[Classification and therapeutic management of monoclonal gammopathies of renal significance]. / Classification et prise en charge thérapeutique des gammapathies monoclonales de signification rénale.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

Current anti-myeloma therapies in renal manifestations of monoclonal light chain-associated Fanconi syndrome: a retrospective series of 49 patients.

We retrospectively reviewed 49 patients with light chain (LC) Fanconi syndrome (FS). Patients presented with chronic kidney disease (median estimated glomerular filtration rate (eGFR) of 33 ml/min/1.73 m2) and tubular proteinuria. All patients tested had elevated fractional excretion of phosphate, uric acid, generalized aminoaciduria and/or normoglycemic glycosuria. Thirty-eight patients had monoclonal gammopathy of renal significance and eleven patients had an overt hematological malignancy. The monoclonal LC isotype was kappa in 46/49 cases. Kidney biopsy in 39 patients showed various proximal tubular lesions and characteristic LC intracytoplasmic crystalline inclusions in 24 patients. Forty-two patients received chemotherapy. Patients with plasma cell proliferation (n=38) received bortezomib-based regimens (n=11), immunomodulatory agents (n=7) or alkylating agents (n=6). High-dose melphalan (HDM) followed by autologous stem cell transplantation was performed in 14 patients. Hematological response was obtained in 90% of evaluable patients, assessed on serum free light chains (FLC). GFR remained stable as long as hematological response was maintained and declined when serum FLC level rebounded. Improvement in proximal tubule function occurred in 13 patients. In patients with LC-associated FS, chemotherapy using HDM and/or new generation anti-myeloma agents can stabilize renal function and improve proximal tubule function. Serum FLC should be used to assess the hematological response, related to renal outcome.

[AL amyloidosis]. / Amylose AL.

AL amyloidosis belongs to the group of conformational diseases. It is the most common type of amyloidosis with an estimated 500 new cases per year in France. It is due to a small and usually indolent plasma cell clone which synthesizes an unstable, misfolded monoclonal immunoglobulin light chain that is prone to aggregate and form amyloid fibrils. Non-invasive biopsy such as abdominal fat aspiration or minor salivary gland biopsy should be performed to confirm the diagnosis and if negative, involved tissues have to be examined. Clinical presentation is very diverse, as AL amyloidosis can affect almost any organ or tissue in the body, other than the brain. The kidney is the most frequent organ involved, whereas heart disease characterized by restrictive cardiomyopathy is the most severe. Early diagnosis, before advanced cardiomyopathy, is essential for improving outcome. The association of alkylating agent and high-dose dexamethasone is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylating agents achieve high response rates. Close monitoring of clonal and organ response is mandatory to guide therapy changes and duration. New treatments designed to eliminate amyloid deposits are under development.

Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome.

Atypical hemolytic and uremic syndrome (aHUS) is a severe disease strongly associated with genetic abnormalities in the complement alternative pathway. In renal posttransplantation, few data are available on recurrence risk and graft outcome according to genetic background in aHUS patients. The aim of this study was to identify risk factors for recurrence and transplant outcome and, in particular, the role of complement gene abnormalities. We retrospectively studied 57 aHUS patients who had received 71 renal transplants. A mutation in complement gene was identified in 39 (68%), in factor H (CFH), factor I (CFI), membrane cofactor-protein (MCP), C3 and factor B (CFB). At 5 years, death-censored graft survival was 51%. Disease recurrence was associated with graft loss (p = 0.001). Mutations in complement genes were associated with higher risk of recurrence (p = 0.009). Patients with CFH or gain of function (C3, CFB) mutations had a highest risk of recurrence. M-TOR inhibitor was associated with significant risk of recurrence (p = 0.043) but not calcineurin inhibitor immunosuppressive treatment (p = 0.29). Preemptive plasmatherapy was associated with a trend to decrease recurrence (p = 0.07). Our study highlights that characterization of complement genetic abnormalities predicts the risk of recurrence-related graft loss and paves the way for future genetically based individualized prophylactic therapeutic strategies.

[Long-term outcome of renal transplantation: impact of surgical complications on graft survival]. / Impact à long terme des complications chirurgicales sur la survie du transplant rénal.

