International comparison and time trends of first kidney transplant recipient characteristics across Europe: an ERA Registry study.

BACKGROUND: The aim of this study was to provide an overview of age, sex and primary renal disease (PRD) distribution among first kidney transplant recipients across Europe. METHOD: The European Renal Association (ERA) Registry database was used to obtain data on patients aged 20 years or older receiving their first kidney transplant between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year. RESULTS: In total, 99 543 adults received a first kidney transplant. Overall, 23% of the recipients were 65 years or older, 36% were female, and 21% had glomerulonephritis and 15% diabetes mellitus as PRD. Compared with deceased donor kidney transplant recipients, living donor kidney transplant recipients were less often 65 years or older (13% versus 26%), more often had glomerulonephritis (25% versus 20%) and less often diabetes mellitus (8% versus 17%) as PRD. We found large international differences, which were most prominent for age and PRD and less prominent for sex. Over time, the largest change in recipient characteristics was observed for the percentage of recipients aged 65 years or older, increasing from 18% in 2010 to 28% in 2019 for all countries combined with a similar trend in most countries. CONCLUSION: We observed large differences for age and PRD distribution between recipients of living and deceased donor kidneys and between European countries. Over time, the percentage of older first kidney transplant recipients increased.

Incidence and outcomes of kidney replacement therapy for end-stage kidney disease due to primary glomerular disease in Europe: findings from the ERA Registry.

BACKGROUND AND HYPOTHESIS: Primary glomerular disease (PGD) is a major cause of end-stage kidney disease (ESKD) leading to kidney replacement therapy (KRT). We aimed to describe incidence (trends) in individuals starting KRT for ESKD due to PGD and to examine their survival and causes of death. METHODS: We used data from the European Renal Association (ERA) Registry on 69 854 patients who started KRT for ESKD due to PGD between 2000 and 2019. ERA primary renal disease codes were used to define six PGD subgroups. We examined age and sex standardized incidence, trend of the incidence, and survival. RESULTS: The standardized incidence of KRT for ESKD due to PGD was 16.6 per million population (pmp), ranging from 8.6 pmp in Serbia to 20.0 pmp in France. IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) had the highest incidence of 4.6 pmp and 2.6 pmp, respectively. Histologically non-examined PGDs represented over 50% of cases in Serbia, Bosnia and Herzegovina, and Romania and were also common in Greece, Estonia, Belgium, and Sweden. The incidence declined from 18.6 pmp in 2000 to 14.5 pmp in 2013, after which it stabilized. All PGD subgroups had five-year survival probabilities above 50%, with crescentic glomerulonephritis having the highest risk of death (adjusted hazard ratio: 1.8 [95% confidence interval: 1.6-1.9]) compared with IgAN. Cardiovascular disease was the most common cause of death (33.9%). CONCLUSION: The incidence of KRT for ESKD due to PGD showed large differences between countries and was highest and increasing for IgAN and FSGS. Lack of kidney biopsy facilities in some countries may have affected accurate assignment of the cause of ESKD. The recognition of the incidence and outcomes of KRT among different PGD subgroups may contribute to a more individualized patient care approach.

Time trends in preemptive kidney transplantation in Europe: an era registry study.

BACKGROUND: Preemptive kidney transplantation has better outcomes when compared to transplantation after dialysis. We aimed to examine trends in preemptive kidney transplantation between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives. METHODS: Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around preemptive kidney transplantation. RESULTS: Between 2000 and 2019, 20 251 adults underwent preemptive kidney transplantation (11 169 from living donors, 8937 from deceased donors). The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for living donor kidney recipients (from 21% to 43%) and deceased donor kidney recipients (from 4% to 11%). Large international differences were found. The increase in preemptive kidney transplantation was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor or recipient work-up. Suggested initiatives included raising awareness on the possibility of preemptive kidney transplantation, earlier start and shorter work-up time for recipient and living donor. CONCLUSIONS: Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and deceased donor kidney recipients.

Trends in kidney transplantation rate across Europe: study from the ERA Registry.

