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Background Post-transplant prediabetes (PreDM) and diabetes (PTDM) are common and have an impact on cardiovascular events. We sought to investigate the pathogenesis and best approach for prediction. Methods We prospectively studied 115 waitlisted patients from a single center without manifest diabetes. An oral glucose tolerance test (OGTT) was performed yearly until transplantation and 12 months later. Insulin secretion, insulin sensitivity (IS) and disposition index (DI) were derived from the OGTT. Results PreDM and PTDM were observed in 27% and 28.6% of patients, respectively. Pretransplant age, body mass index (BMI), 120 min glucose, IS, DI, and prediabetes or undiagnosed diabetes were significantly associated with these alterations. In multivariate analysis, pretransplant age [odds ratio (OR) 1.5; 95% confidence interval (CI) 1.04–2.1], BMI (OR 1.16; 95% CI 1.04–1.3) and cumulative steroids (OR 1.5; 95% CI 1.02–2.2) were predictors of PreDM or PTDM. Receiver operating characteristic curve analysis showed that pretransplant BMI and 120 min glucose had the highest area under the curve (0.72; 95% CI 0.62–0.8; and 0.69; 95% CI 0.59–0.79, respectively). The highest discrimination cut-off for BMI (≥28.5 kg/m2) and 120 min glucose (≥123.5 mg/dL) yielded a similar number needed to diagnose (2.5). Conclusions PreDM or PTDM develops in waitlisted patients with an ineffective insulin secretion and BMI shows a similar diagnostic capacity to OGTT. Pretransplant interventions may reduce post-transplant glucose alterations.

Background In living kidney transplantation there are two different individuals, a healthy donor and a renal transplant recipient. This is an excellent human model to study factors that influence kidney function in the context of reduced renal mass and the adaptation of two comparable kidneys to different metabolic demands. Methods We analyzed the changes in measured glomerular filtration rate (GFR, iohexol) from pretransplantation to 12 months after transplantation in 30 donor–recipient pairs. Each donor was compared with his/her recipient. We defined a priori three different groups based on GFR differences at 12 months: donor > recipient (Group A; 78 ± 8 versus 57 ± 8 mL/min), donor Results In Group A donors were mostly male and recipients were female (75% each). Donors had a higher baseline weight than their recipients. During follow-up, weight remained stable in donors but increased 7% in recipients. In Group B donors were mostly female (60%) and recipients male. At baseline, donors had a lower weight than recipients. At 12 months, weight was stable in donors but increased in recipients. In Group C donors were mostly (75%) female and recipients male. At baseline, donors had a higher BMI than their recipients. At 12 months, BMI was stable in donors but increased 14% in recipients. In multivariable analysis, higher GFR at 12 months was associated with higher baseline weight and GFR in donors and with male gender and higher baseline weight in recipients. Conclusions Kidneys from living donors are more ‘plastic’ than originally thought and respond to metabolic demands and weight changes of their new host. These changes should be taken into account when assessing GFR outcomes in this population.

Background Diabetes is a risk factor for cancer in the general population. However, few data are available on the association between post-transplant diabetes mellitus (PTDM) and cancer after transplantation. Methods We analyzed this issue in a Spanish cohort of patients without diabetes before transplantation. PTDM was diagnosed with consensus criteria at 12 months after transplantation and 12 months before the diagnosis of cancer. The association between PTDM and cancer (overall and specific types) was evaluated with regression analysis. Results During a follow-up of 12 years (interquartile range 8–14), 85 cases of 603 developed cancer (829/100 000/year) and 164 (27%) PTDM. The most frequent cancers were renal cell cancer (RCC) n = 15, 146/cases/100 000/year), lung (n = 12, 117/cases/100 000/year), colon (n = 9, 88/cases/100 000/year) and prostate (n = 9, 88/cases/100 000/year). In logistic regression, PTDM was not associated with cancer. Eight of the 164 patients with PTDM (4.9%) vs 7 of the 439 without PTDM developed RCC (1.6%) (P = .027). In multivariate analysis, PTDM was independently associated with RCC [odds ratio (OR) 2.92, confidence interval (CI) 1.03–8.27], adjusting for smoking (OR 4.020, 95% CI 1.34–12.02) and other covariates. PTDM was not associated with other types of cancer. Conclusions Patients with PTDM must be considered a population at risk for RCC and accordingly, the subject of active surveillance.

