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Jean-Pierre Grünfeld

Publications and source records attributed to Jean-Pierre Grünfeld.

At least 19 recordsLinked to original sources
PubMed2006

Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.

INTRODUCTION: Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors. METHODS: We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations. RESULTS: Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation. CONCLUSION: HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.

Adolescent↗
PubMed2006

Cyclosporin therapy in patients with Alport syndrome.

Alport syndrome (AS) is a hereditary disorder of type IV collagen characterized by the association of progressive hematuric nephritis and sensorineural hearing loss. An increase in proteinuria is linked with progressive renal failure. Preliminary data have shown that cyclosporin therapy reduces proteinuria, thereby suggesting that it may also slow the progression of AS nephropathy. We treated nine AS patients manifesting proteinuria >1 g/m(2)/day and a glomerular filtration rate (GFR) >50 ml/min/1.73 m(2) with cyclosporin for at least 6 months. At the end of this 6-month period, mean proteinuria had decreased from 2+/-1.06 to 0.65+/-0.73 g/day, and mean albuminemia had increased from 29+/-5.2 to 35+/-6.5 g/l. Mean inulin clearance had decreased from 102+/-29 to 74+/-16.3 ml/min/1.73 m(2). Cyclosporin treatment was stopped in four patients because of inefficacy or adverse effects and continued in the remaining five patients for an additional 14-42 months. At the end of this second treatment period, control renal biopsies revealed significant lesions of cyclosporin nephrotoxicity in three patients. Based on these results we conclude that while cyclosporin therapy can decrease proteinuria in most patients with AS, it may be associated with nephrotoxicity, thereby precluding its long-term use.

Adolescent↗
PubMed2006

[Continued late referral of patients with chronic kidney disease. Causes, consequences, and approaches to improvement].

OBJECTIVES: Efforts in recent years have aimed at increasing physicians' awareness of the frequent and harmful consequences of late referral to nephrologists of patients with chronic kidney disease (CKD), shown in repeated concordant studies. We sought to determine whether these efforts have led to improved predialysis care of these patients. METHODS: This study included all 1391 consecutive patients who began maintenance dialysis at Necker Hospital between January 1989 and December 2000. We examined baseline data and outcomes and determined for four three-year periods the percentage of patients who received early specialized care (at least 6 months before onset of dialysis). RESULTS: Late referral (<6 months before dialysis) did not change significantly over the four periods, remaining around 30%, even during the most recent period (1998-2000). Clinical condition and laboratory indicators of patients referred early but not those referred late improved in the latest period, compared with the initial period (1989-1991). Overall, prevalence of major cardiovascular events (myocardial or cerebral infarction, peripheral arteriopathy, or heart failure) was more than twice as high in patients who received nephrologic care for less than 6 months and nearly twice as high even in those followed 6-35 months than in patients followed for at least 36 months before beginning dialysis. Subsequent mortality after maintenance dialysis was also significantly higher in patients with late referral than in those followed at least 3 years before dialysis. Multivariate Cox proportional model analysis identified graded duration of predialysis nephrologic care as a significant independent factor predictive of risk of mortality while on dialysis. CONCLUSION: Late referral of CKD patients for specialist care remains frequent, around 30%, although it is most often unjustified. Late referral deprives the patient of early implementation of a reno- and cardioprotective therapeutic strategy that reduces cardiovascular comorbidity and mortality. Better coordinated cooperation between family doctors and nephrologists, through the implementation of regional healthcare networks, now appears as the most effective way to improve the care of CKD patients.

Acute Kidney Injury↗
PubMed2005

Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that occurs mainly in young adults. Acquired cases are usually a result of antibodies directed against ADAMTS13 (a disintegrin-like and metalloprotease [reprolysin type] with thrombospondin type 1 motif 13), a protease that cleaves the von Willebrand factor multimers. Prognosis has been improved by plasma therapy, but some acute severe forms are refractory to this treatment and achieving a sustained remission is still a challenge in chronic relapsing forms. We therefore conducted a multicentric open-label prospective trial to test the efficacy of rituximab, an anti-B-cell monoclonal antibody, as a curative and prophylactic treatment in patients with TTP as a result of anti-ADAMTS13 antibodies. Six patients were included during an acute refractory TTP episode. Five patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies were prophylactically treated during remission. All patients received 4 weekly infusions of rituximab. The target of treatment was to restore a significant ADAMTS13 plasma activity (> 10%). Treatment with rituximab led to clinical remission in all cases of acute refractory TTP. In all patients, anti-ADAMTS13 antibodies disappeared, and a significant (18%-75%) plasma ADAMTS13 activity was detected following treatment. Tolerance of rituximab was good. Rituximab is a promising first-line immunosuppressive treatment in patients with acute refractory and severe relapsing TTP related to anti-ADAMTS13 antibodies.

ADAM Proteins↗
PubMed2005

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.

ADAM Proteins↗
PubMed2005

Renal and thymic pathology in thymoma-associated nephropathy: report of 21 cases and review of the literature.

