Anne Modesto

Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation.

Polyomavirus‐associated nephropathy (PVAN) affects 1–10% of kidney‐transplant (KT) patients, with graft failure/loss in approximately 90% of cases. Reducing immunosuppression is the key treatment option, but addition of leflunomide may improve BK Virus (BKV) clearance and graft survival. In a prospective open‐labeled study, 12 KT patients with biopsy‐proven PVAN were treated with reduced immunosuppression and leflunomide. BKV viremia and graft function were followed. PVAN was diagnosed at 6 months (3–192) post‐transplant; median serum creatinine concentration (sCC) was 189 μmol/l (92–265). After 16 months (8–30) of follow‐up, the sCC was 150 μmol/l (90–378, NS). Renal function improved in six cases (50%), remained stable in two (16.6%) and deteriorated in four (33.4%), with graft loss in two (17%). Clearance of BKV viremia was observed in five (42%) cases. Side effects included anemia in six cases leading to leflunomide withdrawal in two patients, and mild thrombocytopenia. In KT patients diagnosed with PVAN, leflunomide plus reduced immunosuppression improved graft function in 66.6%, cleared BKV viremia in 42%, and resulted in side effects in 17%. This limited efficacy contrasts with other reports and falls short of expectation. We conclude that active screening, earlier diagnosis and intervention remain the cornerstones of treatment.

Oxalate Nephropathy Associated with Chronic Pancreatitis

BACKGROUND AND OBJECTIVES Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis-associated AON followed in four French renal units. RESULTS Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. CONCLUSION AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented.

Abdominal fat tissue aspirate in human amyloidosis: light, electron, and immunofluorescence microscopic studies.

Abdominal fat tissue aspirates from 12 patients with biopsy-proved amyloidosis were investigated by different morphologic techniques. By light microscopy, after staining of the fat tissue aspirates with Congo red and examination with a polarizing microscope, positive results were obtained in nine patients with amyloidosis, two of the three with primary (AL) amyloidosis and seven of the nine with secondary (AA) amyloidosis. By indirect immunofluorescence, using AA antiserum, positive results were obtained in five of the nine cases of AA amyloidosis (aspirates from these five patients were positive on Congo red staining). By electron microscopy, amyloid fibrils were observed in five cases of amyloidosis (two of the AL and three of the AA type, all positive on Congo red staining). Although amyloid was demonstrated less frequently by immunofluorescence and electron microscopy, perhaps because of the small numbers of fat particles examined, it seems that, with Congo red staining, abdominal fat tissue aspiration is a simple and sensitive method for the diagnosis of amyloidosis. Immunofluorescence studies allow discrimination between the different types of amyloidosis. The method could be used in patients in whom other types of tissue biopsy are not recommended because of risks of bleeding or other problems.

IgA Nephropathy Complicating Diabetic Glomerulosclerosis

A retrospective study was done on 66 diabetic patients who had renal biopsies performed during 1979–1994. This review shows 10 patients who presented IgA nephropathy associated with diabetic nephropathy. Six patients had insulin-dependent diabetes mellitus and 4 patients non-insulin-dependent diabetes mellitus. All patients presented with proteinuria and 7 had hematuria. Four patients presented with renal impairment. Histologic evaluation disclosed the presence of thickened glomerular basement membranes and increased mesangial matrix in all cases, associated with nodular sclerosis in 8 cases. By immunofluorescence, diffuse mesangial IgA deposits were observed in all cases. The high incidence of the coexistence of IgA nephropathy and diabetes seems not merely coincidental. Structural and/or functional abnormalities of the glomerular basement membranes might facilitate the development of immune complex glomerular diseases. In patients with diabetes, the appearance of urinary abnormalities and/or deterioration in renal function altered the clinical history of diabetic nephropathy. The disorders are clinically suggestive of the presence of nondiabetic renal disease and raised the possibility of another pathogenetic mechanism.

Fanconi’s Syndrome, Kappa Light-Chain Myeloma, Non-Amyloid Fibrils and Cytoplasmic Crystals in Renal Tubular Epithelium

A 59-year-old woman with kappa light-chain myeloma had Fanconis syndrome characterized by renal glycosuria, generalized aminoaciduria, bicarbonaturia and decrease of phosphorus and uric acid reabsorption. A bone marrow biopsy showed the presence of 27% of dystrophic plasma cells; the cytoplasm of these cells was intensely stained with anti-kappa light-chain monoclonal antibodies. By light microscopy, the renal biopsy revealed a tubulointerstitial nephritis without glomerular lesions and with intratubular casts. By immunofluorescence, no deposits were observed along the glomerular and tubular basement membranes, but a positivity with anti-kappa light chain was noticed in some tubular epithelia and casts. By electron microscopy, fibrils (35-nm diameter) were observed in the cytoplasm of proximal tubular cells. These fibrils were situated in vesicles (100- to 600-nm diameter) in the luminal side of tubular cells. In the basal pole of the cell, fibrils seemed to group in crystals (120- to 200-nm diameter). Only kappa light-chain protein was demonstrated in these fibrils and crystals by an immunoelectron microscopic technique. These data suggested the pathogenic role of the fibrils and crystals present in tubular epithelium in the tubular proximal syndrome.

