Raphaël Kormann

Aims/hypothesis Māori, a Polynesian population, have an earlier age of onset of type 2 diabetes and higher risk of diabetes-related complications compared with New Zealanders of European descent, and an increased incident rate ratio for end stage kidney disease. No data are available regarding the evolutive characteristics of diabetic kidney disease (DKD) in individuals living in French Polynesia. Methods We aimed to compare the retrospectively collected characteristics and outcomes of 92 and 63 individuals from French Polynesia and mainland France, respectively, presenting type 2 diabetes and biopsy-confirmed DKD, focusing on kidney survival, analysis of the Renal Pathology Society (RPS) score and participant survival. Results At the time of biopsy, Polynesian participants were younger (56.5 vs 66.9 years, ppp=0.008). Polynesian participants had a more severe RPS classification (pp value for interaction, 0.048), while a higher uPCR was more strongly associated with kidney survival in participants from mainland France (p value for interaction, <0.001). Older age and Polynesian origin were also independent risk factors for death. Conclusions/interpretation Starting at an earlier age, the evolutive course of DKD is also more severe in individuals from French Polynesia than from mainland Western Europe. Strong differences in clinical, histological and predictive outcomes of diabetic nephropathy were found in these different ethnic groups. Graphical Abstract

Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Background: Recent data have shown that severe acute respiratory syndrome coronavirus 2 can infect renal proximal tubular cells via Angiotensin Converting Enzyme 2 (ACE2) . Our objective was to determine whether Fanconi syndrome is a frequent clinical feature in coronavirus disease 2019 (COVID-19) patients. Methods: A retrospective cohort of 42 laboratory-confirmed COVID-19 patients without history of kidney disease hospitalized in University Hospital of Nancy was investigated. Patients were admitted to the intensive care unit (ICU) (n = 28) or the Medical department (n = 14) and were screened at least once for four markers of proximal tubulopathy. Results: The mean (standard deviation) follow-up was 19.7 (±12.2) days. Of the patients, 75% (30/40) showed at least two proximal tubule abnormalities (incomplete Fanconi syndrome). The main disorders were proteinuria (88%, n = 35), renal phosphate leak defined by renal phosphate threshold/glomerular filtration rate (TmPi/GFR) <0.77 (55%, n = 22), hyperuricosuria (43%, n = 17) and normoglycaemic glycosuria (30%, n = 12). At the time of the first renal evaluation, ICU patients presented more frequent (96 versus 62%, P = 0.0095) and more severe (844 ± 343 versus 350 ± 221 mg/g, P = 0.0001) proteinuria, and a trend for an increased number of proximal tubule abnormalities (P = 0.038). During follow-up, they presented a lower nadir of serum phosphate [median (interquartile range) 0.68 (0.43–0.76) versus 0.77 (0.66–1.07) mmol/L, P = 0.044] and Acute kidney Injury (AKI) during the hospitalization (P = 0.045). Fanconi syndrome preceded severe AKI KDIGO Stages 2 and 3 in 88% (7/8) of patients. Proximal tubular abnormalities (such as proteinuria, TmPi/GFR and glycosuria in five, two and two patients, respectively) were not detected anymore in recovering patients before hospital discharge. Conclusion: Incomplete Fanconi syndrome is highly frequent in COVID-19 patients and precedes AKI or disappears during the recovery phase.

