[Kidney biopsy in Reunion Island between 2015 and 2017, an epidemiological study]. / Données épidémiologiques des biopsies rénales à l'île de la Réunion entre 2015 et 2017.

INTRODUCTION: Reunion Island's population is characterized by a multiethnic origin, which makes it impossible to transpose epidemiological data of Metropolitan France. Only REIN Registry provides a macroscopic view of kidney disease, limited to the causes of end stage renal disease. METHODS: This is a regional retrospective study whose main objective is to describe renal pathologies in Reunion Island's adults over a period of 3 years. Kidney transplants are excluded. RESULTS: Between 2015 and 2017, 338 native adult kidney biopsies performed on the island are collected. The annual biopsy rate is 132/million/year with preponderance in the northern part of the island due to a higher density of nephrologists. Nephrotic syndrome is the first indication with 30% of cases. The four main results are represented by IgA nephropathy (16%), diabetic nephropathy (12.4%), lupus nephropathy (11.2%) and isolated vascular nephropathy (11%). Incidence of glomerulopathies is similar to the worldwide incidence, nevertheless a preponderant place of diabetic nephropathy is found. On the biopsies performed, incidence of complications is evaluated at 7.5%, with no difference between the detection technique used. CONCLUSION: This is the first study illustrating main renal pathologies in Reunion Island. Diabetes' frequency in general population is a major confounding factor in diagnosis and management of kidney diseases on the island.

Atypical anti-glomerular basement membrane disease presenting as macroscopic haematuria, loin pain and acute kidney injury after intensive exercise.

We report a 35-year-old man who suffered from recurrent macroscopic haematuria after intensive exercise. One episode was associated with bilateral loin (flank) pain and severe acute kidney injury. His kidney biopsy revealed an atypical anti-glomerular basement membrane (GBM) disease typified by bright linear GBM staining for monotypic immunoglobulin G but without a diffuse crescentic phenotype and no circulating anti-GBM antibody. Outcome was spontaneously favourable. The patient had no recurrence or urine abnormality without running. The original presentation emphasized that exercise could reveal an underlying glomerulopathy.

Nocardiosis in the south of France over a 10-years period, 2004-2014.

BACKGROUND: Nocardiosis is a rare disease with polymorphic presentations. The epidemiology and clinical presentation could change with the increasing number of immunocompromised patients. METHODS: The medical records and microbiological data of patients affected by nocardiosis and treated at the university hospitals of Marseille between 2004 and 2014 were analyzed retrospectively. RESULTS: The cases of 34 patients infected by Nocardia spp during this period were analyzed. The main underlying conditions were transplantation (n=15), malignancy (n=9), cystic fibrosis (n=4), and immune disease (n=3); no immunodeficiency condition was observed for three patients. No case of AIDS was observed. At diagnosis, 61.8% had received steroids for over 3 months. Four clinical presentations were identified, depending on the underlying condition: the disseminated form (50.0%) and the visceral isolated form (26.5%) in severely immunocompromised patients, the bronchial form (14.7%) in patients with chronic lung disease, and the cutaneous isolated form (8.8%) in immunocompetent patients. Nocardia farcinica was the main species identified (26.5%). Trimethoprim-sulfamethoxazole was prescribed in 68.0% of patients, and 38.0% underwent surgery. Mortality was 11.7%, and the patients who died had disseminated or visceral nocardiosis. CONCLUSIONS: The clinical presentation and outcome of nocardiosis depend on the patient's initial immune status and underlying pulmonary condition. Severe forms were all iatrogenic, occurring after treatments altering the immune system.

[Beware, polyarteritis nodosa still exists in nephrology!] / Attention, la périartérite noueuse existe encore en néphrologie !

