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Thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of antiphospholipid syndrome nephropathy (APSN). These lesions are at high risk of recurrence after kidney transplantation. The complement pathway is thought to be active in this process. We used eculizumab to treat three consecutive kidney transplant recipients with posttransplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies. Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all three patients and in improvement of the TMA lesions within the graft. None of these patients had TMA flares after eculizumab was withdrawn. At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b-9 and C4d depositions at the endothelial cell surface of the injured vessels. Moreover, C5b-9 colocalized with vessels exhibiting a high rate of apoptotic cells. Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared but the C5b-9 deposits persisted for several months as a footprint of the TMA. Finally, we noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN. Eculizumab seems to be an efficient method for treating severe forms of posttransplant TMA due to APSN recurrence. Terminal complement inhibition does not prevent the development of chronic APSN.

C4d on erythrocytes (EC4d), C4d peritubular capillary deposition (PTC-C4d) staining and histology were compared in a cross-sectional cohort of 146 renal allograft biopsies (132 patients). EC4d levels paralleled PTC-C4d staining, but were more predictive of peritubular capillaritis (PTC). Donor-specific antibodies (DSA), PTC-C4d, EC4d and PTC were analyzed in an independent longitudinal follow-up cohort (96 biopsies, 76 patients). Seventy-six samples were PTC and EC4d concordant, 11 positive and 65 negative, 7 PTC-EC4d+ and 13 PTC+EC4d-. EC4d levels were related to DSA occurrence. With ABMR defined by PTC and DSA, all apparently discordant patients, EC4d negative, were correctly reassigned comparing EC4d level curves with rejection kinetics, with positive EC4d samples predating biopsy or late biopsies compared with ABMR flare-ups. All EC4d-positive patients without PTC or DSA had permanent high EC4d levels unrelated to rejection. EC4d was more abundant in PTC-positive (mean = 108.5%± 3.4; n = 50) than PTC-negative samples (mean = 88.1%± 1.3; n= 96; p < 0.0001). Sensitivity, specificity, positive predictive value and negative predictive value of PTC-C4d and EC4d for PTC were, respectively, 75%, 79%; 64%, 76% (p < 0.05); 28%, 46% (p < 0.05) and 93%, 94%. Values were similar for DSA. A noninvasive blood test, EC4d, and particularly longitudinally monitoring EC4d levels, may increase surrogate ABMR testing options.

International audience; Screening renal biopsies (RB) may assess early changes of interstitial fibrosis (IF) after transplantation. The aim of this study was to quantify IF by automatic color image analysis on sequential RB. We analyzed RB performed at day (D) 0, month (M) 3 and M12 from 140 renal transplant recipients with a program of color segmentation imaging. The mean IF score was 19 ± 9% at D0, 27 ± 11% at M3 and 32 ± 11% at M12 with a 8% progression during the first 3 months and 5% between M3 and M12. IF at M3 was correlated with estimated glomerular rate (eGFR) at M3, 12 and 24 (p < 0.02) and IF at M12 with eGFR at M12 and 48 (p < 0.05). Furthermore, IF evolution between D0 and M3 (ΔIFM3-D0) was correlated with eGFR at M24, 36 and 48 (p < 0.03). IF at M12 was significantly associated with male donor gender and tacrolimus dose (p = 0.03). ΔIFM3-D0 was significantly associated with male donor gender, acute rejection episodes (p = 0.04) and diabetes mellitus (p = 0.02). Thus, significant IF is already present before transplantation. IF evolution is more important during the first 3 months and has some predictive ability for change in GFR. Intervention to decrease IF should be applied early, i.e. before 3 months, after transplantation.

The results of our last 5 years activity in kidney transplantation clearly show that it is possible to perform high-risk transplantations with very acceptable results: ECD kidneys, dual transplantation, recipients with DSAs. In depth statistical analysis of these data should allow a clearer definition of the best strategies to use in these situations.

