Outcomes In Renal Transplant Recipients Research Articles

Exploring the potential effect of paricalcitol on markers of inflammation in de novo renal transplant recipients.

Following a successful renal transplantation circulating markers of inflammation may remain elevated, and systemic inflammation is associated with worse clinical outcome in renal transplant recipients (RTRs). Vitamin D-receptor (VDR) activation is postulated to modulate inflammation and endothelial function. We aimed to explore if a synthetic vitamin D, paricalcitol, could influence systemic inflammation and immune activation in RTRs. Newly transplanted RTRs were included in an open-label randomized controlled trial on the effect of paricalcitol on top of standard care over the first post-transplant year. Fourteen pre-defined circulating biomarkers reflecting leukocyte activation, endothelial activation, fibrosis and general inflammatory burden were analyzed in 74 RTRs at 8 weeks (baseline) and 1 year post-engraftment. Mean changes in plasma biomarker concentrations were compared by t-test. The expression of genes coding for the same biomarkers were investigated in 1-year surveillance graft biopsies (n = 60). In patients treated with paricalcitol circulating osteoprotegerin levels increased by 0.19 ng/ml, compared with a 0.05 ng/ml increase in controls (p = 0.030). In graft tissue, a 21% higher median gene expression level of TNFRSF11B coding for osteoprotegerin was found in paricalcitol-treated patients compared with controls (p = 0.026). Paricalcitol treatment did not significantly affect the blood- or tissue levels of any other investigated inflammatory marker. In RTRs, paricalcitol treatment might increase both circulating and tissue levels of osteoprotegerin, a modulator of calcification, but potential anti-inflammatory treatment effects in RTRs are likely very modest. [NCT01694160 (2012/107D)]; [www.clinicaltrials.gov].

Outcome of desensitization in human leukocyte antigen and ABO incompatible living donor kidney transplantation: Single center experience of first 200 incompatible transplants.

Although desensitization is well established, concerns about graft outcome, patient survival and rejection still exist. The present study aims at comparing outcomes of renal transplant recipients across simultaneous ABO and human leukocyte antigen (HLA) incompatibility barriers to those with ABO or HLA incompatibility alone. This was a retrospective study conducted from October 2015 to December 2018. All patients with a clinical diagnosis of chronic kidney disease, who were prospective HLA incompatible (HLAi) and/or ABO incompatible (ABOi) renal transplant recipients were included. A total of 400 cases including 36 ABOi transplants, 154 HLAi transplants, 10 simultaneously ABO and HLA incompatible transplants, and 200 ABO (ABOc) and HLA (HLAc) compatible kidney transplants from living donors were included. There were significantly more number of blood transfusions, previous transplants and pregnancies in HLAi transplant recipients relative to the ABOi or the control group. Mean number of therapeutic plasma exchange procedures per patient and mean plasma volume processed per procedure were slightly higher in the ABOi + HLAi category. The incidence of graft dysfunction due to suspected antibody-mediated rejection during first year was highest in the ABOi + HLAi group, followed by ABOc + HLAi and ABOi + HLAc, lowest in the ABOc + HLAc category. Mean time to first episode of graft dysfunction was significantly shorter with incompatible transplants. There were no kidney transplant recipient deaths in the study. Patient outcome and graft outcomes observed with incompatible transplants were not worse than those observed with compatible transplants.

Neutrophil-to-Lymphocyte Ratio Predicts Mortality in Adult Renal Transplant Recipients with Severe Community-Acquired Pneumonia.

Mortality of renal transplant recipients with severe community-acquired pneumonia (CAP) remains high, despite advances in critical care management. There is still a lack of biomarkers for predicting prognosis of these patients. The present study aimed to investigate the association between neutrophil-to-lymphocyte ratio (NLR) and mortality in renal transplant recipients with severe CAP. A total of 111 renal transplant recipients with severe CAP admitted to the intensive care unit (ICU) were screened for eligibility between 1 January 2009 and 30 November 2018. Patient characteristics and laboratory test results at ICU admission were retrospectively collected. There were 18 non-survivors (22.2%) among 81 patients with severe CAP who were finally included. Non-survivors had a higher NLR level than survivors (26.8 vs. 12.3, p < 0.001). NLR had the greatest power to predict mortality as suggested by area under the curve (0.88 ± 0.04; p < 0.0001) compared to platelet-to-lymphocyte ratio (0.75 ± 0.06; p < 0.01), pneumonia severity index (0.65 ± 0.08; p = 0.05), CURB-65 (0.65 ± 0.08; p = 0.05), and neutrophil count (0.68 ± 0.07; p < 0.01). Multivariate logistic regression models revealed that NLR was associated with hospital and ICU mortality in renal transplant recipients with severe CAP. NLR levels were independently associated with mortality and may be a useful biomarker for predicting poor outcome in renal transplant recipients with severe CAP.

