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.

Robustness versus productivity during evolutionary community assembly: short-term synergies and long-term trade-offs.

The realization that evolutionary feedbacks need to be considered to fully grasp ecological dynamics has sparked interest in the effect of evolution on community properties like coexistence and productivity. However, little is known about the evolution of community robustness and productivity along diversification processes in species-rich systems. We leverage the recent structural approach to coexistence together with adaptive dynamics to study such properties and their relationships in a general trait-based model of competition on a niche axis. We show that the effects of coevolution on coexistence are two-fold and contrasting depending on the time scale considered. In the short term, evolution of niche differentiation strengthens coexistence, while long-term diversification leads to niche packing and decreased robustness. Moreover, we find that coevolved communities tend to be on average more robust and more productive than non-evolutionary assemblages. We illustrate how our theoretical predictions echo in observed empirical patterns and the implications of our results for empiricists and applied ecologists. We suggest that some of our results such as the improved robustness of Evolutionarily Stable Communities could be tested experimentally in suitable model systems.

Experimental evidence of the importance of multitrophic structure for species persistence.

Ecological theory predicts that species interactions embedded in multitrophic networks shape the opportunities for species to persist. However, the lack of experimental support of this prediction has limited our understanding of how species interactions occurring within and across trophic levels simultaneously regulate the maintenance of biodiversity. Here, we integrate a mathematical approach and detailed experiments in plant-pollinator communities to demonstrate the need to jointly account for species interactions within and across trophic levels when estimating the ability of species to persist. Within the plant trophic level, we show that the persistence probability of plant species increases when introducing the effects of plant-pollinator interactions. Across trophic levels, we show that the persistence probabilities of both plants and pollinators exhibit idiosyncratic changes when experimentally manipulating the multitrophic structure. Importantly, these idiosyncratic effects are not recovered by traditional simulations. Our work provides tractable experimental and theoretical platforms upon which it is possible to investigate the multitrophic factors affecting species persistence in ecological communities.

The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease.

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

Circular RNA-based biomarkers in blood of patients with Fabry disease and related phenotypes.

BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disease caused by mutations in the galactosidase α gene. Deficient activity of α-galactosidase A leads to glycosphingolipid accumulations in multiple organs. Circular RNAs represent strong regulators of gene expression. Their circular structure ensures high stability in blood. We hypothesised that blood-based circular RNA profiles improve phenotypic assignment and therapeutic monitoring of Fabry disease. METHODS: A genome-wide circular RNA expression analysis was performed in blood of genetically diagnosed patients with Fabry disease (n=58), age-matched and sex-matched healthy volunteers (n=14) and disease control patients with acute kidney injury (n=109). Most highly dysregulated circular RNAs were validated by quantitative real-time PCR. Circular RNA biomarker sensitivity, specificity, predictive values and area under the curve (AUC) were determined. Linear regression analyses were conducted for validated circular RNA biomarkers and clinical patient characteristics. RESULTS: A distinct circular RNA transcriptome signature identified patients with Fabry disease. Level of circular RNAs hsa_circ_0006853 (AUC=0.73), hsa_circ_0083766 (AUC=0.8) and hsa_circ_0002397 (AUC=0.8) distinguished patients with Fabry disease from both healthy controls and patients with acute kidney injury. Hsa_circ_0002397 was, furthermore, female-specifically expressed. Circular RNA level were significantly related to galactosidase α gene mutations, early symptoms, phenotypes, disease severities, specific therapies and long-term complications of Fabry disease. CONCLUSION: The discovery of circular RNA-based and Fabry disease-specific biomarkers may advance future diagnosis of Fabry disease and help to distinguish related phenotypes.

Use of Omniflow® II Biosynthetic Graft for the Treatment of Vascular Graft and Endograft Infections.