No treatment has consistently induced long-term remission of proteinuria in adult patients with focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation. We undertook an open-label, nonrandomized pilot trial of intensive and prolonged treatment of FSGS recurrence. Over an 18-month period, 10 adult kidney transplant recipients with FSGS recurrence received concomitantly high-dose steroids, intravenous cyclosporine for 14 days followed by oral cyclosporine therapy, and an intensive and prolonged course of plasma exchanges (PE). We compared this treatment with those of a control group of 19 patients with a FSGS recurrence transplanted between 1997 and 2005. Complete, rapid (mean 23 +/- 7 days) and sustained remission was obtained in 9/10 patients (90%) as opposed to 27% in the control group. At month 3 and month 12, proteinuria was 0.16 g/day (range 0.05-0.3 g/day) and 0.19 g/day (range 0.05-1 g/day) respectively. Only one patient remained in partial remission at month 12 but he had already lost two previous grafts due to FSGS recurrence. PEs were stopped at month 9 in all patients except for the patient with a partial remission who remains PE-dependent. This small pilot study provides very encouraging results demonstrating that this treatment rapidly achieves complete and sustained remission in a high proportion of patients.

The effects of posttransplant prophylactic intravenous immunoglobulin (IVIg) were investigated in renal transplant recipients at high immunological risk. Thirty-eight deceased-donor kidney transplant recipients with previous positive complement-dependent cytotoxicity crossmatch (n=30), and/or donor-specific anti-HLA antibodies (n=14) were recruited. IVIg (2 g/kg) was administrated on days 0, 21, 42 and 63 with quadruple immunosuppression. Biopsy-proven acute cellular and humoral rejection rates at month 12 were 18% and 10%, respectively. Glomerulitis was observed in 31% and 60% of patients at months 3 and 12, respectively, while allograft glomerulopathy rose from 3% at month 3 to 28% at 12 months. Interstitial fibrosis/tubular atrophy increased from 18% at day 0 to 51% and 72% at months 3 and 12 (p0.0001). GFR was 50 +/- 17 mL/min/1.73 m(2) and 48 +/- 17 mL/min/1.73 m(2) at 3 and 12 months. PRA decreased significantly after IVIg (class I: from 18 +/- 27% to 5 +/- 12%, p0.01; class II: from 25 +/- 30% to 7 +/- 16%, p0.001). Patient and graft survival were 97% and 95%, respectively and no graft was lost due to rejection (mean follow-up 25 months). In conclusion, prophylactic IVIg in high-immunological risk patients is associated with good one-year outcomes, with adequate GFR and a profound decrease in PRA level, but a significant increase in allograft nephropathy.

Cyclosporine A (CsA) nephrotoxicity is a nonimmunologic factor of chronic allograft dysfunction (CAD) in kidney transplant recipients. Mycophenolate mofetil (MMF) may allow CsA dosage reduction or even complete withdrawal in selected populations with CsA nephrotoxicity or CAD. The aim of the present study was to evaluate the efficacy and safety of CsA withdrawal after azathioprine (AZA)-MMF conversion in a population of stable renal transplant recipients.Twenty-eight first cadaver kidney recipients were included. AZA was then discontinued, MMF was introduced and after 4 months CsA was completely withdrawn. All patients underwent inuline clearance measurement and renal biopsy at inclusion and at the end of the follow-up (40 wk).CsA was completely discontinued in 20 patients. No patient lost his graft during the study period, but 1 patient experienced a reversible acute rejection episode. Inuline clearance improved significantly in the whole series. At the end of follow-up, histological worsening was observed in 50% of patients without any specific risk factor. In these patients, inuline clearance did not improve. Systolic blood pressure, the need for anti-hypertensive drugs and HDL cholesterol improved.In stable kidney transplant recipients, CsA withdrawal after AZA replacement by MMF switch was safe with regard to acute rejection. It improved blood pressure and the lipid profile, but, in 50% of patients was associated with histologic deterioration.

