Urinary Biomarkers for Cell Cycle Arrest TIMP-2 and IGFBP7 for Prediction of Graft Function Recovery after Kidney Transplantation.

TIMP-2 and IGFBP7 have been identified and validated for the early detection of renal injury in critically ill patients, but data on recovery of allograft function after kidney transplantation (KTx) are scarce. In a prospective observational multicenter cohort study of renal transplant recipients, urinary [TIMP-2] × [IGFBP7] was evaluated daily from day 1 to 7 after KTx. Different stages of early graft function were defined: immediate graft function (IGF) (decrease ≥ 10% in serum creatinine (s-crea) within 24 h post KTx); slow graft function (SGF) (decrease in s-crea < 10% within 24 h post KTx); and delayed graft function (DGF) (any dialysis needed within the first week after KTx). A total of 186 patients were analyzed. [TIMP-2] × [IGFBP7] was significantly elevated as early as day 1 in patients with DGF compared to SGF and IGF. ROC analysis of [TIMP-2] × [IGFBP7] at day 1 post-transplant for event "Non-DGF" revealed a cut-off value of 0.9 (ng/mL)2/1000 with a sensitivity of 87% and a specificity of 71%. The positive predictive value for non-DGF was 93%. [TIMP-2] × [IGFBP7] measured at day 1 after KTx can predict early recovery of transplant function and is therefore a valuable biomarker for clinical decision making.

Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Immunogenicity of High-Dose Versus MF59-Adjuvanted Versus Standard Influenza Vaccine in Solid Organ Transplant Recipients: The Swiss/Spanish Trial in Solid Organ Transplantation on Prevention of Influenza (STOP-FLU Trial).

BACKGROUND: The immunogenicity of the standard influenza vaccine is reduced in solid-organ transplant (SOT) recipients, so new vaccination strategies are needed in this population. METHODS: Adult SOT recipients from 9 transplant clinics in Switzerland and Spain were enrolled if they were >3 months after transplantation. Patients were randomized (1:1:1) to a MF59-adjuvanted or a high-dose vaccine (intervention), or a standard vaccine (control), with stratification by organ and time from transplant. The primary outcome was vaccine response rate, defined as a ≥4-fold increase of hemagglutination-inhibition titers to at least 1 vaccine strain at 28 days postvaccination. Secondary outcomes included polymerase chain reaction-confirmed influenza and vaccine reactogenicity. RESULTS: A total of 619 patients were randomized, 616 received the assigned vaccines, and 598 had serum available for analysis of the primary endpoint (standard, n = 198; MF59-adjuvanted, n = 205; high-dose, n = 195 patients). Vaccine response rates were 42% (84/198) in the standard vaccine group, 60% (122/205) in the MF59-adjuvanted vaccine group, and 66% (129/195) in the high-dose vaccine group (difference in intervention vaccines vs standard vaccine, 0.20; 97.5% confidence interval [CI], .12-1); P < .001; difference in high-dose vs standard vaccine, 0.24 [95% CI, .16-1]; P < .001; difference in MF59-adjuvanted vs standard vaccine, 0.17 [97.5% CI, .08-1]; P < .001). Influenza occurred in 6% of the standard, 5% in the MF59-adjuvanted, and 7% in the high-dose vaccine groups. Vaccine-related adverse events occurred more frequently in the intervention vaccine groups, but most of the events were mild. CONCLUSIONS: In SOT recipients, use of an MF59-adjuvanted or a high-dose influenza vaccine was safe and resulted in a higher vaccine response rate. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT03699839.

Worse cardiovascular and renal outcome in male SLE patients.

