ANCA-related crescentic glomerulonephritis in systemic sclerosis: revisiting the "normotensive scleroderma renal crisis".

The scleroderma renal crisis is characterized by acute onset of severe hypertension and by rapidly progressive hyperreninemic renal failure. There is, however, a very limited subset of patients with rapidly progressive renal failure who remain normotensive and develop ANCA-positive crescentic glomerulonephritis. We report a case of normotensive acute renal failure secondary to anti-MPO antibody-associated crescentic glomerulonephritis in a patient with diffuse systemic sclerosis. She was referred to our department with normal blood pressure and no extrarenal clinical manifestation ofvasculitis. She presented with rapidly progressive renal failure, microscopic hematuria and minimal proteinuria. P-ANCA were positive by immunofluorescence, with ELISA-confirmed specificity for myeloperoxidase. Renal biopsy revealed typical features of pauciimmune glomerulonephritis with crescent formation and fibrinoid necrosis. The patient was initially treated with i.v. cyclophosphamide only. Because of ongoing deteriorating renal function, additional treatment with intravenous pulses of methylprednisolone followed by oral prednisone was started and allowed renal function improvement. After 9 months, serum creatinine had almost returned to normal level with minimal proteinuria, no hematuria and negative ANCA testing. Control kidney biopsy only revealed scar lesions. The association of ANCA-positive crescentic glomerulonephritis and systemic sclerosis is a very rare event. Treatment with intravenous cyclophosphamide and corticosteroids allows rapid and long-term improvement of renal function. The onset of typical scleroderma renal crisis triggered by high-dose corticosteroids is unlikely but requires a close follow-up of patients with overlapping systemic sclerosis. Diagnosis and treatment are discussed and previously published cases are reviewed.

Multiple myeloma and severe renal failure: a clinicopathologic study of outcome and prognosis in 34 patients.

Renal failure (RF) occurring in the course of multiple myeloma is often judged irreversible and generally considered an ominous complication. The aim of the present study was to re-evaluate the outcome, triggering conditions and prognostic factors of severe RF in a series of 34 patients, 33 to 90 years old. RF was totally reversible in 7 patients and partially reversible in 9 although 6 of them had to be temporarily dialyzed. However, the improvement in renal function was often very slow as indicated by an average recovery time of 115 days. The high rate of RF reversibility was associated with markedly lengthened survival. Review of triggering events confirmed the leading role of dehydration and hypercalcemia, but further suggested that intake of nonsteroidal anti-inflammatory drugs and renal infection might play a part in the development of RF. Systematic statistical analysis of potential prognostic factors showed that the outcome was significantly more severe in females, but age, myeloma characteristics including tumor mass, calcemia, and triggering events had no predictive value. The most reliable prognostic indicators were provided by analysis of kidney biopsy performed in 30 patients. Complete recovery from RF was observed only in the absence of global tubular atrophy and interstitial damage. In contrast, cast-induced tubular obstruction detected by the presence of Tamm-Horsfall protein in urinary space of glomeruli did not seem to influence the outcome of RF. Finally, we analyzed the prognostic value of immunochemical properties of light chains (LC). Lambda LC were unexpectedly detected in 2 of 3 patients, as compared to a ratio of 1 to 3 in the population of normal and monoclonal Ig, but LC type did not correlate with the course of RF. Isoelectric points of LC measured in 32 patients were dispersed from 5.2 to 8.9 and bore only weak prognostic significance. These results underline the value of kidney biopsy and justify aggressive treatment including dialysis and chemotherapy.

Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

Hemolytic uremic syndrome. Recurrence after renal transplantation. Groupe Coopératif de l'Ile-de-France (GCIF).

