Renal function is highly associated with podiatric risk in diabetic patients.

Background: Chronic kidney disease (CKD) is correlated with the incidence of diabetic foot ulcer (DFU). Furthermore, the International Working Group on the Diabetic Foot (IWGDF) has proposed a classification of the risk factors for DFU. The purpose of this study was to investigate the relationship between the IWGDF risk classification and the glomerular filtration rate level estimated by the CKD Epidemiology Collaboration formula (eGFR). Methods: We conducted a prospective multicentric study. Patients were recruited from either diabetology or nephrology departments. The secondary objectives were to determine this relationship after excluding people on dialysis and to identify the factors associated with podiatric risk. Results: Four hundred and eighty-six patients were included, with a mean age of 64.2 years (±15.7) and a mean diabetes duration of 15.7 years (±12.1). Based on the IWGDF classification, 53.5% of the population were in podiatric stage 0, 11.7% in stage 1 and 34.8% in stage 2 or 3. The mean eGFR level was significantly lower in patients with podiatric risk ≥2 (36.8 ± 33.9 mL/min/1.73 m2 vs 71.9 ± 35.3 mL/min/1.73 m2, P < .0001) and a significant association was found between the eGFR and the podiatric risk. This association remained significant after the exclusion of the hemodialysis patients. After receiver operating characteristic analysis, a cutoff of 45 ± 11 mL/min/1.73 m2 (area under the curve 0.76) was found discriminant to define a group of CKD patients at higher risk for podiatric stage ≥2. Conclusion: eGFR levels are linked to podiatric stages in diabetes mellitus. Patients with eGFR <45 mL/min/1.73 m2 and dialysis patients should be carefully managed in collaboration with diabetic foot specialized centers.

C5b-9 Glomerular Deposits Are Associated With Poor Renal Survival in Membranous Nephropathy.

Introduction: Membranous nephropathy (MN) is the first cause of nephrotic syndrome in patients without diabetes. Its prognosis is variable, and treatment remains controversial because of potential toxicity. Currently, there is no reliable prognostic marker common to all etiologies of MN and routinely available to predict the disease course and guide therapeutic management. Despite the major role of complement in the glomerular damage of MN, its prognostic impact has never been studied. We investigated the frequency and prognostic impact of glomerular deposition of C5b-9 in MN. Methods: We retrospectively selected adults diagnosed with MN (primary or secondary) at Montpellier University Hospital between December 2004 and December 2015. To be included, all patients were required to have complete medical data and a kidney tissue sample for further immunohistochemistry. We performed PLA2R1, C4d, and C5b-9 staining by immunohistochemistry. Results: Sixty-four adults were included: 45 with primary MN and 19 with secondary MN. C4d was positive in the glomeruli of 61 adults (95.3%). Twenty-nine adults (45.3%) had glomerular deposition of C5b-9. Patients with glomerular deposition of C5b-9 had more severe nephrotic syndrome on diagnosis and lower remission and renal survival rates than adults without. Conclusion: C5b-9 glomerular staining is a powerful and easily accessible tool for stratifying adults according to their renal prognosis. The efficacy of complement inhibitors should be tested in adults with glomerular deposition of C5b-9.

IgG3 donor-specific antibodies with a proinflammatory glycosylation profile may be associated with the risk of antibody-mediated rejection after kidney transplantation.

The pathogenicity of de novo donor-specific antibodies (dnDSA) varies according to their characteristics. While their MFI, complement-fixing ability, and IgG3 subclass are associated with ABMR occurrence and graft loss, they are not fully predictive of outcomes. We investigated the role of the Fc glycosylation of IgG3 dnDSA in ABMR occurrence using mass spectrometry after isolation by single HLA antigen beads. Between 2014 and 2018, we enrolled 54 patients who developed dnDSA (ABMR- n = 24; ABMR+ n = 30) in two French transplant centers. Fucosylation, galactosylation, GlcNAc bisection, and sialylation of IgG3 dnDSA were compared between ABMR+ and ABMR- patients. IgG3 dnDSA from ABMR+ patients exhibited significantly lower sialylation (7.5% vs. 10.5%, p < .001) and higher GlcNAc bisection (20.6% vs. 17.4%, p = .008). Fucosylation and galactosylation were similar in both groups. DSA glycosylation was not correlated with DSA MFI. In a multivariate analysis, low IgG3 sialylation, high IgG3%, time from transplantation to kidney biopsy, and tacrolimus-free regimen were independent predictive factors of ABMR. We conclude that a proinflammatory glycosylation profile of IgG3 dnDSA is associated with a risk of ABMR occurrence. Further studies are needed to confirm the clinical interest of DSA glycosylation and to clarify its role in determining the risk of ABMR and graft survival.

