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Steroid-resistant nephrotic syndrome with either minimal changes or focal and segmental glomerular sclerosis on initial biopsy is a severe condition as more than 50% of patients with the disease progress to end-stage renal failure within 10 years. We recently identified a distinct form of idiopathic nephrotic syndrome with an autosomal recessive mode of inheritance and were able to map the gene on the long arm of chromosome 1. The absence of recurrence of the disease after renal transplantation suggest a primary defect in a glomerular basement membrane protein. Several reports suggest that cyclosporine is effective in a proportion of patients with steroid-resistant idiopathic nephrotic syndrome, particularly when used in combination with corticosteroids. There are also data suggesting that high doses of cyclosporine may be necessary in patients with severe hypercholesterolemia. However, cyclosporine treatment should be carefully monitored in view of the high risk of nephrotoxicity, as shown by the results of repeat renal biopsies. The beneficial role of cyclosporine in recurrent steroid-resistant nephrotic syndrome is still debated. Preliminary observations suggest that the early use of intravenous cyclosporine may be effective in these patients.

Mitochondrial cytopathies are metabolic diseases, expressing mutations in nuclear DNA, punctiform mutations or depletions in mitochondrial DNA. These genetic lesions alter mitochondrial oxidative phosphorylation, with a reduction in energy produced for cell activity. Renal disease may be the first sign of mitochondrial cytopathy, or it may appear together with neurological and neuromuscular signs. Fanconi's syndrome, a benign sign of renal tubulopathy, is particularly frequent in newborns with mitochondrial cytopathy, whereas tubulointerstitial nephropathy, which affects infants and adults, is more serious because it develops into terminal uremia. Findings of hyperlactatemia and reduced enzymatic activity on the respiratory chain in tissue biopsies are of diagnostic significance in mitochondrial cytopathy. A breakthrough is being made in our understanding of genetic alterations in mitochondrial DNA, and with future therapy, the kidney, a target organ, may be safeguarded.

Background There is increasing evidence from clinical trials on which to base a rational approach to the care of lupus nephritis (LN). Objectives To develop recommendations for the management of LN. Methods Questions were compiled using a modified Delphi technique. A systematic PubMed search was performed, and evidence-based and expert-opinion approach was followed to prepare recommendations. Results No clinical, serologic or laboratory tests can accurately predict renal biopsy findings in SLE; any sign of renal involvement, especially proteinuria >0.5 g/24-hr, should be an indication for biopsy. Assessment should include glomerular changes, activity and chronicity indices, tubulointerstitial lesions, and vascular lesions. Because of more favourable efficacy/toxicity ratio, for most patients with ISN/RPS2003 Class IIIA or A/C and Class IVA or A/C (±V) LN, mycophenolate mofetil (MMF) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. Induction regimens should be combined initially with three daily pulses of IV methylprednisolone, followed by oral prednisolone 0.5 mg/kg/day. In patients with adverse clinical or histological features, CY can also be prescribed monthly at higher doses (0.75-1g/m2) for 6 months or orally for 3 months. For pure class V disease with nephrotic-range proteinuria, MMF in combination with oral prednisolone may be used initially. In patients responding to initial therapy (≥50% reduction in proteinuria and stable/improved GFR) within 6-12 months, maintenance immunosuppression is recommended with MMF or azathioprine for at least 3 years. For MMF or CY failures, we recommend switching to the other or rituximab. Pregnancy should be planned in stable patients with inactive lupus and serum creatinine

Evaluation of fetal renal function by analysis of fetal urine sampled in utero may improve perinatal care after a prenatal diagnosis of bilateral obstructive uropathy. We provide reference intervals for 10 fetal urinary compounds and examine their variation with gestational age. Forty-one fetuses with bilateral obstructive uropathy (urine sampled between 20 and 38 weeks of gestational age) had normal, healthy values for serum creatinine (or = 50 mumol/L) at ages 1-2 years. These cases were thus assumed to represent a reasonable approximation to healthy values. Sodium and beta 2-microglobulin concentrations significantly decreased with gestational age; calcium, ammonia, and creatinine significantly increased; glucose, phosphorus, chloride, urea, and total protein concentrations did not vary. Our results provide reference values for prenatal evaluation of fetal renal function and suggest that glomerular filtration of macromolecules and tubular reabsorption of glucose and phosphorus are mature by 20 weeks of gestation, whereas tubular reabsorption of sodium and beta 2-microglobulin increases progressively during the second half of gestation.