Significance Statement: Studies in animal models and human biopsy specimens have associated the matricellular protein periostin with CKD progression, but its role in AKI is unknown. To investigate periostin’s role in AKI in an ischemia-reperfusion injury model, they used mice with tubule-specific overexpression of periostin and mice lacking periostin expression. They also conducted in vitro studies in primary cultures of isolated tubular cells subjected to hypoxia reoxygenation. Periostin produced by damaged epithelial cells after acute ischemic injury protected epithelial cells from persistent cell cycle arrest and death and promoted a proregenerative macrophage phenotype, both of which contribute to more efficient repair of the injured epithelium. The study’s findings implicate periostin as a novel mediator of renal repair after AKI, and may provide insights into repair mechanisms after AKI. Background: The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown. Methods: We used mice with conditional tubule-specific overexpression of periostin or knockout mice lacking periostin expression in the renal ischemia-reperfusion injury model, and primary cultures of isolated tubular cells in a hypoxia-reoxygenation model. Results: Tubular epithelial cells showed strong production of periostin during the repair phase of ischemia reperfusion. Periostin overexpression protected mice from renal injury compared with controls, whereas knockout mice showed increased tubular injury and deteriorated renal function. Periostin interacted with its receptor, integrin-β1, to inhibit tubular cell cycle arrest and apoptosis in in vivo and in vitro models. After ischemia-reperfusion injury, periostin-overexpressing mice exhibited diminished expression of proinflammatory molecules and had more F4/80⁺ macrophages compared with knockout mice. Macrophages from periostin-overexpressing mice showed increased proliferation and expression of proregenerative factors after ischemia-reperfusion injury, whereas knockout mice exhibited the opposite. Coculturing a macrophage cell line with hypoxia-treated primary tubules overexpressing periostin, or treating such macrophages with recombinant periostin, directly induced macrophage proliferation and expression of proregenerative molecules. Conclusions: In contrast to the detrimental role of periostin in CKD, we discovered a protective role of periostin in AKI. Our findings suggest periostin may be a novel and important mediator of mechanisms controlling renal repair after AKI.

Background: The increased survival of patients with multiple myeloma (MM) raises the question of kidney transplantation (KT) in patients with end-stage renal disease (ESRD).Methods: We included 13 patients with MM or smoldering myeloma (SMM) and ESRD transplanted between 2007 and 2015, including 7 MM with cast nephropathy, 3 with MM-associated amyloid light chain amyloidosis or light chain deposition disease and 3 SMM and compared them with 65 control-matched kidney-transplanted patients. Nine of the MM patients with KT were also compared with 63 matched MM patients on haemodialysis.Results: Pre-transplantation parameters were comparable, except for the duration of renal replacement therapy (57.8 versus 37.0 months; P = 0.029) in MM versus control patients, respectively. The median follow-up post-KT was 44.4 versus 36.4 months (P = 0.40). The median MM graft and patient survival were 80.1 and 117.2 months, respectively, and were not significantly different from control patients, although mortality tended to be higher in the 10 symptomatic MM patients (P = 0.059). MM patients had significantly more viral and fungal infections and immunosuppressive maintenance therapy modifications while they received lower induction therapy. Two MM patients relapsed and two SMM cases evolved to MM after KT. Three cast nephropathies occurred, two of them leading to ESRD. Moreover, survival of MM with KT increased relative to control haemodialysed patients (P = 0.002).Conclusions: Selected MM patients may benefit from KT but need careful surveillance in the case of KT complications and MM evolution.

Introduction: La périostine est une protéine de la matrice extracellulaire, capable de lier certaines intégrines pour activer des voies de signalisation intracellulaires spécifiques. Son expression tissulaire et urinaire est corrélée avec le degré de fibrose et d’insuffisance rénale chronique dans plusieurs maladies glomérulaires chez l’homme, et également dans la néphropathie chronique d’allogreffe. Elle joue un rôle néfaste dans plusieurs modèles de néphropathie chronique, où son inhibition protège contre la fibrose et l’infiltrat inflammatoire. Le rôle de la périostine dans l’insuffisance rénale aiguë et la réparation rénale est inconnu. Patients/Matériels et méthodes Étude de souris WT et délétées pour le gène de la périostine (KO), 24 h, 72 h, 7 jours et 6 semaines après une ischémie-reperfusion rénale unilatérale associée à une néphrectomie controlatérale (modèle I/R). Observation/Résultats La périostine est exprimée de novo autour des tubules lésés (principalement tubulaires proximaux) 24 h après I/R, et son expression persiste à 72 h, 7 jours et 6 semaines. Les souris KO présentent une insuffisance rénale aiguë plus sévère à 24 h, et une récupération ralentie à 72 h, aussi bien sur le plan de la fonction rénale que des lésions histologiques observables. Sept jours après I/R, les 2 groupes ont une fonction rénale et des lésions histologiques comparables. La périostine co-localise avec l’intégrine β1 au niveau tubulaire, et l’apoptose tubulaire est augmentée à 24 h et 72 h chez les souris KO (marquage TUNEL et cleaved caspase 3). In vivo (I/R), la périostine stimule la phosphorylation d’AKT, et limite l’expression de gènes pro-apoptotiques : P53 et BAX. En microscopie électronique, les altérations mitochondriales sont plus sévères chez les souris KO après I/R. In vitro, les cellules tubulaires issus de culture primaire WT résistent mieux au traitement par H₂0₂ que les KO. Par ailleurs, l’infiltrat macrophagique est augmenté chez les souris WT après I/R. De plus, le phénotype de ces macrophages est plus orienté vers le type M2. Enfin, la fibrose rénale et le degré d’insuffisance rénale 6 semaines après I/R est plus important chez les souris KO. Discussion/Conclusion La périostine protège les cellules tubulaires de l’apoptose, et augmente l’infiltrat inflammatoire macrophagique et leur polarisation M2 après I/R, ces deux effets résultant probablement en une diminution de la fibrose rénale après I/R. Ce résultat suggère que contrairement aux modèles de néphropathie chronique, la périostine joue un rôle protecteur dans ce modèle d’insuffisance rénale aiguë, à la fois à la phase précoce et tardive.