BACKGROUND: Vascular graft/endograft infection is a rare but life-threatening complication of cardiovascular surgery and remains a surgical challenge. Several different graft materials are available for the treatment of vascular graft/endograft infection, each having its own advantages and disadvantages. Biosynthetic vascular grafts have shown low reinfection rates and could be a potential second best after autologous veins in the treatment of vascular graft/endograft infection. Therefore, the aim of our study was to evaluate the efficacy and morbidity of Omniflow® II for the treatment of vascular graft/endograft infection. METHODS: A multicenter retrospective cohort study was performed to evaluate the use of Omniflow® II in the abdominal and peripheral region to treat vascular graft/endograft infection between January 2014 and December 2021. Primary outcome was recurrent vascular graft infection. Secondary outcomes included primary patency, primary assisted patency, secondary patency, all-cause mortality, and major amputation. RESULTS: Fifty-two patients were included with a median follow-up duration of 26.5 (10.8-54.8) months. Nine (17%) grafts were implanted in intracavitary position and 43 (83%) in peripheral position. Most grafts were used as femoral interposition (n = 12, 23%), femoro-femoral crossover (n = 10, 19%), femoro-popliteal (n = 8, 15%), and aorto-bifemoral (n = 8, 15%) graft. Fifteen (29%) grafts were implanted extra-anatomically and 37 (71%) in situ. Eight patients (15%) presented with reinfection during follow-up, most of these patients received an aorto-bifemoral graft (n = 3, 38%). Intracavitary vascular grafting had a 33% (n = 3) reinfection rate and peripheral grafting 12% (n = 5; P = 0.025). The estimated primary patencies at 1, 2, and 3 years were 75%, 72%, and 72% for peripherally located grafts and 58% (at all timepoints) for intracavitary grafts (P = 0.815). Secondary patencies at 1, 2, and 3 years were 77% (at all timepoints) for peripherally located prostheses and 75% (at all timepoints) for intracavitary prostheses (P = 0.731). A significantly higher mortality during follow-up was observed in patients who received an intracavitary graft compared to patients with a peripheral graft (P = 0.003). CONCLUSIONS: This study highlights the efficacy and safety of the Omniflow® II biosynthetic prosthesis for the treatment of vascular graft/endograft infection, in absence of suitable venous material, with acceptable reinfection, patency, and freedom of amputation prevalences, especially in replacing peripheral vascular graft/endograft infection. However, a control group with either venous reconstruction or another alternative graft is needed to make firmer conclusions.

Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases.

Diseases of the glomerular basement membrane (GBM), such as Goodpasture's disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure and an unmet medical need. Collagen IVα345 is an important architectural element of the GBM that was discovered in previous research on GP and AS. How this collagen enables GBM to function as a permselective filter and how structural defects cause renal failure remain an enigma. We found a distinctive genetic variant of collagen IVα345 in both a familial GP case and four AS kindreds that provided insights into these mechanisms. The variant is an 8-residue appendage at the C-terminus of the α3 subunit of the α345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the α345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Boudko et al. and Pedchenko et al. Bioactive sites on the hexamer surface were identified where pathogenic pathways of GP and AS converge and, potentially, that of diabetic nephropathy (DN). We conclude that the hexamer functions include signaling and organizing macromolecular complexes, which enable GBM assembly and function. Therapeutic modulation or replacement of α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies.

Acute Respiratory Distress in Aged, SARS-CoV-2-Infected African Green Monkeys but Not Rhesus Macaques.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a wide range of disease severity, ranging from asymptomatic infection to a life-threating illness, particularly in the elderly population and individuals with comorbid conditions. Among individuals with serious coronavirus 2019 (COVID-19) disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19-induced ARDS and evaluate therapeutic strategies. We report two cases of ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that had pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic, and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. Notable increases in circulating cytokines were observed in three of four infected, aged AGMs but not in infected RMs. All the AGMs had increased levels of plasma IL-6 compared with baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2. Together, our results indicate that both RMs and AGMs are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations, including ARDS.

Entering the Third Decade After Kidney Transplantation: Excellent Graft Function Refers to Superior Graft but Not Patient Survival.