Juvenile chronic arthritis (JCA) was diagnosed in 2 young girls. In one of them, antinuclear antibodies (ANA) were strongly positive during the course of erosive polyarthritis. After 5 years followup, severe renal insufficiency occurred. Antineutrophil cytoplasmic antibodies (ANCA) were positive with a perinuclear pattern on indirect immunofluorescence (IIF) and antimyeloperoxidase (MPO) specificity. Renal biopsy showed severe crescentic glomerulonephritis without significant deposits on IIF. Treatment consisted of prednisone and monthly intravenous cyclophosphamide pulse. Renal failure worsened and hemodialysis was necessary. A 2nd patient was referred for polyarthritis with positive rheumatoid factors without positive ANA. The presence of microscopic hematuria led to the discovery of crescentic glomerulonephritis with positive ANCA of anti-MPO specificity. At latest examination, after prednisone for 10 months and azathioprine for 6 months, the patient had moderate proteinuria with normal renal function. These observations emphasize that in juvenile onset chronic polyarthritis, renal microscopic angiitis with ANCA of anti-MPO specificity may occur.

We recently described a case of anaphylaxis occurring at the time of retreatment with OKT3 of a renal allograft recipient in whom, for the first time, high anti-OKT3 IgE levels were documented. This led us to examine a large series of sera from 181 OKT3-treated patients to better define the frequency of IgE sensitization, its fine specificity (anti-isotypic and/or anti-idiotypic) and its relation to the appearance of IgG anti-OKT3 antibodies (Abs). Six patients out of the 181 assayed have developed anti-OKT3 IgE Abs as detected by ELISA. The earliest time of appearance of IgE anti-OKT3 Abs was 10 days after starting OKT3 (range, 10-25). The IgE response peaked by day 18 (range, 11-35) and had usually disappeared at 3 months after treatment. A more careful dissection of the fine specificity of the IgE response revealed that three of the four patients tested had developed an exclusive anti-idiotypic response. In the last patient, an anti-isotypic component was present since anti-OKT3 IgE Abs also reacted with control IgG2a, IgG2b, and IgG3 monoclonal antibodies. Importantly, anti-OKT3 IgE Abs were only detected in heavily sensitized patients also showing high titers of IgG specific Abs by ELISA (or = 1/1000) as well as "blocking" anti-OKT3 antibodies, as assessed by immunofluorescence. We conclude that (1) exposure to OKT3 may lead to specific IgE sensitization that, however, only appears in about 38% of the patients; (2) IgE Abs mostly appear in patients also showing high levels of conventional IgG anti-OKT3 Abs including the presence of "blocking" anti-idiotypic Abs, and (3) IgE Abs may be directed to both idiotypic and isotypic determinants of the monoclonal antibody.

Sixty-five children with steroid-resistant idiopathic nephrosis were treated with cyclosporine, 150 to 200 mg/m2, in combination with prednisone, 30 mg/m2, daily for 1 month and on alternate days for 5 months. Renal biopsy had shown minimal change disease in 45 children and focal segmental glomerular sclerosis in 20. Twenty-seven patients achieved complete remission. At latest examination, 14 to 60 months after initiation of the treatment (mean, 38 months), 17 patients were in complete remission, 8 had had a relapse but had become steroid sensitive, and 2 had a nephrotic syndrome. Four children responded partially to the treatment. At latest examination, 28 to 58 months after initiation of the treatment, 1 was in complete remission, 1 was in partial remission, 1 had a nephrotic syndrome, and 1 had end-stage renal failure. Thirty-four children did not respond to the combined treatment. At latest examination, 12 to 63 months after initiation of the treatment (mean, 38 months), 5 of these patients were in complete remission, 2 were in partial remission, 15 had a persistent nephrotic syndrome (with moderate renal failure in 5), and 12 children had end-stage renal failure. Forty-eight percent of the patients with minimal change disease and 30% of those with focal segmental glomerular sclerosis achieved complete remission (p = 0.27). We conclude that cyclosporine in combination with prednisone can induce a complete remission in some children with steroid-resistant idiopathic nephrosis.