BackgroundReliable 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.MethodsWe 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 ResultsNinety-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.ConclusionThe 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 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.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.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%.Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.

Background The use of mycophenolic acid (MPA) in women during pregnancy causes an increase in miscarriages and birth defects with a typical embryopathy profile. Although epidemiological data does not suggest a greater risk among the offspring of male kidney transplant recipients, the European Medicines Agency and The Spanish Agency of Medicines and Medical Devices introduced the recommendation of using contraceptive methods. Methods We conducted a national retrospective study in 15 Spanish Kidney Transplant Centers to evaluate the frequency of miscarriages and birth defects between the offspring from male kidney transplants recipients. We included 151 males who had fathered 239 offspring, 225 under MPA and 14 without MPA. Results The results of our study showed an incidence of miscarriages in the MPA group of 9.8%, and of birth defects of 4%. Conclusions We observed an incidence of miscarriages between the offspring fathered by kidney transplant males under MPA lower than the general population. The incidence of birth defects was similar to the incidence described in other studies and the fact that we did not find the typical embryopathy profile makes it difficult to associate them to the use of MPA. Because of that, we urge the European and Spanish Agencies to reconsider their recommendations for males.

Background and Aims Mycophenolic acid (MPA) is one of the most used immunosuppressive drugs. It is teratogenic in women with a typical embryopathy profile. Regarding its effect on the children of male kidney transplant recipients, although clinical evidence does not indicate a greater risk of malformations, the European Medicines Agency and the Spanish Agency for Medicines and Health Products introduced in 2015 the recommendation to use contraceptive methods because of their genotoxic potential. For this reason, we propose to study the results of the Spanish Kidney Transplant Centers. Method Multicenter retrospective observational study in which 15 Kidney Transplant Centers have participated. Of 3934 men ≤ 60 years old that received a kidney transplant between 2000 and 2015, 3023 were contacted, and 159 men who fathered at least one post-transplant pregnancy (total 252 fetuses) were included. We compared the incidence of abortions and live births with malformations among those who received MPA at the time of conception vs. those who did not. Results In the 252 fetuses (characteristics in table 1) there was an exitus and no differences were detected in the incidence of abortions between the group exposed to MPA (n = 230) and the unexposed group (n = 22), 11.3% vs 18.2%, p = 0.31. Among the 221 live-born fetuses, no differences were found in congenital malformations between the group exposed to MPA (n = 203) and the unexposed (n = 18) 4.9% vs. 16.7%, p = 0.07. Among the malformations described, the typical embryopathy profile of the MPA was not found. Conclusion According to the data of this retrospective national multicenter study, the use of MPA in male kidney transplant recipients does not cause a greater number of abortions or congenital malformations. For these reasons, and given the evidence also published by other groups, it seems necessary to reevaluate the recommendation given on contraception in men treated with MPA.

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.

Prediabetes and post-transplant diabetes mellitus affect about 20-30% of renal transplant patients. The latter is a risk factor for cardiovascular disease. However, no clear evidence linking prediabetes and cardiovascular disease is available. To study this we analyzed the impact of prediabetes on cardiovascular disease in 603 renal transplant patients followed with repeated oral glucose tests for up to five years and a long term survival evaluation. Prediabetes and post-transplant diabetes mellitus were defined at 12 months after transplantation to avoid their high reversibility rate before this period. 73 cardiovascular events were observed. The incidence of events was significantly higher in patients with either prediabetes, (17%; 0.023 person/year) or post-transplant diabetes mellitus (20%; 0.028 person/year) than in normal individuals, (7%; 0.0095 person/year). The incidence of events was comparable between prediabetes and post-transplant diabetes mellitus. Prediabetes at 12 months was a risk factor for cardiovascular events in univariate and multivariate Cox survival analyses (hazard ratio 2.24, 95% confidence interval 1.11-4.52). Prediabetes at three months and hemoglobin A1c at 12 months were not significantly associated with cardiovascular disease. Thus, prediabetes is a risk factor for cardiovascular disease in renal transplantation, a population at high risk for cardiovascular events. Since prediabetes is potentially a reversible condition, there is an opportunity to prevent cardiovascular disease in this population.

