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.

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.

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.

[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.

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.

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.

Natural killer cell alterations correlate with loss of renal function and dialysis duration in uraemic patients.

BACKGROUND: Natural killer (NK) cells provide a first line of immune defence towards infections and tumours, and participate in atherosclerosis and pregnancy diseases, of which there is a higher incidence in uraemic patients. Still, their relative contribution to the immunodeficient state associated with renal failure is poorly documented. METHODS: A multivariate and comparative analysis of lymphocyte subsets in haemodialysed (HD) and undialysed (UD) uraemic patients in comparison to healthy donors (HC) is provided in this article. NK-mediated cytotoxicity, degranulation and interferon secretion were compared in HD and HC. RESULTS: Evaluation of NK cells in 210 HD patients concluded with a decrease in NK cell counts in comparison to HC. Multivariate analysis associated lowered NK cell counts in UD patients with decreased renal clearance and higher NK counts HD with male gender and age. The 32% NK cell count decrease observed in sex- and age-matched groups (n = 88) was associated with B- and CD8(+)T-lymphocyte defects. NK cell functions were similar in subgroups of HD and HC matched for NK cell counts. Longer dialysis duration was associated with improved NK cytototoxic activity. While the expression of receptors modulating NK cytotoxicity were not modified, expression of the activation markers CD69 and NKp44, CD94 and chemokine receptors CX3CR1 and CXCR4 was altered in HD. CONCLUSIONS: This study is the first to associate decrease in renal function with selective fading of NK cell number and identify haemodialysis duration as a factor influencing NK cell function. It further shows that lower cell counts rather than intrinsic NK cell dysfunction per se characterize immune disorders in HD.

Cold ischemia time in renal transplantation is reduced by a timesheet in a French transplant center.

BACKGROUND: Cold ischemia time (CIT) is associated with delayed graft function (DGF) and transplant outcome. Several strategies to reduce CIT have been proposed. We retrospectively analyzed the effect of using a timesheet on CIT in our center. METHODS: In the last 2 years, we have introduced a timesheet to study the course of organ procurement and transplantation during CIT. Results of our 2-year program (121 transplantations) were compared to those in the preceding 2 years (151 transplantations). The timing of each intervention and the influence of national sharing policy and priority recipients were recorded. RESULTS: CIT decreased significantly from 21.45 to 13.27 hours (P<0.0001) and the DGF rate from 34.7 to 20.7% (P=0.011). Usually, human leukocyte antigen typing was done before kidney removal and the recipient was evaluated in the evening or at night for a transplant procedure starting in the morning. Only 1 of 121 transplantations started during the night. The availability of an operating room was the limiting factor. Sharing organs for national priority with a crossmatch having been performed increased CIT twofold (P<0.0001). CONCLUSION: Using a timesheet significantly reduced CIT to the shortest in France. The timesheet is an indicator of motivation and requires the collaboration of all transplantation personnel. It identified certain habits that may be improved to minimize CIT without reorganizing the unit. Providing quicker access to the operating room should further reduce CIT, the key to better graft survival.

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.

Tacrolimus/mycophenolate mofetil improved natural killer lymphocyte reconstitution one year after kidney transplant by reference to cyclosporine/azathioprine.

BACKGROUND: Recently introduced immunosuppressive drugs are more potent to control graft rejection, but current concerns are raised regarding their potential to increase long-term neoplastic and infectious complications. Considering the role of B, T, or natural killer (NK) lymphocyte in controlling alloreactive, anti-infectious, and antitumoral immune responses, we compared the impact of two immunosuppressive regimens on lymphocyte subsets one year following kidney transplant. METHODS: Multivariate regression analysis of variables affecting lymphocyte subset counts was retrospectively performed on 91 kidney-transplanted patients, analyzed before graft, at day 15 and 1-year postgraft. These patients were included in a randomized prospective open trial comparing tacrolimus/mycophenolate mofetil (FK/MMF) versus cyclosporine/azathioprine (CSA/Aza), both used in association with rabbit antithymocyte globulines (rATG) induction and prednisone. RESULTS: Fifteen days postgraft, severe T and NK lymphocyte depletion were observed in all patients, while B cell counts were selectively higher in the FK/MMF group as compared to before graft. One-year posttransplant, NK cell counts and NK cell cytotoxicity was significantly higher in patients receiving FK/MMF therapy, as compared to CSA/Aza. Cytomegalovirus (CMV) infection during the first year posttransplant was also associated to higher NK, CD8, and CD4CD8 T cell counts at month 12. CONCLUSIONS: In addition to its higher potential in preventing graft rejection, we show that after one year of transplant, FK/MMF better preserves NK innate immune effector cells and their cytotoxic potential. These data prompt to further evaluate the role of NK cells in relation to antiviral and tumoral surveillance of transplanted patients, which are common complications of long-term immunosuppression.

Identification by single-strand conformational polymorphism analysis of known and new mutations of the CYP3A5 gene in a French population.

The cytochrome P450 3A5 (CYP3A5) has been shown to be highly involved in the metabolism of many therapeutic agents. To date, several polymorphisms affecting the CYP3A5 gene have been identified but few studies have shown a complete description of the variability of the CYP3A5 in the French population. Therefore, the extent of CYP3A5 genetic polymorphism was investigated in a French population of 114 patients. The screening of the coding region with their intron-exon boundaries and the proximal flanking regions was performed using a PCR-SSCP strategy. Eighteen polymorphisms were identified, including four new mutations. They correspond to -19 T>C upstream of the exon 1, 7360 T>C in intron 4, 12991 T>C in intron 5 and 29788 delG in exon 12. We also identified 13 alleles including six new alleles. As expected, the most frequent allelic variant is CYP3A5*3, with a frequency of 87% of all alleles. These data confirmed that CYP3A5 gene is highly polymorphic. Furthermore, it will be now interesting to evaluate the impact of this polymorphism on the pharmacokinetic parameters of different drugs.

[About two cases of hypokaliemic periodic paralysis]. / A propos de deux cas de paralysie périodique hypokaliémique.

We report on two cases of hypokaliemic periodic paralysis due to a potassium shift from the extracellular to the intracellular compartment of skeletal muscle cells. The first case occurred in a 15-year-old boy who experienced rapid onset flaccid tetraplegia without neurological abnormalities. Physical exam revealed facial dysmorphy, and EKG a long QT. Biology evidenced shift hypokalemia that was quickly reversible after administration of intravenous potassium. After exclusion of Andersen-Tawil syndrom, hypokalemic familial paralysis (Westphall disease) was diagnosed by molecular genetic testing (disease-causing mutation in CACNA1S) in the proband and in three other family members. The second case occurred in a 24-year-old male who experienced rapid onset flaccid tetraplegia due to intracellular potassium shift that was quickly reversible after administration of intravenous potassium. Biology revealed thyrotoxicosis due to Grave's disease. To the best of our knowledge, this is the first case described in a people from pacific origin. The clinical, biological, and electromyographic findings of the most frequent causes of periodic paralysis are underlined as well as the molecular genetic diagnosis in familial forms.

[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.

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.

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.