Contactin-1 is a novel target antigen in membranous nephropathy associated with chronic inflammatory demyelinating polyneuropathy.

Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound contactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-contactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated.

Measuring intradialyser transmembrane and hydrostatic pressures: pitfalls and relevance in haemodialysis and haemodiafiltration.

BACKGROUND: Post-dilutional haemodiafiltration (HDF) with high convection volumes (HCVs) could improve survival. HCV-HDF requires a significant pressure to be applied to the dialyser membrane. The aim of this study was to assess the pressure applied to the dialysers in HCV-HDF, evaluate the influence of transmembrane pressure (TMP) calculation methods on TMP values and check how they relate to the safety limits proposed by guidelines. METHODS: Nine stable dialysis patients were treated with post-dilutional HCV-HDF with three different convection volumes [including haemodialysis (HD)]. The pressures at blood inlet (Bi), blood outlet (Bo) and dialysate outlet (Do) were continuously recorded. TMP was calculated using two pressures (TMP2: Bo, Do) or three pressures (TMP3: Bo, Do, Bi). Dialysis parameters were analysed at the start of the session and at the end of treatment or at the first occurrence of a manual intervention to decrease convection due to TMP alarms. RESULTS: During HD sessions, TMP2 and TMP3 remained stable. During HCV-HDF, TMP2 remained stable while TMP3 clearly increased. For the same condition, TMP3 could be 3-fold greater than TMP2. This shows that the TMP limit of 300 mmHg as recommended by guidelines could have different effects according to the TMP calculation method. In HCV-HDF, the pressure at the Bi increased over time and exceeded the safety limits of 600 mmHg provided by the manufacturer, even when respecting TMP safety limits. CONCLUSIONS: This study draws our attention to the dangers of using a two-pressure points TMP calculation, particularly when performing HCV-HDF.

Distribution of de novo Donor-Specific Antibody Subclasses Quantified by Mass Spectrometry: High IgG3 Proportion Is Associated With Antibody-Mediated Rejection Occurrence and Severity.

Donor-specific antibodies (DSAs) are the main risk factor for antibody-mediated rejection (ABMR) and graft loss but could have variable pathogenicity according to their IgG subclass composition. Luminex-based test might lack sensitivity for the detection of IgG subclasses and this test does not allow quantifying the relative abundance of each IgG subclass. We investigated the precise repartition of each DSA subclass and their role in ABMR occurrence and severity, using an innovative mass spectrometry-based method. Between 2014 and 2018, we enrolled 69 patients who developed de novo DSA (n = 29 without ABMR, and n = 40 with ABMR) in two transplant centers. All IgG subclasses were detected in every samples tested: 62.7% were IgG1, 26.6% were IgG2, 6.6% were IgG3, and 4.2% were IgG4. The IgG3 proportion was significantly higher in the ABMR+ compared to the ABMR- group (8.4% vs. 5.6%, p = 0.003). The proportion of IgG1, IgG2, and IgG4 of DSA was similar between the two groups. Higher IgG3 level was associated with higher C4d deposition, higher microvascular inflammation scores, and glomerular filtration rate decline >25%. IgG3 proportion was not correlated with DSA MFI. Multivariate analysis showed that proteinuria and high level of IgG3 DSA were the only two factors independently associated with ABMR. In conclusion, de novo DSA are always composed of the four IgG subclasses, but in different proportions. High IgG3 proportion is associated with ABMR occurrence and severity and with poorer outcome, independently of DSA MFI.

C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Successful treatment of a Streptococcus pneumoniae-associated haemolytic uraemic syndrome by eculizumab.

Haemolytic uraemic syndrome (HUS) is a rare complication of invasive infection by Streptococcus pneumoniae (SP-HUS), especially in adults. Here we report an unusual case of a 53-year-old man presenting SP-HUS with severe multivisceral involvement. After failure of supportive care and plasma exchanges, eculizumab (anti-C5 antibody) resulted in a favourable outcome.

Correction: Consequences of increasing convection onto patient care and protein removal in hemodialysis.