BACKGROUND: The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. METHODS: The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. RESULTS: The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East-West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). CONCLUSIONS: The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries.

Autologous Mesenchymal Stem Cells for Treatment of Chronic Active Antibody-Mediated Kidney Graft Rejection: Report of the Phase I/II Clinical Trial Case Series.

Mesenchymal stem cell (MSCs) therapy has already been studied in kidney transplant recipients (KTRs), and the available data showed that it is safe and well tolerated. The aim of this study was to evaluate the safety and efficacy of autologous MSCs in combination with standard therapy in KTRs with biopsy-proven chronic active antibody-mediated rejection (AMR). Patients with biopsy-proven chronic active AMR received treatment with autologous bone marrow-derived MSCs (3 × 106 cells/kg iv) after completion of standard therapy and were followed for up to 12 months. The primary endpoints were safety by assessment of adverse events. Secondary endpoints included assessment of kidney graft function, immunological and histological changes related to AMR activity and chronicity assessed by conventional microscopy and molecular transcripts. A total of 3 patients were enrolled in the study before it was terminated prematurely because of adverse events. We found that AMR did not improve in any of the patients after treatment with MSCs. In addition, serious adverse events were observed in one case when autologous MSCs therapy was administered in the late phase after kidney transplantation, which requires further elucidation.

Quantitative contrast-enhanced ultrasound for the differentiation of kidney allografts with significant histopathological injury.

OBJECTIVE: To identify specific quantitative contrast-enhanced ultrasound (CEUS) parameters that could distinguish kidney transplants with significant histopathological injury. METHODS: Sixty-four patients were enrolled in this prospective observational study. Biopsies were performed following CEUS and blood examination. RESULTS: 28 biopsy specimens had minimal changes (MC group), while 36 had significant injury (SI group). Of these, 12 had rejection (RI group) and 24 non-rejection injury (NRI group). In RI and NRI groups, temporal difference in time to peak (TTP) between medulla and cortex (ΔTTPm-c) was significantly shorter compared to the MC group (5.77, 5.92, and 7.94 s, P = 0.048 and 0.026, respectively). Additionally, RI group had significantly shorter medullary TTP compared to the MC group (27.75 vs. 32.26 s; P = 0.03). In a subset of 41 patients with protocol biopsy at 1-year post-transplant, ΔTTPm-c was significantly shorter in the SI compared to the MC group (5.67 vs. 7.67 s; P = 0.024). Area under receiver operating characteristic curves (AUROCs) for ΔTTPm-c was 0.69 in all patients and 0.71 in patients with protocol biopsy. CONCLUSIONS: RI and NRI groups had shorter ΔTTPm-c compared to the MC group. AUROCs for both patient groups were good, making ΔTTPm-c a promising CEUS parameter for distinguishing patients with significant histopathological injury.

COVID-19-related mortality in kidney transplant and haemodialysis patients: a comparative, prospective registry-based study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has exposed haemodialysis (HD) patients and kidney transplant (KT) recipients to an unprecedented life-threatening infectious disease, raising concerns about kidney replacement therapy (KRT) strategy during the pandemic. This study investigated the association of the type of KRT with COVID-19 severity, adjusting for differences in individual characteristics. METHODS: Data on KT recipients and HD patients diagnosed with COVID-19 between 1 February 2020 and 1 December 2020 were retrieved from the European Renal Association COVID-19 Database. Cox regression models adjusted for age, sex, frailty and comorbidities were used to estimate hazard ratios (HRs) for 28-day mortality risk in all patients and in the subsets that were tested because of symptoms. RESULTS: A total of 1670 patients (496 functional KT and 1174 HD) were included; 16.9% of KT and 23.9% of HD patients died within 28 days of presentation. The unadjusted 28-day mortality risk was 33% lower in KT recipients compared with HD patients {HR 0.67 [95% confidence interval (CI) 0.52-0.85]}. In a fully adjusted model, the risk was 78% higher in KT recipients [HR 1.78 (95% CI 1.22-2.61)] compared with HD patients. This association was similar in patients tested because of symptoms [fully adjusted model HR 2.00 (95% CI 1.31-3.06)]. This risk was dramatically increased during the first post-transplant year. Results were similar for other endpoints (e.g. hospitalization, intensive care unit admission and mortality >28 days) and across subgroups. CONCLUSIONS: KT recipients had a greater risk of a more severe course of COVID-19 compared with HD patients, therefore they require specific infection mitigation strategies.

