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Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Background Two prospective studies that were performed before the era of highly sensitive solid-phase assays have shown a lower incidence of acute rejection in highly sensitized kidney-transplant patients given polyclonal antibodies compared with those given anti-CD25 monoclonal antibodies. Methods This prospective pilot randomized French multicenter study aimed to compare anti–T-lymphocyte Ig (ATLG) (n = 32) and basiliximab (n = 27) in highly sensitized kidney-transplant patients without preformed donor-specific antibodies (pDSAs) as assessed by a Luminex Single-Antigen flow bead assay. Only patients with a calculated panel reactive antibody ≥50%, with at least 1 antibody with a mean fluorescence intensity ≥5000 and without a historical pDSA and without a pDSA on the day of transplantation were included. Results Treatment failure as defined by biopsy-proven acute rejection, patient lost to follow-up, graft loss, and death was observed in 18.8% (95% confidence interval [CI], 8.9%–37.1%) and 18.8% (95% CI, 8.9%–37.1%) in patients who received ATLG and 14.8% (95% CI, 5.8%–34.8%) and 28.2% (95% CI, 14.2%–51.2%) of patients who received basiliximab, respectively at 6 (P = 0.66) and 12 (P = 0.62) months post-transplantation. One T cell–mediated rejection was observed in ATLG-treated patients (3.1%). One antibody-mediated rejection due to a de novo donor-specific antibody (DSA) occurred in basiliximab-treated patients (3.7%). Patient survival, graft survival, kidney parameters, and infection rate were similar in the 2 groups. Conclusion This pilot study indicates that in highly sensitized kidney-transplant patients without pDSAs, both ATLG and basiliximab can be used efficiently and safely. However, because of the lack of power, these results should be interpreted with caution., Graphical abstract

International audience; Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA-based vaccine for the prevention of CMV-related mortality and end-organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double-blind, placebo-controlled study in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10-100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43-1.47; P = .307). There were similar numbers of transplant recipients with treatment-emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV-seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.

One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n = 99) or no CS (−CS; n = 98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the −CS group (5-year follow-up, p = 0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p = 0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p = 0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p = 0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in −CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.

Resume Nous rapportons 2 cas de greffes renaux sous tacrolimus ayant presente un syndrome douloureux des genoux au premier et troisieme mois de greffe. Le tacrolimus est un immunosuppresseur agissant, comme la cyclosporine, par inhibition de l’activite phosphatasique de la calcineurine. Ce syndrome semble similaire a celui decrit en 1989 avec la cyclosporine. La scintigraphie osseuse montre des hyperfixations des epiphyses douloureuses, et l’imagerie par resonance magnetique des modifications du signal en faveur d’un œdeme medullaire. Si les taux residuels de tacrolimus ne sont pas trop eleves, la diminution de posologie ne semble pas toujours necessaire. L’evolution est favorable en quelques mois. La surveillance radiologique doit eliminer une osteonecrose. Les hypotheses pathogeniques sont evoquees. L’utilisation du tacrolimus etant encore recente, il est utile que les observations similaires soient rapportees.

We report a case of longitudinal tibial fracture as the first manifestation of bone insufficiency in a 50-year-old patient who had received a renal transplant 12 years earlier. The epidemiological, clinical, and imaging features of these fractures are reviewed. Bone loss occurs in the long term in about half of renal transplant recipients. The main causes are preexisting renal osteodystrophy; glucocorticoid therapy; and hyperparathyroidism, whether residual or secondary to imperfect graft function. The effects of cyclosporine therapy on bone metabolism remain unclear. Identification of patients at very high risk of fracture and available options for early prophylaxis are discussed.

Resume Nous rapportons un cas de fracture de contrainte longitudinale du tibia revelant une insuffisance osseuse chez un patient de 50 ans, transplante renal a l’âge de 38 ans. Les particularites epidemiologiques et cliniques de ce type de fracture de contrainte sont resumees, ainsi que les indications de l’imagerie. L’insuffisance osseuse apres transplantation renale est un probleme frequent, concernant jusqu’a 1 patient sur 2 a long terme. Les principales causes sont l’osteodystrophie renale preexistante, la corticotherapie, l’hyperparathyroidie residuelle ou secondaire a une fonction imparfaite du greffon. Le role de la ciclosporine sur le metabolisme osseux reste encore imprecis. Les criteres de selection des patients les plus a risque de fracture et les possibilites de traitement preventif precoce sont discutes.