Background. The aim of the present study was to describe the histologic features disclosed by protocol kidney transplant biopsies in patients who experienced neither acute rejection nor acute renal failure during the 2 years after transplantation. Methods. We studied 10 recipients of HLA-identical kidneys from living-related donors and 31 recipients of cadaveric kidneys. They were selected because, during the 2 years after transplantation, they did not experience clinical acute or chronic rejection, their renal function was normal and stable, and they underwent a protocol kidney biopsy at 3 months and at 2 years after transplantation. Results. Histologic chronic allograft nephropathy was present in 25% of patients at 3 months and in 50% at 2 years, but was absent in the recipients of HLA-identical kidneys. Histologic worsening was associated with increased donor age, the presence of asymptomatic grade I acute rejection at 3 months, and an increased cyclosporine trough level. Conclusions. Protocol biopsies contribute important information that could be used to improve the prophylaxis of chronic allograft nephropathy.

Renal granulomas are a relatively infrequent finding in the kidney biopsy. They have been described in a number of syndromes such as Wegener's granulomatosis, anti-GBM glomerulonephritis, and sarcoidosis, and are commonly believed to be indicative of a fulminant clinical course. In leading textbooks, diverse definitions of renal granulomas are presented, which has led to controversies in identifying them. This, in combination with their rare occurrence, makes it difficult for the general pathologist to identify them. We present the clinical data of 16 patients with renal granulomas, from a total group of 157 patients with systemic vasculitis. Their renal functioning was not significantly different from the other 141 patients in whose renal biopsies renal granulomas were present. Furthermore, we present two practical definitions for the recognition of renal granulomas in the kidney biopsy, and we show a number of examples of their various histopathological shapes.

Antiglomerular basement membrane (anti-GBM) glomerulonephritis (GN) is rare and is characterized by rapidly progressive GN with IgG linear deposits along the GBM in immunofluorescence study and circulating anti-GBM antibodies. This form of GN usually occurs without previous renal disease, but some cases of membranous GN have been reported with secondary development of antiGBM disease [1,2]. Administration of drugs such as D-penicillamine, which are useful for the treatment of rhumatoid arthritis, can be complicated by glomerular disease, more Fig. 2. Linear diffuse IgG deposits on the residual GBM precisely membranous GN, but also minimal-change (Immunofluorescence, ×1000). GN, and crescentic GN [3–5]. Mechanisms for the

Repeat renal biopsies and serial serum creatinine measurements were done in 36 adults who were treated for steroid-dependent or -resistant idiopathic nephrotic syndrome with 5.54 +/- 0.81 mg/kg/day of cyclosporin A (CsA). Pre-CsA renal biopsy (RB1) had been carried out 11.6 +/- 12.2 months prior to CsA treatment. It showed minimal glomerular changes (MCD) in 22, and 1 to 16 glomeruli with lesions of focal segmental glomerulosclerosis (FSGS) per biopsy in 14. Pretreatment serum creatinine levels were (mumol/liter) 97.6 +/- 39.4 and were higher in FSGS (117.1 +/- 48.3) than in MCD (85.2 +/- 26.9; P0.04). Repeat biopsy (RB2) was done after 19.6 +/- 15.2 months (6 to 78) of CsA treatment. At this time, in 15 patients the minimal glomerular lesions observed on RB1 were unchanged, whereas in 7 patients lesions of FSGS were now visible. In patients with FSGS on RB1 and RB2, serum creatinine at the end of CsA treatment was 130.6 +/- 60.1 mumol/liter, significantly greater (P = 0.022) than the corresponding levels in the subset with MCD (87.3 +/- 24.8). The contrast between the remarkable stability of renal function in the patients with MCD and the worsening of renal function in the subgroup with FSGS was explained in the latter by an aggravation of renal histologic lesions, with a greater number of glomeruli with FSGS, of obsolescent glomeruli, and of interstitial fibrosis/infiltrates. This aggravation of the primary renal disease was observed in some cases where CsA had obtained partial or even complete remission. Few of the tubular lesions and of vascular changes were typical of CsA toxicity but rather suggested development of the primary renal disease. In contrast, although some increase in the degree of tubulointerstitial lesions was observed on RB2, the rating of such lesions was much less severe in patients whose renal biopsy showed persistently normal glomeruli after exposure to CsA. Overall, the most severe interstitial/vascular lesions were observed in patients treated with the highest CsA dosages, and the "cut-off" of dosage safety appeared to be 5.5 mg/kg/day. Two patients died during the study period. Long-term surveillance of the extant 34 patients showed that 8, all of whom had FSGS, evolved to end-stage renal failure due to progression of their primary renal disease after ending CsA treatment. Four patients were failures of CsA and returned to conventional therapy. CsA treatment was continued for 12 to 60 months in fourteen patients who achieved remission.(ABSTRACT TRUNCATED AT 400 WORDS)