Systemic lupus erythematosus (SLE) in males is rare and poorly understood. Thus, still little is known about sex differences in SLE. We set out to identify sex differences regarding clinical manifestations as well as renal and cardiovascular outcomes of SLE. We analyzed patient data from the Swiss SLE Cohort Study. Cumulative clinical manifestations according to the updated American College of Rheumatology criteria were recorded at inclusion. Cardiovascular events were recorded within Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC-SDI). Renal failure was defined as eGFR < 15 ml/min/1.73 m2, initiation of renal replacement therapy or doubling of serum creatinine which were all assessed yearly or documented as end stage renal disease in SLICC-SDI. Risk differences were calculated using logistic regression and cox regression models. We analyzed 93 men and 529 women with a median follow up time of 2 years. Males were significantly older at diagnosis (44.4 versus 33.1 years, p < 0.001) and had less often arthritis (57% versus 74%, p = 0.001) and dermatological disorders (61% versus 76%, p < 0.01). In multivariate analysis female sex remained a significantly associated with arthritis and dermatological disorders. In multivariate analysis men had a significantly higher hazard ratio of 2.3 for renal failure (95% confidence interval (95%-CI) 1.1-5.2, p < 0.04). Total SLICC-SDI Score was comparable. Men had significantly more coronary artery disease (CAD) (17% versus 4%, p < 0.001) and myocardial infarction (10% versus 2%, p < 0.01). In multivariate analysis, male sex remained a significant risk factor for CAD (odds ratio (OR) 5.6, 95%-CI 2.3-13.7, p < 0.001) and myocardial infarction (OR 8.3, 95%-CI 2.1-32.6, p = 0.002). This first sex study in a western European population demonstrates significant sex differences in SLE. Male sex is a risk factor for cardiovascular events and renal failure in SLE. Potential etiological pathomechanisms such as hormonal or X-chromosomal factors remain to be further investigated.

ITGAM rs1143679 Variant in Systemic Lupus Erythematosus Is Associated with Increased Serum Calcification Propensity.

OBJECTIVES: CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). METHODS: Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. RESULTS: Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42' vs. 297 ± 50' in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). CONCLUSIONS: SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B.

Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients. METHODS: The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m2 and 89 mL/min per 1·73 m2, stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996. FINDINGS: Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death. INTERPRETATION: In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis. FUNDING: Swiss National Science Foundation.

Impact of Hyponatremia after Renal Transplantation on Decline of Renal Function, Graft Loss and Patient Survival: A Prospective Cohort Study.

BACKGROUND: Hyponatremia is one of the most common electrolyte disorders observed in hospitalized and ambulatory patients. Hyponatremia is associated with increased falls, fractures, prolonged hospitalisation and mortality. The clinical importance of hyponatremia in the renal transplant field is not well established, so the aim of this study was to determine the relationships between hyponatremia and mortality as main outcome and renal function decline and graft loss as secondary outcome among a prospective cohort of renal transplant recipients. METHODS: This prospective cohort study included 1315 patients between 1 May 2008 and 31 December 2014. Hyponatremia was defined as sodium concentration below 136 mmol/L at 6 months after transplantation. The main endpoint was mortality. A secondary composite endpoint was also defined as: rapid decline in renal function (≥5 mL/min/1.73 m2 drop of the eGFR/year), graft loss or mortality. RESULTS: Mean sodium was 140 ± 3.08 mmol/L. 97 patients displayed hyponatremia with a mean of 132.9 ± 3.05 mmol/L. Hyponatremia at 6 months after transplantation was associated neither with mortality (HR: 1.02; p = 0.97, 95% CI: 0.47-2.19), nor with the composite outcome defined as rapid decline in renal function, graft loss or mortality (logrank test p = 0.9). CONCLUSIONS: Hyponatremia 6 months after transplantation is not associated with mortality in kidney allograft patients.

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study.

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis.

Age at Time of Kidney Transplantation as a Predictor for Mortality, Graft Loss and Self-Rated Health Status: Results From the Swiss Transplant Cohort Study.