Background: Prediabetes and post-transplant diabetes mellitus (PTDM) affect about 20-30% of renal transplant patients. PTDM is a risk factor for cardiovascular disease. However, no clear evidence linking prediabetes and cardiovascular disease is available. Methods: We analyzed the impact of prediabetes on cardiovascular disease in 603 renal transplant patients followed with repeated OGTTs up to 5 years and a long term survival evaluation. Findings: Prediabetes and PTDM were defined at 12 months after transplantation to avoid their high reversibility rate before this period. 73 cardiovascular events were observed. The incidence of events was higher in patients with prediabetes, 28 (17%) or PTDM 20 (20%) than in normal subjects, 25 (7%), p = 0·001 and < 0·0001, respectively. The incidence of events was comparable between prediabetes and PTDM (p = 0·27). Prediabetes at 12 months was a risk factor for cardiovascular events in univariate and multivariate COX survival analyses (HR:2·24 95% CI 1·11-4·52). Prediabetes at 3 months and HbA1c at 12 months were not significant. Interpretation: Prediabetes was a risk factor for cardiovascular disease in renal transplantation, a population at high risk for cardiovascular events. Prediabetes is a potentially reversible condition, which offers the opportunity to prevent cardiovascular disease in this population. Funding Statement: Instituto de Salud Carlos III: The authors would like to acknowledge (a) the IMBRAIN project (FP7-RE6-POT-2012-CT2012- 31637-IMBRAIN) funded under the 7th Frameworks Programme (capacities), (b) the Instituto de Salud Carlos III (Fondo de Investigacioen Sanitaria: FIS) and Fondos FEDER for the following grants: PI 07/0732, the REDINREN RD/0021/0008 and PI10/02428 and (c) the funding of the Spanish Research Network for Kidney Diseases (REDINREN RD12/0021/0008). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Ethics Committee of each hospital and followed the Declaration of Helsinki.

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 Chronic kidney disease (CKD) affects 10-13% of the population worldwide. CKD classification stratifies patients in five stages of risk for progressive renal disease based on estimated glomerular filtration rate (eGFR) by formulas and albuminuria. However, the reliability of formulas to reflect real renal function is a matter of debate. The effect of the error of formulas in the CKD classification is unclear, particularly for cystatin C-based equations. Methods We evaluated the reliability of a large number of cystatin C and/or creatinine-based formulas in the definition of the stages of CKD in 882 subjects with different clinical situations over a wide range of glomerular filtration rates (GFRs) (4.2-173.7 mL/min). Results Misclassification was a constant for all 61 formulas evaluated and averaged 50% for creatinine-based and 35% for cystatin C-based equations. Most of the cases were misclassified as one stage higher or lower. However, in 10% of the subjects, one stage was skipped and patients were classified two stages above or below their real stage. No clinically relevant improvement was observed with cystatin C-based formulas compared with those based on creatinine. Conclusions The error in the classification of CKD stages by formulas was extremely common. Our study questions the reliability of both cystatin C and creatinine-based formulas to correctly classify CKD stages. Thus the correct classification of CKD stages based on estimated GFR is a matter of chance. This is a strong limitation in evaluating the severity of renal disease, the risk for progression and the evolution of renal dysfunction over time.