Kidney transplant recipients (KTRs) with ultralong-term survival represent a growing, yet insufficiently studied patient cohort. In this single-center retrospective study, we analyzed 248 ultralong-term survivors (≥20 years). KTRs were classified into those with superior graft function (defined as eGFR ≥45 ml/min + proteinuria ≤300 mg/day + eGFR-slope ≤ 2 ml/min/1.73 m2/year) and inferior graft function regarding the risk of CKD progression. 20 years post-transplant, median eGFR was 54 ml/min (11-114), proteinuria 200 mg/24 h (0-7,620), eGFR decline 0.45 ml/min/1.73 m2/year (11.7 6.5) and DSA had been detected in 19.7% of KTRs. We identified 96 KTRs (38.7%) with superior (group 1) and 152 KTRs (61.3%) with inferior graft function (group 2). Donation after cardiac death, female sex, glomerulonephritis as primary disease, and early TCMR were independently associated with inferior graft function. Graft survival was significantly better in group 1 compared to group 2 (LogRank, p < 0.001). Besides group affiliation (HR 20.515, p = 0.003), multivariable analysis identified DSA development (HR 3.081, p = 0.023) and donor age (HR 1.032, p = 0.024) as independent factors. Interestingly, there was no significant difference in patient survival (LogRank, p = 0.350). In ultralong-term survivors, excellent graft function refers to superior graft survival but does not extend ultimate patient survival. DSA-formation should be taken seriously even in the ultralong-term.

Renal AAV2-Mediated Overexpression of Long Non-Coding RNA H19 Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p.

BACKGROUND: Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA H19, which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury. METHODS: Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated H19 in vitro. In vivo analyses used constitutive H19 knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying H19 caused overexpression in the kidney. Expression of H19 in kidney transplant patients with I/R injury was investigated. RESULTS: H19 is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and ex vivo sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-α, LHX8, and SPI1 activate H19 in ECs and TECs. H19 overexpression promotes angiogenesis in vitro and in vivo. In vivo, transient AAV2-mediated H19 overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1. CONCLUSIONS: H19 overexpression confers protection against renal injury by stimulating proangiogenic signaling. H19 overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.

Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid-base balance.

BACKGROUND: Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with a higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy are associated with altered expression of proteins involved in renal acid-base metabolism. METHODS: We retrospectively collected kidney biopsies from 22 patients. Of these patients, nine had no acidosis, nine had metabolic acidosis [plasma bicarbonate (HCO3- <22 mmol/L) and four had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling. RESULTS: We found that the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule (PT) amino acid and lipid metabolism and energy homoeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 potassium channel, an important regulator of PT HCO3- metabolism and transport, acyl-CoA dehydrogenase short/branched chain and serine hydroxymethyltransferase 1, genes involved in beta oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the PT NBCe1 HCO3- transporter in kidneys from acidotic patients who recovered with alkali therapy. In addition, the HCO3- exchanger pendrin was affected by acidosis and alkali therapy. CONCLUSIONS: Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from PT were also affected by acidosis and alkali therapy, suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients.

Use of letermovir-valganciclovir combination as a step-down treatment after foscarnet for ganciclovir-resistant CMV infection in kidney transplant recipients.

BACKGROUND: Letermovir (LTV) might be an alternative treatment to nephrotoxic foscarnet (FOS) in Ganciclovir (GCV) resistant cytomegalovirus (CMV) infection. However, its efficacy in controlling active CMV viremia is unclear, as it is only approved for CMV prophylaxis in hematopoietic stem-cell transplantation. METHODS: This case series describes 14 kidney transplant recipients (KTR) with moderate-level GCV resistant CMV infection, treated by different step-down strategies after initial FOS therapy: (1) Observation without antiviral follow-up or switch to valganciclovir (VGCV) (pre-LTV era), and (2) Switch to LTV±VGCV (LTV era). RESULTS: One patient died under FOS. Thirteen patients were followed under step-down regimens. All but two patients had ongoing CMV viremia when stopping FOS. In pre-LTV era, 5/9 (56%) experienced a CMV breakthrough > 10 000 IU/ml calling for another course of FOS, as compared to 1/4 (25%) in the LTV era. Addition of VGCV to LTV at low-level viral breakthrough, addressing a possible developing resistance against LTV, prevented viral surge in two patients. In the pre-LTV era, CMV-related death or graft loss occurred in three of nine (33%), compared to no death or graft loss in the LTV era. CONCLUSION: A step-down strategy combining LTV+VGCV, might allow to safely stop FOS at ongoing low-level viremia.

Intravenous immunoglobulins do not prove beneficial to reduce alloimmunity among kidney transplant recipients with BKV-associated nephropathy.