Hemolytic uremic syndrome (HUS) is an uncommon cause of end-stage renal failure in adults, and few data are available concerning the outcome of renal transplantation in these patients. We conducted this retrospective multicentric study to appreciate the outcome of adult renal transplant recipients whose primary disease was HUS. Sixteen patients, transplanted between 1975 and 1995, were included in the study. In each case, initial diagnosis of HUS was documented by a kidney biopsy. These 16 patients received a total of 25 allografts: 1 graft for 9 patients, 2 grafts for 5 patients, and 3 grafts for 2 patients. Nine patients (56%) developed definite clinical and pathologic evidence of recurrence on at least 1 graft. Four additional patients (25%) demonstrated only some clinical or pathologic evidence of recurrence which could not be distinguished from acute vascular rejection. Three patients had no sign of recurrence of the initial disease. The 1-year graft survival rate was 63% and the 5-year graft survival rate was 18.5%. In the group of patients with proven or possible recurrence (n = 13), the 1-year and 5-year graft survival rates were 49% and less than 10%, respectively. The recurrence was an early event, occurring before the end of the first month after transplantation in half the cases. The recurrence rate was 92% in non-nephrectomized patients and 50% in patients with bilateral nephrectomy. In the literature, 71 adult patients with primary HUS had received a total of 90 kidney grafts. Among them, 54% had a recurrence on their graft, which was diagnosed in 52% of the kidney transplants. It is note-worthy that when data from the literature are pooled with our results, the rate of recurrence appears to be significantly lower in binephrectomized patients than in patients with their native kidneys at the time of transplantation (5 of 14 versus 27 of 35 patients, respectively, p = 0.0155). By univariate analysis, no other risk factor for recurrence could be identified. Treatment with cyclosporine A did not influence the recurrence rate. We conclude that recurrence of HUS after renal transplantation is a frequent, early, and severe complication, leading rapidly to graft loss. Prospective studies are needed to confirm that bilateral nephrectomy prior to transplantation decreases the rate of recurrence.

Bacterial endocarditis associated with crescentic glomerulonephritis in a kidney transplant patient: first case report.

BACKGROUND: Endocarditis-induced crescentic glomerulonephritis is a well-described complication in nontransplant patients. Its occurrence in transplant patients has not been reported to date. METHODS: A 50-year-old man who had received a renal allograft 13 years before and been treated with prednisone, 10 mg/day, was admitted for progressive renal failure, purpura, edema of the lower limbs, and fever. RESULTS: Blood cultures isolated Streptococcus bovis and cardiac ultrasound examination revealed a 23-mm-large vegetation on the mitral valve. His plasma creatinine level was 478 micromol/L and his proteinuria was 5.5 g/day. A renal biopsy showed diffuse crescentic glomerulonephritis. Long-term antibiotic treatment and three methylprednisolone pulses were effective in treating the endocarditis and glomerulonephritis. CONCLUSION: Endocarditis-induced glomerulonephritis is an immune-mediated disease that can also occur on a renal allograft. It is likely that a low daily dose of immunosuppressive treatment may have been a facilitating factor.

MPO-ANCA necrotizing glomerulonephritis related to rheumatoid arthritis.

Two patients with rheumatoid arthritis (RA) developed necrotizing crescentic glomerulonephritis with high titers of anti-myeloperoxidase antibodies (MPO) in the absence of overt extrarenal vasculitis. We therefore suggest that in some patients with RA, MPO-ANCA necrotizing glomerulonephritis (GN) may occur as a kidney-limited form of rheumatoid vasculitis, and that RA should be added to the list of diseases potentially associated with necrotizing GN with anti-MPO antibodies. These observations also point out the importance of repeatedly evaluating titers of anti-MPO antibodies in the course of RA, especially if renal impairment or abnormal urinary sediment are present.

Plasma cell dyscrasia-related glomerulopathies and Fanconi's syndrome: a molecular approach.

Considerable advances in the understanding of renal complications of dysglobulinemia have occurred in the last 10 years. They mostly result from sequence studies of nephritogenic immunoglobulin chains and comparison with sequence database, and from a careful analysis of clinicopathological features including electron microscopy characteristics of immunoglobulin deposits. These advances should help define subpopulations of patients with plasma cell dyscrasia at risk of developing renal complications and to design novel therapeutic approaches. Although renal complications of plasma cell dyscrasias may be considered as anecdotal diseases, understanding their pathophysiology may help dissect the mechanisms of glomerular and proteinuria-induced interstitial fibrosis.

Association of chronic interstitial cystitis, protein-losing enteropathy and paralytic ileus with seronegative systemic lupus erythematosus: case report and review of the literature.

We report the case of a female patient with seronegative lupus and predominant bladder and intestinal involvement in the form of interstitial cystitis and protein-losing enteropathy. This association is exceptional in the literature but may be underestimated because of frequent latency of interstitial cystitis. It may define a peculiar subgroup of lupus patients usually responsive to steroid therapy. In this case, only cyclophosphamide markedly improved the protein-losing enteropathy but did not influence the bladder disease.

Plasminogen activator inhibitor 1 in renal fibrin deposits of human nephropathies.