[This corrects the article DOI: 10.1371/journal.pone.0171179.].

Geographical Variations in Blood Pressure Level and Seasonality in Hemodialysis Patients.

Seasons and climate influence the regulation of blood pressure (BP) in the general population and in hemodialysis patients. It is unknown whether this phenomenon varies across the world. Our objective was to estimate BP seasonality in hemodialysis patients from different geographical locations. Patients from 7 European countries (Spain, Italy, France, Belgium, Germany, United Kingdom, and Sweden) participating in the DOPPS (Dialysis Outcomes and Practice Patterns Study) on years 2005 to 2011 were studied. Factors influencing pre- and postdialysis systolic BP and diastolic BP levels were analyzed by mixed models. There were 9655 patients (median age, 68; 59% male) from 263 facilities, seen every 4 months during a median duration of 1.3 years. Pre- and postdialysis systolic BP increased by a mean estimate of 5.1 mm Hg (95% confidence interval [CI], 3.7-6.4 mm Hg) and 4.4 mm Hg (95% CI, 2.9-5.9 mm Hg) for each 10° increase in latitude (1111 km to the North). In the longitudinal analysis, predialysis systolic BP was lower in summer and higher in winter (difference, 1.7 mm Hg; 95% CI, 1.3-2.2 mm Hg), with greater differences in southern locations (Pinteraction=0.04). Predialysis systolic BP was inversely associated with outdoor temperature (-0.8 mm Hg/7.2°C; 95% CI, -1.0 to -0.5 mm Hg/7.2°C), with steeper slopes in southern locations (Pinteraction=0.005). Results were similar for predialysis diastolic BP. In conclusion, there is a geographical and seasonal gradient of BP in European hemodialysis patients. There is a need to consider these effects when evaluating and treating BP in this population and potentially in others.

Consequences of increasing convection onto patient care and protein removal in hemodialysis.

INTRODUCTION: Recent randomised controlled trials suggest that on-line hemodiafiltration (OL-HDF) improves survival, provided that it reaches high convective volumes. However, there is scant information on the feasibility and the consequences of modifying convection volumes in clinics. METHODS: Twelve stable dialysis patients were treated with high-flux 1.8 m2 polysulphone dialyzers and 4 levels of convection flows (QUF) based on GKD-UF monitoring of the system, for 1 week each. The consequences on dialysis delivery (transmembrane pressure (TMP), number of alarms, % of achieved prescribed convection) and efficacy (mass removal of low and high molecular weight compounds) were analysed. RESULTS: TMP increased exponentially with QUF (p<0.001 for N >56,000 monitoring values). Beyond 21 L/session, this resulted into frequent TMP alarms requiring nursing staff interventions (mean ± SEM: 10.3 ± 2.2 alarms per session, p<0.001 compared to lower convection volumes). Optimal convection volumes as assessed by GKD-UF-max were 20.6 ± 0.4 L/session, whilst 4 supplementary litres were obtained in the maximum situation (24.5 ± 0.6 L/session) but the proportion of sessions achieving the prescribed convection volume decreased from 94% to only 33% (p<0.001). Convection increased high molecular weight compound removal and shifted the membrane cut-off towards the higher molecular weight range. CONCLUSIONS: Reaching high convection volumes as recommended by the recent RCTs (> 20L) is feasible by setting an HDF system at its optimal conditions based upon the GKD-UF monitoring. Prescribing higher convection volumes resulted in instability of the system, provoked alarms, was bothersome for the nursing staff and the patients, rarely achieved the prescribed convection volumes and increased removal of high molecular weight compounds, notably albumin.

Primary sclerosing cholangitis: a new cause of distal renal tubular acidosis.

We describe the first case of distal renal tubular acidosis (dRTA) associated with primary sclerosing cholangitis. A 26-year-old Lao-Thai male patient presented with severe jaundice, metabolic acidosis and hypokalaemia. He was diagnosed of dRTA. Liver transplantation resulted in correction of electrolyte disturbances and hyperbilirubinaemia. A fludrocortisone-furosemide test revealed normal urinary acidification, demonstrating no residual dRTA. This observation suggests that dRTA may be an early manifestation of bilirubin-associated nephropathy or the consequence of an immune mechanism.

[Dialysis after graft failure: How to improve survival?]. / Retour en dialyse après échec de transplantation : comment améliorer les résultats dans cette population fragile ?

