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Low-molecular weight heparins (LMWH) are widely used for preventing clotting during hemodialysis (HD). Although injection in the venous blood line is recommended to avoid initial loss of LMWH through the dialyzer, LMWH is still frequently administered in the arterial blood line at the start of dialysis. This study aimed to compare the safety and efficacy of the same enoxaparin dose administered through the venous blood line or arterial blood line. We also evaluated antifactor Xa (aXa) activity according to the injection route and dialysis modalities: high-flux (HF) HD, medium cut-off (MCO) HD, and online hemodiafiltration (OL-HDF). Forty-three patients were studied over 18 consecutive dialysis sessions using a fixed enoxaparin dose (20 or 40 mg), first administered through the arterial blood line bolus and then through the venous blood line for another 18 sessions. Compared to arterial blood line administration, venous blood line bolus resulted in a significant increase in median post-dialysis aXa activity: 0.16 (0.1-0.6) IU/ml versus 0.31 (0.1-1.3) IU/ml, respectively, p = 0.006. After arterial blood line bolus of 40 mg enoxaparin, median post-dialysis aXa activity was significantly lower with OL-HDF compared to HF-HD: 0.14 (0.1-0.35) versus 0.32 (0.15-0.49), p = 0.02. A trend for lower clotting within lines and bubble trap using venous blood line bolus was observed. In conclusion, venous blood line enoxaparin injection is safe in OL-HDF patients. However, in HF-HD and MCO-HD, venous blood line injection of 40 mg enoxaparin may increase overdosing risk. Thus, aXa activity should be monitored in HF-HD and MCO-HD patients at risk of bleeding and/or on vitamin K antagonists and careful surveillance is required when administering a 40 mg enoxaparin dose through the venous blood line route.

Light chain cast nephropathy (LCCN) in multiple myeloma often leads to severe and poorly reversible acute kidney injury. Severe renal impairment influences the allocation of chemotherapy and its tolerability; it also affects patient survival. Whether renal biopsy findings add to the clinical assessment in predicting renal and patient outcomes in LCCN is uncertain. We retrospectively reviewed clinical presentation, chemotherapy regimens, hematologic response, and renal and patient outcomes in 178 patients with biopsy-proven LCCN from 10 centers in Europe and North America. A detailed pathology review, including assessment of the extent of cast formation, was performed to study correlations with initial presentation and outcomes. Patients presented with a mean estimated glomerular filtration rate (eGFR) of 13 ± 11 mL/min/1.73 m2, and 82% had stage 3 acute kidney injury. The mean number of casts was 3.2/mm2 in the cortex. Tubulointerstitial lesions were frequent: acute tubular injury (94%), tubulitis (82%), tubular rupture (62%), giant cell reaction (60%), and cortical and medullary inflammation (95% and 75%, respectively). Medullary inflammation, giant cell reaction, and the extent of cast formation correlated with eGFR value at LCCN diagnosis. During a median follow-up of 22 months, mean eGFR increased to 43 ± 30 mL/min/1.73 m2. Age, β2-microglobulin, best hematologic response, number of cortical casts per square millimeter, and degree of interstitial fibrosis/tubular atrophy (IFTA) were independently associated with a higher eGFR during follow-up. This eGFR value correlated with overall survival, independently of the hematologic response. This study shows that extent of cast formation and IFTA in LCCN predicts the quality of renal response, which, in turn, is associated with overall survival.