Renal Transplant Patients Undergo Abdominal Aortic Aneurysm Repair at a Younger Age and Experience More Complications: Review of the Healthcare Cost and Utilization Project Database

ObjectiveThe objective of this study was to determine whether history of kidney transplant is a risk factor for increased complications in patients who undergo abdominal aortic aneurysm (AAA) repair. BackgroundThe incidence of renal failure and subsequent kidney transplant is steadily rising. Many risk factors leading to AAA overlap with those of renal disease. Due to these similarities, a rising incidence of kidney transplant patients undergoing AAA repair is expected. We surmised a notable difference in AAA surgical repair outcomes in renal transplant recipients compared to the general population. MethodsA retrospective analysis was performed on 59,836 adult patients with history of AAA repair and kidney transplant from 2008 to 2015. Data were obtained from the Nationwide Inpatient Sample database developed for the Healthcare Cost and Utilization Project. ResultsSignificant differences in age, race, hospital characteristics, and complications were identified. The results suggest that patients with prior transplant generally have AAA repair at a significantly younger age (P < .001). A difference in race (P = .017), with 75% vs 87.4% non-Hispanic whites and 5% vs 1.5% Asian/Pacific Islander in the transplant and nontransplant groups, respectively, was shown. Procedures at transplant centers had significantly longer lengths of stay (P < .001) and higher total charges (P < .001). In addition, transplant recipients exhibited a higher in-hospital mortality index (P < .001) than the nontransplanted population. ConclusionA history of kidney transplant significantly influences multiple aspects of care and complications regarding future AAA repair and is associated with increased in-hospital mortality index. Significant findings include increased total charges, longer lengths of stay, postoperative complications, and differences in age and race.

Dietary Diversity Score: Implications for Obesity Prevention and Nutrient Adequacy in Renal Transplant Recipients.

Obesity affects both medical and surgical outcomes in renal transplant recipients (RTRs). Dietary diversity, an important component of a healthy diet, might be a useful nutritional strategy for monitoring patients with obesity. In this cross-sectional study, the data of 85 eligible RTRs were analyzed. Demographic data, routine laboratory data, and 3-day dietary data were collected. Participants were grouped into nonobesity and obesity groups based on body mass index (BMI) (for Asian adults, the cutoff point is 27 kg/m2). Dietary diversity score (DDS) was computed by estimating scores for the six food groups emphasized in the Food Guide. The mean age and BMI of participants were 49.7 ± 12.6 years and 24.0 ± 3.8 kg/m2, respectively. In the study population, 20.0% (n = 17) were obese. DDS was significantly lower in obese participants than in those who were not obese (1.53 ± 0.87 vs. 2.13 ± 0.98; p = 0.029). In addition, DDS was correlated with nutrition adequacy of the diet. Multivariate analysis showed that the odds of obesity decreased with each unit increase in DDS (odds ratio, 0.278; 95% confidence interval, 0.101–0.766; p = 0.013). We conclude that patients with higher dietary diversity have a lower prevalence of obesity.

Central nervous system infections in renal transplant recipients.

The aim of this study is to determine the incidence, etiology, clinical characteristics, and outcomes of renal transplant recipients diagnosed and treated for central nervous system (CNS) infection at our institution. We analyzed data from all renal transplant recipients between January 2007 and December 2019 that were diagnosed and treated for CNS infections at our institution. Of 1374 patients who received renal allografts, 13 were diagnosed with CNS infections (9 males), with a mean age of 53.5years. Patients were diagnosed with CNS infections between 2months and 11years after the transplantation. Causative agents included JC virus, Streptococcus pneumoniae, Cryptococcus neoformans, Herpes zoster virus, Mycobacterium tuberculosis, Listeria monocytogenes, and West Nile virus. One patient had concomitant Nocardia and Neisseria infection. Immunosuppression was reduced in all patients. The patient with JC encephalitis and the patient with concomitant Neisseria and Nocardia meningitis died. One patient was returned to dialysis. Other patients recovered with differing levels of neurologic sequelae. Central nervous system infections in renal transplant recipients are rare. However, they are associated with significant morbidity and mortality. A high level of awareness is needed: neurological symptoms may be nonspecific and caused by non-infectious conditions related to the underlying disease, or side-effects of immunosuppressive drugs.