Introduction: The effect of age on health outcomes in kidney transplantation remains inconclusive. This study aimed to analyze the relationship between age at time of kidney transplantation with mortality, graft loss and self-rated health status in adult kidney transplant recipients. Methods: This study used data from the Swiss Transplant Cohort Study and included prospective data of kidney transplant recipients between 2008 and 2017. Time-to-event analysis was performed using Cox' regression analysis, and -in the case of graft loss- competing risk analysis. A random-intercept regression model was applied to analyse self-rated health status. Results: We included 2,366 kidney transplant recipients. Age at transplantation linearly predicted mortality. It was also predictive for graft loss, though nonlinearly, showing that recipients aged between 35 and 55 years presented with the lowest risk of experiencing graft loss. No relationship of age with self-rated health status was detected. Conclusion: Higher mortality in older recipients complies with data from the general population. The non-linear relationship between age and graft loss and the higher scored self-rated health status at all follow-up time-points compared to the pre-transplant status -regardless of age- highlight that age alone might not be an accurate measure for risk prediction and clinical decision making in kidney transplantation.

Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: A case series and review of the literature.

Ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection is a common problem among solid organ transplant (SOT) recipients without prior CMV immunity (CMV D+/R-). GCV-resistant CMV represents a particular challenge for CMV management. Letermovir is a recently licensed antiviral agent for primary CMV prophylaxis in allogenic hematopoietic stem cell transplant (HSCT) recipients. Given the favorable safety profile and its oral bioavailability letermovir may be considered a valuable off-label option for secondary prophylaxis of GCV-resistant CMV in SOT recipients. Here, we describe our experience with letermovir as secondary prophylaxis for GCV-resistant CMV in two renal transplant recipients and review the literature in regard of previously published cases. Letermovir resistance emerged after a few months of secondary prophylaxis in the two renal transplant recipients. In both cases, the previously described UL56 C325Y letermovir resistance mutation was detected. In vitro studies of letermovir suggest a relatively low genetic barrier to resistance. Therefore, caution is warranted when using letermovir as secondary prophylaxis for GCV-resistant CMV infection.

Ten caveats of learning analytics in health professions education: A consumer's perspective.

A group of 22 medical educators from different European countries, gathered in a meeting in Utrecht in July 2019, discussed the topic of learning analytics (LA) in an open conversation and addressed its definition, its purposes and potential risks for learners and teachers. LA was seen as a significant advance with important potential to improve education, but the group felt that potential drawbacks of using LA may yet be under-exposed in the literature. After transcription and interpretation of the discussion's conclusions, a document was drafted and fed back to the group in two rounds to arrive at a series of 10 caveats educators should be aware of when developing and using LA, including too much standardized learning, with undue consequences of over-efficiency and pressure on learners and teachers, and a decrease of the variety of 'valid' learning resources. Learning analytics may misalign with eventual clinical performance and can run the risk of privacy breaches and inescapability of documented failures. These consequences may not happen, but the authors, on behalf of the full group of educators, felt it worth to signal these caveats from a consumers' perspective.

Dialysis after graft loss: a Swiss experience.

BACKGROUND: Patients returning to dialysis after graft loss have high early morbidity and mortality. METHODS: We used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded. RESULTS: Seventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft. CONCLUSION: In summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.

Evaluation of Nutrition Risk Screening Score 2002 (NRS) assessment in hospitalized chronic kidney disease patient.

BACKGROUND: Although chronic kidney disease (CKD) patients are particularly prone to malnutrition, systematic nutritional screening is rarely routinely performed during hospitalization. The primary aim of this study was to determine the prevalence of malnutrition (as captured by the nutritional screening score NRS) in hospitalized CKD patients and explore the impact of malnutrition on hospital mortality. METHODS: All patients admitted to the tertiary nephrology department of the University hospital of Bern Inselspital over a period of 12 months were included in this observational study. The risk for malnutrition was assessed within 24h of admission by the NRS. Demographic, clinical, and outcome data were extracted from the patient database. The primary outcome was in-hospital mortality. The secondary outcomes were length of hospitalization and hospitalization costs. Multilevel mixed-effect logistic regression model analysis was performed to determine the association of in-hospital mortality and risk of malnutrition (NRS score≥3). RESULTS: We included 696 eligible hospitalizations of 489 CKD patients. Hospitalized patients had a median age of 64 years (interquartile range (IQR), 52-72), 35.6% were at risk of malnutrition (NRS≥3). After adjustment for the identified confounders (Case weight, Barthel index, and CKD stage) multivariate analysis confirmed an independent and significant association between higher in-hospital mortality with NRS≥3 [OR 2.92 (95% CI: 1.33-6.39), P<0.001]. Furthermore, in multivariate analysis the risk of malnutrition was associated with longer length of hospitalization [Geometric mean ratio: 1.8 (95% CI: 1.5-2.0), p<0.001] and with increased hospitalization costs [Geometric mean ratio: 1.7 (95% CI: 1.5-1.9), p<0.001]). CONCLUSIONS: Malnutrition in CKD patients, as captured by NRS>3, is highly prevalent among hospitalized CKD patient and associated with prolonged hospital stay and increased in-hospital mortality.