OBJECTIVE: To determine the incidence of surgical complications of renal transplantation at one institution, relate this to donor and recipient factors and to long-term graft survival. PATIENTS AND METHODS: A consecutive series of 145 renal transplants were audited, and a database of donor and recipient characteristics created for risk-factor analysis. An unstented Barry-Sarramon anastomosis was the most used method of ureteric reimplantation. Lich-Gregoir anastomosis was used in 28.9% of cases. The mean follow-up time was 14.4 ± 6.23 years. RESULTS: There were 67 surgical complications including ten vascular, 39 urological and 18 parietal complications. Among urological complications, 13 were urinary leaks, four distal ureteric necrosis, 13 symptomatic ureteric reflux, six primary ureteric obstructions, and one ureteric stone at some time after transplantation. The overall incidence of urological complications was 26.2%. There was no association with recipient or donor age, cold ischaemic times before organ reimplantation, dialysis duration before transplantation, operating times, or ureteric stenting. Overall surgical complications had a significant pejorative impact on graft survival (Hazard Ratio [HR]=1.805; P=0.32), but as we studied them separately, we highlighted that in fact only vascular complications had an impact on long-term graft survival (HR=17.442, P<5E-10). There was no association between urological (P=0.566) or parietal (P=0.797) complications and long-term graft outcome. CONCLUSION: The onset of a urological or a parietal complication had no impact in this series on long-term graft survival. Vascular complications dramatically increase the rate of graft loss.

Identification of invariant natural killer T cells in porcine peripheral blood.

The pig is a relevant preclinical model for numerous pathologies used to validate therapeutic strategies for translation to human. Although invariant natural killer T (iNKT) lymphocytes are a component of innate immunity implicated in many pathological processes, little is known on their characterization in swine. By addressing this issue using mouse α-galactosylceramide-loaded CD1d tetramers (α-GC-CD1dTT), which are commonly used to track iNKT cells, we were able to unequivocally identify CD3(+)α-GC-CD1dTT(+) cells in porcine peripheral blood, hereafter referred to as swine iNKT cells. These lymphocytes are enriched in CD4(-)CD8(+) and CD4(-)CD8(-) cells, harbor an activated-memory phenotype (SLA-DR(+)CD45RA(-)), express the intracellular promyelocytic-leukemia-zinc-finger (PLZF) transcription factor and are significantly enriched in IFN-γ-producing cells after in vitro activation in comparison with conventional T cells. Importantly, in presence of IL-2 and IL-15, the iNKT cell ligand α-GC induces selective expansion of CD3(+)α-GC-CD1dTT(+) cells, confirming the reactivity of swine iNKT cells against α-GC. When associated with α-GC, IL-33, an alarmin of IL-1 family recently described to target iNKT cells, leads to a greater expansion of CD3(+)α-GC-CD1dTT(+) cells than IL-2 and IL-15. Altogether, our results provide the first phenotypic and functional description of swine iNKT cells allowing to further study the critical role of iNKT cells in porcine models of organ injury.

PP066. Renal artery stenosis revealed by an early-onset preeclampsia: A series of 6 cases.

INTRODUCTION: Renovascular hypertension (HT) due to an renal artery stenosis (RAS) is uncommon. Therefore, it is actually very rare to diagnose RAS during a pregnancy; very few cases have been published. OBJECTIVES: We report here a series of RAS diagnosed after an early-onset preeclampsia (EOPE). METHODS: We reviewed the files of women who had been seen at our Obstetric Medicine Clinic after an EOPE over a 19-year period. EOPE was defined by occurrence of proteinuria ⩾0.30g/d before 32 weeks of gestation (WG) with permanent HT ⩾ 140mmHg for systolic pressure and/or 90 for diastolic pressure. RESULTS: Six cases of RAS complicated with EOPE were included in the study (see table). Mean age at the time of EOPE was 27.8 years (24-35), mean term of appearance of EOPE was 22.8 WG (10-31) and mean parity was 1.5 (1-3). HELLP syndrome was found in one case, no patient had renal failure. Fetal death had occurred in three cases (two medical terminations of the pregnancy and one in utero fetal death). The mean birth weight of surviving neonates was 1235g (1070-1410). Physical examination revealed an abdominal bruit in two cases. RAS was suggested with duplex sonography in two cases, and evidenced with conventional percutaneous contrast angiography in five cases. RAS was secondary to a fibromuscular dysplasia in five cases and to atheromatosis in one case. Angioplasty was performed during conventional angiography procedure in four cases. During the follow-up, two women had a subsequent uneventful pregnancy. Restenosis was diagnosed in one case five years after angioplasty. PE: Pre-eclampsia. WG : Weeks of Gestation. MTP: Medical Termination of Pregnancy. IUFD : Intra-Uterine Fetal Death. RAS : Renal Artery Stenosis. NA : Not Applicable CONCLUSION: This series shows the necessity of exploring every case of HT with clinical features suggestive of secondary HT. Moreover, after an adverse obstetrical event, mainly after an EOPE and namely if it had occurred very early (before 28 WG), renovascular HT must be excluded before a subsequent pregnancy. Doppler ultrasound of the renal arteries is the first imaging modality to use since it is simple and noninvasive. Magnetic resonance angiography or computed axial tomography are also convenient. However, conventional percutaneous contrast angiography remains the gold standard for diagnosis of RAS, since it shows directly renal arteries and allows intervention in the same time with angioplasty and/or stent placement.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

