Low incidence of acute rejection within 6 months of kidney transplantation in HIV-infected recipients treated with raltegravir: the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) 153 TREVE trial.

OBJECTIVES: High rates of clinical acute rejection after kidney transplantation have been reported in people living with HIV (PLHIV), probably as a consequence of drug interactions. We therefore investigated the incidence of acute rejection within 6 months of transplantation in HIV-infected recipients treated with a protease-inhibitor-free raltegravir-based regimen. METHODS: The Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS) 153 TREVE (NCT01453192) study was a prospective multicentre single-arm trial in adult PLHIV awaiting kidney transplantation, with viral load < 50 HIV-1 RNA copies/mL, CD4 T-cell count > 200 cells/µL, and HIV-1 strains sensitive to raltegravir, aiming to demonstrate 6-month clinical acute rejection rates < 30%. Time to transplantation was compared with that for uninfected subjects matched for age, sex and registration date. RESULTS: In total, 61 participants were enrolled in the study, and 26 underwent kidney transplantation. Two participants experienced clinical acute rejection, corresponding to an estimated clinical acute rejection rate of 8% [95% confidence interval (CI) 2-24%] at 6 and 12 months post-transplantation. HIV infection remained under control in all but one participant, who temporarily stopped antiretroviral treatment. Median time to transplantation was longer in PLHIV than in controls (4.3 versus 2.8 years, respectively; P = 0.002) and was not influenced by blood group. CONCLUSIONS: Acute rejection rates were low after kidney transplantation in PLHIV treated with a raltegravir-based regimen. However, PLHIV have poorer access to transplantation than HIV-uninfected individuals after registration on the waiting list.

Estimated or Measured GFR in Living Kidney Donors Work-up?

The value of estimated glomerular filtration rate (eGFR) in living kidney donors screening is unclear. A recently published web-based application derived from large cohorts, but not living donors, calculates the probability of a measured GFR (mGFR) lower than a determined threshold. Our objectives were to validate the clinical utility of this tool in a cohort of living donors and to test two other strategies based on chronic kidney disease epidemiology collaboration (CKD-EPI) and on MDRD-eGFR. GFR was measured using 51 Cr- ethylene-diamine tetraacetic acid urinary clearance in 311 potential living kidney donors (178 women, mean age 50 ± 11.6 years). The web-based tool was used to predict those with mGFR < 80 mL/min/1.73 m2 . Inputs to the application were sex, age, ethnicity, and plasma creatinine. In our cohort, a web-based probability of mGFR <90 mL/min/1.73 m2 higher than 2% had 100% sensitivity for detection of actual mGFR <80 mL/min/1.73 m2 . The positive predictive value was 0.19. A CKD-EPI-eGFR threshold of 104 mL/min/1.73 m2 and an MDRD-eGFR threshold of 100 mL/min/1.73 m2 had 100% sensitivity to detect donors with actual mGFR <80 mL/min/1.73 m2 . We obtained similar results in an external cohort of 354 living donors. We confirm the usefulness of the web-based application to identify potential donors who should benefit from GFR measurement.

Severe infections requiring intensive care unit admission in kidney transplant recipients: impact on graft outcome.

BACKGROUND: Kidney transplant recipients are at risk for life-threatening infections, which may affect the long-term prognosis. METHODS: We retrospectively included all kidney transplant recipients admitted for sepsis, severe sepsis, or septic shock to the medical intensive care unit (ICU) of the Saint-Louis Hospital, Paris, France, between 2000 and 2010. The main objective was to identify factors associated with survival without graft impairment 90 days after ICU discharge. RESULTS: Data were available for 83 of 100 eligible patients. The main sites of infection were the lungs (54%), urinary tract (24%), and bloodstream (22%). Among documented infections (55/83), 80% were bacterial. Fungal infections were more common among patients transplanted after 2005 (5% vs. 23%, P = 0.02). Mechanical ventilation was used in 46 (56%) patients, vasopressors in 39 (47%), and renal replacement therapy (RRT) in 34 (41%). In-hospital and day-90 mortality rates were 20% and 22%, respectively. On day 90, among the 65 survivors, 39 (47%) had recovered their previous graft function and 26 (31%) had impaired graft function, including 16 (19%) who were dependent on RRT. Factors independently associated with day-90 survival and graft function recovery were baseline serum creatinine (odds ratio [OR] for a 10 µmol/L increase 0.94, 95% confidence interval [CI] 0.88-1.00) and cyclosporine therapy (OR 0.30, 95% CI 0.11-0.79). CONCLUSION: Sepsis was chiefly related to bacterial pneumonia or urinary tract infection. Pneumocystis jirovecii was the leading opportunistic agent, with a trend toward an increase over time. Infections often induced severe graft function impairment. Baseline creatinine and cyclosporine therapy independently predicted the outcome.