Renal involvement of systemic vasculitides is an emergency in nephrology. Although it has become very rare, the diagnosis of polyarteritis nodosa must be considered in some patients. A 70-year-old patient, previously healthy, presented with acute renal failure and malignant hypertension and abundant albuminuria. Subcutaneous nodule, orchitis and mononeuritis appeared subsequently. The search for auto-immunity or viral infection was negative. Markers of thrombotic microangiopathy, present initially, resolved after blood pressure control. After a renal computed tomography with contrast medium injection was considered normal, without any micro-aneurysm, a renal biopsy was performed. It showed vascular lesions and glomerular ischemia. It was complicated by hemorragic shock after 36hours. The diagnosis of periarteritis nodosa was finally made after arterial angiography showed millimetric renal micro-aneurysms. In case of systemic vasculitis with renal involvement, periarteritis nodosa must be part of differential diagnosis, especially in case of malignant hypertension, subcutaneous nodosa and orchitis, and despite albuminuria. This implies the search for micro-aneurysms with arterial angiography, and the contraindication of renal biopsy, associated with a high risk of severe hemorrhage. Periarteritis nodosa still exists in nephrology, even without hepatitis B infection. The association of acute renal failure with medium vessel vasculitis, with negative ANCA, must alert the nephrologist and lead to arterial angiography not to renal biopsy.

Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies.

Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1(+) cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of immunosuppressive treatments, robust ADCC responsiveness can be maintained in some KTRs. Because it evaluates both the Fab recognition of alloantigens and Fc-driven NK cell activation, the NK-CHAT represents a potentially valuable tool for the non-invasive and individualized evaluation of humoral risk during transplantation.

Considerable decrease in antibodies against hepatitis B surface antigen following kidney transplantation.

BACKGROUND: Immunization against hepatitis B virus (HBV) in kidney transplantation (KT) candidates and recipients is recommended. If anti-HBV surface antigen antibody (anti-HBsAb) titer of 10 IU/L is admitted to be protective, the optimal threshold, at and after KT, is unknown. In addition, the natural evolution of anti-HBsAb titers after KT is not reported. OBJECTIVES: To describe rates of protective immunity to HBV at time of KT (baseline) and evolution of anti-HBsAb titers during the following year. STUDY DESIGN: We retrospectively analyzed HBV serology at baseline, 15 days, and 4 and 12 months post-KT. No patient received vaccination during the study period, but information about previous vaccination was unavailable. RESULTS: At baseline 80% of 141 recipients had anti-HBsAb titer ≥10 IU/L. Among these 113 patients, 84 had subsequent HBV serologies at day 15 and month 4, and 67 had also serology at month 12. At month 12, 25% of patients had lost protective anti-HBsAb titers (p<0.001). The duration of protective anti-HBsAb titers was significantly longer when the initial titer was ≥ 100 IU/L versus <100 IU/L (log-rank test p<0.0001). Protective titers at month 12 persisted in 93% of patients with initial titer ≥100 IU/L compared to 33% with 10-100IU/L titer (p<0.0001). In contrast, duration of protective titers did not differ according to the anti-HBV core antigen antibody status at baseline. CONCLUSIONS: Despite a high prevalence of protective anti-HBsAb titer at KT, the loss of protective immunity during the following year was considerable, particularly when initial anti-HBsAb titer was <100 IU/L.

Systematic serological testing for hepatitis E virus in kidney transplant recipients.

Hepatitis E virus (HEV) genotype 3 is endemic in Europe and hyperendemic in southern France. Recent reports of a high prevalence of HEV RNA in blood donations and in culinary specialties from this geographical area confirmed the endemicity of HEV and sources of viral transmission in this geographical area. HEV causes acute and chronic hepatitis in solid organ transplant recipients. Since March 2012, we have implemented systematic HEV serological testing in our cohort of kidney transplant recipients (KTRs) in Marseille in southeastern France. The aim of our study was to assess HEV exposure in this cohort between March 2012 and May 2014. During these 27 months, we found that 39% of the patients who underwent kidney transplantation had an anti-HEV IgG response using a sensitive microplate enzyme immunoassay. This seroprevalence was approximately 43% at both 1 and 8 years after, using the same assay. In addition, systematic HEV serological testing detected 6 cases of HEV infection among 578 KTRs (1%) during the 27 months of the study, with 5 at an acute stage and 1 at a chronic stage. In conclusion, continuous HEV monitoring in this population is useful for better understanding the epidemiology of HEV in France, because these patients are a well-monitored population. Moreover, HEV monitoring in KTRs is clinically relevant because HEV represents a clinical threat in these patients. Nevertheless, HEV serological testing may be more fruitful for identifying HEV infections when performed in cases of biological liver abnormalities than when performed systematically.