Erythropoietin, Fibroblast Growth Factor 23, and Death After Kidney Transplantation.

Elevated levels of erythropoietin (EPO) are associated with an increased risk of death in renal transplant recipients (RTRs), but the underlying mechanisms remain unclear. Emerging data suggest that EPO stimulates production of the phosphaturic hormone fibroblast growth factor 23 (FGF23), another strong risk factor for death in RTRs. We hypothesized that the hitherto unexplained association between EPO levels and adverse outcomes may be attributable to increased levels of FGF23. We included 579 RTRs (age 51 ± 12 years, 55% males) from the TransplantLines Insulin Resistance and Inflammation Cohort study (NCT03272854). During a follow-up of 7.0 years, 121 RTRs died, of which 62 were due to cardiovascular cause. In multivariable Cox regression analysis, EPO was independently associated with all-cause (HR, 1.66; 95% CI 1.16–2.36; P = 0.005) and cardiovascular death (HR, 1.87; 95% CI 1.14–3.06; P = 0.01). However, the associations were abrogated following adjustment for FGF23 (HR, 1.28; 95% CI 0.87–1.88; P = 0.20, and HR, 1.45; 95% CI 0.84–2.48; P = 0.18, respectively). In subsequent mediation analysis, FGF23 mediated 72% and 50% of the association between EPO and all-cause and cardiovascular death, respectively. Our results underline the strong relationship between EPO and FGF23 physiology, and provide a potential mechanism underlying the relationship between increased EPO levels and adverse outcomes in RTRs.

Post-Kidney Transplant Visit-to-Visit Body Mass Index Variability as a Risk of Post-Transplant Systolic Hypertension

Abstract Objectives Overweight and obesity are associated with hypertension (HTN) in renal transplant recipients (RTR). Body weight variability is known to be associated with HTN and poor cardiovascular (CV) outcomes in diabetic patients. After successful kidney transplantation (KT), weight change is very common due partly to perioperative and immunological factors. Association between body weight variability and HTN in RTR is unknown. We hypothesize that high body weight variability is associated with post-transplant HTN. Methods Body weight variability of RTR from a single transplant center was assessed as visit-to-visit body mass index variability (VVBMIV) by using average successive variability (ASV = the average absolute difference between successive values of BMI measured at 4, 12, 24, 36, and 48 weeks after KT). Multi-variable Cox proportional hazard regression analysis was used to examine association between post-transplant VVBMIV and systolic and diastolic HTN (SHTN and DHTN), which are defined as SBP and DBP ≥130 and 80 mmHg, respectively. Results Of 104 RTR, mean ± SD age was 54.29 ± 11.65 years and 62% were female. The majority (36%) were obese followed by normal weight (33%), and overweight (31%). Incidence of SBP was 0.041 person-weeks and median time to event was 12.86 weeks; while the incidence of DBP was 0.036 person-weeks with a slightly longer median time-to-event of 13 weeks. Mean ASV of BMI was 1.26 ± 0.82 kg/m2 (0.47 to 2.18). Risk of SHTN is increased 32% for every 1 kg/m2 increase in VVBMIV (HR 1.32, 95%CI 1.04 to 1.68, P 0.022). After adjusted for age, gender, and their interaction terms, very 1 kg/m2 increase in VVBMIV is associated with a 29% greater risk of developing SHTN (HR 1.29, 95% CI 1.01 to 1.65, P 0.043). However, increase in VVBMIV is not associated with an increased risk of DHTN for both univariable (HR 1.15, 95%CI 0.88 to 1.49, P 0.308) and multi-variable Cox regressions models (HR 1.13, 95%CI 0.86 to 1.49, P 0.391). Conclusions Post-kidney transplant VVBMIV is independently associated post-transplant SHTN, but not DHTN. Further studies is needed to examine mechanism of body weight variability and blood pressure outcomes in RTR. Funding Sources None.