Fourty-two children with idiopathic nephrosis that had not been well controlled by other forms of therapy were treated with ciclosporine. Thirty-three of them were steroid dependent, 2 were partial steroid responders and 7 were steroid resistant. On pretreatment renal biopsy, performed in all patients less than 6 months before starting ciclosporine, minimal change disease (MCD) was diagnosed in 37 children and focal glomerular sclerosis (FGS) in 5. In order to evaluate the morphological changes of the renal parenchyma possibly induced by the drug, posttreatment biopsies were performed in these 42 patients: one in all patients after 4 to 28 months of ciclosporine, 2 in 23 patients after 18 to 42 months of treatment, 3 in 8 patients after 30 to 63 months of treatment and 4 in 2 patients who had been treated respectively for 62 and 63 months. The morphological changes on pre- and posttreatment biopsies were scored according to the severity of tubulointerstitial lesions. Grade I was considered when there were no significant changes of the renal parenchyma or when occasional scattered tubules with thickened basement membranes were present. Grade II was diagnosed when the biopsy showed several small foci of atrophic tubules with thickened basement membranes within stripes of interstitial fibrosis and grade III when confluent or extensive areas of interstitial fibrosis with atrophic and/or collapsed tubules were observed. On pretreatment renal biopsy, only one patient showed tubulointerstitial lesions (grade II). On the latest biopsy obtained, 18 patients showed grade I tubulointerstitial lesions, 15 grade II and 9 grade III. Unspecific arteriolopathy was observed in 10 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Several cases of haemolysis after bone marrow or organ transplantation have been reported. An allospecific anti-erythrocyte antibody has been described in each case. We report a similar case after renal transplantation. Berger's disease led to end-stage renal failure in an 18-year-old girl. During haemodialysis carried out for 6 years, the patient had received 9 transfusions of phenotyped, filtered, packed red blood cells. The recipient was grouped as O Rh positive, CcDee, Kell negative, HLA-A24 A11 B35 B-DR1 DR2. The donor was her father, grouped as O Rh negative, ccddee, Kell negative, HLA-A24 A- B35 B- DR2 DR-. Screening for erythrocyte antibodies was negative in the recipient as were screening for lymphocytotoxic antibodies and compatibility testing. However anti-D antibody was present in the donor who had received a transfusion of Rh positive blood several years before renal donation. The recipient was given 2 units of O Rh positive, phenotyped and filtered red blood cell concentrates during transplantation. Immunosuppressive therapy associated azathioprine and prednisone. The onset of graft function was immediate. Haemoglobin fell to 52 g/l on day 14 post transplantation (103 g/l on day 6). Anti-D antibody was identified in the serum. The direct antiglobulin test was positive with anti-IgG, antiglobulin and the eluate contained an antibody exhibiting also anti-D specificity. The anti-D of the patient and the donor had the same Gm allotyping. The outcome was favourable though the antibody was persistent for several months. This case of haemolysis is consistent with the fact that immunocompetent B lymphocytes transferred with the grafted organ are still able to produce clinically significant antibodies.

The authors report on a infant who presented with an auto-immune enteropathy characterized by the association of a protracted diarrhea, a neonatal insulin-dependent diabetes, and a dermatitis and who developed a nephrotic syndrome at 4 months of age. A renal biopsy showed a membranous glomerulonephritis (MGN) with IgG linear deposits along the tubular basement membranes (TMB). By indirect immunofluorescence anti-enterocyte antibodies together with anti-TMB antibodies and anti-renal brush border (BB) antibodies were found in the serum of the patient. The patient received various immunosuppressive drugs that failed to improve the disease. In the course of the disease the anti-TBM antibodies disappeared progressively but the BB antibodies persisted. A review of the literature indicates that renal involvement is not uncommon in auto-immune enteropathy and in 5 cases it has been reported as being characterized by a nephrotic syndrome related to the presence of a MGN. In 4 of these cases MGN was associated with the presence of anti-TBM antibodies and in the remaining one with anti-BB antibodies. This case report shows that in human pathology, auto-antibodies to BB proteins may, as well as in experimental models, be responsible for the development of a MGN. It suggests a close relationship (probably a common epitope) between the renal BB proteins and the proteins of the gut epithelium.