Pericarditis in uremic patients: serum albumin and size of pericardial effusion predict drainage necessity.

BACKGROUND: Pericardial effusion in uremic patients (UPE) was first described by R. Bright in 1836. It is generally agreed that patients require emergency pericardial drainage when tamponade signs are present, but in patients with no tamponade the optimal timing for drainage remains unclear. METHODS: To define patients who will require pericardial drainage, we retrospectively studied risk factors for pericardial drainage in patients admitted with pericardial effusion and chronic renal failure. RESULTS: Between 2000 and 2012, 44 UPE patients were identified using the database of our institution: 43% were under hemodialysis, 7% under peritoneal dialysis, 11% transplanted, 39% had chronic kidney disease (CKD) stage 4 or 5. Cause of UPE was uremic pericarditis in 45.5%, dialysis pericarditis in 45.5%, and other in 9%. On initial echocardiography, UPE was estimated small (<300 ml) in 38%, moderate (300-500 ml) in 32%, and large (>500 ml) in 30%. Tamponade signs were observed in 16% of patients. During follow-up, 100 % of large effusions required drainage (70% immediate, 30% delayed). For moderate and small UPE, the initial size on echocardiography was not discriminating. Serum albumin level was highly predictive of the risk of drainage: when albuminemia was ≤31 g/l, 35% patients were drained vs. only 7% when albuminemia was >31 g/l. CONCLUSION: In this first study reporting UPE drainage risk factors, all large UPE required drainage even when extra-renal epuration intensification or medical treatment were tried. This suggests that large UPE should be drained without delay. For small and moderate UPE, size of effusion on echocardiography does not predict drainage requirement but serum albumin level does.

Undercorrection of hypernatremia is frequent and associated with mortality.

BACKGROUND: About 1% of patients admitted to the Emergency Department (ED) have hypernatremia, a condition associated with a mortality rate of 20 to 60%. Management recommendations originate from intensive care unit studies, in which patients and medical diseases differ from those in ED. METHODS: We retrospectively studied clinical characteristics, treatments, and outcomes of severely hypernatremic patients in the ED and risk factors associated with death occurrence during hospitalization. RESULTS: During 2010, 85 cases of severe hypernatremia ≥ 150 mmol/l were admitted to ED. Hypernatremia occurred in frail patients: mean age 79.7 years, 55% institutionalized, 28% with dementia.Twenty four percent of patients died during hospitalization. Male gender and low mean blood pressure (MBP) were independently associated with death, as well as slow natremia correction speed, but not the severity of hyperosmolarity at admission. Infusion solute was inappropriate for 45% of patients with MBP <70 mmHg who received hypotonic solutes and 22% of patients with MBP ≥ 70 mmHg who received isotonic solutes or were not perfused. CONCLUSIONS: This is the first study assessing outcome of hypernatremic patients in the ED according to the treatment provided. It appears that not only a too quick, but also a too slow correction speed is associated with an increased risk of death regardless of initial natremia. Medical management of hypernatremic patients must be improved regarding evaluation and treatment.

Humoral immunity after kidney transplantation: impact of two randomized immunosuppressive protocols.