Statin Use Is Prospectively Associated With New-Onset Diabetes After Transplantation in Renal Transplant Recipients.

New-onset diabetes after transplantation (NODAT) is frequent and worsens graft and patient outcomes in renal transplant recipients (RTRs). In the general population, statins are diabetogenic. This study investigated whether statins also increase NODAT risk in RTRs. From a prospective longitudinal study of 606 RTRs (functioning allograft >1 year, single academic center, follow-up: median 9.6 [range, 6.6-10.2] years), 95 patients using statins were age- and sex-matched to RTRs not on statins (all diabetes-free at inclusion). NODAT incidence was 7.2% (73.3% of these on statins). In Kaplan-Meier (log-rank test, P = 0.017) and Cox regression analyses (HR 3.86 [95% CI 1.21-12.27]; P = 0.022), statins were prospectively associated with incident NODAT, even independent of several relevant confounders including immunosuppressive medication and biomarkers of glucose homeostasis. This study demonstrates that statin use is prospectively associated with the development of NODAT in RTRs independent of other recognized risk factors.

An Analysis of Epidemiology, Etiology, and Outcomes of Acute Pancreatitis in Renal Transplant Recipients

Background and objectivesAcute pancreatitis after renal transplantation is seldom seen yet a dreadful complication. The causes include traditional causes and immunosuppressive medications and viral infections. Classical symptoms are not always present at onset, causing delay in diagnosis. The available literature on pancreatitis in renal transplants is either as case reports or case series. Large studies with longer follow-up periods and outcome in renal transplant patients with pancreatitis are lacking. We conducted this retrospective study to analyze the incidence, clinical features, and causes of pancreatitis in our institute in post-azathioprine era. DesignWe conducted a single center retrospective study of renal transplant recipients who suffered at least 1 episode of acute pancreatitis during a period from January 2002 to September 2018. We followed International Association of Pancreatology/American Pancreatic Association evidence-based guidelines for confirming diagnosis of acute pancreatitis and included only patients who fulfilled these criteria. Once the diagnosis is confirmed we retrospectively analyzed the etiology, clinical features, management and outcomes of renal transplant recipients with pancreatitis. ResultsTwenty-six patients (men 81%; mean age 38.5 years) were included. Etiology included gallstones (19.3%), structural lesions (11.5%), viral infections (7.8%), and drugs. Clinical presentations, laboratory parameters were like pancreatitis in non-transplant patients. Graft dysfunction was noted in 20 patients (77%) and all showed either partial or complete recovery. Patient survival was high with 88% of the patients surviving the episode. ConclusionPancreatitis after renal transplantation is a rare complication with outcomes better than what has been reported in the past.

Urinary Excretion of 6-Sulfatoxymelatonin, the Main Metabolite of Melatonin, and Mortality in Stable Outpatient Renal Transplant Recipients.

Melatonin is a multifaceted hormone which rises upon the onset of darkness. Pineal synthesis of melatonin is known to be disturbed in patients with end-stage renal disease, but it is not known if its production is restored to normal after successful renal transplantation. We hypothesized that urinary excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin, is lower in renal transplant recipients (RTRs) compared to healthy controls and that this is associated with excess mortality. Urinary 6-sulfatoxymelatonin was measured via LC-MS/MS in 701 stable outpatient RTRs and 285 healthy controls. Median urinary 6-sulfatoxymelatonin in RTR was 13.2 nmol/24 h, which was 47% lower than in healthy controls. Urinary 6-sufatoxymelatonin appeared undetectable in the majority of 36 RTRs with diabetic nephropathy as primary renal disease. Therefore, this subgroup was excluded from further analyses. Of the remaining 665 RTRs, during 5.4 years of follow-up, 110 RTRs died, of whom 38 died due to a cardiovascular cause. In Cox-regression analyses, urinary 6-sulfatoxymelatonin was significantly associated with all-cause mortality (0.60 (0.44–0.81), p = 0.001) and cardiovascular mortality (0.49 (0.29–0.84), p = 0.009), independent of conventional risk factors and kidney function parameters. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTRs.