Introduction Le tolvaptan (JINARC®) est le premier traitement de la polykystose renale autosomique dominante (PKRAD) dont la Commission de la Transparence (HAS) a defini les criteres d’eligibilite en 2015. Description Cree en 2010, la cohorte GENKYST comprend 3200 patients dans 28 centres sur 13 departements du Grand Ouest Francais. Methodes Nous rapportons les resultats en vie reelle des patients Genkyst traites par tolvaptan suivis prospectivement depuis l’initiation du traitement. Pour chacun des patients, la pente du DFG en fonction du nombre de mois est calculee par regression lineaire, avant traitement puis apres debut du traitement. Resultats 108 patients ont ete traites dans 17 centres : âge moyen 47 ans, DFG moyen 55 ml/min. 89 % des patients traites etaient porteurs d’une mutation de PKD1. Le volume total renal moyen etait de 1422 ml/m (405 a 4643) : 96 % des patients avaient un score de la Mayo Clinic > 1 C et 70 % un score PRO-PKD > 3. La titration a ete hebdomadaire (25 %) ou mensuelle (56 %) et 72 % des patients ont pu atteindre et conserver la dose de 90-30 mg avec une duree moyenne de traitement de 22 mois. Au total, 30 % des patients ont du stopper le tolvaptan dont la moitie pour les effets aquaretiques. Trois cas d’augmentation importante des transaminases ont ete rapportes, spontanement resolutifs a l’arret du traitement. La perte moyenne de DFG etait de 5,16 ml/min/an avant traitement et passe a 3,48 ml/min/an apres traitement. En regression lineaire la moyenne des pentes par patient est significativement differente avant et apres traitement (p = 0,031). Conclusion Les indications de traitement ont ete globalement conformes aux indications de la HAS. Le traitement par tolvaptan en dehors de protocoles cliniques montre une tolerance plus faible (30 % d’arret). Pour la premiere fois, nous montrons une efficacite en vie reelle en comparant les donnees avant et apres traitement.

International audience; The clinicopathological characteristics of kidney infiltration in B-cell lymphoproliferative disorders remain poorly described. We retrospectively studied 52 adults with biopsy-proven malignant B-cell kidney infiltration, including Waldenström's macroglobulinemia (n=21), chronic lymphocytic leukemia (n=11), diffuse large B-cell lymphoma (DLBCL) (n=8), other lymphoma (n=11), and multiple myeloma (n=1). Kidney disease varied according to the underlying lymphoproliferative disorder. In DLBCL, malignant kidney infiltration was prominent, resulting in acute kidney injury (AKI, 75%) and kidney enlargement (88%). In the other types, associated immunoglobulin-related nephropathy (most commonly AL amyloidosis) was more common (45%), and chronic kidney disease with proteinuria was the primary presentation. All patients received chemotherapy. Over a median follow-up of 31 months, 20 patients died and 21 reached end-stage kidney disease. Renal response, achieved in 25 patients (48%), was associated with higher overall survival (97 vs. 37 months in non-renal responders). In univariate analysis, percentage of sclerotic glomeruli, kidney enlargement, and complete hematological response at 6 months were predictive of renal response. In multivariate analysis, concomitant immunoglobulin-related nephropathy was the sole independent predictor of poor renal outcome. In conclusion, clinical presentation of renal lymphomatous infiltration depends on the nature of the underlying lymphoproliferative disorder. In DLBCL, massive renal infiltration manifests with enlarged kidneys and AKI, and the diagnosis primarily relies on lymph node biopsy. In other B-cell lymphoproliferative disorders, the clinicopathological spectrum is more heterogeneous, with a high frequency of immunoglobulin-related nephropathy that may affect renal outcome; thus kidney biopsy is required for early diagnosis and prognostic assessment. © 2019 International Society of Nephrology