The effect of a previous created distal arteriovenous-fistula on radial bone DXA measurements in prevalent renal transplant recipients.

BACKGROUND: Accelerated bone loss occurs rapidly following renal transplantation due to intensive immunosuppression and persistent hyperparathyroidism. In renal transplant recipients (RTRs) due to the hyperparathyroidism the non-dominant forearm is often utilized as a peripheral measurement site for dual-energy x-ray absorptiometry (DXA) measurements. The forearm is also the site of previous created distal arteriovenous fistulas (AVF). Although AVF remain patent long after successful transplantation, there are no data available concerning their impact on radial bone DXA measurements. METHODS: In this cross-sectional study we performed DXA in 40 RTRs with preexisting distal AVF (RTRs-AVF) to assess areal bone mineral density (aBMD) differences between both forearms (three areas) and compared our findings to patients with chronic kidney disease (CKD, n = 40), pre-emptive RTRs (RTRs-pre, n = 15) and healthy volunteers (n = 20). In addition, we assessed relevant demographic, biochemical and clinical aspects. RESULTS: We found a marked radial asymmetry between the forearms in RTRs with preexisting AVF. The radial aBMD at the distal AVF forearm was lower compared to the contralateral forearm, resulting in significant differences for all three areas analyzed: the Rad-1/3: median (interquartile range) in g/cm2, Rad-1/3: 0.760 (0.641-0.804) vs. 0.742 (0.642, 0.794), p = 0.016; ultradistal radius, Rad-UD: 0.433 (0.392-0.507) vs. 0.420 (0.356, 0.475), p = 0.004; and total radius, Rad-total: 0.603 (0.518, 0.655) vs. 0.599 (0.504, 0.642), p = 0.001). No such asymmetries were observed in any other groups. Lower aBMD in AVF forearm subregions resulted in misclassification of osteoporosis. CONCLUSIONS: In renal transplant recipients, a previously created distal fistula may exert a negative impact on the radial bone leading to significant site-to-site aBMD differences, which can result in diagnostic misclassifications.

CD4+ T Cell Help Is Mandatory for Naive and Memory Donor-Specific Antibody Responses: Impact of Therapeutic Immunosuppression.

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)-producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.

Serum calcification propensity is independently associated with disease activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations. METHODS: A total of 168 patients with ≥ 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry. RESULTS: The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ≥4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman's rho -0.233, P = 0.02). CONCLUSIONS: Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients.

Residual Activatability of Circulating Tfh17 Predicts Humoral Response to Thymodependent Antigens in Patients on Therapeutic Immunosuppression.