From 1976 through 1991, 50 renal transplants (with 7 kidneys from living related donors and 43 cadaver kidneys) were performed in 47 children under five years of age (range 11 to 59 months) at the Enfants-Malades Hospital, Paris, France. Donor age ranged from 3 months to 53 years. Six of the seven kidneys from living related donors are currently functioning after a follow-up of 6 months to 8 years, whereas actuarial survival of cadaver kidneys was 70% at one year and 66% at five years. The main cause of graft loss was vascular thrombosis (40% of lost kidneys). In the most recent years of the study period, graft survival was substantially improved by routine prophylactic anticoagulant therapy with low-molecular weight heparin: one-year graft survival rate was 83% in the 23 children grafted between 1989 and 1991. Posttransplantation growth was closely related to quality of graft function: among the 29 children with sufficiently long follow-up the 19 patients with normal renal function exhibited normal or catch-up growth, whereas the ten patients with chronic renal failure or recent rejection had poor growth. Complications were uncommon with the exception of hypertension. Mortality rate was 12%, i.e., only slightly higher than in older pediatric kidney recipients. Achievement at school was normal in most cases (with a lag in only five patients). Provided effective therapy is given to prevent the main adverse outcome (i.e., vascular thrombosis), renal transplantation does not involve excessive risks even in infants as young as one year of age.

Despite the absence of anti-HLA antibodies (Ab) about 10 to 20 percent of renal transplants are lost during the first months from rejection. The role of humoral rejection seems more likely than cellular rejection since they do not respond to standard anti-rejection therapy. We studied 37 patients who rejected their graft despite negative T and B lymphocytes cross-match during the first eight months (m: 59 days, range: 2-240) following kidney transplantation. These patients were compared with 57 patients who experienced a favorable outcome. The sera were tested for the presence of Ab against epidermis of a panel of 5 normal skins and against an epithelial-endothelial hybrid cell line (EA hy 926, Dr C.J.S. Edgell), expressing both endothelial and epithelial antigens. Among the 37 patients who rejected theirs grafts, 8 had anti-keratinocytes Ab, 11 had Ab against epithelial-endothelial hybrid cell line, 9 were positive for both tests. Among the 8 pts who lost their graft before 25 days, 5 were positive for at least our test. Conversely, 7 among the 57 pts with favorable outcome had Ab: 2 against keratinocytes, 5 against hybrid cell line. These data suggest that non anti-HLA Ab may play a role in graft rejection. Furthermore the detection of such Ab prior to transplantation may predict patients at risk of severe rejection. In such cases, plasma exchanges may be proposed if they develop steroid-resistant rejection.

Forty children with steroid-dependent idiopathic nephrotic syndrome and signs of steroid toxicity were randomly assigned to receive either cyclosporin 6 mg/kg body wt. per day for 3 months and at tapering doses over the next 3 months or chlorambucil at a cumulative dose of 8 mg/kg body wt. The two groups of patients did not differ significantly in sex distribution, age of onset of disease, duration of disease, number of relapses and histological findings. Of the 20 patients treated with cyclosporin, 4 relapsed before or on discontinuation of prednisone, 7 relapsed when the initial dose of cyclosporin was tapered, and 8 after withdrawal of cyclosporin. Of the 20 patients treated with chlorambucil, 14 relapsed while 6 were still in remission 27-49 months after completion of the treatment course. Thus the actuarial remission rate at 2 years was 45% after a course of chlorambucil compared with only 5% after a 3-month course of cyclosporin. We believe that children with steroid-dependent idiopathic nephrotic syndrome should be treated with a course of chlorambucil before resorting to cyclosporin.