Outcomes of Renal Transplant Recipients after Percutaneous Coronary Intervention

Renal transplantation (RT) can improve life expectancy in hemodialysis (HD) patients. However, little is known about the outcomes of renal transplant recipients after percutaneous coronary intervention (PCI). This study aimed to elucidate the effect of RT on clinical outcomes after PCI. Renal transplant recipients who underwent PCI from 2002 to 2017 were enrolled. To evaluate the effectiveness of RT, we retrospectively reviewed HD patients who underwent PCI. Propensity-score matching was performed using logistic regression to control for differences in baseline characteristics. The primary outcome was the incidence of major adverse cardiac events. After propensity matching, patients were classified into the RT (n = 50) group and HD (n = 50) group. Kaplan-Meier analysis revealed that the incidence of major adverse cardiac events was significantly lower in the RT group than in the HD group (p < 0.0001). Moreover, RT was associated with a lower risk for all-cause death (odds ratio 0.04; 95% confidence interval 0.002 to 0.03; p = 0.0054) and target vessel revascularization (OR 0.27; 95% CI 0.07 to 0.79; p = 0.015). RT may improve clinical outcomes after PCI, and it is encouraged for HD patients to increase life expectancy and reduce the occurrence of adverse events after PCI. Further research would be warranted to support this finding.

Torquetenovirus Serum Load and Long-Term Outcomes in Renal Transplant Recipients

Following transplantation, patients must take immunosuppressive medication for life. Torquetenovirus (TTV) is thought to be marker for immunosuppression, and TTV–DNA levels after organ transplantation have been investigated, showing high TTV levels, associated with increased risk of infections, and low TTV levels associated with increased risk of rejection. However, this has been investigated in studies with relatively short follow-up periods. We hypothesized that TTV levels can be used to assess long term outcomes after renal transplantation. Serum samples of 666 renal transplant recipients were tested for TTV DNA. Samples were taken at least one year after renal transplantation, when TTV levels are thought to be relatively stable. Patient data was reviewed for graft failure, all-cause mortality and death due to infectious causes. Our data indicates that high TTV levels, sampled more than one year post-transplantation, are associated with all-cause mortality with a hazard ratio (HR) of 1.12 (95% CI, 1.02–1.23) per log10 increase in TTV viral load, (p = 0.02). Additionally, high TTV levels were also associated with death due to infectious causes (HR 1.20 (95% CI 1.01–1.43), p = 0.04). TTV levels decrease in the years following renal transplantation, but remain elevated longer than previously thought. This study shows that TTV level may aid in predicting long-term outcomes, all-cause mortality and death due to an infectious cause in renal transplant patients sampled over one year post-transplantation.

Physical Activity and the Development of Post-Transplant Diabetes Mellitus, and Cardiovascular- and All-Cause Mortality in Renal Transplant Recipients.

(1) Background: Little is currently known about the health impacts of daily-life moderate-to-vigorous physical activity (MVPA) in relation to the development of post-transplant diabetes mellitus (PTDM) and the long-term survival of renal transplant recipients (RTRs). (2) Methods: We analyzed self-reported data on MVPA within non-occupational and occupational domains, estimated with the SQUASH questionnaire, from a prospective cohort study of RTRs (n = 650) with a functioning graft exceeding 1 year. PTDM diagnoses were based on plasma glucose levels (≥126 mg/dL), HbA1c (≥6.5%), and the use of antidiabetic medication. Mortality data were retrieved from patient files up to the end of September 2015. (3) Results: During a median follow-up period of 5.3 years, 50 patients (10%) developed PTDM and 129 (19.8%) died. Of these deaths, 53 (8.9%) were caused by cardiovascular disease. Cox regression analyses showed that higher MVPA levels among patients were associated with a lower risk of PTDM (hazard ratio (HR); 95% confidence interval (95%CI) = 0.49; 0.25–0.96, p = 0.04), cardiovascular- (0.34; 0.15–0.77, p = 0.01), and all-cause mortality (0.37; 0.24–0.58, p < 0.001) compared with No-MVPA patients, independently of age, sex, and kidney function parameters. Associations of MVPA with cardiovascular and all-cause mortality remained significant and materially unchanged following further adjustments made for transplant characteristics, lifestyle factors, metabolic parameters, medication use, and creatinine excretion (muscle mass). However, the association between MVPA and PTDM was no longer significant after we adjusted for metabolic confounders and glucose levels. (4) Conclusion: Higher MVPA levels are associated with long-term health outcomes in RTRs.