BACKGROUND: Controlling alloimmune humoral response is a challenge in transplantation. Few studies have evaluated the impact of maintenance immunosuppression on blood humoral parameters. MATERIAL/METHODS: We performed a post-hoc analysis on 307 kidney transplant recipients included in a prospective randomized trial comparing tacrolimus/mycophenolate mofetil (Tac/MMF) vs. cyclosporine/azathioprine (CsA/AZA), both used with antithymocyte globulin induction and steroids. Humoral parameters were analyzed at D0, D15, and M12. RESULTS: IgG, IgA, and IgM levels decreased significantly as soon as D15 in both groups (­35%, ­26%, and ­35% respectively, vs. D0). At M12, although peripheral B-cell counts did not differ between the groups, Tac/MMF regimen was associated with lower IgG, IgA, and IgM levels than CsA/AZA (­5.9%, ­14.6%, and ­34%, respectively). Hypogammaglobulinemia at D15 was not associated with an increased risk of infections during the first year. The proportion of HLA-sensitized patients decreased in the Tac/MMF group (15.9% at D0 and 6.7% at M12, p=0.02) and remained stable in the CsA/AZA group (10.3% at D0 and 8.9% at M12, p=0.5). More patients sensitized at baseline became non-sensitized at M12 with Tac/MMF than with CsA/AZA. CONCLUSIONS: Our results suggest humoral immunosuppression is better with Tac/MMF than with CsA/AZA during the first year of kidney transplantation.

Thrombocytopenia is not mandatory to diagnose haemolytic and uremic syndrome.

BACKGROUND: Hemolytic and uremic syndrome (HUS) diagnosis involves association of non immune hemolytic anemia, thrombocytopenia, and renal failure. HUS without thrombocytopenia has been observed, we call it partial HUS. Its real frequency and outcome are unknown. The aim of this study was to determine the prevalence of patients with normal platelets count in two HUS cohorts and to compare their outcome to patients with thrombocytopenia. METHODS: We retrospectively identified HUS diagnosis in two different cohorts. The first cohort was from a single center and consisted of all cases of HUS whatever the aetiology, the second was multicentric and consisted of atypical HUS patients. These cohorts were divided into two groups depending on the presence or absence of thrombocytopenia. Clinical and biological data were compared between thrombopenic and non thrombopenic group. RESULTS: We identified 13% (20/150) of patients with normal platelets count: 10 episodes (18%) of HUS in six patients (14%) in the monocentric cohort and 14 patients (13%) with 17 episodes (12%) in the multicentric cohort of atypical HUS. Groups differed in platelets count and LDH level. In both cohorts, renal outcome was similar to patient presenting with thrombocytopenia. CONCLUSION: HUS with normal platelets count is not infrequent. Relative to classical clinical presentation of HUS, partial HUS has similar characteristics and identical poor renal outcome and so must be treated in the same way.

A randomized trial with steroids and antithymocyte globulins comparing cyclosporine/azathioprine versus tacrolimus/mycophenolate mofetil (CATM2) in renal transplantation.

BACKGROUND: The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption. METHODS: We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years. RESULTS: During the first year, 21 patients had clinically suspected acute rejection with CsA/Aza (14.4%) vs. 11 (7.7%) with Tac/MMF (P=0.07). BPAR, including borderline, was more frequent in the CsA/Aza group (14.4%) than in the Tac/MMF group (5.6%; P=0.013). At 1 year, patient and graft survivals were not different, and eGFR was 48±1 in the CsA/Aza group and 53±1 mL/min/1.73 m in the Tac/MMF group (P=0.007). There was no significant difference in diabetes after transplantation (16.8% and 18.8%, respectively). CONCLUSIONS: With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between CsA/Aza and Tac/MMF arms. Analysis of secondary endpoints showed a lower rate of BPAR, including border line, and a higher eGFR in the Tac/MMF group. CsA/Aza allowed a low acute rejection rate, but Tac/MMF seemed as a better regimen regarding severe secondary outcomes.

Hemodialysis without heparin: a randomized, controlled, crossover study of two dialysis membranes (AN69ST and polysulfone F60).