Idiopathic nephrosis, the most common cause of nephrotic syndrome, is histologically defined by minimal glomerular changes, diffuse mesangial proliferation or focal and segmental glomerulosclerosis. The response to corticosteroids carries greater prognostic weight than the histological features seen on the initial renal biopsy. The severity of the condition lies in the risk of relapses which occurs in more than half of cases when steroid dosage is decreased (steroid dependency), then requiring, in case of steroid toxicity, the use of alkylating agents or, more recently, cyclosporine. In 10% of the cases, nephrosis is steroid resistant and the severity of the disease lies in the risk of developing end stage renal failure which occurs in nearly one half of those cases.

Clinical and biological features, histologic findings, and outcome were studied in 32 children with systemic lupus erythematosus who underwent at least two renal biopsies during the course of their disease. Results showed that renal biopsy was a useful aid for therapy in that it demonstrated the presence or absence of disease activity, but was unhelpful for predicting the long term outcome. Repeat renal biopsies proved an excellent means for monitoring the course of the nephropathy. This study showed that the various patterns of glomerulonephritis seen in SLE may exhibit changes over time, with either improvement or progression. Regression of lesions was seen mainly after treatment, whereas progression was associated with renal or extrarenal exacerbations of the disease. The absence of clinical improvement may reflect transformation to histologic forms which are unresponsive to therapy.

Vascular thrombosis is one of the main causes of early transplant failure in pediatric patients. This paper reports the results of an open trial of the low molecular weight heparin (Enoxaparine) used to prevent renal graft thrombosis in pediatric recipients with risk factors including donor or recipient age under 5 years, multiple arteries supplying the transplant, and positive history for recurrent thrombosis. During 1989, 42 of 67 children given a renal transplant were prophylactically treated with Enoxaparin. Only one transplant was lost to thrombosis among treated patients (1.5%), versus 9 transplants among 73 (12%) children who received their kidney in 1988 without prophylactic Enoxaparin. Risk factors were comparable in both groups of recipients. Enoxaparine therapy was associated with an increased rate of bleeding (12/42) without severe consequences. In conclusion, Enoxaparin is effective in preventing renal graft thrombosis. Availability of this prophylactic therapy makes it possible to use transplants removed from the youngest donors considered as inadequate by some groups.

We report a transient neonatal nephrotic syndrome in two infants born to a mother with idiopathic nephrotic syndromes (INS). The mother, born in Mali in 1966, had a normal first pregnancy, with a normal live child. Six months later a nephrotic syndrome appeared with normal renal function; renal biopsy disclosed slight lesions of focal and segmental glomerulosclerosis. Prednisone and ciclosporin were totally ineffective. In 1986 and 1988 two pregnancies occurred with normal gestation outcome; however, the two births were premature (35 weeks) with hypotrophic infantas (2.160 and 2.080 kg). In both cases urine analysis revealed neonatal heavy proteinuria, with low serum protein and hypoalbuminemia; proteinuria decreased and disappeared within 2 and 3 weeks respectively; simultaneously protidemia and albuminemia were normalized. Thus, a transitory nephrotic syndrome, resolving spontaneously, occurred in two successive offsprings of a patient with INS. These cases are in keeping with the hypothesis that heavy proteinuria in nephrotic syndrome might be linked to a circulating humoral factor and that INS is a disorder linked to T-lymphocyte function with enhanced production of a lymphokine acting on vascular permeability.

Cyclosporin A (CyA, Sandimmun) was given to 71 children with idiopathic nephrotic syndrome, 45 of whom were steroid-dependent with signs of steroid toxicity, and 23 who were steroid-resistant. Cyclosporin A was effective in 80% of the steroid-dependent patients, allowing cessation of corticosteroid treatment. However, most of these patients relapsed when CyA was tapered or withdrawn. In these patients, CyA may be required for long periods of time. Conversely, CyA was less effective in steroid-resistant patients; only 7% achieved remission with CyA alone. Cyclosporin A in association with prednisone may be an effective alternative as 8 out of 14 patients entered remission with this treatment combination. Serial renal biopsies were performed in 43 patients to evaluate the potential nephrotoxicity of the treatment. Eighteen patients developed significant tubulointerstitial lesions which were attributable to CyA nephrotoxicity. The risk of developing chronic nephrotoxicity appears to be higher in steroid-resistant patients, and was not related to the duration of treatment. Cyclosporin A nephrotoxicity can develop in patients with normal renal function.