Association of soluble ST2 with all-cause and cardiovascular mortality in renal transplant recipients: a single-centre cohort study

BackgroundSoluble ST2 is a novel biomarker of myocardial fibrosis with an established role in prognostication of patients with heart failure. Its role in cardiovascular risk prediction for renal transplant recipients has not been investigated despite promising results for ST2 in other populations with renal disease.MethodsIn this prospective cohort study, 367 renal transplant recipients were followed up for a median of 16.2 years to investigate the association of soluble ST2 concentration with all-cause mortality. Cardiovascular mortality and major adverse cardiovascular events were secondary outcomes. Cox regression models were used to calculate hazard ratios and 95% confidence intervals for ST2 before and after adjustments. ST2 concentration was analysed both as a continuous variable and following categorisation according to the recommended cut-point of 35 ng/ml.ResultsA twofold higher ST2 concentration was associated with a 36% increased risk of all-cause mortality after adjustment for conventional cardiovascular risk factors and high-sensitivity C-reactive protein (adjusted hazard ratio 1.36; 95% confidence interval 1.06–1.75; p = 0.016). Associations with ST2 concentration were similar for cardiovascular events (adjusted hazard ratio 1.31; 95% confidence interval 1.00–1.73; p = 0.054), but were stronger for cardiovascular mortality (adjusted hazard ratio 1.61; 95% confidence interval 1.07–2.41; p = 0.022). Addition of ST2 to risk prediction models for mortality and cardiovascular events failed to improve their predictive accuracy.ConclusionsST2 is associated with, but does not improve prediction of, adverse outcomes in renal transplant recipients.

Association of polymorphisms in leptin and adiponectin genes with long-term outcomes in renal transplant recipients.

The effect of polymorphims in leptin and adiponectin genes on long-term outcomes of renal transplantation is unknown. In 349 renal transplant recipients (RTR), we aimed to determine associations between five SNPs in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes and these outcomes. Follow-up time ranged from 2 to 25 years (mean 10.29 ± 5.16 years). Two SNPs showed associations with long-term outcomes and their statistical significance greatly increased after 39 RTR with a history of cardiovascular events prior to transplantation were removed from the analysis. Adjusted odds ratios (OR) for LEPR rs1805094 and ADIPOQ rs1501299 and risk of graft loss were 0.35 (0.16-0.74) p = 0.006 and 2.37 (1.28-4.37) p = 0.006, respectively. The assessment of risk for global mortality revealed OR values of 0.20 (0.06-0.62), p = 0.005, and 2.43 (1.08-5.44), p = 0.031 for LEPR rs1805094 and ADIPOQ rs1501299, respectively. Our results show that polymorphism in genes involved in leptin and adiponectin function modify long-term outcomes in renal transplantation.

Urinary Properdin and sC5b-9 Are Independently Associated With Increased Risk for Graft Failure in Renal Transplant Recipients.

The pathophysiology of late kidney-allograft failure remains complex and poorly understood. Activation of filtered or locally produced complement may contribute to the progression of renal failure through tubular C5b-9 formation. This study aimed to determine urinary properdin and sC5b-9 excretion and assess their association with long-term outcome in renal transplant recipients (RTR).Methods: We measured urinary properdin and soluble C5b-9 in a well-defined cross-sectional cohort of RTR. Urinary specimens were taken from a morning urine portion, and properdin and sC5b-9 were measured using an enzyme-linked-immunosorbent assay (ELISA). Cox proportional hazard regression analyses were used to investigate prospective associations with death-censored graft failure.Results: We included 639 stable RTR at a median [interquartile range] 5.3 (1.8–12.2) years after transplantation. Urinary properdin and sC5b-9 excretion were detectable in 161 (27%) and 102 (17%) RTR, respectively, with a median properdin level of 27.6 (8.6–68.1) ng/mL and a median sC5b-9 level of 5.1 (2.8–12.8) ng/mL. In multivariable-adjusted Cox regression analyses, including adjustment for proteinuria, urinary properdin (HR, 1.12; 95% CI 1.02–1.28; P = 0.008) and sC5b-9 excretion (HR, 1.34; 95% CI 1.10–1.63; P = 0.003) were associated with an increased risk of graft failure. If both urinary properdin and sC5b-9 were detectable, the risk of graft failure was further increased (HR, 3.12; 95% CI 1.69–5.77; P < 0.001).Conclusions: Our findings point toward a potential role for urinary complement activation in the pathogenesis of chronic allograft failure. Urinary properdin and sC5b-9 might be useful biomarkers for complement activation and chronic kidney allograft deterioration, suggesting a potential role for an alternative pathway blockade in RTR.