Introduction La maladie de Dent est une tubulopathie renale genetique (mutation des genes CLCN5 ou OCRL1) caracterisee par un dysfonctionnement tubulaire proximal associe a une nephrocalcinose, une nephrolithiase et une insuffisance renale progressive. Methodes Notre objectif est de decrire l’evolution des patients atteints d’une maladie de Dent apres transplantation renale. Entre 2010 et 2018, douze patients presentant une maladie de Dent et ayant beneficie d’une transplantation renale ont ete selectionnes dans neuf centres francais. Nous rapportons les resultats preliminaires de onze greffes concernant neuf patients. Resultats obtenus ou attendus Tous les patients etaient des hommes. La maladie etait diagnostiquee entre 10 et 51 ans. Cinq avaient une mutation identifiee sur le gene CLCN5. Aucun patient n’avait beneficie d’un bilan urodynamique avant greffe. Un patient avait presente des coliques nephretiques. L’âge moyen a la greffe etait de 39,1 ans. Trois greffes etaient realisees de maniere preemptive et deux a partir d’un donneur vivant. Tous les patients avaient une diurese conservee le jour de greffe. On notait six reprises differees de fonction (54,5 %). L’ischemie froide moyenne etait de 11 heures. L’hospitalisation pour la greffe durait en moyenne 19,3 jours (de 12 a 30 jours). Trois patients (33,3 %) presentaient une vessie hyposensible et de forte capacite entrainant des pyelonephrites precoces du greffon. Une insuffisance renale fonctionnelle secondaire a une polyurie compliquait deux greffes motivant une nephrectomie d’un rein propre dans les deux cas. Six greffes (54,5 %) se compliquaient de rejet aigu dont trois rejets humoraux avec perte de greffon dans deux cas a cinq et douze mois post-greffe. La fonction renale au dernier suivi (suivi median de six ans) etait correcte avec une creatininemie moyenne a 156,4 μmol/L sans proteinurie significative. Conclusion Pour prevenir les complications, il convient de bien evaluer la compliance vesicale avant la greffe et de surveiller attentivement la diurese au cours du suivi post-greffe.

BACKGROUND Light chain myeloma cast nephropathy (MCN) is the major cause of renal failure in multiple myeloma and strongly impacts patient survival. The role of kidney biopsy in the management of MCN is unclear. METHODS Renal pathological findings were retrospectively studied in 70 patients with multiple myeloma and MCN. Patients were categorized according to the achievement or not of renal response, as defined by estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m(2) and/or dialysis independence at 3 months. RESULTS Thirty-two patients (46%) achieved a renal response. In the whole study population, the following parameters differed significantly between patients with and without renal response, respectively: baseline median eGFR (13.3 versus 9.3 mL/min/1.73 m(2), P = 0.017), Acute Kidney Injury Network Stage 3 (68.8 versus 92.1%, P = 0.019), haematological response rate (94 versus 34%, P < 0.0001), median percentage of free light chain (FLC) reduction at Day 21 (92 versus 24%, P = 0.006) and median number of casts/10 fields (14 versus 25, P = 0.005). The extent of interstitial fibrosis and tubular atrophy was similar. In multivariate analysis, only FLC reduction at Day 21 was significantly associated with renal response. However, when considering only the subgroup of haematological responders, both median number of casts [odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.88-0.98, P = 0.01] and extent of tubular atrophy (OR = 0.03, 95% CI: 0.00-0.52, P = 0.02) were independent predictors of renal response. CONCLUSIONS In MCN, the presence of numerous casts and diffuse tubular atrophy is associated with poor renal prognosis. These data suggest that additional strategies to reduce FLC burden should be considered in patients with extensive cast formation.

International audience; Background - PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. Study design - Case series, January 2010 to March 2016. Settings & participants - Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. Outcomes - Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. Results - The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. Limitations - Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. Conclusions - Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