From 1987 to 1991, 2500 sera were tested for presence of anti-neutrophil cytoplasmic antibodies (ANCA) by standard indirect immunofluorescence (IIF) and specific proteinase 3 (PR3) and myeloperoxydase (MPO) ELISA. Clinical and histological data leading to precise diagnosis were retrospectively obtained in 98 patients with ANCA positivity by IIF and then a comparative study based on ANCA specificity was performed. Vasculitis was present in all cases. Among patients with anti-PR3 (n = 38), 19 had Wegener's granulomatosis (WG), 15 microscopic polyarteritis (mPA), 2 idiopathic necrotizing and crescentic glomerulonephritis (NCGN) and 2 relapsing polychondritis (RP). Among patients with anti-MPO (n = 45), 26 had mPA, 3 classical polyarteritis nodosa (PAN), 5 WG, 8 NCGN, 2 systemic lupus erythematosus (SLE) and one Churg-Strauss syndrome (CSS). Negative MPO and PR3 specific ELISA despite positive IIF were observed in 15 patients (13 WG, 1 mPA, 1 PAN). In the PR3 group, males predominated (66%) and the mean age was 49 years (range 13-85); in the MPO group, females predominated (62%) and the mean age was 57 years (range 13-85). These differences were statistically significant (p0.05). Renal involvement was present in 92% of patients and renal biopsy showed pauci-immune necrotizing and crescentic glomerulonephritis in nearly all cases. PR3 specificity was associated with frequent eye involvement (32%) and presence of granulomas (45%), but was not associated with other autoantibodies. MPO specificity was associated with a higher prevalence of pulmonary hemorrhage (40%) and various autoimmune disorders, especially antinuclear antibodies. Cholestasis was observed in 50% of WG with negative MPO and PR3 ELISA. Renal and patient survival at the 75th percentile was 15 months with MPO-ANCA and 16 months with PR3, and was similar for patients with WG and mPA. Relapses occurred in 20% of patients with anti-MPO and 36% of patients with anti-PR3. Serological follow-up was obtained in 44 patients. With immunosuppressive treatment, ANCA disappeared in 66% of cases and this disappearance was always associated with absence of disease activity.1. This study confirms that the presence of ANCA is a good marker of vasculitis. 2. Despite some clinical differences, MPO and PR3-associated vasculitis have a similar prognosis. 3. The titer of ANCA determined by ELISA is not correlated with the severity of vasculitis but disappearance of ANCA is always associated with absence of disease activity.

Clinical and histological data leading to precise diagnosis were retrospectively obtained in 98 patients with antineutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence (IIF). Specificity was determined by myeloperoxidase (MPO) and proteinase 3 (PR3) specific ELISA in all and a comparative study based on ANCA specificity was performed. Vasculitis was present in all cases. PR3-ANCA occurred predominantly in males (25/38) with WG (19/38). MPO-ANCA occurred predominantly in older women and were often associated with various autoimmune disorders. There was a high prevalence of lung hemorrhage (18/45) and mPA (26/45) in this group. Patients with negative MPO and PR3 specific ELISA despite positive IIF (n = 15) were almost exclusively WG (13/15) and were characterized by a high prevalence of hepatic and digestive manifestations. Renal and patient survival at the 75th percentile was 15 months with MPO-ANCA and 16 months with PR3, and was similar for patients with WG and mPA. With immunosuppressive treatment, ANCA disappeared in 66% of cases and this disappearance was always associated with absence of disease activity.