Long-Term Follow-Up of Monoclonal Gammopathy of Undetermined Significance in Transplant Patients

We report the long-term follow-up of 5 patients (4 kidney, 1 heart recipients) having a pretransplant monoclonal gammopathy of undetermined significance (MGUS). The follow-up of MGUS before transplantation was 41.2 +/- 40.7 months (range 2-108). The monoclonal component isotype was IgG-kappa in 3 cases and IgA-lambda in 2. The pretransplant level of the monoclonal component was 11.1 +/- 4.8 g/l (range 4-15.6). The transplant recipients who had MGUS were older than our other transplant patients. All but one of them received ciclosporine A. They did not experience more rejection or infectious complications than the others. Their posttransplant follow-up ranged from 3 to 9 years. The monoclonal component level remained stable in 2 patients but increased in 3 (33-225%). This was not correlated with bone marrow plasmocytosis. Two patients developed smoldering myeloma indicated by bone marrow immunochemistry studies which showed monomorph monoclonal plasma cells; nevertheless, they did not have cytopenia or bone lytic lesions. This percentage is higher than in the Kyle study but we cannot assume that it is due to ciclosporine A since our study sample is too small. In conclusion, MGUS is not a contraindication to organ transplantation.

Serological Markers of Autoimmunity in Renal Transplant Patients with Chronic Hepatitis C

The aims of this prospective study were to assess the frequency of serological markers of autoimmunity and cryoglobulins in renal transplant (RT) patients presenting with chronic hepatitis C, and to correlate them with serum alanine aminotransferase (ALT) levels, hepatitis C virus (HCV) genotypes and viremia, and HLA-DR phenotypes. Three groups of patients were studied: group I comprised 74 HCV+ve RT patients; group II, 33 HCV–ve RT patients, and group III, 13 HCV–ve/hepatitis B virus (HBV)-positive RT patients. The three groups did not differ significantly according to their mean age, sex ratio and baseline immunosuppression.Serum specimens of these patients were tested for complement (hemolytic activity (CH50), C3, C4 and properdin factor B (PFB) components, rheumatoid factor (RF), immunoglobulin patterns, circulating immune complexes, and autoantibodies including antinuclear (ANA), anti-smooth muscle (ASMA), antimitochondrial, antithyroid microsomal (ATM), antithyroglobulin (ATG) and anti-LKM1 autoantibodies. We also looked for the presence of cryoglobulins in groups I and III. Cryoglobulinemia of type II was present in 2 patients of group I (2.7%) which was associated in 1 case with de novo membranoproliferative glomerulonephritis but was not found in any of the patients of group III. RF (>40 U/ml) were more frequently observed in groups I (55.4%) and III (46%) than in group II (20.6%), although the difference was not statistically significant (p = 0.06). Oligoclonal or monoclonal serum immunoglobulin patterns were present in 16.2% of the patients in group I, 15.4% in group III and only 3.3% in group II (p = 0.07). There was no significant difference between the prevalence of at least one autoantibody in the three groups (ranging from 38.5 to 50%), and neither was the frequency of ANA (23–36.6%), even at a high titer i.e. above 1:320, or ASMA (13.5–23%) significantly different. Conversely, tissue-specific autoantibodies, i.e. ATM, ATG and anti-LKM1, were only observed in HCV+ve patients. CH50, C3, C4 and PFB levels were significantly lower in group I than in group II, although values below the normal ranges were observed only for CH50 and C3 and were mostly found in the HCV+ve RT patients. Circulating immune complexes detected by nephelometry were at similar levels in the three groups, within the normal ranges. The occurrence of at least one autoantibody and/or the presence of RF >40 U/ml did not correlate with either serum ALT levels or a given HLA-DR phenotype in any of the three groups, nor did they correlate with HCV genotype or HCV viremia in group I. In conclusion, this study shows that contrary to HCV+ve immunocompetent patients, HCV+ve RT patients rarely present with cryoglobulinemia and have the same frequency of non-organ-specific autoantibodies as HCV–ve RT patients. Conversely, antithyroid autoantibodies are only observed in the former group. Finally, serological markers of autoimmunity are not related to serum ALT levels, HLA-DR phenotype, HCV viremia or HCV genotype in HCV+ve RT patients.

Rapidly Progressive Glomerulonephritis Associated with Bacterial Endocarditis: Efficacy of Antibiotic Therapy Alone

A 65-year-old woman presented rapidly progressive glomerulonephritis with purpura and mitral insufficiency. Blood cultures grew Streptococcus mitis. By light microscopy, the renal biopsy revealed necrotizing glomerulonephritis 56% associated with cellular crescents and tubulointerstitial changes. By immunofluorescence, deposits of IgM and C3 were found to be present in the mesangium. Electron-microscopic study showed subendothelial and intramembranous deposits. Treatment with antibiotics alone resulted in renal recovery with disappearance of proteinuria, circulating immune complexes and cryoglobulinemia. A 2nd renal biopsy, performed after 3 months, showed segmental sclerosis and tubulointerstitial lesions. Eight months after the first hospitalization, cardiac insufficiency occurred. Four years later, a valve replacement was performed. No abnormal serum creatinine, serum creatinine clearance or urinalysis levels were present. These data suggest that rapidly progressive glomerulonephritis associated with bacterial endocarditis may be treated by antibiotics alone and result in normal and stable renal function.