Reduced immunosuppression during BKV-DNAemia has been associated with T-cell mediated rejection (TCMR), de novo donor-specific antibodies (DSA) and antibody-mediated rejection (ABMR). Intravenous immunoglobulins (IVIG) may reduce alloimmunity. We studied 860 kidney transplant recipients (KTRs) for the development of BKV-DNAuria and BKV-DNAemia (low-level <10 000 IE/ml, high-level >10 000 IE/ml). 52/131 KTRs with high-level BKV-DNAemia received IVIG. The HLA-related immunological risk was stratified by the Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) algorithm. BKV-DNAuria only was observed in 86 KTRs (10.0%), low-level BKV-DNAemia in 180 KTRs (20.9%) and high-level BKV-DNAemia in 131 KTRs (15.2%). KTRs with low-level BKV-DNAemia showed significantly less TCMR compared to KTRs with high-level BKV-DNAemia (5.2% vs. 25.5%; P < 0.001) and no BKV-replication (13.2%; P = 0.014), lowest rates of de novo DSA (21.3%), ABMR (9.2%) and flattest glomerular filtration rate (GFR) slope (-0.8 ml/min). KTRs with low-level BKV-DNAemia showed significantly higher median (interquartile range) total PIRCHE if they developed TCMR [100.22 (72.6) vs. 69.52 (49.97); P = 0.020] or ABMR [128.86 (52.99) vs. 69.52 (49.96); P = 0.005]. Administration of IVIG did not shorten duration of BKV-DNAemia (P = 0.798) or reduce TCMR, de novo DSA and ABMR (P > 0.05). KTRs with low-level BKV-DNAemia showed best protection against alloimmunity, with a high number of PIRCHE co-determining the remaining risk. The administration of IVIG, however, was not beneficial in reducing alloimmunity.

Safety of Kidney Biopsy when Performed as an Outpatient Procedure.

INTRODUCTION: Kidney biopsy remains the gold standard for the diagnosis of most renal diseases. A major obstacle to performing a biopsy is safety concerns. However, many safety measures are not evidence based and therefore vary widely between centers. We sought to determine the rate and timing of kidney biopsy complications in our center, to compare the complication rate between native and transplant kidney biopsies, to evaluate the feasibility of performing kidney biopsies as an outpatient procedure and the value of a postbiopsy ultrasound before discharge, and to identify risk factors for complications. METHODS: We performed a single-center, retrospective, observational study at the Division of Nephrology of the University Hospital Zurich including all patients who underwent renal biopsy between January 2005 and December 2017. Major bleeding (primary outcome) and any other bleeding or nonbleeding complications (secondary outcomes) were compared between native and transplant kidney biopsies and between inpatient and outpatient procedures and correlated with clinical factors possibly affecting bleeding risk. RESULTS: Overall, 2,239 biopsies were performed in 1,468 patients, 732 as inpatient and 1,507 as outpatient procedures. Major bleeding was observed in 28 (3.8%) inpatient and in 15 (1.0%) outpatient procedures, totaling to 43 (1.9%) of all biopsies. Major bleeding requiring intervention amounted to 1.0% (0.5% of outpatient procedures). Rate of major bleeding was similar between native and transplant kidneys. 13/15 (87%) bleeding episodes in planned outpatient procedures were detected during the 4-h surveillance period. Risk factors for bleeding were aspirin use, low eGFR, anemia, cirrhosis, and amyloidosis. Routine postbiopsy ultrasound did not change management. CONCLUSIONS: Kidney biopsy is an overall safe procedure and can be performed as an outpatient procedure in most patients with an observation period as short as 4 h. The value of routine postbiopsy ultrasound is questionable.

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.

Trio housing of adult male rhesus macaques (Macaca mulatta): Methodology and outcome predictors.