Acute enteritis associated with Coxsackievirus A19 in a kidney transplant patient.

Diarrhea is a frequent complication after kidney transplantation, with an incidence rate between 22% and 51%. In many cases, the cause remains unknown. We describe here the first case, to our knowledge, of persistent diarrhea associated with Coxsackievirus A19 (CVA19) in a kidney transplant recipient. The patient was a 46-year-old man who received a deceased-donor kidney. He experienced delayed graft function because of donor kidney donation after circulatory determination of death. Maintenance immunosuppression consisted of low-dose cyclosporine, high-dose mycophenolate mofetil (MMF) (3 g/day), and prednisone (10 mg/day). He had severe diarrhea for 2 weeks associated with acute renal failure. No pathogens were found in the stool cultures. Enterovirus detection was positive by real-time polymerase chain reaction, and sequence analysis found CVA19 (from Enterovirus C group). Area under the curve of MMF was 48 mg.h/L. Because of the persistence of diarrhea, MMF was stopped and replaced by azathioprine. The diarrhea disappeared, but serum creatinine did not return to baseline. CVA19 rarely causes gastroenteritis. This case illustrates that MMF is not always the direct cause of diarrhea, and that new clinical infectious diseases will be detected with the expansion of molecular-based DNA diagnostics.

French ENT Society (SFORL) guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin.

OBJECTIVES: The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. MATERIALS AND METHODS: The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi's sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. RESULTS: Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi's sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. CONCLUSION: Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken.

Human de novo papillary renal-cell carcinomas in a kidney graft: evidence of recipient origin with adenoma-carcinoma sequence.

Papillary renal-cell carcinoma (pRCC) is unusual for its occurrence in kidneys with chronic dysfunction, for its frequent multifocality and for its common association with papillary adenoma, a benign renal lesion morphologically indistinguishable from pRCC. Concomitant development of papillary adenoma and pRCC in five transplanted kidneys, where donor and recipient characteristics are well established, provided a unique opportunity for molecular studies of de novo pRCC carcinogenesis. We aimed to study this tumor type to determine whether or not the different papillary tumors have the same origin, and whether or not papillary adenomas are precursor lesions of pRCC. We performed XY-FISH in sex-mismatched kidney transplants, and polymorphic microsatellite DNA and high-resolution melting of mitochondrial DNA analyzes in all five patients on laser-microdissected tumor cells, then compared these molecular profiles to donor and recipient profiles. This study (i) identified the recipient origin of de novo papillary adenomas and pRCCs in a kidney transplant, (ii) demonstrated an identical origin for precursor cells of papillary adenomas and pRCCs and (iii) showed additional genetic alterations in pRCCs compared to papillary adenomas. This molecular approach of papillary tumors developed in transplanted kidney identified successive steps in carcinogenesis of human de novo papillary renal-cell carcinoma.

Renal transplantation in HIV-infected patients: the Paris experience.

Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long-term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m² (range 23-98) and 65.4 mL/min/1.73 m² (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV-infected patients with few adverse events and a low incidence of acute rejection.

Polyarthritis and anemia in a hemodialysis patient: systemic lupus erythematosus following treatment with interferon alpha.

Autoimmune manifestations may occur with interferon alpha (IFNalpha) therapy. However IFNalpha-induced systemic lupus erythematosus is a rare event. We report a 33-year-old hemodialysis patient who presented polyarthritis and anemia 4 months after initiation of IFNalpha for chronic hepatitis C. Systemic lupus erythematosus was diagnosed. Clinical symptoms improved rapidly with interruption of the treatment and a low-dose steroid therapy. This is the first case of IFN-induced SLE in a hemodialysis patient to confirm the major role of IFNalpha in the lupus physiopathology. Treatment with steroid therapy does not seem to worsen the HCV infection.

Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after discontinuation of prophylaxis: a case­control study.

A case-control study was conducted to identify risk factors for Pneumocystis jirovecii pneumonia (PCP) in renal transplant recipients. Eleven cases of PCP were matched with 22 controls. Cases occurred a median of 18 months after transplantation, and none of the recipients was receiving prophylaxis. Univariate analysis showed that graft rejection, duration of steroid use, use of mammalian target of rapamycin (mTOR) inhibitors and lymphocytopenia at the time of prophylaxis discontinuation were risk factors for PCP. In the multivariate model, only graft rejection (OR 8.66, p 0.017) remained significantly associated with PCP. In patients with a history of graft rejection, PCP prophylaxis should be maintained, especially among those with lymphocytopenia.

[What tests are necessary before registration on the kidney transplant waiting list?]. / Quelles explorations faut-il réaliser avant l'inscription sur une liste de transplantation rénale ?

