elsewhere in the world and to search for possible etiological similarities with BEN.

Hantavirus nephropathy.

Pathogenic rodent-borne hantaviruses cause in humans generalized infections that involve the peripheral vascular bed and severely affect their permeability. We describe a 30-yr-old male patient with clinical symptoms characterizing five conventional phases of hemorrhagic fever with renal syndrome after an uncommonly severe hantavirus infection with the Puumala strain. Renal biopsy in this situation typically demonstrates acute hemorrhagic interstitial nephritis, particularly pronounced in the outer medulla. Hantaviruses are not cytopathic for most cells, and their interactions with endothelial cells that activate immune mechanisms play a key role in the pathogenesis of vascular dysfunction characterizing this disease.