Temporal trends in the quality of deceased donor kidneys and kidney transplant outcomes in Europe: an analysis by the ERA-EDTA Registry.

BACKGROUND: We investigated 10-year trends in deceased donor kidney quality expressed as the kidney donor risk index (KDRI) and subsequent effects on survival outcomes in a European transplant population. METHODS: Time trends in the crude and standardized KDRI between 2005 and 2015 by recipient age, sex, diabetic status and country were examined in 24 177 adult kidney transplant recipients in seven European countries. We determined 5-year patient and graft survival probabilities and the risk of death and graft loss by transplant cohort (Cohort 1: 2005-06, Cohort 2: 2007-08, Cohort 3: 2009-10) and KDRI quintile. RESULTS: The median crude KDRI increased by 1.3% annually, from 1.31 [interquartile range (IQR) 1.08-1.63] in 2005 to 1.47 (IQR 1.16-1.90) in 2015. This increase, i.e. lower kidney quality, was driven predominantly by increases in donor age, hypertension and donation after circulatory death. With time, the gap between the median standardized KDRI in the youngest (18-44 years) and oldest (>65 years) recipients widened. There was no difference in the median standardized KDRI by recipient sex. The median standardized KDRI was highest in Austria, the Netherlands and the Basque Country (Spain). Within each transplant cohort, the 5-year patient and graft survival probability were higher for the lowest KDRIs. There was no difference in the patient and graft survival outcomes across transplant cohorts, however, over time the survival probabilities for the highest KDRIs improved. CONCLUSIONS: The overall quality of deceased donor kidneys transplanted between 2005 and 2015 has decreased and varies between age groups and countries. Overall patient and graft outcomes remain unchanged.

Chronic hepatitis B virus infection in Slovenian national cohort of kidney transplant patients.

AIMS: To estimate the prevalence of anti-HBc-positive patients with functioning kidney graft, to detect the anti-HBc-positive patients in danger for hepatitis B virus (HBV) reactivation and to update Slovenian guidelines on hepatitis B follow-up, vaccination, introduction of chemoprophylaxis or treatment. MATERIALS AND METHODS: The Slovenian national cohort of kidney transplant patients with functioning graft managed at the University Medical Center Ljubljana was included. In a cross-sectional study between March and September 2020, all included patients were screened for the presence of anti-HBc; all anti-HBc-positive patients were additionally tested for anti-HBs, HBsAg, and HBV DNA. RESULTS: Out of a total of 778 included patients, 72 were anti-HBc positive (9.2%). Eight patients (1%) presented with asymptomatic chronic HBV infection: 6 were HBsAg-positive/HBV DNA-negative, and 2 were HBsAg-negative/HBV DNA positive. In one of the latter, HBsAg mutant variant P120QD144E was proven. By the time of the study, 12 anti-HBc-positive patients (16.6%) have already been receiving chemoprophylaxis. CONCLUSION: The prevalence of anti-HBc-positive patients in the national cohort of kidney transplant patients in Slovenia was 9.2%. Based on the specific combination of HBV markers (anti-HBc, anti-HBs, HBsAg, HBV DNA) we stratified patients into six subgroups. Algorithm on follow-up, hepatitis B vaccination, chemoprophylaxis, or treatment is presented for each of the specific subgroups.

Optimization of isolation protocol and characterization of urinary extracellular vesicles as biomarkers of kidney allograft injury.