In order to appreciate the frequency of hepatitis B virus (HBV) infection in patients with glomerular diseases in France, a low endemic country, we reviewed the series of patients biopsied in the years 1983-1989 in 2 departments of nephrology differing by the characteristics of the population. In Saint-Brieuc, where the population is almost exclusively Caucasian, with nearly no immigrant, HBsAg was not detected in any of the 86 patients. In Paris, a large number of patients come from highly or intermediately endemic regions. HBsAg was detected in 3 of 209 patients, 2 of the 75 patients with membranous nephropathy and 1 of the 32 patients with minimal-change nephrotic syndrome. These patients came from Africa and Asia. Therefore, in low endemic countries, the role of HBV infection in the etiology of glomerulonephritis is minimal. But, because of the late severity of the disease, screening remains essential in patients belonging to the high-risk groups.

Antineutrophil cytoplasmic autoantibodies have been recently reported in sera from patients with inflammatory bowel disease. We report our experience based on 90 patients with ulcerative colitis, 148 patients with Crohn's disease, and 60 controls. Determination of antineutrophil cytoplasmic autoantibodies was performed by the indirect immunofluorescence technique on ethanol fixed leucocytes. The specificities for proteinase 3, myeloperoxidase, and lactoferrin were tested by enzyme-linked immunosorbent assay. Forty-three out of 90 (48%) patients with ulcerative colitis, 10 out of 148 (7%) patients with Crohn's disease, and none of controls were positive by indirect immunofluorescence technique. All patients but two with positive immunofluorescence exhibited a perinuclear staining pattern. Among patients with ulcerative colitis, there was no relationship between the presence of perinuclear antineutrophil cytoplasmic autoantibodies and disease location or activity. Seven out of 20 (35%) patients with ulcerative colitis who had a previous colectomy (including 1 with ileoanal anastomosis) had perinuclear antineutrophil cytoplasmic autoantibodies. Antineutrophil cytoplasmic autoantibody specificity was not directed against myeloperoxidase, proteinase 3 or lactoferrin in sera from patients with inflammatory bowel diseases. Inflammatory bowel diseases are associated with a new subset of antineutrophil cytoplasmic autoantibodies. Among patients with Crohn's disease and ulcerative colitis, the sensitivity and specificity of the presence of perinuclear antineutrophil cytoplasmic autoantibodies for ulcerative colitis was 46% and 93%, respectively. Their presence reinforces the likelihood of underlying immunologic dysregulation in ulcerative colitis. Identification of the autoantigen(s) to which these antibodies are directed might facilitate the understanding of inflammatory bowel disease pathophysiology.

The incidence of beta 2-microglobulin deposits appears to increase with time on dialysis. However, the precise prevalence of the disease is not known at present because adequate, noninvasive diagnostic procedures are still lacking. We performed systematic synovial biopsies of the sternoclavicular joint during surgical parathyroidectomy in 22 chronic hemodialysis patients with severe hyperparathyroidism. Nine of the patients proved to have beta 2-microglobulin amyloid deposits as demonstrated by Congo red staining and by immunofluorescence. They had undergone dialysis for longer time periods (12.6 vs 8.5 years, p less than 0.02) and tended to be older than the 13 amyloid-negative patients. They also had a significantly higher body aluminum overload, as demonstrated by a higher increase of plasma aluminum after desferrioxamine infusion. Finally, the presence of Congo-red-positive deposits correlated well with clinical and x-ray findings suggestive of dialysis amyloidosis.

In a retrospective study of 82 adults with idiopathic membranous nephropathy, we have studied the predictive factors of renal death. Thirty one patients developed renal failure, sixteen of them progressed to end-stage renal failure (ESRF) (13 males and 3 females). Nine patients developed ESRF in the first 5 years following the renal biopsy. The males and the patients with a nephrotic syndrome have a high risk of ESRF. The age is not a predictive factor of poor outcome. Hypertension seems to be more frequent in patients who developed early but slowly progressive renal failure. Extensive renal interstitial lesions are indicative of poor renal prognosis.

Six cases of chronic renal failure related to granulomatous renal sarcoidosis are reported and compared with data in the literature. The particular features of sarcoidosis granulomatous interstitial nephritis should be emphasised because presentation may be misleading. Renal failure usually presents with a rapidly progressive course, either isolated or associated with mild proteinuria and sterile leukocyturia, while extrarenal localisations may be absent. Diagnosis should be suspected on the basis of elevated or paradoxically normal serum calcium concentrations, due to increased plasma concentrations of calcitriol, while immunoreactive circulating parathormone concentrations are depressed. Calcitriol as well as angiotensin-converting enzyme could represent unregulated secretion products from granulomatous tissue and their plasma concentrations may roughly reflect activity of the disease. Early corticosteroid treatment dramatically improves renal function but long-term renal prognosis may be oblitered due to progressive chronic renal failure related to fibrosis scarring.