The monoclonal antibody OKT3, administered for 2 to 3 weeks in a dosage of 0.1 mg/kg, in combination with azathioprine and prednisone, proved more effective than conventional antilymphocyte serum for the prevention of renal transplant rejection. Side effects were less marked with OKT3 than with antilymphocyte serum. Infectious complications, especially viral, occurred with the same incidence in both groups. In the long term, following discontinuation of OKT3 or antilymphocyte serum, incidence of rejection episodes and graft survival rates were identical in both groups. OKT3 in a lower dosage of 0.05 mg/kg was less effective, with several patients developing rejection during treatment, and induced more common and earlier anti-OKT3 immunization.

With the worldwide use of immunofluorescence microscopy, idiopathic IgA nephropathy (Berger's disease) has been recognized as a distinct form of primary glomerular disease. IgA nephropathy is the most common form of GN in many parts of the world. However, since the criteria for diagnosis are exclusively based on the findings of predominant IgA in the mesangium, the boundaries of this “entity” are not well delineated and it has become clear that several different clinical conditions share this common immunopathology. IgA nephropathy should, therefore be regarded as a syndrome. Schonlein-Henoch purpura (SHP) and Berger's disease represent the primary form of this syndrome. The clinical features of both diseases in children are reviewed. Although the clinical symptoms may appear different there is a close relationship between SHP and IgA nephropathy. They share the same pathology, the same pathogenesis, and they may both recur on a transplanted kidney. Moreover, both diseases can occur in a single family. When pathologic mechanisms are more defined, SHP may prove to be 1 end of a spectrum of diseases associated with microvascular immune deposits in which IgA is the predominant immunoglobulin seen, the other end being Berger's disease.

9551 Background: Ifosfamide-induced nephrotoxicity is a significant issue in patients treated for tumours during childhood. This study aimed at documenting incidence of late renal toxicity of ifosfamide and its risk factors. Methods: 183 patients have been investigated. 100 were male. Median age at treatment was 9.3 years (0.4–18 years). Median dose of ifosfamide was 54 g/m2 (18–77 g/m2). No patients received cisplatin and/or carboplatinum. Diagnoses included rhabdomyosarcoma (77), other soft tissue sarcoma (39), Ewing (39), and osteosarcoma (28). Investigations were performed at a median interval of 10.3 years (5–20.7) after the end of the treatment, at a median age of 21.6 years (7.1–44.2). No patient had electrolyte or vitamine supplementation. Glomerular and tubular functions were graded according to the Skinner's system. Results: After 5 year minimal follow-up 55% had normal tubular and 79% had normal glomerular functions. Natraemia, kalaemia, serum HCO3 and calcaemia were normal in all patients. Hypomagnesaemia was observed in 4, hypophosphaetemia in 8 %. The tubular threshold for phosphate was reduced in 44% of the patients (grade 2 or 3 in 15%, grade 3 in 1 pt). Significant glycosuria (> 0.5 g/24h) was detected in 5 % of the patients but it was clearly abnormal only in 5 patients. 34% of the patients had beta2 microglobulinuria, however, proteinuria was observed in only 12%. Cumulative dose of ifosfamide, older age at treatment and follow-up since treatment were predictor for tubulopathy in univariate and multivariate analyse. The glomerular filtration rate was normal in 79% of the patients. 21% had a grade 1 toxicity and 1 patient a grade 2. Univariate analysis did not find any prognostic factor for glomerular toxicity apart from the association with tubular toxicity. Conclusions: Since ifosfamide-induced renal toxicity can be severe, long term evaluation is important and this risk should be balanced carefully against efficacy. No significant financial relationships to disclose.