Summary: In African‐American patients with sickle cell disease (SCD), APOL1 G1 and G2 variants are associated with increased risk of sickle cell nephropathy (SCN). To determine the role of APOL1 variants in SCD patients living in Europe, we genotyped 152 SCD patients [aged 30·4 (24·3–36·4) years], mainly of Sub‐Saharan African ancestry, for APOL1 G1 and G2 and for variants of four genes with kidney tropism (GSTM1, GSTT1, GSTP1, and HMOX1). Homozygous or double‐heterozygous APOL G1 and G2 genotypes were strongly associated with end stage renal disease (P = 0·003) and worse Kidney Disease: Improving Global Outcomes stages (P = 0·001). Further, these genotypes were associated in an age‐dependent manner with lower estimated glomerular filtration rate (eGFR, P = 0·008), proteinuria (P = 0·009) and albuminuria (P < 0·001) but not with other SCD complications. Compared to APOL1 G1/wild type (WT), the APOL1 G2/WT genotype was associated with a lower eGFR (P = 0·04) in an age‐dependent manner, suggesting that the G2/WT patients are likely to have worse kidney prognosis. Other genes variants analysed were not associated with SCN or other SCD complications. Our data indicate that APOL1 screening should be considered for the management of SCD patients, including those of non‐African‐American origin, as those with homozygous or double heterozygous variants are clearly at higher risk of SCN.

Although post-transplant lymphoproliferative disorder (PTLD) is the second most common type of cancer in kidney transplantation (KT), plasma cell neoplasia (PCN) occurs only rarely after KT, and little is known about its characteristics and evolution. We included twenty-two cases of post-transplant PCN occurring between 1991 and 2013. These included 12 symptomatic multiple myeloma, eight indolent myeloma and two plasmacytomas. The median age at diagnosis was 56.5 years and the median onset after transplantation was 66.7 months (2–252). Four of the eight indolent myelomas evolved into symptomatic myeloma after a median time of 33 months (6–72). PCN-related kidney graft dysfunction was observed in nine patients, including six cast nephropathies, two light chain deposition disease and one amyloidosis. Serum creatinine was higher at the time of PCN diagnosis than before, increasing from 135.7 (±71.6) to 195.9 (±123.7) μmol/l (p = 0.008). Following transplantation, the annual rate of bacterial infections was significantly higher after the diagnosis of PCN, increasing from 0.16 (±0.37) to 1.09 (±1.30) (p = 0.0005). No difference was found regarding viral infections before and after PCN. Acute rejection risk was decreased after the diagnosis of PCN (36% before versus 0% after, p = 0.004), suggesting a decreased allogeneic response. Thirteen patients (59%) died, including twelve directly related to the hematologic disease. Median graft and patient survival was 31.7 and 49.4 months, respectively. PCN after KT occurs in younger patients compared to the general population, shares the same clinical characteristics, but is associated with frequent bacterial infections and relapses of the hematologic disease that severely impact the survival of grafts and patients.