Microchimerism after allogeneic organ transplantation may be a mechanism for induction of donor-specific graft acceptance. However, the frequency of chimerism and its relevance in long-term tolerance are uncertain. We studied 15 long-surviving (more than 20 years) cadaveric-kidney transplant recipients for the systemic presence of donor alleles with allele-specific genomic amplification of DRB1 and H-Y loci. Microchimerism was observed in 1 case in peripheral blood and in 4 cases in skin. Chimerism and number of HLA alleles shared by donor and recipient were not correlated. This low frequency of microchimerism in long-term kidney allograft recipients raises doubts about a major participation of chimerism in donor-specific tolerance.

Twenty-three uremic patients on intermittent hemodialysis for eight to eighteen years provided the material for the present pathological study. In all of them, there was evidence for dialysis related amyloidosis based on previous clinical or histological findings or both. The material examined consisted of nine skin biopsies, five abdominal fat aspirates, eight trans-iliac bone biopsies and numerous post-mortem specimens of various visceral organs from eight cases. None of the skin biopsies or fat aspirates showed amyloid deposits. In only one bone biopsy could a small Congo red positive area be recognized that showed characteristic birefringence under polarizing light. Autopsy material findings were negative except for one case: this patient had been dialyzed for 18 years. Very minute amyloid deposits with a positive immunofluorescence staining for beta 2-microglobulin (beta 2-M) were found in the walls of small vessels from her lung, heart, liver and intestine. Thus, in chronic hemodialysis patients the accumulation of beta 2-M amyloid fibrils in tissues other than joints and juxta-articular structures appears to have a low incidence, to occur lately and to be of limited size. Although extra-articular amyloid deposits may progressively occur and extend with increasing survival time on dialysis, tiny deposits such as those observed in only two of our patients will hardly lead to serious complications.

The authors have studied 6 cases of systemic AA amyloidosis associated with ankylosing spondylitis. Renal failure occurred in all patients a mean of 19 years after the clinical onset of the rheumatic disease. Three patients progressed rapidly (between 3 months and 3 years) to end-stage renal failure. Such an outcome did not depend upon early onset of the renal impairment, degree of inflammation or treatment with colchicine. All patients were alive 2 to 10 years later, and this confirms a better prognosis than with AL amyloidosis. The utility of combining Wright's permaganate reaction with immunological methods to characterize the amyloid deposits was also confirmed. It is concluded that amyloidosis is a rare complication of ankylosing spondylitis and probably depends on a genetic predisposition. The possibility of amyloidosis should be kept in mind when proteinuria or renal failure appear in the course of ankylosing spondylitis.

Six families including 27 patients with adult nephronophthisis were studied. The diagnosis was based on the evidence of heredofamilial chronic tubulointerstitial renal disease, not related to urologic abnormality, and progressing to renal failure in at least 2 members of each kindred. In two families, the mode of inheritance is compatible with recessive autosomal transmission; retinal heredodegeneration was found in both kindreds; mean age at end-stage renal failure (ESRF) was 22 years. In one additional case, kidney involvement is apparently sporadic, and associated with retinal changes and blindness. In one kindred, the mode of inheritance could not be determined. In the last 3 families, pedigrees are compatible with dominant autosomal transmission; retinal involvement was found in none; ESRF developed at a mean age of 47 years. Renal cysts were detected by ultrasonography in 9 of 12 patients; they were located at the cortico-medullary junction or in the medulla in 5 cases. Renal biopsy showed rather similar changes in the various kindreds. These results are compared with those already reported from 29 families with adult nephronophthisis.