Introduction Les profils d’evolution de la creatininemie (SCr) en post-greffe renale immediat sont variables d’un patient a l’autre. L’objectif etait d’identifier les differents types de trajectoires de SCr pendant le sejour hospitalier de greffe et estimer leur valeur pronostique sur la perte du greffon. Methodes Il s’agit d’une etude monocentrique retrospective, realisee chez des patients transplantes renaux de rang 1, entre 2008 et 2017 au CHU de Poitiers. Les donnees repetees de SCr determinees quotidiennement pendant le sejour hospitalier de la greffe ont ete recueillies et ont ete modelisees par des modeles mixtes a classes latentes. Le nombre de classes latentes a ete choisi en fonction des la valeur du critere BIC. L’association trajectoire–Survie du greffon a ete evaluee par un modele de Cox. Resultats obtenus ou attendus Sur les 496 patients suivis en moyenne 5,3 ± 2,9 ans , quatre trajectoires de SCr ont ete mises en evidence (A, B, C et D correspondant respectivement a 345, 77, 44, 30 patients) ( Fig. 1 ). Les variables associees aux trajectoires etaient le sexe et l’âge du receveur, la greffe preemptive, le nombre d’incompatibilites HLA-DR, la premiere determination post-greffe de creatinine. A la fin du suivi, 439 greffons etaient fonctionnels. La survie du greffon etait significativement differente entre les quatre trajectoires (p = 0,0005) apres ajustement sur le temps d’ischemie froide et le type de donneur (ECD). Le risque de perte de greffons etait multiplie par 2,4, 3,6 et 4,0 pour les profils B, C et D respectivement. Conclusion La trajectoire de creatininemie en post-greffe immediat, definie par modeles mixtes a classes latentes, pourrait constituer un facteur pronostique de la survie du greffon.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).

Introduction Le tolvaptan est maintenant disponible depuis plusieurs mois. Nous rapportons l’experience du groupe Genkyst sur 66 patients traites. Patients/Materiels et methodes Les patients polykystiques traites par le tolvaptan sont suivis prospectivement au sein de la cohorte Genkyst. Ils sont tous genotypes et un volume renal calcule avant traitement pour la majorite des patients. Nous avons etudie le profil des patients traites par tolvaptan, les conditions de titration et la tolerance de la molecule. Observation/Resultats Il s’agissait de 66 patients (52 % d’homme) âges de 30 a 71 ans. La majorite des patients etaient actifs. Au moment de l’initiation du traitement 15 % etaient au stade 1 de la MRC, 10 % au stade 2 ; 69 % au stade 3 et 6 % au stade 4. Le volume total renal moyen etait de 1475 mL/m (602 a 4643). Sur le plan genetique, 70 % des patients etaient porteurs d’une mutation tronquante de PKD1, 20 % d’une mutation non tronquante de PKD1 et seulement 8 % d’une mutation de PKD2. Si on applique le score de la Mayo Clinic [1] tous les patients appartenaient aux classes 1 C a 1E (classes a fort risque de progression). Concernant le score PROPKD [2] : 68 % des patients avaient un score > 3. La titration a ete soit hebdomadaire (50 %) soit mensuelle. La totalite des patients a presente a l’initiation un syndrome polyuropolydipsique (volume des boissons de 4 a 8 litres au debut), entrainant des mictions horaires en moyenne et de 2 a 5 levers nocturnes. A distance de la titration : 50 % des patients recevaient la dose maximale 90/30, 15 % 60/30, 10 % 45/45, 20 % avaient stoppe le traitement essentiellement pour les effets secondaires aquaretiques. Dans un sous-groupe de 30 patients, on constate une augmentation de la natremie au debut du traitement (3 mmol/L) et une petite perte de fonction renale et une osmolarite urinaire constamment Discussion/Conclusion Nous rapportons l’experience dans la vraie vie de l’utilisation du tolvaptan. On constate que pour l’instant, les patients traites sont majoritairement au stade 3 de la MRC et qu’ils presentent des criteres de progression rapide. La tolerance semble un peu moins bonne que dans les essais cliniques (20 % d’arret).