Urinary Epidermal Growth Factor/Creatinine Ratio and Graft Failure in Renal Transplant Recipients: A Prospective Cohort Study.

Graft failure (GF) remains a significant limitation to improve long-term outcomes in renal transplant recipients (RTR). Urinary epidermal growth factor (uEGF) is involved in kidney tissue integrity, with a reduction of its urinary excretion being associated with fibrotic processes and a wide range of renal pathologies. We aimed to investigate whether, in RTR, uEGF is prospectively associated with GF. In this prospective cohort study, RTR with a functioning allograft ≥1-year were recruited and followed-up for three years. uEGF was measured in 24-hours urine samples and normalized by urinary creatinine (Cr). Its association with risk of GF was assessed by Cox-regression analyses and its predictive ability by C-statistic. In 706 patients, uEGF/Cr at enrollment was 6.43 [IQR 4.07–10.77] ng/mg. During follow-up, 41(6%) RTR developed GF. uEGF/Cr was inversely associated with the risk of GF (HR 0.68 [95% CI 0.59–0.78]; P < 0.001), which remained significant after adjustment for immunosuppressive therapy, estimated Glomerular Filtration Rate, and proteinuria. C-statistic of uEGF/Cr for GF was 0.81 (P < 0.001). We concluded that uEGF/Cr is independently and inversely associated with the risk of GF and depicts strong prediction ability for this outcome. Further studies seem warranted to elucidate whether uEGF might be a promising marker for use in clinical practice.

Long-Term Outcomes of Renal Transplant in Patients With End-Stage Renal Failure Due to Systemic Lupus Erythematosus and Granulomatosis With Polyangiitis.

Systemic lupus erythematosus and granulomatosis with polyangiitis are systemic inflammatory conditions associated with renalfailure that can recur after renal transplant. Patients with these conditions are treated with chronic immunosuppression, potentially increasing risk of secondary malignancies. Here, we investigated long-term outcomes in renal transplant recipients with these conditions. Transplant recipients with end-stage kidney disease due to systemic lupus erythematosus and granulomatosis with polyangiitis seen between 1982 and 2016 at a national kidney transplant center were included. Primary outcome variables were long-term allograft survival and incidence of secondary malignancy. Secondary outcome measures were incidence of delayed graft function, primary disease recurrence, and serum creatinine at follow-up. Ninety-eight transplant procedures (90 from deceased donors) in 92 consecutive patients (mean age 42.3 ± 14.4 y) were included: 55 with systemic lupus erythematosus and 37 with granulomatosis with polyangiitis. Follow-up duration was 110.53 ± 81.95 months (range, 1-393 mo). Overall renal allograft survival was 94.7% at 1 year, 85.4% at 5 years, and 75.4% at 10 years posttransplant. Patientswith systemic lupus erythematosus showed overall allograft survival of 91.6% at 1 year, 84.3% at 5 years, and 74.4% at 10 years. There was 1 allograft failure due to recurrence of primary disease in this group. Patients with granulomatosis with polyangiitis showed overall allograft survival of 100% at 1 year, 92.4% at 5 years, and 92.4% at 10 years. There were 21 mortalities, with 5 (23.8%) due to secondary malignancy. In total, 46 malignancies were diagnosed in 31 patients. We found excellent long-term renal allograft survival rates in patients with systemic lupus erythematosus and granulomatosis with polyangiitis, with secondary malignancy rates similar to those shown in recipients without autoimmune diseases. These findings provide clinicians with long-term data on transplant recipients with end-stage renal failure due to systemic inflammatory conditions.

High plasma guanidinoacetate-to-homoarginine ratio is associated with high all-cause and cardiovascular mortality rate in adult renal transplant recipients.

L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.