PURPOSE: It has been suggested that clotting of the extracorporeal circuit during hemodialysis (HD) without heparin could be reduced by using the polyacrylonitrile AN69ST membrane. However, this has never been demonstrated in a controlled study. The objective of this study was to compare the AN69ST with a polysulfone membrane during HD without heparin in a controlled study. METHODS: This was a prospective, randomized, crossover study. Each patient had two 3-h test sessions without heparin, one with polysulfone F60 (Fresenius Medical Care, Bad Homburg, Germany), and the other with AN69ST (Hospal-Gambro, Meyzieu, France). The extracorporeal circuit was pre-rinsed with saline containing unfractionated heparin. The order of the test sessions was randomized. The test sessions were performed one week apart, during the midweek day. The participants were stable HD patients without bleeding risk. The measurements were the number of sessions with partial or complete circuit clotting. RESULTS: Fifty-four patients were included in the study. The number of sessions interrupted for circuit clotting was 8 (15%) with AN69ST, and 10 (19%) with polysulfone (p=0.60). Complete circuit clotting occurred in 3 (6%) sessions with the two dialyzers. Partial circuit clotting manifested by a persistent increase in venous pressure occurred in 5 (9%) sessions with AN69ST, and in 7 (13%) sessions with polysulfone (p=0.54). Mean urea reduction ratio was 62±7% for AN69ST, and 63±7% for polysulfone (p=0.62). CONCLUSIONS: The AN69ST membrane did not decrease the rate of circuit clotting during HD without heparin compared to the polysulfone F60 membrane.

Fractalkine expression induces endothelial progenitor cell lysis by natural killer cells.

BACKGROUND: Circulating CD34(+) cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN) could target progenitor cell injury by Natural Killer (NK) cells, thereby limiting their availability for vascular repair. METHODOLOGY/PRINCIPAL FINDINGS: We show that CD34(+)-derived Endothelial Colony Forming Cells (ECFC) can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34(+) progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34(+) cells expressing FKN was identified as an independent variable inversely correlated to CD34(+) progenitor cell count. We further showed that treatment of CD34(+) circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. CONCLUSIONS: Our data highlights a novel mechanism by which FKN expression on CD34(+) progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients.

Pitfall of hepatitis B surface antigen testing in a kidney transplant recipient presenting hepatitis B reactivation.

Diagnosis of hepatitis B virus (HBV) infection based on hepatitis B surface antigen (HBsAg) detection can be hampered in the setting of HBV reactivation in immunocompromized patients with prior serology indicating past cured infection, and can be associated with severe or fulminant and fatal hepatitis. We present a case of HBV reactivation in a renal transplant patient in whom HBsAg failed to be confirmed as a true positive result. One year after transplantation, systematic testing showed HBsAg positivity with a titer at 244 pg/mL, anti-hepatitis B core antibody and concurrent anti-hepatitis B surface antibody positivity. Confirmation of HBsAg detection by seroneutralization did not confirm HBsAg positivity, indicating that HBsAg detection was a false positive result. Notwithstanding, HBV DNA titer in serum was concurrently 8.6 Log IU/mL. HBV DNA sequencing showed a genotype D and several amino acid substitutions within HBsAg, including some previously involved in impaired diagnosis and altered immunogenicity. Although no perturbation of liver biochemical markers was observed, treatment with tenofovir was introduced. One month later, HBV DNA level had decreased by 2.6 Log IU/mL and no clinical and biochemical symptoms of hepatitis had occurred. The present case underlines that serologic diagnosis of HBV reactivation can be tricky in transplant recipients with a prior serology indicating past HBV infection. This prompts to perform HBV DNA testing in case of positive HBsAg testing, regardless of the result of neutralization by anti-HBs antibodies.

Osseous metaplasia in a kidney allograft.

Osseous metaplasia is defined by the presence of heterotopic normal bone tissue in a soft tissue. The bone matrix is associated with osteoblasts, osteoclasts, adipocytes and haematopoietic stem cells. Osseous metaplasia pathophysiology is not well known, but many factors have been incriminated including chronic inflammation and chronic ischaemia. We describe the second case of osseous metaplasia in a kidney allograft. Numerous factors might favour its development including factors linked to transplantation failure environment.