Systemic lambda light-chain deposition occurred in a 73-year-old man with myeloma. An initial renal biopsy specimen showed the features of myeloma kidney. When he died 22 months later lambda light chains were detected by immunofluorescence in kidneys, liver, spleen, and heart. They were probably responsible for cardiac dysfunction and the fatal arrhythmia. It is suggested that in this patient deposition was due to a structural alteration of the light chains, possibly induced by cyclophosphamide.

Circulating anticoagulants with antiprothrombinase activity were detected in 14 out of 49 patients (i.e. 29%) presenting with severe forms of systemic lupus erythematosus (SLE) predominantly renal (29) or extrarenal (20). Nine of these 14 patients had thrombopenia and 8 had a falsely positive Wassermann test. The anticoagulants were more frequently encountered in patients with severe extrarenal manifestations (9/20 cases) than in patients with severe proliferative renal lesions (5/29 cases). They were found in 5 out of 10 patients with arterial and/or venous thrombosis. Anticoagulant levels paralleled the course of the disease during treatment. No haemorrhage was observed in 14 percutaneous renal biopsies performed on 11 patients free from outer coagulopathies. This suggests that the presence of antiprothrombinase anticoagulants in the blood of patients without thrombopenia or other coagulation disorders is compatible with surgery or biopsy of the kidney.

In a group of azathioprine-treated patients whose renal allografts functioned immediately, 53 received prophylactic steroid treatment while 54 were given steroids only at the onset of the first renal failure. Three types of renal failure were identified, and their distribution in the patient groups was different, but the incidence of both reversible and irreversible renal failure episodes was identical in the two groups, suggesting that steroid treatment of early rejection episodes may not be necessary.

Direct immunofluorescence studies of graft biopsies from 662 renal transplant recipients demonstrated linear IgG deposition along tubular basement membranes (TBM) in 18 cases. In ten of them, circulating anti-TBM antibodies, whose detectable levels varied from 114 to 1/100, were demonstrated by indirect immunofluorescence on normal human kidneys. These antibodies reacted with every human kidney tested and in two cases, it could be demonstrated that they recognized the TBM of the patient's own end-stage kidney. Hence, they reacted as autoantibodies. Circulating anti-TBM antibodies were detected within the first 6 months after transplantation, remained present for an average of 3 months, and never recurred once they had disappeared. Serial biopsies demonstrated the loss of IgG linear fixation on TBM. Neither tubular nor interstitial injury was significantly associated with the presence of anti-TBM antibodies, and the transplant survival was not different in these patients who developed anti-TBM antibodies compared to our entire population of transplant biopsies.

We report a case of necrotizing glomerulonephritis with linear fixation along the glomerular basement membrane (GBM) atypical by: 1) the absence of significant renal failure or evidence of pulmonary involvement; 2) no detectable circulating anti GBM antibody by indirect immunofluorescence or radioimmunoassay.

Twelve of 767 renal allograft recipients developed linear fixation of IgG along the glomerular basement membrane (GBM) by direct immunofluorescence technique. This was associated with linear fixation along the tubular basement membrane in 7 of them. Circulating anti-GBM antibodies were not detected by indirect immunofluorescence or radioimmunoassay in any patient whereas anti-TBM antibodies were found in 2 of 4 with linear TBM fixation. Among the 12 patients with linear GBM fixation, 5 had Alport's syndrome; the 7 others had various renal diseases, excluding anti-GBM nephritis. Among the 767 patients, 34 had Alport's syndrome or variants (i.e., 4.5%). The incidence of linear GBM fixation is much higher in Alport's syndrome than in other renal diseases. Linear GBM fixation was not clearly related to anti-GBM antibodies and was not accompanied by significant deterioration of graft function. These findings may be relevant, however, to the missing GBM antigen in Alport's syndrome.

