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Introduction: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated., Objectives: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis., Material and Methods: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis., Results: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 ± 0.8, 2.1 ± 1.2 and 1.8 ± 1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant., Conclusions: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Post-transplant diabetes mellitus (PTDM) beyond 12 months (late PTDM) is a severe complication after renal transplantation. Late PTDM develops mostly in subjects with prediabetes. Although exercise may have a potential role in preventing late PTDM, there are no previous data on the effect of exercise in patients with prediabetes., Material and Methods: The design was a 12-month exploratory study to test the capacity of exercise in reverting prediabetes in order to prevent late-PTDM. The outcome was the reversibility of prediabetes, assessed every 3 months with oral glucose tolerance tests (OGTT). The protocol included an incremental plan of aerobic and/or strength training as well as an active plan for promoting adherence (telephone calls, digital technology, and visits). A priori, a sample size cannot be calculated which makes this an exploratory analysis. Based on previous studies, the spontaneous reversibility of prediabetes was 30% and the reversibility induced by exercise will account for another 30%, a total reversibility of 60% (p value < 0.05, assuming a potency of 85%). Ad interim analysis was performed during follow-up to test the certainty of this sample calculation. Patients beyond 12 months after renal transplantation with prediabetes were included., Results: The study was interrupted early due to efficacy after the evaluation of the follow-up of 27 patients. At the end of follow-up, 16 (60%) patients reverted to normal glucose levels at fasting (from 102.13 mg/dL ± 11 to 86.75 ± 6.9, p = 0.006) and at 120 min after the OGTTs (154.44 mg/dL ± 30 to 113.0 ± 13.1, p = 0.002) and 11 patients had persistent prediabetes (40%). Also, insulin sensitivity improved with the reversibility of prediabetes, compared to those with persistent prediabetes: 0.09 [0.08-0.11] versus 0.04 [0.01-0.07], p = 0.001 (Stumvoll index). Most needed at least one increment in the prescription of exercise and compliance. Finally, measures aimed at the improvement of compliance were successful in 22 (80%) patients., Conclusion: Exercise training was effective to improve glucose metabolism in renal transplant patients with prediabetes. Exercise prescription must be conducted considering both the clinical characteristics of the patients and pre-defined strategy to promote adherence. The trial registration number of the study was NCT04489043., (© 2023. The Author(s).)

Background: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population., Methods: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351)., Results: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010)., Conclusions: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes., Methods: We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y., Results: Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%., Conclusions: Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials., Competing Interests: S.L.-L. is a researcher of the Juan Rodés Contract (grant number JR18/00027) of the Instituto de Salud Carlos III (Spain). E.P. is a researcher of the Programme Ramón y Cajal (grant number RYC- 2014-16573) of the Ministerio de Ciencia, Innovación y Universidades (Spain). The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Post-transplant diabetes mellitus (PTDM) is a frequent and severe complication after renal transplantation. In fact, PTDM is a risk factor for both infection and cardiovascular diseases. The prevalence and incidence of PTDM have a bimodal evolution: early (up to 3 months) and late PTDM (beyond 12 months). The majority of late PTDM occurs in subjects with prediabetes after transplantation. So, treating patients with prediabetes, a potentially reversible condition, might help preventing PTDM. In the general population, exercise prevents the evolution from prediabetes to diabetes. However, in renal transplantation, not enough evidence is available in this field., Objectives: We designed an exploratory analysis to evaluate the feasibility of exercise to reverse prediabetes as a first step in the design of a trial to prevent PTDM., Methods: Only patients with prediabetes beyond 12 months after transplantation with capacity to perform exercise will be included. Prediabetes will be diagnosed based on fasting glucose levels and oral glucose tolerance tests (OGTTs). Patients will be treated with a stepped training intervention, starting with aerobic exercise training (brisk walking, swimming, and cycling) 5 times per week and 30 min/day. Aerobic exercise training will be gradually increased to 60 min/day or eventually combined with anaerobic exercise training in case of persistent prediabetes. The reversibility/persistence of prediabetes will be measured with fasting glucose and OGTTs every 3 months. This study will last for 12 months., (© 2020 S. Karger AG, Basel.)