Ten to 15 % of transplant recipients will return to dialysis, or require another transplantation within 5years, rising to 23 % by 10years, and failed transplantation is now one of the major indications for starting dialysis, accounting for almost 5 % of incident dialysis patients in the US and 10 % in France. Patients who resume dialysis post-transplantation have usually experienced an extended period of uraemia and long-term immunosuppressive therapy, and exhibit high rates of anaemia and erythropoietin resistance, hypoalbuminaemia and persistent chronic inflammation from the failed graft. These factors may increase mortality risk during the first year of dialysis, as observed in the US, but not in Canada or France. When compared to a control group of transplant-naive patients followed in the same institution in France, patients with transplant failure have a higher rate of usable arteriovenous fistula or graft, a similar rate of non-planned dialysis, and initiate dialysis with a higher glomerular filtration rate. We suggest that patient survival in dialysis after graft loss is influenced by both patient characteristics and quality of care, and this may explain the favourable outcome of this specific dialysis population in France.

Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients.

BACKGROUND: While much research is devoted to identifying novel biomarkers, addressing the prognostic value of routinely measured clinical parameters is of great interest. We studied early blood pressure (BP) and body weight (BW) trajectories in incident haemodialysis patients and their association with all-cause mortality. METHODS: In a cohort of 357 incident patients, we obtained all records of BP and BW during the first 90 days on dialysis (over 12 800 observations) and analysed trajectories using penalized B-splines and mixed linear regression models. Baseline comorbidities and all-cause mortality (median follow-up: 2.2 years) were obtained from the French Renal Epidemiology and Information Network (REIN) registry, and the association with mortality was assessed by Cox models adjusting for baseline comorbidities. RESULTS: During the initial 90 days on dialysis, there were non-linear decreases in BP and BW, with milder slopes after 15 days [systolic BP (SBP)] or 30 days [diastolic BP (DBP) and BW]. SBP or DBP levels at dialysis initiation and changes in BW occurring in the first month or during the following 2 months were significantly associated with survival. In multivariate models adjusting for baseline comorbidities and prescriptions, higher SBP value and BW slopes were independently associated with a lower risk of mortality. Hazard ratios of mortality and 95% confidence intervals were 0.92 (0.85-0.99) for a 10 mmHg higher SBP and 0.76 (0.66-0.88) for a 1 kg/month higher BW change on Days 30-90. CONCLUSIONS: BW loss in the first weeks on dialysis is a strong and independent predictor of mortality. Low BP is also associated with mortality and is probably the consequence of underlying cardiovascular diseases. These early markers appear to be valuable prognostic factors.

Prevalence and risk factors of noncontrolled and resistant arterial hypertension in renal transplant recipients.

BACKGROUND: Arterial hypertension (HT) is common in renal transplant recipients (RTRs). Control of HT is not optimal in this high-risk population despite recommendations for target blood pressure levels under 130/80 mm Hg. METHODS: We performed a cross-sectional analysis of the prevalence of uncontrolled HT, and using a Cox regression model, we identified the risk factors associated with resistant HT. RESULTS: Eight hundred eleven RTRs (>1 year after transplantation) were included. A total of 10.5% were normotensive (<130/80 mm Hg without treatment), 41% had controlled HT, 32.5% uncontrolled HT, and 16% resistant HT. In univariate analysis, compared to controlled HT, the RH group had significantly higher body mass index and older donors, delayed graft function, prevalence of metabolic syndrome (69.2 vs. 51.9%), fast glycemia and glycated hemoglobin, albuminuria, triglycerides and uric acid levels, and worse measured glomerular filtration rate (mGFR). In multivariate analysis, recipient age (P < 0,001), mGFR (P = 0.037), albuminuria (P < 0.001), and metabolic syndrome (P = 0.007) were significantly associated with RH. Association of metabolic syndrome with RH was much stronger than each of its components. CONCLUSION: Our data show that despite the recommendations issued by scientific societies, blood pressure control in RTRs is far from the recommended targets. At least a third of our patients (uncontrolled HT) did not receive optimal treatment and suffered therapeutic inertia. Decreased mGFR, metabolic syndrome, and urinary albumin excretion emerged as strong predictors of poor HT control. Whether prevention and management of the metabolic syndrome and reduction of albuminuria could help to more consistently reach the blood pressure recommended targets deserves further investigation.

Influence of anemia on patient and graft survival after renal transplantation: results from the French DIVAT cohort.