[Disseminated arterial occlusions revealing bilateral venous thrombosis with paradoxical embolisms]. / Occlusions artérielles disséminées révélant une thrombose veineuse bilatérale avec embolies paradoxales.

Paradoxical embolism is a diagnosis of exclusion. Clinical triad associates deep venous thrombosis with or without pulmonary embolism, arterial embolism, and intracardiac communication with right-to-left shunt. The intracardiac communication is generally related to a patent foramen ovale (PFO). We report a 75-year-old patient, who presented with bilateral deep venous thrombosis of the legs, complicated by massive pulmonary embolism and paradoxical embolisms through a PFO. This resulted in cerebral, mesenteric, splenic and bilateral kidney infarctions. A promptly initiated anticoagulant treatment allowed a favourable outcome.

[Effects of smoking on the thyroid gland, digestive system, kidney and bone]. / Effets du tabagisme sur la thyroïde, le tube digestif, le rein et l'os.

INTRODUCTION: In addition to being a major cardiovascular risk factor, smoking promotes or worsens thyroid, digestive, renal and bone diseases. BACKGROUND: Smoking is positively associated with hyperthyroidism. It is associated with Graves' disease and it especially increases the risk of the development of severe exophthalmos. In contrast, smoking might exert a protective action for thyroid carcinoma. Smoking increases the severity of hepatic lesions in patients with chronic hepatitis C. Smoking accelerates the progression of primary biliary cirrhosis and increases the risk of hepatocellular carcinoma. Smoking increases risk of both hyperplastic and adenomatous polyps. While Crohn's disease is associated with smoking, ulcerative colitis is largely a disease of non smokers. Smoking increases risk of development of both renal cell carcinoma and chronic nephropathies, particularly in types 1 and 2 diabetes. Smoking is a risk factor for decreased bone density and is associated with a significantly increased risk of fracture. Smoking is related to the development of rheumatoid arthritis and may adversely influence its severity. CONCLUSIONS: Smoking might be considered a risk factor for the development of several thyroid, digestive, renal and bone diseases. Consequently, smoking prevention and cessation programs must be strongly encouraged among the patients concerned.

[Quinine-induced renal bilateral cortical necrosis]. / Nécrose corticale rénale bilatérale induite par la quinine.

Acute bilateral renal cortical necrosis is a rare cause of renal failure frequently induced by disseminated intravascular coagulation (Dic) following obstetrical complications, sepsis and drugs. We describe a case of Dic with bilateral cortical necrosis after ingestion of only one tablet of quinine. A 41-year-old woman was admitted for severe abdominal pain, melaena, fever and anuria two hours after quinine tablet intake for nocturnal leg cramps. Her medical history included angioneurotic edema caused by chloroquine for malaria prevention. Physical examination was normal. Laboratory data showed acute renal failure, hemolytic anemia without schistocytes and Dic. Platelet antibodies were negative. Ultrasonographic examination showed a complete defect of renal perfusion with permeable renal arteries. Results of abdominal CT scan and MAG3 scintigraphy led to the diagnosis of bilateral renal cortical necrosis. The patient underwent plasma exchanges with fresh frozen plasma which induced rapid resolution of Dic. She remained dependent on chronic hemodialysis. Quinine-induced microangiopathic hemolytic anemia and Dic is a rare described entity. These complications occur typically in quinine-sensitized subjects. The presence of acute renal failure is generally associated with poor prognosis in case of bilateral renal cortical necrosis. Caution is required for the prescription of quinine derivates, which should be avoided in patients experienced on adverse reaction to the drug.