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Reliable determination of glomerular filtration rate (GFR) is crucial in the evaluation of living kidney donors. Although some guidelines recommend the use of measured GFR (mGFR), many centres still rely on estimated GFR (eGFR) obtained through equations or 24-h creatinine clearance. However, eGFR is neither accurate nor precise in reflecting real renal function. We analysed the impact of eGFR errors on evaluation and decision making regarding potential donors., Methods: We evaluated 103 consecutive living donors who underwent mGFR via iohexol plasma clearance and eGFR by 51 creatinine- and/or cystatin C-based equations. The cut-off for living donation in our centre is GFR > 80 mL/min for donors >35 years of age or 90 mL/min for those <35 years of age. We analysed the misclassification of donors based on the cut-off for donation-based eGFR., Results: Ninety-three subjects (90.3%) had mGFR values above (donors) and 10 [9.7% (95% confidence interval 5.4-17)] below (non-donors) the cut-off. In non-donors, most of the equations gave eGFR values above the cut-off, so donation would have been allowed based on eGFR. All non-donors were female with reduced weight, height and body surface. In donors, up to 32 cases showed eGFR below the cut-off, while mGFR was actually higher. Therefore an important number of donors would not have donated based on eGFR alone., Conclusion: The misclassification of donors around the cut-off for donation is very common with eGFR, making eGFR unreliable for the evaluation of living kidney donors. Whenever possible, mGFR should be implemented in this setting., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: In transplant patients receiving de novo anticalcineurin-free sirolimus (SRL)-based immunosuppression, we determined the influence of cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette, sub-family B (MDR/TAP), member (ABCB1) genotypes on SRL blood levels and medium-term relevant clinical outcomes, in order to improve effectiveness of immunosuppression strategies when anti-mammalian target of rapamycin (anti-mTOR) inhibitor is indicated for clinical reasons., Methods: Forty-eight renal transplant recipients (suffered 48% diabetes mellitus, 91% hypertension, and 47% dyslipidemia) were genotyped for CYP3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Sirolimus blood levels were determined using microparticle enzyme immunoassay technique. Relationships between genotypes and pharmacokinetics, graft function, and patient-graft survival were determined by univariate analysis., Results: CYP3A5*1/*3 showed lower SRL levels than CYP3A5*3/*3 (4.13±1.54 vs. 8.49±4.18 ng/mL; p=0.003) and level/dose ratio (LDR) (92.74±37.47 vs. 178.62±116.45; p=0.019) in early post-transplant period. In ABCB1 polymorphisms, CT genotypes showed higher SRL levels than CC and TT (8.93±2.22 vs. 7.28±2.47 vs. 7.35±1.15 ng/mL; p=0.038) in the late period; LDR in CC and CT were 171.29±36.24 vs. 335.66±138.71 (p=0.003), despite receiving lower doses (p=0.018). Acute rejection rate was 14% vs. 42% for *3/*3 and 14% (TT), 48% (CT), and 31% (CC). Median patient survival was 45 months, significantly lower than that of *3/*3 patients (69 months). Death-censored graft survival during 5-year follow-up was similar for both CYP3A5 genotypes and significantly lower in TT than CT and CC groups, without survival differences., Conclusions: CYP3A5 and ABCB1 polymorphisms influenced SRL levels; preliminary data suggest this may affect patient and graft survival. Genotyping renal transplant patients could help select candidates for SRL (genotype*3/*3 for CYP3A5 and CT for ABCB1), when anti-mTOR immunosuppression is indicated.

Background: Formulas do not estimate renal function with acceptable precision and accuracy., Methods: We compared 51 creatinine-based and/or cystatin c-based formulas with a gold standard (iohexol plasma clearance) in 193 renal transplant recipients using concordance correlation coefficient, total deviation index, coverage probability and the error in chronic kidney disease (CKD) stage classification., Results: No formula showed a concordance correlation coefficient greater than 0.90 (average for creatinine-based formulas: ∼0.70 and for cystatin c-based formulas: ∼0.85). A wide total deviation index was observed: approximately 70% (creatinine-based) and approximately 50% (cystatin c-based), indicating that 90% of the estimations showed bounds of error of ±70% or ±50%, respectively, compared with the gold standard. No formula included 90% of the estimations within a coverage probability of ±10%. Half the CKD stages classified by creatinine-based formulas were incorrect, mainly due to overestimation of renal function. One of 3 CKD stages diagnosed by cystatin c-based formulas was incorrect, with both overestimation and underestimation. Overall, the formulas showed very low precision and accuracy and a high degree of error in reflecting real renal function., Conclusions: In conclusion, formulas do not properly reflect renal function in kidney transplantation, which makes their use in clinical practice unreliable. Moreover, their use in clinical trials should be avoided.