BACKGROUND: Acquired thymic disease (malignant thymoma or thymic hyperplasia) is associated with various autoimmune diseases, such as myasthenia gravis (MG), pure red-cell aplasia (PRCA), pemphigus vulgaris or systemic lupus erythematosus (SLE). Renal disease has rarely been observed in association with thymoma. METHODS: This retrospective, multicentric study collected data on patients with thymic disease and biopsy-proven renal involvement. RESULTS: Twenty-one patients were studied (age: 49+/-14 years; male/female ratio: 8/13). Thymic pathology revealed mostly high-grade malignant thymoma (B2 and AB type); two cases were associated with non-malignant thymic hyperplasia. MG was found in nine out of 21 cases, SLE in three, PRCA in three and pemphigus in two. In 47% of these cases, nephropathy occurred after curative treatment of thymoma (108+/-83 months; range: 8-180 months), mainly based on surgical thymectomy associated with radiotherapy. Clinical and laboratory findings included nephrotic syndrome (75%), renal failure (50%), frequent presence of antinuclear antibodies and hypogammaglobulinaemia. Renal pathology showed minimal change disease in 14 patients and focal segmental glomerulosclerosis (FSGS) in one. Membranous nephropathy was observed in four cases, ANCA-associated glomerulonephritis in two and thrombotic microangiopathy in one. Most patients with minimal change disease or FSGS (11/13) were steroid-sensitive. Despite good response to steroids, 38% of patients died from thymoma and 17% developed end-stage renal failure. CONCLUSIONS: Glomerulopathy can be associated with thymoma or thymic hyperplasia. The present series shows that minimal change disease is the most frequent thymoma-associated glomerular lesion and that it may occur several years after thymectomy.

Adult↗
PubMed2005

Cystic kidney disease, chromophobe renal cell carcinoma and TCF2 (HNF1 beta) mutations.

BACKGROUND: The proband, a 33-year-old woman, presented with renal cysts, mild renal failure and a renal tumor. One of the proband's two sons had hyperechogenic kidneys and the other had renal cortical microcysts. Her 71-year-old mother had mild renal failure and small renal cysts. INVESTIGATIONS: Ultrasonography, blood and urine analysis, MRI, CT scan, and genetic investigations focusing on the transcription factor 2 (TCF2) gene which encodes hepatocyte nuclear factor 1 beta. DIAGNOSIS: The proband was diagnosed with cystic kidney disease and chromophobe renal cell carcinoma, characterized by a 46delC germline mutation of TCF2 and a complete somatic deletion of TCF2 in the renal tumor. The germline TCF2 mutation was also present in the proband's sons and mother. Pancreas atrophy was detected in the proband and her mother. MANAGEMENT: Tumorectomy followed by radical nephrectomy of the left kidney 4 years later. Lisinopril (5 mg/day) and lifelong follow-up. The patient's sons will be regularly screened for progressive renal disease, diabetes mellitus and chromophobe renal cell carcinoma.

Adult↗
PubMed2005

Tubulointerstitial nephritis and Fanconi syndrome in primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic cholestatic liver disease of unknown cause that predominantly affects middle-aged women. Distal tubular acidosis is the main renal complication of primary biliary cirrhosis. Tubulointerstitial nephritis and Fanconi syndrome have been reported more rarely. We report on 2 patients with primary biliary cirrhosis who presented with tubulointerstitial nephritis and Fanconi syndrome and review similar cases published previously. Serum from 1 patient exerted an inhibitory effect on pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, 2 mitochondrial enzymes that are the main targets of antimitochondrial antibodies in primary biliary cirrhosis. Antimitochondrial antibodies may have a role in the genesis of tubulointerstitial nephritis and Fanconi syndrome, 2 typical renal features of mitochondrial cytopathies. Tubulointerstitial nephritis and Fanconi syndrome have to be added to the spectrum of renal diseases associated with primary biliary cirrhosis.

Acidosis, Renal Tubular↗
PubMed2004

Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions.

von Hippel-Lindau (VHL) disease arises from mutations in the VHL gene and predisposes patients to develop a variety of tumors in different organs. In the kidney, single or multiple cysts and renal cell carcinomas (RCC) may occur. Both inter- and intrafamilial heterogeneity in clinical expression are well recognized. To identify VHL-dependent genetic factors, we investigated the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were characterized. The incidence of renal involvement was increased in families with mutations leading to truncated protein (MLTP) or large rearrangement, as compared to families with missense changes (81 vs. 63%, respectively; P=0.03). In the latter group, we identified two mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCC was higher in families with MLTP than in families with missense changes (75 vs. 57%; P=0.04). Furthermore, mutations within MCR-1 but not MCR-2 conferred genetic susceptibility to develop RCC. Overall, our data argued for a substantial contribution of the genetic change in the VHL gene to susceptibility to renal phenotype in VHL patients.