AIMS: Long-term kidney allograft survival requires a personalized approach to allograft injury recognition in a timely and reliable manner. Kidney biopsy is invasive and unsuitable for continuous function assessment. Alternatively, in urine, we find extracellular vesicles (uEVs), stable carriers of kidney pathology signals. Analysis of uEVs and their cargo could allow for more frequent and non-invasive assessment of allograft function. We aimed to optimize the uEVs isolation method applicable for kidney allograft injury biomarker studies. MATERIALS AND METHODS: To this end, we optimized several steps of size-exclusion chromatography (SEC)-based method for uEVs isolation from second morning urine of kidney allograft recipients. uEVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western analysis, and quantitative PCR. RESULTS: According to TEM and NTA, SEC isolated high concentrations (8.64 × 108 EVs/mL of urine) of EVs that showed typical morphology and mean size (171 nm), but addition of EDTA and filtration step were needed to remove impurities. Additionally, typical EV proteins Hsc70, CD63, flotillin, tubulin, GAPDH, and miR hsa-let-7i were detected in isolated uEVs, further confirming their identity. CONCLUSION: Optimized method based on SEC was effective and adequate in isolating pure EVs from urine of kidney allograft recipients and could be used in future biomarker studies.

Glucocorticoid pathway polymorphisms and diabetes after kidney transplantation.

AIMS: To find possible associations between new-onset diabetes after transplantation and polymorphisms in glucocorticoid pathway. MATERIALS AND METHODS: A total of 290 patients from our national cohort of kidney transplant patients with functioning graft transplanted in 6 consecutive years (2010 - 2015) were included in the study. All patients were genotyped for polymorphisms in genes coding for glucocorticoid receptor (NR3C1 rs33389, rs6198 and rs33388), P-glycoprotein (ABCB1 rs1045642, rs1128503, and rs2032582), and glutathione S-transferase P1 (GSTP1 rs1695 and rs1138272). For interim analysis, clinical data were obtained from medical records for 79 patients. RESULTS: 22.8% of patients developed NODAT in the first post-transplant year. GSTP1 rs1695 and rs1138272 polymorphisms were associated with an increased risk for NODAT. NR3C1 rs6198 polymorphism was associated with higher serum glucose at the end of the first post-transplant year. CONCLUSION: The observed incidence of NODAT in the first post-transplant year is in accordance with the literature data. GSTP1 genotypes leading to decreased conjugation capacity were associated with higher probability of NODAT. As these polymorphisms can be determined already before kidney transplantation, they can help planning early glucocorticoid withdrawal if a favorable post-transplant course permits it.

A national cohort study on hemodialysis arteriovenous fistulas after kidney transplantation - long-term patency, use and complications.

OBJECTIVE: To describe the long-term hemodialysis arteriovenous fistula (AVF) patency, incidence of AVF use, incidence and nature of AVF complications and surgery in patients after kidney transplantation. PATIENTS AND METHODS: We retrospectively analysed the AVF outcome and complications in all adult kidney allograft recipients transplanted between January 1st, 2000 and December 31, 2015 with a functional AVF at the time of transplantation. Follow-up was until December 31, 2019. RESULTS: We included 626 patients. Median AVF follow-up was 4.9 years. One month after kidney transplantation estimated AVF patency rate was 90%, at 1 year it was 82%, at 3 years it was 70% and at 5 years it was 61%; median estimated AVF patency was 7.9 years. The main cause of AVF failure was spontaneous thrombosis occurring in 76% of AVF failure cases, whereas 24% of AVFs were ligated or extirpated. In a Cox multivariate model female sex and grafts were independently associated with more frequent AVF thrombosis. AVF was used in about one third of our patients. AVF-related complications occurred in 29% of patients and included: growing aneurysms, complicated thrombosis, high-flow AVF, signs of distal hypoperfusion, venous hypertension, trauma of the AVF arm, or pain in the AVF/arm. CONCLUSIONS: AVFs remain functional after kidney transplantation in the majority of patients and are often re-used after graft failure. AVF-related complications are common and require proper care.

First and second morning spot urine protein measurements for the assessment of proteinuria: a diagnostic accuracy study in kidney transplant recipients.