Background: Although pancreas transplantation (PT) is the treatment of choice in selected diabetic patients, the International Pancreas Transplant Registry (IPTR) has reported important differences in activity between USA and Europe. Of all cases reported, 75% are from USA and only 23% from Europe. Therefore, an analysis of PT activity in selected European countries (SEC) and USA was performed. Materials and methods. We compared national data reports (2002-06) of deceased donors (DD) and deceased solid organ transplantation (DSOT), with special attention to PT activity from 13 SEC countries (375 million inhabitants) and USA (298 million inhabitants)., Results: The number of PT performed in USA was 2-fold higher than in SEC, with the annual rate >2.4 times higher in USA [5.08-4.64 versus 1.61-1.91 per million population (p.m.p.)]. DD and other DSOT activity rates were only slightly higher in USA. In SEC, important differences in PT activity rate were found between countries in the same year (0-6.21 p.m.p.) and in the same country between different years (6.21-2.47 p.m.p.), unrelated to DD or other DSOT activity rate. PT activity rate increased in SEC from 1.61 to 1.91 p.m.p. but decreased in six countries. The waiting list for PT at the end of 2006 was almost 2-fold higher in USA than in SEC., Conclusions: Differences in PT activity rate between 13 SEC countries and USA were not related to DD or other DSOT activity. Different waiting list inclusion criteria or incidence of diabetes complications may be considered in more specific studies.

In our Universitary Hospital of Canarias we iniciated in May 2008 a induction therapy protocol for sensitized patients receiving cadaveric renal graft using intravenous immunoglobulins, plasmapheresis and rituximab plus immunosuppression with prednisone, tacrolimus and mycophenolate mofetil. We present the results of four patients. Everyone had anti-HLA antibodies rate (PRA by CDC) more than 75%, were on a waiting list during 4 to 17 years and follow-up time was 10-14 months after transplantation. Patient and graft survival in this period was 100%. Only one patient suffered a humoral acute rejection and another one cellular rejection, in both cases reversible with treatment. During the first year, no evidence of de novo donor-specific antibodies was detected. All patients had significantly reduced the CD19+ cells percentage after infusion of rituximab. Neurological symptoms suggestive of progressive multifocal leukoencephalopathy or serious viral infections after transplantation have not been observed. Additionally, no immediate side effects were observed after administration of medication. In summary, induction therapy by combining immunoglobulin, plasmapheresis and rituximab in hypersensitive patients allows the realization of deceased kidney transplantation with good results in the short and medium-term without serious side effects. It remains to know whether this success will continue in the long term.

Background: In selected type 1 diabetic (T1DM) patients with end-stage renal disease (ESRD), simultaneous pancreas-kidney transplantation (SPKT) offers higher long-term graft and patient survival, but also higher initial morbidity and mortality than cadaveric kidney transplantation alone (CKTA). The development of new immunosuppressive regimens and surgical approach has improved this initial outcome, but little is known about their effect on short-term renal function and surgical complications related to the renal graft., Methods: We analysed retrospectively the short-term follow-up of 45 T1DM patients consecutively transplanted during 42 months (20 SPKT and 25 CKTA) in order to compare short-term (6 months) renal allograft function and surgical complications related to the renal allograft in both groups., Results: There were no differences in donor characteristics. SPKT recipients had a significantly shorter time on dialysis and cold ischaemia time, with a higher number of HLA mismatches. There was no difference in acute rejection incidence, but delayed kidney graft function was less frequent in SPKT (5% vs 32%; P<0.05). Plasma creatinine level at discharge and 6 months was significantly lower in SPKT (1.1+/-0.3 vs 1.6+/-0.7; P<0.005 and 1.1+/-0.3 vs 1.5+/-0.6; P<0.05, respectively). There were no differences in surgical renal complications (haemorrhage, thrombosis or arterial stenosis, ureter leaks or stricture, lymphoceles or dehiscences). Two SPKT patients needed reintervention on the renal allograft and only one CKTA patient., Conclusions: In the modern transplant era, SPKT in ESRD diabetic patients, offers a slightly better short-term kidney allograft function without significant increase in surgical morbidity, compared with CKTA.

