[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.

IL-33 receptor ST2 deficiency attenuates renal ischaemia-reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice.

AIM: Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia-reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2-/-) on renal IRI in euglycaemic and hyperglycaemic mice. METHODS: Hyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2-/- mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. RESULTS: Urinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2-/- mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2-/- animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. CONCLUSION: Our data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on alarmins and diabetes in ischaemia-related diseases.

Genome-Wide Association Study of Acute Renal Graft Rejection.

Acute renal rejection is a major risk factor for chronic allograft dysfunction and long-term graft loss. We performed a genome-wide association study to detect loci associated with biopsy-proven acute T cell-mediated rejection occurring in the first year after renal transplantation. In a discovery cohort of 4127 European renal allograft recipients transplanted in eight European centers, we used a DNA pooling approach to compare 275 cases and 503 controls. In an independent replication cohort of 2765 patients transplanted in two European countries, we identified 313 cases and 531 controls, in whom we genotyped individually the most significant single nucleotide polymorphisms (SNPs) from the discovery cohort. In the discovery cohort, we found five candidate loci tagged by a number of contiguous SNPs (more than five) that was never reached in iterative in silico permutations of our experimental data. In the replication cohort, two loci remained significantly associated with acute rejection in both univariate and multivariate analysis. One locus encompasses PTPRO, coding for a receptor-type tyrosine kinase essential for B cell receptor signaling. The other locus involves ciliary gene CCDC67, in line with the emerging concept of a shared building design between the immune synapse and the primary cilium.

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.

Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.

Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.

Daclizumab Versus Rabbit Antithymocyte Globulin in High-Risk Renal Transplants: Five-Year Follow-up of a Randomized Study.

We previously reported a randomized controlled trial in which 227 de novo deceased-donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy-proven acute rejection (BPAR) and steroid-resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG-treated patient (0.9%) and one daclizumab-treated patient (1.0%) developed BPAR after 1 year. Five-year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high-immunological-risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low-risk cohorts.

Three-year outcomes in kidney transplant patients randomized to steroid-free immunosuppression or steroid withdrawal, with enteric-coated mycophenolate sodium and cyclosporine: the infinity study.

In a six-month, multicenter, open-label trial, de novo kidney transplant recipients at low immunological risk were randomized to steroid avoidance or steroid withdrawal with IL-2 receptor antibody (IL-2RA) induction, enteric-coated mycophenolate sodium (EC-MPS: 2160 mg/day to week 6, 1440 mg/day thereafter), and cyclosporine. Results from a 30-month observational follow-up study are presented. Of 166 patients who completed the core study on treatment, 131 entered the follow-up study (70 steroid avoidance, 61 steroid withdrawal). The primary efficacy endpoint of treatment failure (clinical biopsy-proven acute rejection (BPAR) graft loss, death, or loss to follow-up) occurred in 21.4% (95% CI 11.8-31.0%) of steroid avoidance patients and 16.4% (95% CI 7.1-25.7%) of steroid withdrawal patients by month 36 (P = 0.46). BPAR had occurred in 20.0% and 11.5%, respectively (P = 0.19). The incidence of adverse events with a suspected relation to steroids during months 6-36 was 22.9% versus 37.1% (P = 0.062). By month 36, 32.4% and 51.7% of patients in the steroid avoidance and steroid withdrawal groups, respectively, were receiving oral steroids. In conclusion, IL-2RA induction with early intensified EC-MPS dosing and CNI therapy in de novo kidney transplant patients at low immunological risk may achieve similar three-year efficacy regardless of whether oral steroids are withheld for at least three months.

[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.

Mothers without HLA antibodies before transplantation have a low risk of alloimmunization post-transplantation.

Human leukocyte antigen antibodies (HLA Abs) are associated with poor renal graft outcome. We selected 134 first kidney transplant recipients without HLA Ab (LABScreen® Luminex) before transplantation despite previous allogeneic exposure whether through blood transfusion (BT) and/or pregnancy (PR). We screened these patients for HLA Ab post-transplantation (yearly) and determined the risk of HLA Ab and donor-specific antibody (DSA) appearance according to BT/PR in a univariate and a multivariate model. Among the 134 patients (43 males/91 females), 56 were BT+/PR-, 41 BT-/PR+ and 37 BT+/PR+. Median delay between last PR or BT and transplantation were 25.9 years (0.5-47.8) and 8 months (0.8-128.0), respectively. Median number of PR and BT were 2 (1-11) and 3 units (1-28), respectively. After transplantation (median follow-up: 47.5 months), 13 patients (9.7%) had HLA Ab and 10 DSA, mainly directed against class II HLA (HLA Ab: 10/13, DSA: 9/10). The risk of HLA Ab and DSA appearance was significantly lower in patients with PR before transplantation (P = 0.032 and P = 0.009, respectively). The risk of DSA appearance (hazard ratio = 0.17, P = 0.027) remained significantly lower after adjustment on donor age, acute rejection and number of class I/II HLA mismatches. In conclusion, we show that parous women non-immunized are at low risk of HLA Ab production after transplantation.

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

The influence of cytomegalovirus infections on patient and renal graft outcome: a 3-year, multicenter, observational study (Post-ECTAZ Study).

Cytomegalovirus (CMV) infections posttransplant may increase the risk of acute rejection, graft failure, patient death, opportunistic infections, malignancy, diabetes, and cardiovascular complications. ECTAZ, a multicenter, randomized trial compared safety and efficacy at 12 months (M12) of two doses daclizumab (54 patients, group D) with thymoglobulin (55 patients, group T), plus cyclosporine (CsA), mycophenolate mofetil and steroids in first cadaveric kidney transplant patients. D+/R- patients received oral ganciclovir prophylaxis for 90 days. Post-ECTAZ is a 36-month, multicenter, observational study including recipients who participated in ECTAZ trial. We studied the indirect effects of CMV infections, whether recipients experienced (CMVi+) or not (CMVi-) a CMV infection/syndrome/disease. We compared 49 patients in the group CMVi+ with 54 patients in the group CMVi-. At month 36 (M36), patient survival, graft survival and renal function were comparable. The incidence of biopsy-proven acute rejection was 16.3% in the CMVi+ group versus 24.1% in the CMVi- group (not significant). The incidence of infections was increased in the CMVi+ group (P = .004), but not diabetes, malignancies, and cardiovascular complications. Our study shows at M36 that CMV infection/syndrome/disease episodes were associated with a higher incidence of infections but no difference for other long-term complications. Our data suggest that anti-CMV prophylaxis could decrease the risk for long-term related CMV complications.

Optimization of initial tacrolimus dose using pharmacogenetic testing.

Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C(0)). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C(0). Whether this improvement will affect clinical outcomes requires further evaluation.

[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.

Relapse of membranous glomerulopathy after kidney transplantation: sustained remittance induced by rituximab.

Membranous glomerulopathy (MG) is a rare cause of chronic kidney disease. However, after kidney transplantation (KT), despite immunosuppression, it often relapses on the allograft. Herein, we report on a male kidney-transplant patient, aged 27 years, who developed overt nephrotic syndrome 11 months after KT. This was related to relapsing MG, as evidenced by the allograft biopsy, which, in addition, showed CD3 (+) and CD20 (+) interstitial lymphocyte infiltration. The patient was treated with rituximab: 375 mg/m2/week for 4 consecutive weeks, followed by one additional injection every 3 months for one year. Remission was observed before the third rituximab injection. After a follow-up of 42 months, the patient was still in remission, i.e., microalbuminuria of 107 mg/day.

[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.

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

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.