BACKGROUND: Quantification of proteinuria in kidney transplant recipients is important for diagnostic and prognostic purposes. Apart from correlation tests, there have been few evaluations of spot urine protein measurements in kidney transplantation. METHODS: In this cross-sectional study involving 151 transplanted patients, we investigated measures of agreement (bias and accuracy) between the estimated protein excretion rate (ePER), determined from the protein-to-creatinine ratio in the first and second morning urine, and 24-h proteinuria and studied their performance at different levels of proteinuria. Measures of agreement were reanalyzed in relation to allograft histology in 76 patients with kidney biopsies performed for cause before enrolment in the study. RESULTS: For ePER in the first morning urine, percent bias ranged from 1 to 28% and accuracy (within 30% of 24-h collection) ranged from 56 to 73%. For the second morning urine, percent bias ranged from 2 to 11%, and accuracy ranged from 71 to 78%. The accuracy of ePER (within 30%) in first and second morning urine progressively increased from 56 and 71% for low-grade proteinuria (150-299 mg/day) to 60 and 74% for moderate proteinuria (300-999 mg/day), and to 73 and 78% for high-grade proteinuria (≥1000 mg/day). Measures of agreement were similar across histologic phenotypes of allograft injury. CONCLUSIONS: The ability of ePER to accurately predict 24-h proteinuria in kidney transplant recipients is modest. However, accuracy improves with an increase in proteinuria. Given the similar accuracy of ePER measurements in first and second morning urine, second morning urine can be used to monitor protein excretion.

THE BEGINNINGS OF KIDNEY TRANSPLANTATION IN SOUTH-EAST EUROPE.

Organ transplantation is one of the most important medical achievements of the 20th century. Kidney transplantation is the most efficient method of renal replacement therapy. The first successful kidney transplantation in human was performed in 1954 in Boston, USA. In former Yugoslavia, the first kidney transplantation was performed on April 16, 1970 in Ljubljana, Slovenia, and second one on January 30, 1971 in Rijeka, Croatia. In both cases, the mother donated kidney to the son. In the article, we describe the prerequisite conditions for this operation, the characteristics of first patients, and the impact of transplantation program on the development of the hospitals and medical schools.

Paricalcitol versus placebo for reduction of proteinuria in kidney transplant recipients: a double-blind, randomized controlled trial.

Proteinuria after kidney transplantation is accompanied by an increased risk of graft failure. In this single-center, placebo-controlled, double-blind trial we studied whether vitamin D receptor activator paricalcitol might reduce proteinuria. Patients with urinary protein-to-creatinine ratio (UPCR) ≥20 mg/mmol despite optimization of the renin angiotensin aldosterone system (RAAS) blockade were randomly assigned to receive 24 weeks' treatment with 2 µg/day paricalcitol or placebo. Primary endpoint was change in UPCR, and main secondary endpoints were change in urinary albumin-to-creatinine ratio (UACR) and 24-h proteinuria. Analysis was by intention to treat. One hundred and sixty-eight patients undergo randomization, and 83 were allocated to paricalcitol, and 85 to placebo. Compared with baseline, UPCR declined in the paricalcitol group (-39%, 95% CI -45 to -31) but not in the placebo group (21%, 95% CI 9 to 35), with a between group difference of -49% (95% CI -57 to -41; P < 0.001). UACR and 24-h proteinuria decreased only on paricalcitol therapy and significantly differed between groups at end-of-treatment (P < 0.001). Paricalcitol was well tolerated but incidence of mild hypercalcemia was higher than in placebo. In conclusion, addition of 2 µg/day paricalcitol lowers residual proteinuria in kidney transplant recipients. Long-term studies are needed to determine if the reduction in proteinuria improves transplant outcomes (ClinicalTrials.gov, number NCT01436747).

Expanded valganciclovir prophylaxis in kidney transplant recipients is associated with lower incidence of cytomegalovirus infection.