We report the 6-year radiographic follow-up of a phalangeal brown tumor in a patient with severe hyperparathyroidism secondary to chronic renal failure treated with hemodialysis. The phalangeal lesion increased in size during the first 3 years, until the patient finally accepted to undergo parathyroidectomy. The initial radiographic change was a small intracortical lytic area. Two years later, an expansile cystic lesion was visible in the phalanx, and computed tomography showed a cortical defect. Ossification of the lesion occurred over the 2.5 years following parathyroidectomy. The epidemiology, radiographic changes and post-treatment evolution of brown tumor in dialysed patients is reviewed. Surgical parathyroidectomy is the standard treatment for brown tumor complicating secondary hyperparathyroidism. The usefulness and limitations of treatment with vitamin D analogs, recently reported in a few case reports, are discussed.

The occurrence of aortoiliac lesions with renal transplantation is an increasingly common combination that causes problems regarding operative strategy and indications for aortoiliac reconstruction and renal transplantation. To gain greater insight into these problems we undertook a retrospective multicenter study based on data from 24 kidney transplantation centers in France. A total of 83 patients who underwent both aortoiliac reconstruction and kidney transplantation were enrolled. Patients were divided into two groups according to the order in which the two procedures were performed. Group I included 36 patients in whom aortoiliac reconstruction was performed before kidney transplantation-either during the same procedure (6 patients) or as separate procedures (30 patients). Group II included 47 patients in whom aortoiliac reconstruction was performed after kidney transplantation. The mean age was 49.9 years. There were 43 abdominal aortic aneurysms (51.8%), 36 occlusive aortoiliac lesions (43.4%), and 4 aortoiliac dissections (4.8%). Prosthetic bypass grafting was performed in 72 cases (86.8%), transluminal angioplasty in 6 cases (7.2%), endarterectomy in 3 cases (3.6%), and arterial autograft bypass in 1 case. Renal transplant protection was used during aortoiliac clamping in only 3 patients in group II (7.3%). One month after the second procedure (i.e., kidney transplantation in group I and aortoiliac reconstruction in group II), creatinemia was200 micromol/L in 27 patients (87.1%) in group I and in 37 patients (88.1%) in group II. The graft survival rate was 86.1% in group I and 89.3% in group II. The overall postoperative morbidity rate was 36.1% (13 cases) in group I and 36.1% (17 cases) in group II. One year after the second procedure creatinemia was200 micromol/L in 29 patients (93.5%) in group I and 36 patients (93%) in group II. The graft survival rate was 86.1% in group I and 85.1% in group II. The outcome of kidney transplantation is comparable regardless of whether the procedure is performed alone or in association with aortoiliac reconstruction. This finding indicates that kidney transplantation should be performed in patients presenting indications for prior aortoiliac reconstruction. The outcome of aortoiliac reconstruction without graft protection in kidney transplant patients is comparable to the outcome of conventional aortoiliac reconstruction in patients with native kidneys.

5-Fluorouracil (5-FU) and d,1-folinic acid (FA) are used in association to treat a wide variety of malignancies. The stability and the compatibility of 5-FU and FA in combination in intravenous admixtures were studied under various storage conditions and with drug concentrations matching their clinical use (0.9% sodium chloride, 5% dextrose, protected from light or not). 5-FU and FA concentrations (mg/ml) were 6.5 or 50 and 4.0 or 30.8, respectively. Successive aliquots of the drugs mixtures were withdrawn during 60 h from 500 ml glass bottles and 500 ml polyvinyl chloride (PVC) bags (at room temperature) and during 120 h from cassettes (at 32 degrees C). Drug concentrations were measured by high performance liquid chromatography. For all conditions tested, the changes in 5-FU and FA relative to the initial concentrations remained within the assay reproducibility (10%). In complement, infrared Fourier transformation spectrophotometry has not shown a significant fixation of FA or 5-FU on the PVC bags, in all tested conditions. Under the conditions examined above 5-FU and FA can be mixed in the same container for their use in cancer chemotherapy. This can have practical consequences by simplifying the widely used treatment protocols associating 5-FU and FA.

Results obtained in organ transplantation have considerably improved with the introduction of Cyclosporine (CsA). However, the management of the drug in the sandimmun formulation is hampered by its low, highly variable bioavailability as well as the inter- and intrasubject variability of its pharmacokinetic parameters. The new galenic formulation of CsA, Neoral, based on the microemulsion principle, makes CsA absorption less dependent on gastric repletion, the presence of biliary salts and pancreatic enzymes, and concomitant administration of food. Digestive absorption and, subsequently, drug bioavailability are improved. Pharmacological studies in healthy volunteers and transplanted patients 1,2 have shown that pharmacokinetic profile of CsA becomes more reproducible from patient to patient as well as in the same patient over time. The aim of our study was to analyze the clinical outcome and the variations in the parameters of CsA monitoring after conversion from CsA-Sandimmun (SIM) to CsA-Neoral (NEO) in stable kidney recipients transplanted for more than 6 months.