From 1962 to 1977, 79 patients with Alport's syndrome underwent serial fundoscopic examination. In 29 patients (24 males, 5 females), symmetric bilateral perimacular changes were found, consisting of bright, whitish or yellowish dense granulations, surrounding the foveal area. Fluorescein angiography was normal in 8/8 studied cases. All 29 patients had bilateral lenticonus and neural hearing loss; ultrastructural lesion of glomerular basement membrane was present in 11/11 studied patients. Chronic renal failure developed in 26 patients, with 20 treated by maintenance hemodialysis. In contrast, perimacular lesions were absent in the other 50 patients (27 males, 23 females). Anterior lenticonus was detected in none; perceptive deafness was demonstrated in only 20; kidney ultrastructural lesions in 16 of 30 studied cases. Patients with perimacular changes had significantly earlier renal failure (P less than 0.001) than patients without. In conclusion, perimacular changes appear as a simple and reliable indicator of Alport's syndrome, often associated with early renal failure.

A nonsteroid antiinflammatory agent (Ibuprofen) was used in a controlled randomized study to determine its ability to replace steroids in the prophylaxis of cadaveric kidney rejection. Thirty-three cadaver kidney recipients were randomly assigned either to a control group (16 patients) receiving azathioprine, high doses of prednisolone, and antithymocyte globulin (ATGAM) for three months, or to an experimental group (17 patients) receiving azathioprine and ATGAM according to the same protocol, ibuprofen instead of steroids. The frequency of rejection was higher in the experimental group (2.18 episodes per patient) than in the control group (1.44 episodes per patient). Nevertheless, in the experimental group 5 patients had no early rejection episode, 60% of early rejections were totally reversible without steroids, and 3 patients never received steroids at all during the first year and had normal renal function and biopsies. Steroids had to be introduced in the treatment of 14 patients, but after an average period of 32.5 days after surgery OKT3+ cell level was higher in the experimental group than in the control group, but similar to the OKT3+ cell level of patients receiving conventional therapy without ATGAM. Whatever the type of treatment, an increase in the OKT4+/OKT8+ ratio was associated in most cases with increased serum creatinine values. Conversely, a decreased OKT4+/OKT8+ ratio associated with renal failure was found in cases showing biological evidence of cytomegalovirus infection.

Discoid lupus (DL) and systemic lupus erythematosus (SLE) patients have been comparatively evaluated for complement and immunoglobulin deposits at the dermoepidermal junction (DEJ) by immunofluorescence (IF). When IF was positive, Clq deposits were quasi-constantly found in SLE patients with or without skin lesions (90%), while Clq was found in only 29% of the DL patients. Of the 42 DL patients followed-up to at least 2 years, 4 have eventually evolved a systemic disease. In these 4, neither cryoglobulinemia nor significant titers of ANA had been found at the time of presentation. Only 1 of these 4 patients had initially circulating immune complexes (P.E.G) and a positive IF in a normal sunprotected area. Clq deposits at the DEJ were present in all these 4. Of the remaining 38 DL patients, none has progressed to SLE: 8 had had significant titers of ANA, 5 had had circulating immune complexes, and 3 others had had cryoglobulinemia. Thus Clq deposits in DL cases are associated with a relatively high incidence of eventual systemic disease. Taken together, these data suggest that Clq deposits in skin may be a marker for systemic lupus.

Out of 55 patients with severe systemic lupus erythematosus (SLE) retrospectively studied from 1962 to 1979, 32 had diffuse proliderative glomerulonephritis and 23 had one or several extrarenal and/or haematological manifestations of the disease. All received corticosteroids in high dosage (0,8 to 1,5 up period was 48 months from the beginning of treatment. The actuarial survival rates for the whole groupe after 1,5 and 10 years were 92,4%, 83,4% and 77,2% respectively. Eight patients died: 5 of SLE and 3 of iatrogenic complications. Four are kept alive by maintenance haemodialysis. At the end of the study period, SLE was quiescent in 37 patients, including 14 who had discontinued corticosteroids for 5 to 72 months. The five-year survival rates were very similar in patients with renal and extrarenal involvement (86,4% and 81,6% respectively). In the latter group myocardial insufficiency, thrombopenia and thromboembolic complications were the main factors of morbidity and mortality. Corticosteroids were administered alone to 25 patients and in combination with cyclophosphamide to the remaining 30. Cyclophosphamide was given initially in 13 cases or subsequently on account of intolerance (7 cases) or resistance (10 cases) to steroids. Similar results were obtained with these two therapeutic regimens, but it must be noted that cyclophosphamide was mainly used in the more severe forms of SLE.