BACKGROUND: This study evaluated the feasibility of trio housing caged adult male rhesus macaques and attempted to identify outcome predictors for trio housing formation and its intermediary introduction steps. METHODS: Subjects were familiarized consecutively to each potential group member via protected contact prior to introduction into the trio. Seven trios were attempted, involving 18 males, with three males attempted in two different trios. RESULTS: One group was deemed successful, with a tenure of 51 days. Five were disbanded within minutes, and one was deemed unsuccessful the following morning. Two males sustained wounds requiring veterinary care over the course of the study. Outcome of the protected contact phase was predicted by age and temperament disparities as well as initial behavior. CONCLUSIONS: While outcomes were poor, it suggests that attempts can be made relatively safely, and alternative introduction strategies should be explored to increase the feasibility of trio housing for adult males.

Predictive Power of Bone Turnover Biomarkers to Estimate Bone Mineral Density after Kidney Transplantation with or without Denosumab: A post hoc Analysis of the POSTOP Study.

BACKGROUND: Low bone mineral density (BMD) represents a major risk factor for bone fractures in patients with chronic kidney disease (CKD) as well as after kidney transplantation. However, modalities to solidly predict patients at fracture risk are yet to be defined. Better understanding of bone turnover biomarkers (BTMs) may close this diagnostic gap. This study strives to correlate BTMs to BMD in kidney transplant recipients. METHODS: Changes in BTMs - procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BSAP), ß-isomer of the C-terminal telopeptide of type I collagen, and urine deoxypyridinoline/Cr - at the time of transplant and 3 months were correlated to changes in BMD measured by dual-energy X-ray absorptiometry at the time of transplant, 6, and 12 months, respectively. Half of the collective was treated with denosumab twice yearly in addition to the standard treatment with calcium and vitamin D. RESULTS: Changes in bone formation markers BSAP and P1NP within 3 months showed a significant negative correlation to changes in BMD at the hip within 6 months in denosumab-naïve patients. This correlation was abrogated by denosumab treatment. CONCLUSIONS: Changes in BSAP and P1NP showed promise in short-term prediction of BMD. We suggest further trials expanding on the knowledge of these BTMs with assessment of fracture risk, sequential measurements of BTMs within the first 6 months, and the additional use of computed tomography to assess BMD.

Increased Temperature Disrupts the Biodiversity-Ecosystem Functioning Relationship.

Gaining knowledge of how ecosystems provide essential services to humans is of primary importance, especially with the current threat of climate change. Yet little is known about how increased temperature will impact the biodiversity-ecosystem functioning (BEF) relationship. We tackled this subject theoretically and experimentally. We developed a BEF theory based on mechanistic population dynamic models, which allows the inclusion of the effect of temperature. Using experimentally established relationships between attack rate and temperature, the model predicts that temperature increase will intensify competition, and consequently the BEF relationship will flatten or even become negative. We conducted a laboratory experiment with natural microbial microcosms, and the results were in agreement with the model predictions. The experimental results also revealed that an increase in both temperature average and variation had a more intense effect than an increase in temperature average alone. Our results indicate that under climate change, high diversity may not guarantee high ecosystem functioning.

Circular RNAs in Urine of Kidney Transplant Patients with Acute T Cell-Mediated Allograft Rejection.

BACKGROUND: Circular RNAs (circRNAs) have recently been described as novel noncoding regulators of gene expression. They are detectable in the blood of patients with acute kidney injury. We tested whether circRNAs were present in urine and could serve as new predictors of outcome in renal transplant patients with acute rejection. METHODS: A global circRNA expression analysis using RNA from urine of patients with acute T cell-mediated renal allograft rejection and control transplant patients was performed. Dysregulated circRNAs were confirmed in a cohort of 62 patients with acute rejection, 10 patients after successful antirejection therapy, 18 control transplant patients without rejection, and 13 stable transplant patients with urinary tract infection. RESULTS: A global screen revealed several circRNAs to be altered in urine of patients with acute rejection. Concentrations of 2 circRNAs including hsa_circ_0001334 and hsa_circ_0071475 were significantly increased. These were validated in the whole cohort of patients. hsa_circ_0001334 was upregulated in patients with acute rejection compared with controls. Concentrations of hsa_circ_0001334 normalized in patients with acute rejection following successful antirejection therapy. hsa_circ_0001334 was associated with higher decline in glomerular filtration rate 1 year after transplantation. CONCLUSIONS: CircRNA concentrations are significantly dysregulated in patients with acute rejection at subclinical time points. Urinary hsa_circ_0001334 is a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function.