The persistency of fibrin deposits in the kidney during renal diseases could reflect either a defective release of plasminogen activators (PA) or a local excess of PAI. In order to investigate this question, we studied human renal biopsies by immunofluorescence technique with specific antibodies for fibrin, tissue-type plasminogen activator (t-PA), urokinase (u-PA), PAI-1 and PAI-2. By this technique t-PA could be detected in the glomerular flocculus and the endothelium of small arteries of the normal control kidneys. We failed to detect significant fluorescence with other antibodies in normal kidneys. Conversely, in cases of vascular nephropathy with thrombosis the positive fluorescence obtained with anti-fibrin antibodies at the site of thrombosis was associated with a positive fluorescence with anti-PAI-1 and to a lesser extent with anti-t-PA antibodies. u-PA and PAI-2 were not detected in these lesions. Similarly in the most severe forms of crescentic glomerulonephritis, extracapillary fibrin deposits were associated with PAI-1. In one case u-PA was also detected. This is in agreement with our previous findings that glomerular epithelial cells release both PAI-1 and the inactive form of u-PA (pro u-PA). Thus, our results support the hypothesis that PAI-1, which is able to inhibit both t-PA and u-PA, may play a major role in the persistency of fibrin deposits in the human kidneys during pathological conditions.

Renal failure in myeloma: relationship with isoelectric point of immunoglobulin light chains.

Renal failure is a frequent but inconstant complication of myeloma related to light chain excretion. Since it has been suggested that cationic light chains (lc) are most likely to induce renal damage, we have studied the isoelectric point (pI) of light chains produced by 17 patients with myeloma and related the results to the type and severity of renal damage assessed clinically and pathologically. In order to do so, we have applied immunoenzymatic techniques which allow identification of light chain types as well as measurement of pI without prior purification. Ten of fifteen patients with renal failure produced lambda light chains. There was no simple relationship between the isoelectric point and nephrotoxicity. However, light chains with the lowest pI observed in this series were associated with normal renal function in two cases and with acute reversible but severe renal failure requiring dialysis in five cases. By contrast, pI values above 6.0 observed in the remaining patients were associated with moderate renal failure in six patients with recently diagnosed myeloma and with irreversible renal failure, and in two patients in whom myeloma had been evolutive for several years. We thus suggest that further pI measurements may help to identify light chains with different nephrotoxic potentials.

Proximal tubular dysfunction in primary Sjögren's syndrome: a clinicopathological study of 2 cases.

Tubulointerstitial nephritis is the most common renal complication in primary Sjögren's syndrome (SS). It is usually associated with symptoms of distal tubular dysfunction, type I (distal) renal tubular acidosis (RTA) and nephrogenic diabetes insipidus. Proximal tubular abnormalities are considered to be less frequent, and Fanconi's syndrome has been only exceptionally reported in patients with SS. We describe 2 patients with primary SS, characterized by xerostomia, dry eyes, extensive lymphocytic infiltrate on salivary gland biopsy, positive tests for anti-SSA/SSB antibodies and/or antinuclear antibodies, who presented in renal failure with proteinuria, microscopic hematuria and type I RTA. Further studies revealed proximal tubular dysfunction, including renal glucosuria, generalized aminoaciduria, phosphaturia, uricosuria, together with proximal (type II) RTA in 1 case. Neither of these patients had Bence Jones proteinuria or monoclonal gammopathy. Kidney biopsy showed focal proximal tubulitis, associated with proximal tubular cell atrophy and dedifferentiation, and diffuse interstitial nephritis with fibrosis. No significant glomerular or peritubular deposits of immunoglobulin light or heavy chain were observed. These findings demonstrate that diffuse, distal and proximal, tubular dysfunction may occur in patients with SS and interstitial nephritis. Lymphocytic infiltration of proximal tubular cells is probably involved in the pathogenesis of Fanconi's syndrome in SS. However, the mechanisms involved in the alteration of sodium-dependent apical transports remain to be elucidated.

[Renal cholesterol embolism. Apropos of 13 cases]. / Embolies rénales de cholestérol. A propos de 13 observations.

Between January 1981 and April 1988, histologically proven renal cholesterol embolism was diagnosed in 13 men over 60 years of age with a previous history of hypertension and atherosclerosis. Six patients developed acute renal failure, usually induced by a triggering factor such as angiographic procedure or anticoagulation, and associated with peripheral and visceral cholesterol embolism, eosinophilia and a high sedimentation rate. In this group of patients, whose protean clinical manifestations and laboratory data mimicked necrotizing angiitis despite the absence of antineutrophil cytoplasmic antibodies, skin lesion biopsy established the diagnosis and made renal biopsy unnecessary. Six patients had chronic renal failure and elevated sedimentation rate, and the last patient had isolated microhematuria. In these 7 patients, percutaneous renal biopsy was an adequate procedure for the diagnosis of cholesterol embolism. As medical management of cholesterol embolism is essentially preventive, these unusual presentations must be emphasized.