The generation of antibodies against protein antigens (such as donor-specific HLA molecules) requires that T follicular helper cells (Tfh) provide help to B cells. Immunosuppressive (IS) armamentarium prevents T cell activation, yet a significant proportion of renal transplant patients develop donor-specific antibodies (DSA), which suggests that IS drugs do not efficiently block T follicular helper cells. To test this hypothesis, the number of circulating Tfh, their polarization profile, and ability to up-regulate (i) the co-stimulatory molecules CD40L and ICOS, and (ii) the activation marker CD25, following in vitro stimulation in presence of IS drugs, were compared between 36 renal transplant patients (6-72 months post transplantation) and nine healthy controls. IS drugs reduced the number of Tfh1 and 2 but had little impact on Tfh17, which was the dominant subset in transplant patients. Although, IS drugs decreased activation-induced expression of co-stimulatory molecules by Tfh, the impact was highly variable between individuals. Furthermore, 20% of transplant patients displayed normal expression of CD25 on Tfh following in vitro stimulation (i.e., "residual activatability"). To test whether residual activatability of Tfh correlates with antibody response against thymo-dependent antigens we took advantage of the 2015 influenza vaccination campaign, which provided a normalized setting for antigenic stimulation. In line with our hypothesis, responders to influenza vaccine exhibited significantly higher percentage of CD25-expressing Tfh17 after in vitro stimulation. A results that was confirmed retrospectively in nine transplanted patients at the time of first DSA detection. We concluded that "residual activatability" of Tfh17 might be used as a non-invasive biomarker to identify transplant patients at higher risk to develop DSA under immunosuppression. If validated in larger studies, this assay might help optimizing the prevention of DSA through personalized adaptation of immunosuppressive regimen.

Disseminated cryptococcal infection in a patient who had kidney transplant: discrepancy between clinical symptoms and microbiological findings.

A 29-year-old man complained of a 2-day history of frontal headache and new-onset fever but no other symptoms. Two months prior to admission, he underwent his third kidney transplantation. Clinical and laboratory examinations were unremarkable. Brain MRI showed a meningeal irritation consistent with viral meningitis. A diagnosis of cryptococcal meningitis and fungaemia was made after detection of a remarkably high and visible load of Cryptococcus neoformans in the cerebrospinal fluid.

[Renal replacement therapies ­ Past, present and future]. / Nierenersatzverfahren - gestern, heute und morgen.

Extracorporeal renal replacement therapy is one of the most successful stories of artificial organ replacement. The current article describes the important steps in the evolution of renal replacement therapy towards modern state of the art peritoneal dialysis and hemodialysis. Open questions and possibilities for future developments are discussed. Today patients have a choice with respect to the method used to replace their failing kidney. However, in order to carefully plan and select the best possible method for a patient, he has to be seen and confronted with the various methods by a nephrologist at least six month before the necessity to start renal replacement therapy. Late referral increases mortality and the necessity for a temporary central venous access represents an additional thrombotic and infectious risk. A patient first seen by the nephrologist at the occasion of an emergeny dialysis will never have the possibility to profit from a preemptive living kidney donation. Furthermore, such patients usually stay in the center and are difficult to motivate for home or selfcare dialysis.

Lymphangiogenesis is upregulated in kidneys of patients with multiple myeloma.

Neolymphangiogenesis has recently been demonstrated in transplanted kidneys as well as in chronic interstitial nephritis and IgA nephropathy. However, its significance in kidney disease remains to be defined and a systematic study of renal lymphangiogenesis is warranted. We investigated patients with multiple myeloma (MM) presenting in the great majority with acute renal insufficiency. Controls were allograft kidney donors and patients with renal insufficiency due to acute renal failure (ARF). Lymph vessel length density (LVD) was quantified immunohistochemically by means of antipodoplanin staining followed by computer-assisted stereology. The mean LVD in kidneys of patients with MM (23.19 mm(-2)) was higher when compared with allograft donors (7.42 mm(-2), P = 0.0003) and patients with ARF (6.78 mm(-2), P = 0.0002). The higher LVD was significantly associated with interstitial inflammation, and the newly formed lymph vessels were accompanied by diffuse and nodular interstitial infiltrates composed mainly of CD20(+) B cells and CD27(+) plasma cells. The infiltrates in patients with MM also displayed a higher expression of the B-cell chemoattractant CXCL13. These results demonstrate for the first time that lymphangiogenesis is a prominent feature in MM kidneys and that it is associated with a significant accumulation of macrophages, CD20(+) and CD27(+) B lymphocytes. Further studies should clarify whether these changes represent a beneficial or detrimental factor in the progression of the myeloma-related kidney damage.