International audience; BACKGROUND:Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response.STUDY DESIGN:Case series.SETTING & PARTICIPANTS:35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases.PREDICTORS:Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1).OUTCOMES:Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m2 in patients with glomerular and tubulointerstitial disorders, respectively).RESULTS:Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients.LIMITATIONS:Retrospective study; insufficient population to establish the impact of chemotherapy.CONCLUSIONS:IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

Abstract 3949 Acute kidney injury (AKI) is a common but serious sequela of multiple myeloma. Recently, the International Myeloma Working Group (IMWG) introduced a new renal response criteria with complete (CRenal), partial (PRenal) and minimal (MRenal) responses. This study compares the IMWG criteria with other models to determine their correlation with overall survival (OS). Patients with multiple myeloma and AKI were identified from centers around the world. OS was calculated from the day of AKI. Renal function was assessed by estimated glomerular filtration rate (eGFR) via MDRD method. Hematologic response was the best achieved as assessed by International Uniform Response Criteria for Multiple Myeloma. Only patients with peak serum creatinine (Scr) ≥ 2.0 mg/dl were included. Separate analyses were performed on the newly diagnosed (ND) versus previously treated (PT) patients. A total of 158 patients were collected from centers in United States, United Kingdom, France and Austria. Fourteen patients were excluded for having peak Scr < 2.0 mg/dl and one for repeated episodes of AKI. Median age of the 143 patients was 64 (34 – 87) years, 58.7% were male and 115 were newly diagnosed. Median Scr was 5.1 (2.0 to 18.6) mg/dl and median eGFR was 10.6 (2.8 – 36.5) ml/min/1.72 m2. Dialysis was required in 49.3%, and 72.9% were dialysis independent at the end of the study. By IMWG criteria, median OS ranged between 6.0 months (m) in PT patients with no renal response (NRenal) to 23.7m in patients with CRenal, p = 0.34 (Table 1). In ND patients, OS was 31.4m in NRenal vs 73.8m in CRenal (p = 0.08). However, OS was similar between PRenal and CRenal, p = 0.70 (Figure 1). If only patients with a hematologic PR or better were analyzed, the OS range was 6.0m in NRenal to 23.7m in CRenal in PT patients (p = 0.85) and 36.6m in NRenal to 73.8m in CRenal in ND patients, p = 0.73.Table 1.Previously TreatedNMedian SurvivalNMedian Survival (>PR) CRenal323.7 m323.7 m PRenal413.1 m312.8 m MRenal512.0 m119.2 m NRenal166.0 m56.0 m p-value0.340.85Newly Diagnosed CRenal2273.8 m2273.8 m PRenal27Not Reached23Not Reached MRenal2265.6 m1965.6 m NRenal4331.4 m2136.6 m p-value0.080.73Figure 1.Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08.Figure 1. Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08. The best model tested was one that defined renal response (RR) as regaining or maintaining dialysis independence and no response (NR) as dialysis dependence. RR was associated with a superior survival for both PT patients (13.5 m vs 6.0m (NR), p = 0.03) and ND patients (73.8m vs 20.1m (NR), p < 0.001). RR increased with the depth of hematologic response, p = 0.04. RR occurred in 75% of the PT patients with hematologic PR or better and 66.7% in those with less than PR, p = 0.64. In ND patients, RR occurred in 85.7% of those with PR or better and 54.6% of those with PR or less, p = 0.003. This may explain the differences in OS when hematologic response was considered. In PT patients with hematologic PR or better, renal response did not improve OS (21m vs 6m, p = 0.28) but it remained beneficial in the ND patients (73.8m vs 35.1m, p = 0.04, Figure 2). Renal response was not significantly associated with OS for any patient with hematologic response that was VGPR or better. In a multivariate analysis, RR (p = 0.001), ND (p The results of our study suggest renal response is important to OS but the depth of response was not as important. Renal response was most important when the hematologic response was less than a VGPR. This supports renal response as part of the overall response assessment in multiple myeloma patients. Based on our results, reducing the number of response categories and simplifying the current consensus criteria seems justified. Median survival of the 143 patients evaluated by the IMWG renal response criteria. Overall survival was calculated by Kaplan Meier method. Differences in survival were evaluated by Log-Rank test. Disclosures: Ludwig: Mundipharma, Janssen-Cilag: Research Funding, Speakers Bureau. Hutchison:The Binding Site: Honoraria.