Predicting Factors of Long-Term Results of OKT3 Therapy for Steroid Resistant Acute Rejection following Cadaveric Renal Transplantation

In this retrospective study, we evaluated the histological and biological predictors of long-term response of renal transplant (RT) patients treated with orthoclone OKT3 for steroid resistant acute rejection (AR). Seventy-three patients, aged 37 ± 12 years, were included in this study between March 1987 and December 1996. All the patients but one had received sequential quadruple immunosuppression (polyclonal antilymphocyte globulins; steroids; azathioprine, and cyclosporin A). OKT3 (5 mg/day for 10 days) was administered for biopsy-proven steroid resistant AR i.e., after 3 consecutive pulses of methylprednisolone (10 mg/kg each). This was the first AR in 46 cases, the second AR in 22 cases and the third AR in 4 cases. Renal histology (Banff) showed borderline (BL) changes in 18 patients, grade I AR in 28 patients; grade II AR in 22 patients, and grade III AR in 5 patients. When treatment with OKT3 commenced (107 ± 18 days post-transplantation) the mean serum creatinine (SCr) level was 325 ± 195 μmol/l; this had decreased to 191 ± 106 μmol/l by the end of OKT3 therapy. The immediate response to OKT3 therapy i.e., within the first month, was not dependent on the histological score. Twenty-six patients (35%) subsequently experienced at least one more AR episode of whom 4 were retreated with OKT3. The overall patient’s survival was 94.5% at last follow-up. The overall cumulative graft survival was 64.5% at 2 years, 52.5% at 5 years, and 40.5% at 8 years. The graft survival (5 years) tended to depend on the initial histological score, i.e. BL 30%; grade I 66%; grades II and III 55.5% (p = 0.08). In a multiple logistic regression analysis we tried to identify independent factors that would predict that a graft would still be functioning at least 2 years after OKT3 therapy. We therefore analyzed the following parameters: donor and recipient’s age; gender; cold ischemia time; HLA matching; panel reactive antibodies (PRA) prior to grafting; previous transplantation(s); total number of AR episodes; the time of onset of the AR treated by OKT3 compared to the other AR; the time of onset of the AR treated by OKT3; SCr levels at days 0, 10 and 30 after OKT3 therapy; histological score (Banff) i.e., the magnitude of AR and the presence or absence of chronic lesions. The only independent factors which would predict that a graft was still functioning 2 years after OKT3 therapy were: PRA <25% (Odds ratio (OR) 7.68 (1.15–51.3); p = 0.035); a grade I AR (OR 10.52 (1.18–93.5); p = 0.035); SCr level 1 month after OKT3 therapy (OR 0.935 (0.87–1.002); p = 0.05). HLA matching and the presence of histological chronic lesions were nearly significant (p = 0.06 and 0.09 respectively). In conclusion, this retrospective study shows that independent predictors of the long-term response to OKT3 therapy for AR in RT patients are the magnitude of pre-transplant PRA, the histological score, and the SCr level one month after OKT3 therapy.

Henoch-Schönlein purpura in a patient with diabetic nephropathy.

A 46-year-old man presented with Henoch-Schönlein purpura and diabetic nephropathy. At 30 years of age, the patient had presented with an acute and severe nephritic syndrome with severe renal impairment. The renal function returned to normal 6 months after this first attack. At the age of 38 years, the patient was diagnosed as having type II diabetes and was treated with diet alone. At 44 years of age, a renal biopsy was performed because of proteinuria and hematuria. In this renal biopsy, mesangial expansion, medial arterial hyperplasia, and focal interstitial fibrosis were found to be present. Mesangial and subendothelial deposits of immunoglobulin A (IgA) were demonstrated by immunofluorescence. At 45 years of age, cutaneous vasculitis appeared, and at 47 years of age, the patient presented with necrotic purpura, non-insulin-dependent diabetes, renal impairment, proteinuria, and hematuria. A skin biopsy demonstrated leukocytoclastic skin vasculitis with IgA deposits in the arterial walls. A second renal biopsy was performed that showed diabetic glomerulosclerosis associated with a marked vascular and interstitial fibrosis. Mesangial and subendothelial deposits of IgA and C3 and linear IgG deposits along the glomerular basement membranes were demonstrated by immunofluorescence. Electron microscopy showed that the glomerular basement membranes were thickened; a fusion of foot processes was observed and electron-dense deposits were present in the widened mesangium. In summary, we describe a patient with a history of ancient glomerulonephritis who presented with an IgA mesangial nephropathy consistent with Henoch-Schönlein purpura associated with diabetic glomerulosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)