AIMS: The aim of this study was to compare the efficacy and safety of two subsequent CMV prophylaxis regimens for prevention of cytomegalovirus (CMV) infection and disease in our kidney transplant recipients (KTRs). METHODS: In an historic-cohort of KTRs, two CMV prophylaxis protocols were compared: short protocol in which CMV IgG seronegative recipients (R-) of CMV IgG seropositive donors (D+) received valganciclovir for 3 months post-transplant (group 1: 2005 - 2010); and expanded protocol in which prophylaxis for high-risk recipients was extended to 6 months, and a 3-month prophylaxis for D+/R+ and D-/R+ was introduced (group 2: 2011 - 2016). Incidences of CMV viremia, disease, and adverse events were assessed 12 months after transplant. RESULTS: Of 457 KTRs, 167 received short (group 1) and 290 expanded (group 2) CMV prophylaxis. The incidence of CMV viremia was significantly lower in group 2 than in group 1: 17.6% vs. 29.2%, respectively (p = 0.001). The incidence of CMV disease was 5.2% in group 2 vs. 10.2% in group 1 (p = 0.04). After comparing group 2 and group 1 according to the risk of CMV infection, incidences of CMV viremia were 50% vs. 47.4% in D+/R- (p = 0.79), 3.1% vs. 5.7% in D-/R+ (p = 0.05), and 9.7% vs. 23.6% in D+/R+ (p = 0.0004). The incidence of neutropenia was 41.7% in group 2 and 33.5% in group 1 (p = 0.09). CONCLUSIONS: The results show a significant reduction of CMV viremia in D+/R+ and D-/R+ KTRs after introduction of 3-month prophylaxis with valganciclovir. Extension of CMV prophylaxis to 6 months in D+/R- was not associated with reduction in CMV viremia at 12 months after transplant.
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The role of single nucleotide polymorphisms of CYP3A and ABCB1 on tacrolimus predose concentration in kidney transplant recipients.

BACKGROUND: Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C0) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients. METHODS: In the observational part of the study, we intend to determine allelic variants of CYP3A4, CYP3A5, and ABCB1 gene in a national cohort of 700 kidney transplants recipients. Clinical and laboratory data of this historic cohort will be added to assess patient's immunologic risk. Based on these data, a prediction model will be constructed that will be validated in a prospective randomized study in 60 de-novo kidney transplant recipients. RESULTS: Our interim cross-sectional observational results show higher variability of ABCB1 genotypes when compared to CYP3A genes, with more than two thirds of the population carrying at least one polymorphic allele. On the other hand, less than 1% of our transplant recipients possess the CYP3A genotype, which requires high daily tacrolimus dose. CONCLUSIONS: Due to high inter- and intrapatient tacrolimus variability, a patient-tailored approach to define the optimal maintenance tacrolimus C0 for each individual patient is needed. Our model will rely on individual pharmacogenomic and clinical data to cover different patient-specific risk factors for adverse outcomes.
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Effects of paricalcitol on biomarkers of inflammation and fibrosis in kidney transplant recipients: results of a randomized controlled trial.

AIMS: Paricalcitol, a selective vitamin D activator, decreases proteinuria and may reduce graft failure risk in kidney transplant recipients. In this study, we evaluated the effect of paricalcitol on renin-angiotensin system (RAS) activity as well as interleukin (IL)-6 and transforming growth factor (TGF)-ß plasma concentrations as biomarkers of inflammation and fibrosis. METHODS: This placebo-controlled, double-blind trial enrolled a national cohort of kidney transplant recipients with urinary protein-to-creatinine ratio (UPCR) ≥ 20 mg/mmol despite optimization of the RAS blockade. Patients were randomly assigned to receive 24 weeks of treatment with 2 µg/day paricalcitol or placebo. The primary endpoint was the percent change in geometric mean UPCR. In this secondary analysis, we examined the effect of paricalcitol on plasma renin activity (PRA) and aldosterone levels as well as IL-6 and TGF-ß plasma concentrations from baseline to last measurement during treatment. RESULTS: Of the 168 patients with UPCR ≥ 20 mg/mmol who consented to undergoing randomization, 83 were allocated to paricalcitol and 85 to placebo. Baseline patient demographics, clinical characteristics, PRA, and aldosterone levels were similar between groups. Mean change in IL-6 was -29% (from 2.53 to 2.02 pg/mL) in the paricalcitol group and 23% (from 2.07 to 2.54 pg/mL) in the placebo group (p < 0.001). Mean change in TGF-ß was -12% (from 8,011 to 6,935 pg/mL) in the paricalcitol group and 21% (from 7,418 to 8,992 pg/mL) in the placebo group (p < 0.001). CONCLUSION: In kidney transplant recipients, the addition of 2 µg/day paricalcitol to RAS inhibition lowers IL-6 and TGF-ß concentrations, which may be beneficial for reducing graft inflammation and fibrosis.
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Outcome of polyomavirus nephropathy in renal transplant patients: a single-center experience.