Adult↗
PubMed2004

Comparison between siblings and twins supports a role for modifier genes in ADPKD.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by intrafamilial variability in renal disease progression, which could result from a combination of environmental and genetic factors. Although a role for modifier genes has been evidenced in mouse models, direct evidence in ADPKD patients is lacking. The analysis of variability in affected siblings and monozygotic (MZ) twins would help evaluate the relative contribution of environment and genetic factors on renal disease progression in ADPKD. METHODS: The difference in the age at end-stage renal disease (ESRD) and the intraclass correlation coefficient (ICC) were quantified in a large series of ADPKD siblings from western Europe and compared with the values obtained in a series of MZ ADPKD twins from the same geographic area. RESULTS: Fifty-six sibships (including 129 patients) and nine pairs of MZ twins were included. The difference in the age at ESRD was significantly higher in siblings (6.9 +/- 6.0 years, range 2 months to 23 years) than in MZ twins (2.1 +/- 1.9 years, range 1 month to 6 years; P = 0.02). Furthermore, the intraclass correlation coefficient was significantly lower in siblings than in MZ twins (0.49 vs. 0.92, respectively; P = 0.003). The intrafamilial difference in the age at ESRD was not influenced by gender. CONCLUSION: These data substantiate the existence of a large intrafamilial variability in renal disease progression in ADPKD siblings. The fact that the variability in siblings is in a significant excess of that found in MZ twins strongly suggests that modifier genes account for a significant part of this variability.

Adult↗
PubMed2003

The expanding spectrum of renal diseases associated with antiphospholipid syndrome.

BACKGROUND: The association of thrombotic events and/or pregnancy complications with circulating antiphospholipid antibodies defines antiphospholipid syndrome (APS). In previous reports, renal involvement in APS consisted mainly of thrombotic vascular complications involving large vessels or intrarenal small-sized vessels (APS nephropathy). We report 9 cases of glomerulonephritis associated with APS. These cases are characterized by predominant pathological features distinct from vascular APS nephropathy. METHODS: We reviewed consecutive renal biopsies examined in 2 French university hospitals between 1980 and 2002 and identified renal biopsies performed in patients with primary APS. RESULTS: We identified 29 biopsies performed in patients with APS. Twenty biopsies showed characteristic features of APS nephropathy. In 9 cases, predominant pathological features distinct from vascular APS nephropathy were noted: membranous nephropathy (3 cases), minimal change disease/focal segmental glomerulosclerosis (3 cases), mesangial C3 nephropathy (2 cases), and pauci-immune crescentic glomerulonephritis (1 case). In 7 cases, the presentation of renal symptoms was subacute or chronic. Two patients experienced episodes of acute renal failure. At referral, median creatinine clearance was 50 mL/min (0.83 mL/s) (range, 18 to 117 mL/min [0.30 to 1.95 mL/s]). Proteinuria was noted in all cases (range, 1.5 to 15 g/d), with nephrotic syndrome in 4 cases. Lupus anticoagulant was present in all cases, and anticardiolipin antibodies, in 8 cases. Anti-DNA antibodies repeatedly were negative in all cases. Treatment consisted of antihypertensive therapy (6 cases), anticoagulant drugs (5 cases), steroids (4 cases), and antiplatelet drugs (3 cases). At last follow-up, renal function remained stable in 7 patients. Of 2 patients presenting with acute renal failure, 1 patient recovered normal renal function, whereas the other patient progressed to end-stage renal failure. CONCLUSION: The cases reported here represent a new aspect of the expanding spectrum of renal diseases encountered in association with APS.

Adrenal Cortex Hormones↗
PubMed2003

Lithium-induced nephropathy: Rate of progression and prognostic factors.

BACKGROUND: Long-term lithium administration in humans may lead to chronic tubulointerstitial nephritis, which develops very slowly. Its progression to end-stage renal disease (ESRD) has been rarely reported. The aim of this study is to document the rate of progression of lithium-induced nephropathy and its prognostic factors, and to provide an estimation of the percentage of lithium-induced ESRD in France. METHODS: Two groups have been studied: 54 patients with lithium-induced renal failure, nine of whom underwent renal biopsy; and 20 patients who were referred for systematic renal biopsy, 14 of whom were subsequently followed up. In addition, a survey of lithium-induced ESRD was conducted in French dialysis centers. RESULTS: The mean annual loss of creatinine clearance in patients with lithium-induced nephropathy was 2.29 mL/min. Among 74 patients, 12 reached ESRD at a mean age of 65 years. Creatinine clearance at referral and at last follow-up was inversely related to the duration of lithium therapy in both univariate and multivariate analyses adjusting for age, gender, hypertension, and proteinuria. The degree of interstitial fibrosis on renal biopsy was also related to the lithium duration and cumulative dose. It was predictive of the final creatinine clearance. About 35% of the patients tested had moderate hypercalcemia, due to hyperparathyroidism. The prevalence of lithium-related ESRD in France was estimated as two per 1000 dialysis patients. The average latency between onset of lithium therapy and ESRD was 20 years. CONCLUSION: Lithium-induced chronic renal disease is slowly progressive. Its rate of progression is related to the duration of lithium administration. Lithium-related ESRD represents 0.22% of all causes of ESRD in France. Regular monitoring of estimated creatinine clearance is mandatory in long-term lithium-treated patients.

Adult↗