BACKGROUND AND OBJECTIVES: Contradictory results are reported concerning the influence of anemia on patient and graft survival after renal transplantation. Assuming that level of renal function and anemia are strongly correlated, posttransplantation anemia (PTA) may have a different impact depending on the stage of chronic kidney disease (CKD). METHODS: This study is a retrospective multicenter analysis using the DIVAT French database. The prevalence, risk factors, and influence of 12-month PTA (World Health Organization's definition) on patient and graft survival were analyzed according to CKD stage (Modification of Diet in Renal Disease equation). RESULTS: The prevalence of 12-month PTA in our cohort of 4217 patients was 41.1%. Multivariate analysis demonstrated that worse renal function, donor age, period of transplantation, induction therapy, and mTOR inhibitors were significant risk factors for PTA. Posttransplantation anemia was a significant risk factor for all-cause mortality in CKD stages 1 to 2T (hazard ratio, 2.39; 95% confidence interval, 1.99-4.40) and 3T (hazard ratio, 1.52; 95% confidence interval, 1.08-2.15) and for cardiovascular mortality only on CKD stages 1T and 2T. In renal transplant recipients with CKD stages 4 to 5T, patient and graft survival were similar in patients with versus without anemia. Graft survival was not influenced by PTA, whatever the CKD stage. CONCLUSIONS: Posttransplantation anemia is associated with decreased patient survival only in CKD stages 1T, 2T, and 3T. Posttransplantation anemia has no influence on graft survival regardless of CKD stage.

[Toxoplasma infection, a rare but life-threatening complication after kidney transplantation: report of two cases]. / La toxoplasmose, une complication exceptionnelle mais grave chez le transplanté rénal : à propos de deux observations.

Toxoplasma infection is uncommon after renal transplantation. As a result, Toxoplasma gondii is often missed from the list of microbial agents which may be responsible of an infectious complication after renal transplantation. However, establishing this diagnosis is very important because toxoplasmosis can be life-threatening in an immunocompromised host, particularly when the diagnosis is too delayed. Here we report two cases of severe toxoplasmosis after renal transplantation. In the first case, primary infection transmitted by a cat developed in a seronegative recipient five years after renal transplantation. In the second case, reactivation of latent infection developed in a seropositive recipient 9 months after transplantation. In both cases, systematic screening for Toxoplasma gondii using polymerase chain reaction (PCR) in biological fluids was essential to suggest the diagnosis. Both recipients rapidly recovered after institution of antiparasitic therapy.

The use of SDS-PAGE scanning of spent dialysate to assess uraemic toxin removal by dialysis.

BACKGROUND: Uraemic toxins in the 8 to 60 kDa molecular weight range have been attracting increasing attention in dialysis therapy. However, there are no available standardized methods to evaluate their removal. Using new filtering membranes, we evaluated SDS-PAGE of spent dialysate to assess cut-off ranges and removal capacities into dialysate, while also measuring classical markers of dialyser function. METHODS: Eighteen dialysis patients were washed out for 2 weeks with FX 100 (Helixone(®)), followed by randomization to Xevonta Hi 23 (Amembris(®)) or FX dialysers for 2 weeks, then crossed over for an additional 2 weeks, and finally placed on Xenium 210 (Purema(®)) for 2 weeks. SDS-PAGE scanning of the removed proteins contained in the spent dialysate was performed during all dialysis sessions. Total mass of urea, creatinine, total proteins, beta 2 microglobulin (ß2m), retinol-binding protein (RBP) and albumin were measured. The reduction rates of serum urea, creatinine, ß2m, leptin, RBP, alpha 1-antitrypsin, albumin and total proteins were also determined. RESULTS: SDS-PAGE scanning identified four major protein peaks (10-18, 20-22.5, 23-30 and 60-80 kDa molecular weight) and showed clear differences in the amounts of removed proteins between the dialysers, particularly in the 20-22.5, 23-30 and 60-80 kDa ranges. Total mass of removed ß2m, RBP and albumin were in agreement with SDS-PAGE, while serum assays showed differing results. CONCLUSIONS: SDS-PAGE scanning provided a good characterization of protein patterns in the spent dialysate; it extended and agreed with protein determinations and allowed a better assessment of dialyser performance in removing 10 to 80 kDa molecular weight substances. It also identified differences between the three mainly filtrating polysulfone dialysers that were not detected with blood measurements.