BACKGROUND: Reduction of immunosuppression is a common therapeutic strategy in patients with polyomavirus nephropathy (PVN) but may be associated with acute rejection. This study aimed to evaluate the morphology of PVN in renal biopsies after reduction of immunosuppression. METHODS: Eight of 241 patients who received a kidney transplant between January 2012 and December 2015 presented with BK viremia and biopsy-proven PVN. Morphological evaluation according to Banff criteria and correlation with viremia and kidney function after immunosuppression reduction was performed. RESULTS: PVN grades A and B were diagnosed on average 4.7 months post-transplant in 1 and 7 patients, respectively. Indication biopsies after immunosuppression reduction showed an increase in tubulitis and interstitial inflammation score compared to those at the time of the PVN diagnosis. Surveillance biopsies 1 year after transplantation revealed resolution of interstitial inflammation and tubulitis accompanied by clearance of BK viremia in 4 patients (50%), including 1 patient with rejection. One patient showed residual interstitial inflammation after viral clearance. In these patients, renal function returned to baseline. One patient with persisting low BK virus (BKV) in serum and kidney showed a decrease of tubulointerstitial inflammation but scarring was seen. Rejection occurred in 3 patients (38%). CONCLUSION: PVN-associated interstitial inflammation and tubulitis cannot be differentiated morphologically from T-cell-mediated tubulointerstitial rejection. Significant interstitial inflammation and tubulitis in PVN under low-dose immunosuppression might represent immune reconstitution injury, which is reduced after successful BKV clearance from the serum and kidney. Concomitant rejection in PVN patients on low immunosuppression might be efficiently treated with transient pulse immunosuppressive therapy.
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Increase in spot urine protein excretion is associated with late kidney graft rejection and predicts rejection phenotype.

AIMS: A noninvasive test that foretells kidney graft rejection before loss of kidney function would be desirable. We hypothesized that an increase in estimated protein excretion rate (ePER) from spot urine samples is associated with graft rejection and predicts rejection phenotype. METHODS: 151 patients who had undergone first-indication kidney biopsy due to graft dysfunction beyond 3 months after transplant were identified from a national cohort of 616 transplant recipients between 2000 and 2012 (25%). ePER were calculated from spot urine protein-to-creatinine ratios at baseline, 3 months before biopsy (ePER-3m), and at the time of biopsy (ePERbiopsy) and were correlated with histologic biopsy findings. RESULTS: Levels of ePER 3 months before biopsy and at the time of biopsy were greater in 32 patients with antibody-mediated rejection (ABMR) than in 77 patients with T-cell-mediated rejection (TCMR) and 42 patients with other findings (median ePER-3m 912 vs. 320 vs. 232 mg/day/1.73m2; and median ePERbiopsy 1,672 vs. 356 vs. 268 mg/day/1.73m2; p < 0.001). Receiver operator characteristics (ROC) analyses demonstrated that ePER-3m and ePERbiopsy had good diagnostic accuracy to discriminate between biopsy specimens showing ABMR vs. those showing TCMR or other histologic findings (area under the ROC curve 0.84, 95% CI 0.75 - 0.93 and 0.89, 95% CI 0.82 - 0.97, respectively; p < 0.001). CONCLUSIONS: An increase in ePER before kidney graft dysfunction appears to be associated with graft rejection and predicts ABMR phenotype.
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