Maryvonne Hourmant

Type of PKD1 Mutation Influences Renal Outcome in ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is heterogeneous with regard to genic and allelic heterogeneity, as well as phenotypic variability. The genotype-phenotype relationship in ADPKD is not completely understood. Here, we studied 741 patients with ADPKD from 519 pedigrees in the Genkyst cohort and confirmed that renal survival associated with PKD2 mutations was approximately 20 years longer than that associated with PKD1 mutations. The median age at onset of ESRD was 58 years for PKD1 carriers and 79 years for PKD2 carriers. Regarding the allelic effect on phenotype, in contrast to previous studies, we found that the type of PKD1 mutation, but not its position, correlated strongly with renal survival. The median age at onset of ESRD was 55 years for carriers of a truncating mutation and 67 years for carriers of a nontruncating mutation. This observation allows the integration of genic and allelic effects into a single scheme, which may have prognostic value.

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0-3 points), intermediate risk (4-6 points), and high risk (7-9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.

Elevated Soluble Flt1 Inhibits Endothelial Repair in PR3-ANCA–Associated Vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis exhibits endothelial damage, but the capacity for vessel repair in this disorder is not well understood. Here, we observed a marked increase in serum levels of soluble Flt1 (sFlt1), a potent inhibitor of vascular endothelial growth factor, in patients with active ANCA-associated vasculitis compared with patients during remission and other controls. Serum levels of sFlt1 correlated with C5a, an anaphylatoxin released after complement activation. Serum from patients with acute ANCA-associated vasculitis disrupted blood flow in the chicken chorioallantoic membrane assay, suggesting an antiangiogenic effect. Preincubation with excess human vascular endothelial growth factor prevented this effect. Anti-proteinase-3 (PR3) mAb and serum containing PR3-ANCA from patients with active vasculitis both induced a significant and sustained release of sFlt1 from monocytes, whereas anti-myeloperoxidase (MPO) mAb or polyclonal antibodies did not. However, the serum containing polyclonal PR3-ANCA did not induce release of sFlt1 from cultured human umbilical vein endothelial cells. In summary, these data suggest that anti-PR3 antibodies, and to a much lesser extent anti-MPO antibodies, increase sFlt1 during acute ANCA-associated vasculitis, leading to an antiangiogenic state that hinders endothelial repair.

MICA Mutant A5.1 Influences BK Polyomavirus Reactivation and Associated Nephropathy After Kidney Transplantation

BACKGROUND BK polyomavirus (BKPyV) frequently reactivates in kidney transplant recipients during immunosuppressive therapy and triggers BKPyV-associated nephropathy and graft rejection. Determining effective risk factors for BKPyV reactivation is required to achieve efficient prevention. METHODS This study investigated the role of major histocompatibility complex (MHC) class I-related chain A (MICA) in BKPyV reactivation in a cohort of 144 transplant donor/recipient pairs, including recipients with no reactivation (controllers) and those with mild (virurics) or severe (viremics) BKPyV reactivation after graft receipt. RESULTS We show that, in the kidney, MICA is predominantly expressed in tubule epithelial cells, the natural targets of BKPyV, questioning a role for MICA in the immune control of BKPyV infection. Focusing on MICA genotype, we found a lower incidence of BKPyV reactivation in recipients of a renal graft from a donor carrying the MICA A5.1 mutant, which encodes a truncated nonconventional MICA. We established that a mismatch for MICA A5.1 between transplant donor and recipient is critical for BKPyV reactivation and BKPyV-associated nephropathy. Functionally, we found that a low prevalence of BKPyV reactivation was associated with elevated anti-MICA sensitization and reduced plasma level of soluble MICA in recipients, 2 potential effector mechanisms. DISCUSSIONS These findings identify the MHC-related MICA as an immunogenetic factor that may functionally influence anti-BKPyV immune responses and infection outcomes.

Impact of antiviral prophylaxis in adults Epstein-Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: a retrospective cohort study

Post‐transplantation lymphoproliferative disorder (PTLD) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R−) is the main risk factor for both early PTLD (<1 year post‐transplantation) and late (>1 year). In these at‐risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney–pancreas EBV‐seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty‐seven (50.7%, prophylaxis group) received (val‐)aciclovir or (val‐)ganciclovir for 3–6 months and 36 (49.3%, no‐prophylaxis group) received no‐prophylaxis. Mean follow‐up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no‐prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV‐related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no‐prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD.

Successful treatment of acute promyelocytic leukemia with arsenic trioxide and all-trans retinoic acid in a double lung and kidney transplanted patient

Dear Editor, We report the successful treatment of a case of posttransplant acute promyelocytic leukemia (PT-APL) in a 45-year-old man who underwent double lung transplantation for cystic fibrosis at the age of 32 and renal transplantation, for chronic end-stage renal disease due to anti-calcineurin toxicity, at age 43. This is the 12th reported case of PT-APL so far [1], but the first for whom the treatment applied was chemo-free using arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA). Furthermore, this is the only PT-APL reported in a double organ (lung and kidney) recipient. This patient was severely immunosuppressed and had developed multiple cutaneous carcinomas and BK virus infection, both markers of immune impairment. In April 2015, the propositus presented with pancytopenia. Examination of a bone marrow smear showed 60 % blasts with Auer rods. Karyotypic analysis and fluorescence in situ hybridization (FISH) showed an isolated t(15;17), confirming the diagnosis of acute promyelocytic leukemia (APL). The glomerular filtration rate (GFR) was at 58 mL/min/1.73 m (MDRD). There was no sign of liver failure nor clinical symptoms apart from a mild asthenia (ECOG Performance Status at 1) [2]. In our hematological unit, all cases of APL without leukocytosis are treated according to the regimen published by Lo-Coco et al. [3]. Basically, the ATO/ATRA combination is given at induction until cytological remission (CyR), and afterwards, patients are treated as outpatients for 4 cycles of 1 month each. In this specific patient, induction therapy was initiated at half dose because of the low GFR and comorbidities. After the first 2 weeks, ATRA was increased at full dose without toxicity. An increase of ATO was then attempted, but after 4 days, the patient presented a severe epistaxis which resolved after discontinuing ATO for 24 h. The latter was then resumed at half dose until the end of the treatment duration. The leukocytes count reached 20 × 10/L during induction, without ATRA syndrome and hydroxurea was prescribed with efficacy. Bone marrow examination at day 29 confirmed cytologic remission (CR) with a first point of minimal residual disease (MRD1) positive at 2 × 10, assessed by reverse transcriptase polymerase chain reaction for leukemia-specific transcripts (i.e., PML-RARA, RARA-PML). During consolidation, ATRAwas tapered down at 75 % of full dose, because of headaches. MRD2, performed on peripheral blood just before the 4th cycle, was negative. The patient had no serious infections, GFR remained around 50 mL/min/1.73 m, and there was no side effect of everolimus throughout the procedure. The patient is currently still in CR at one year with undetectable MRD. In conclusion, while a chemotherapy regimen including anthracycline and aracytine would have been of higher * Pierre Peterlin pierre.peterlin@chu-nantes.fr