[Necrotizing extracapillary glomerulonephritis without immunoglobulin deposits. Renal localization of systemic vasculitis with anti-cytoplasm polynuclear antibodies]. / Glomérulonéphrite extracapillaire nécrosante sans dépôts d'immunoglobuline. Localisation rénale d'une vasculite systémique avec anticorps anti-cytoplasme des polynucléaires.

Necrotizing and crescentic glomerulonephritis without immunoglobulin deposits (also called pauci-immune glomerulonephritis) is the cause of approximately 50 percent of acute renal failures of glomerular origin. Our study, based on 40 case-records selected on histological criteria, and on data from the literature, shows that in most cases, if not all, this type of glomerulonephritis is part of a wider systemic vasculitis which predominantly affects the glomerular capillaries. Anti-neutrophil cytoplasm antibodies are detected in three-quarters of the cases, with a specific distribution that varies according to the clinical features. In spite of the patients' age (mean: 62 years), the severity of glomerular lesions and the extra-renal diffusion of the disease, 60 percent of these patients can be cured and recover a normal, or at least acceptable renal function, provided the corticosteroid and sometimes immunosuppressive therapy is initiated at an early stage.

["Idiopathic" extracapillary glomerulonephritides without immune deposits are vascularitides: clinical and serologic analysis]. / Les glomérulonéphrites extracapillaires "idiopathiques" sans depôt immun sont des vascularites: analyse clinique et sérologique.

To determine the spectrum of systemic diseases potentially associated with pauci-immune rapidly progressive glomerulonephritis (GN), most of which being considered as idiopathic, we have analyzed extra-renal manifestations, occurrence of extra-glomerular vasculitis and incidence and specificity of ANCAs in 40 patients selected only on histological criteria. Extra-renal symptoms were unexpectedly observed in all patients but one, and were suggestive of vasculitis in 24 of them. Extra-glomerular vasculitis was evidenced in 18 kidney biopsies and four biopsies from other organs. Among the 33 patients with suspected or established vasculitis, 13 had presumed or biopsy-proven Wegener's granulomatosis (WG), three had a macroscopic form of polyarteritis nodosa and 17 had a clinical presentation compatible with the so-called microscopic polyarteritis previously described in the british literature. An additional patient had clinical signs of WG without clinical and histological evidence of vasculitis. ANCAs were detected in 28/33 and 25/34 sera tested by IF and ELISA, respectively: 19 contained anti-myeloperoxidase (MPO) antibodies and 6 had anti-proteinase 3 (Pr3) activity. Anti-MPO and anti-Pr3 antibodies were present in all clinical subgroups but with various incidences: anti-MPO antibodies were surprisingly more often detected (6/12) than anti-Pr3 (4/12) in patients with suspected or histologically proven WG but anti-Pr3 antibodies were nonetheless 3- to 4-fold more frequent in WG than in non-WG systemic vasculitis (1/12) and necrotizing CGN without evidence of extra-renal vasculitis (1/10). These results strongly suggest that pauci-immune necrotizing CGNs belong to the broad spectrum of necrotizing vasculitides affecting glomerular capillaries. This hypothesis is also supported by the good response of patients to immunosuppressive treatments known for their efficacy in vasculitides, whereas these treatments are usually less successful in severe forms of extra-capillary GN with immune deposits.

[Tubulo-interstitial renal complications of myeloma]. / Complications rénales tubulo-interstitielles du myélome.

Tubulo-interstitial lesions are the main causes of renal failure in patients with myeloma, and they sometimes reveal this tumour. They are mainly found in large tumoral mass myelomas and are characterized by tubular lesions and specific casts of unexplained physiopathology. Symptomatic and aetiological treatments must be instituted at an early stage to obtain the recovery, at least partial, of renal function, as observed in more than 50% of the cases. The persistence of renal failure carries a sombre prognosis, which emphasizes the importance of a preventive treatment that is too often omitted. Functional tubular disorders are frequent but seldom result in Fanconi's syndrome. A better understanding of the mechanisms underlying the nephrotoxicity of monoclonal immunoglobulins should permit to reduce the incidence of tubular lesions in myelomas.