Before registering a patient on the kidney transplant waiting list, the medical file should be carefully studied looking for factors that may complicate the transplantation. Knowledge of the patient's history and the clinical examination will guide the choice of complementary examinations. The objectives of pretransplantation explorations are : 1) preventing graft rejection ; 2) ensuring that arterial and venous anastomoses are possible ; 3) ensuring that urine can be drained ; 4) preventing post-transplantation infections ; 5) not performing a transplantation on a subject with cancer ; and 6) avoiding any post-transplantation cardiovascular events. The list of the necessary explorations for renal transplantation should be as simple as possible so that registration on the transplant waiting list is not delayed, while being as complete as possible to prevent any complications that may compromise the results. It should be individualized to each patient.

Nephron sparing surgery is a feasible and efficient treatment of T1a renal cell carcinoma in kidney transplant: a prospective series from a single center.

PURPOSE: Renal cell carcinoma in a renal graft is a rare condition whose incidence will increase in the future. To our knowledge no standardized treatment has been established for this disease. We performed a prospective study of nephron sparing surgery for small renal cell carcinoma in renal grafts. MATERIALS AND METHODS: From January 2002 to December 2006, 2,050 renal graft recipients were followed at our transplantation center. Of these patients 7 were diagnosed with histologically confirmed renal cell carcinoma in the renal graft, 5 of whom presented with T1a renal cell carcinoma and prospectively underwent nephron sparing surgery. RESULTS: Five patients with 15 to 30 mm (median 20) renal cell carcinoma were included in the study and were treated with nephron sparing surgery. Median operative time was 110 minutes (range 60 to 150). Blood loss was less than 200 ml in each case. All tumors were pT1aN0M0 with negative margins. No postoperative complications were observed (hemorrhage, urinary fistulas, renal failure). Preoperative immunosuppressive treatment was not modified postoperatively. At 3 months after nephron sparing surgery and at a mean of 17.4 months of followup (range 5 to 54) no significant impairment of renal function or recurrence was observed. CONCLUSIONS: Nephron sparing surgery is a safe and efficient procedure for the treatment of renal cell carcinoma in renal grafts, resulting in the preservation of renal function and in short-term cancer control.

Prognostic value of plasminogen activator inhibitor type 1 mRNA in microdissected glomeruli from transplanted kidneys.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) exerts antifibrinolytic and profibrotic activities. Inside the glomerulus, PAI-1 is mainly synthesized by mesangial cells. We hypothesized that thrombin, via its receptor protease activated receptor type 1 (PAR-1), present on the membrane of glomerular cells, is an important mediator of PAI-1 synthesis. METHODS: Using the technique of Peten et al., we microdissected the glomeruli of 23 kidney transplanted patients admitted in our department from 1993 to 1997, and we followed-up these patients for up to 5 years, with sometimes iterative renal biopsies. With this technique, we also microdissected the glomeruli of three patients who have had a nephrectomy for cancer (control patients). We investigated mRNA expression of the PAI-1, the thrombin receptor PAR-1, the alpha2 chain of type IV (alpha2 IV) collagen, and of a housekeeping gene (cyclophilin) by reverse transcription-polymerase chain reaction. The results were correlated with the renal function and the histological findings classified into acute rejection (9 biopsies), chronic rejection (22 biopsies), or normal (8 biopsies). RESULTS: A significant up-regulation of PAI-1 and alpha2 IV collagen mRNA was observed in acute rejection (P<0.05) when compared to normal kidneys. A positive correlation exists between alpha2 IV collagen mRNA level and the degree of cellular infiltration. A negative correlation was found between the level of mRNA of PAR-1 and the degree of vascular thrombosis (P=0.005) and glomerulosclerosis (P=0.04). A positive correlation was found between the degradation of renal function and the mRNA level of PAI-1 at the time of the renal biopsy (P<0.05). CONCLUSIONS: These results suggest that glomerular PAI-1 mRNA may be predictive of the long-term renal graft function.

Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.

BACKGROUND: Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. METHODS: Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis. RESULTS: Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months. CONCLUSIONS: Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

[Indications of central venous access in the context of acute renal insufficiency]. / Indications des accès veineux centraux dans le contexte de l'insuffisance rénale aiguë.

Central vascular access indications in acute renal failure have never been precised by clinical studies. This is probably due to the epidemiology of acute renal failure and to heterogeneity of acute renal failure patients. Schematically, acute renal failure can be divided into three groups of increasing gravity: isolated non complicated acute renal failure, complicated acute renal failure, and severe acute renal failure that arises in the setting of multiple organ failure syndrome. Central vascular access indications, such as catheters type and vascular sites of insertion are actually based on many clinical and technical considerations. These considerations include the gravity of acute renal failure, the need of emergency extracorporeal renal replacement therapy, the modalities of such therapy, and the expected catheterism duration.