Long-term maintenance of calcineurin inhibitor monotherapy reduces the risk for squamous cell carcinomas after kidney transplantation compared with bi- or tritherapy.

The incidence of skin cancer after organ transplantation is mainly related to type, level, and duration of immunosuppression. The immunosuppressive minimization strategy reduces skin malignancies, but no data are available concerning long-term calcineurin inhibitor (CNI) monotherapy compared with bi- or tritherapy. We studied the benefits of long-term CNI monotherapy (>6 years of exposure) with regard to the incidence of squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) compared with bi- or tritherapy, among first renal allograft adult recipients who were more than 6 years posttransplantation. Among 294 renal transplantations performed between 1986 and 1999, 80 patients received CNI monotherapy (MT) and 86 patients bi- or tritherapy (BTT) with a follow-up of more than 6 years. MT patients were older, had longer follow-up, and fewer biopsy-proven acute rejection episodes. The incidence of SCC was 15.9 SCC/1000 patients/year for MT vs 26.2 for BTT (P = .07). The incidence was significantly lower for patients older than 40 years (22.4 vs 56, respectively; P < .01). The incidence of BCC was 28.3 BCC/1000 patients/year for MT and 10.1 for BTT (P = .05), which failed to show a significant difference in patients older than 40 years (39.7 vs 25, respectively; P = .09). The ratio of SCC/BCC in MT was maintained around 1/2 over time, while it exceeded 2/1 in BTT after 12 years posttransplantation. Patient survival was comparable between the 2 groups. A higher graft survival rate was observed in the MT group. CNI monotherapy should be considered to be a beneficial, safe immunosuppressive minimization strategy for SCC in selected recipients.

Maternal history of type 2 diabetes is associated with diabetic nephropathy in type 1 diabetic patients.

AIMS: Insulin resistance is a key feature of type 2 diabetes. It is also involved in the development and progression of microvascular complications. We analysed the relationship between parental history of diabetes, insulin resistance and diabetic nephropathy (DN) and assessed the specific maternal and paternal influences of history of type 2 diabetes on DN in type 1 diabetic offspring. METHODS: We recorded information regarding family history of type 2 diabetes and of cardiovascular disease in 160 consecutive, unrelated type 1 diabetic patients. Insulin resistance was assessed using a validated estimation of the glucose disposal rate (eGDR). RESULTS: Type 1 diabetic patients with a maternal history of type 2 diabetes were more likely to be insulin-resistant (P=0.043) and to have renal complications (P=0.0041) than those from the reference group (without parental history of diabetes), while patients with a paternal history were not different from those from the reference group, regarding eGDR and DN. Time to development of abnormal albuminuria was significantly affected by maternal history of type 2 diabetes (log-rank=12.66; P=0.0004) and by familial history of premature cardiovascular disease (log-rank=5.48; P=0.0234). In multivariate analysis, a maternal history of type 2 diabetes was independently associated with nephropathy after adjustment for sex, diabetes duration and familial history of premature cardiovascular disease. CONCLUSION: Maternal history of type 2 diabetes is independently associated with DN in type 1 diabetic patients. This might suggest the transmission of a maternal trait related to microvascular complications, raising the hypothesis of imprinted genes predisposing to diabetic renal disease.

Acute immuno-allergic interstitial nephritis caused by fluindione.

Fluindione is a vitamin K antagonist that is commonly prescribed for the treatment of cardiovascular disease and venous thromboembolism in France. Bleeding is the most common side effect of fluindione, whereas hypersensitivity reactions are rare. We describe here a patient with acute immuno-allergic interstitial nephritis caused by fluindione. Initial symptoms included fever, eosinophilia, low albuminuria, microscopic hematuria, eosinophiluria and acute renal failure. Kidney biopsy showed severe interstitial nephritis with interstitial edema, inflammatory infiltrates and tubulorrhexis. Fluindione withdrawal and corticosteroid treatment resulted in rapid recovery of renal function. A review of the literature revealed a very low incidence of fluindione-induced interstitial nephritis, with variable renal and extra-renal signs. Early recognition of this rare complication may prevent the development of severe chronic renal injury.