The prognosis of type 1 diabetes mellitus (T1DM) patients with chronic renal failure (CRF) improves after simultaneous pancreas-kidney (SPK) transplantation. In order to evaluate the changes in cardio-vascular risk (CVR) factors after SKP, we studied nine recipients before and 6 months after SPK. There were five females and four males, with a mean age of 37 +/- 8 years, duration of diabetes of 24 +/- 5 years, three of them before starting dialysis, and six on dialysis (hemodialysis = 5; peritoneal dialysis = 1). Before SPK, all patients received anti-hypertensive therapy (1-4 drugs; mean 2.2 +/- 0.9) and eight received statins. At 6 months after SPK, all patients were under triple immunosuppressive therapy (steroids + tacrolimus + MMF) without statins. They had normal renal function (Plasma Creatinine = 1.2 +/- 0.3 mg/dl) and pancreatic endocrine function (glycemia = 80 +/- 8 mg/dl). HbA1c decreased significantly (8.4 +/- 1.2 vs 4.7 +/- 0.6%; p < 0.007) with a value > 7% in seven patients before SPK and in none 6 months after SKP transplantation (p < 0.001). Although Body Mass Index increased (23 +/- 2 vs 25 +/- 3 kg/m2; p < 0.05), plasma triglycerides decreased (130 +/- 51 vs 88 +/- 33 mg/dl; p < 0.05), and total cholesterol, LDL-cholesterol and HDL-cholesterol were similar. Systolic and diastolic blood pressure (BP) decreased (156 +/- 7 vs 133 +/- 15; p < 0.01 and 96 +/- 7 vs 79 +/- 9; p < 0.007) with only two patients on anti-hypertensive therapy (1 drug). Likewise, before transplantation all patients were hypertensive (six grade 1 and three grade 2) while this was observed in only two at the end of follow-up (both grade 1) (p < 0.001). In conclusion, SPK transplantation with good renal and pancreatic function is associated with a short-term improvement in CVR profile.

Unlabelled: High levels of homocysteine (tHcy) are frecuent in MHD patients, and recognized as a risk factor for cardiovascular events. Vitamin supplements have been shown to lower serum Hcys, although optimal dose and efficacy is not well defined. Moreover, methylenetetrahydrofolate reductase (MTHFR) gene polymorphism can modulate its prevalence and response to treatment., Objective: To evaluate efficacy and safety of two vitamin supplement regimens on Hcys serum levels over a 12 month period., Methods: We conducted a prospective, randomised, double-blind trial in 60 stable MHD patients (68 +/- 13 years, 48% male, 50% diabetics). Patients were randomly assigned to one of two treatment regimens: 1) daily renal multivitamin containing folate (FA), vitamin B6 and B12 (5 mg, 10 mg and 0.4 mg respectively) (N = 27); and 2) supraphysiological daily doses (15 mg, 100 mg and 1 mg) (N = 33). These regimens were continued throughout the study period. Hcys levels were compared with a control group from the general population (N = 276) matched for age and gender., Measurements: demographic and clinical data, serum levels of Hcys, FA, B6, B12 at baseline and after 1, 3, 6 and 12 months of treatment; MTHFR gene polymorphism (PCRRT)., Results: At baseline, global prevalence of hyperhomocysteinemia (tHcy > or = 15 micromol/L) was 100% in patients and 22% en controls. Hcys levels were significantly higher in patients versus controls (32.4 +/- 8.9 vs 12.9 +/- 6.8; P < 0.0001). Both regimens were equally effective in reducing Hcys levels. As a whole, Hcys levels were reduced by 23.6% (P < 0.001) after one month of treatment. The highest reduction was observed at the sixth month (28.3%, 32.4 +/- 8.9 vs 22.7 +/- 6.4, P < 0.001) and remained stable thereafter. However, only 12% of patients normalised their plasma levels after 12 months of therapy. The effect of treatment was not influenced by age, gender, diabetes, body weight or time on MHD. Reduction rate of tHcy levels was related to baseline tHcy level (r = 0.500, P < 0.001) and baseline FA levels (r = -0.332, P = 0.009). The MTHFR polimorfism did not significantly modified the effect of the treatment. No side effects were associated with either regimen., Conclusions: Hyperhomocysteinemia is common in patients with conventional HD schedules and this is not related to vitamin deficiencies. Vitamin supplements significantly reduce Hcys levels in a sustained but suboptimal way. Supraphysiological doses did not improve the results. Further studies are requiered to demonstrate that this effect is associated with an improval in morbidity and mortality.