Long-term results of monoclonal anti-Il2-receptor antibody versus polyclonal antilymphocyte antibodies as induction therapy in renal transplantation.

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

Cytomegalovirus prophylaxis with intravenous polyvalent immunoglobulin in high-risk renal transplant recipients.

Cytomegalovirus (CMV) seronegative renal allograft recipients (R-), particularly those with a graft from a CMV-seropositive donor (D+), are at high risk for primary CMV infection. CMV resistance to antiviral oral therapy is an emerging problem in renal transplantation, prompting development of new prophylactic strategies. We retrospectively studied the 1-year posttransplantation incidence of CMV infection in high-risk renal transplant recipients, in whom polyvalent intravenous immunoglobulins (IVIg) were used as prophylaxis. Forty R- patients received immunoprophylaxis by polyvalent IVIg (0.25 g/kg weekly for 8 weeks, starting on the operative day). CMV serological tests remained negative in eight patients (20%). Eight patients (20%) had asymptomatic CMV infection while 24 (60%) developed CMV syndrome and were treated with gancyclovir (10 mg/kg/day intravenously for 3 weeks). None had CMV disease or opportunistic infection. Six patients (15%) had biopsy-proven acute rejection, which followed CMV syndrome in three cases. One-year renal allograft and patient survivals were 95% and 97.5%, respectively. Mean serum creatinine level was 124 +/- 33 micromol/L at 1 year. Clinical tolerance of IVIg was excellent, without any episode of acute renal failure. Polyvalent IVIg provides effective prophylaxis in renal transplant recipients at high risk for CMV infection and is associated with excellent 1-year allograft survival. Because of their immunomodulatory functions, IVIg may have a beneficial effect on the incidence of acute and chronic rejection and allograft survival. A randomized prospective study is required to evaluate long-term effects of CMV prophylaxis with polyvalent IVIg compared to antiviral agents in renal transplant recipients.

Preemptive renal transplantation in adults.

Recent studies have clearly demonstrated that preemptive renal transplantation is associated with better graft and patient survival. It improves the quality of life and is a cost-effective option compared to conventional transplantation. We report our experience with this concept and review the literature. We retrospectively analyzed all adult kidney transplantations performed in our center between March 1986 and May 2004: among 463 renal transplantations 44 were preemptive (9.5%). Mean follow-up was 45.7 +/- 6 months in preemptive versus 62.3 +/- 2.6 months in the other group. At the end of the study, graft survivals were 93.2% and 77.1%, respectively (P = .02). Patient survival rates were similar in both groups. In the preemptive group, grafts were more likely to come from living donors (P < .001) and cold ischemia time was shorter (P = .02). A subgroup case-control study showed that cost saving for dialysis in the preemptive group was about 119,000 Euros per patient. More preemptive patients had professional activity before (P = .0002) and after transplantation (P = .02). Our results and data from the literature support the place of preemptive transplantation as the optimal mode of renal replacement therapy for medical and socioeconomic reasons.

[Immunoglobulin light chain amyloidosis: recent molecular, clinical and therapeutic approach]. / Amylose AL "primitive": aspects physiopathologique, clinique et thérapeutique actuels.

AL amyloidosis is a rare disorder characterised by tissue deposition of a fibrillary proteinaceous material, formed from monoclonal immunoglobulin light (or exceptionally heavy) chains. Although it may complicate multiple myeloma or B-cell lymphomas, AL amyloidosis is often associated with a low burden of clonal plasma cells ("primitive" AL amyloidosis). The mechanisms involved in the formation of AL amyloid deposits remain unclear, but are probably related to structural peculiarities of monoclonal immunoglobulin light chains. AL amyloidosis is usually a systemic disease, often revealed by renal involvement, the most common complication of the disease. The longterm prognosis of AL amyloidosis is poor, mainly related to amyloid restrictive cardiomyopathy leading to congestive heart failure. Oral melphalan and prednisone is considered the standard treatment for AL amyloidosis, but with limited increase in the median survival. High-dose intra-venous melphalan with autologous stem cell transplantation is an effective treatment, aimed at eliminating the clonaly expanded plasma cells, which has been shown to induce complete hematologic remissions and to prolong survival. However, the tolerability of such treatment is low, limiting its use to selected patients. The development of new drugs, able to interfere with amyloid fibril deposition, may provide a new therapeutic approach.