BACKGROUND The long-term clinical evolution of prediabetes and post-transplant diabetes mellitus (PTDM) is unknown. METHODS We analysed, in this cohort study, the reversibility, stability and progression of PTDM and prediabetes in 672 patients using repeated oral glucose tolerance tests (OGTTs) for ≤5 years. RESULTS Most patients were on tacrolimus, steroids and mycophenolate. About half developed either PTDM or prediabetes. The incidence of PTDM was 32% and bimodal: early PTDM (≤3 months) and late PTDM. Early PTDM reverted in 31%; late PTDM developed in patients with post-transplant prediabetes. The use of OGTTs was necessary to detect around half of PTDM. Pretransplant obesity was a major risk factor for early PTDM, for its persistence and for late PTDM {odds ratio [OR] 1.18 [95% confidence interval (CI) 1.09-1.28]}. At 3 months, higher HbA1c promoted [OR 2.37 (95% CI 1.38-4.06)], while insulin sensitivity protected against [OR 0.64 (95% CI 0.48-0.86)] late PTDM. At 3 months, 28% had prediabetes; of these, 36% remained stable, 43% normalized and 21% developed late PTDM. Pretransplant obesity [OR 1.20 (95% CI 1.04-1.39)] and higher HbA1c [OR 3.80 (95% CI 1.45-9.94)] at 3 months promoted while insulin sensitivity protected against [OR 0.57 (95% CI 0.34-0.95)] evolution from prediabetes to late PTDM. Immunosuppressive levels or acute rejection did not influence PTDM. Most (84%) of the patients with normal tests at 3 months remained stable without evolving into PTDM; 14% developed prediabetes. CONCLUSIONS PTDM and prediabetes are very common in renal transplantation. Classic metabolic factors like obesity, prediabetes and insulin resistance promote the evolution of PTDM and prediabetes. Patients with normal glucose metabolism rarely develop PTDM. OGTT is necessary to detect PTDM and prediabetes and thus should be included in clinical practice.

Lipid abnormalities may contribute to chronic allograft nephropathy (CAN). Apolipoprotein E (ApoE) gene polymorphism regulates lipoprotein metabolism, but little is known about an association between CAN and this polymorphism. The ApoE gene (E3/E4) polymorphism was typed by PCR assay (99 E3/E3, 28 E3/E4, 1 E4/E4) on 128 consecutive renal transplant patients with functioning grafts for more than 3 years (6.7 ± 2.8 years). Twenty-eight patients with histological CAN were compared with 100 patients who had no clinical evidence of chronic rejection (no proteinuria and sCr < 2.5 mg%). As expected, univariate analysis revealed that patients with CAN experienced a greater acute rejection rate (78% vs 21%; P = .001), a higher serum creatinine (3.6 ± 1.7 vs 1.4 ± 0.5 mg%; P = .0001), and an older organ donor (43 ± 20 vs 29 ± 13 years; P = .0001). The lipid profiles (total cholesterol and triglycerides levels) were similar in both groups with 60% in each group receiving anti-lipemic drugs. Interestingly, the ApoE epsilon 4 allele was overrepresented in the group with CAN (39% vs 17%, P = .019). Logistic regression analysis showed that the epsilon 4 allele was an independent predictor of CAN (OR: 3.4; CI 95%: 1.07 to 11; P = .040) as were donor age and acute rejection episodes. In conclusion, an interaction between risk factors and genetic factors may determine CAN in this population. This finding may help to target prophylactic interventions in these recipients.

Clinical impact of preexisting vascular calcifications on mortality after renal transplantation. Background Vascular calcifications (VC) are a well-known cardiovascular risk factor (CVRF) in uremic patients. However, their role on mortality after renal transplantation (RT) is unclear. Methods In 1117 RT recipients, we investigated the association between long-term survival and the presence of VC, evaluated by preoperative posteroanterior plain radiography from aorto-iliac region, at the time of RT. The primary study outcome was all-cause mortality. Other perioperative CVRF were also collected. Results VC were observed in 273 patients (24.4%) before RT; additionally, 132 (12%) patients died during follow-up, due, mainly, to cardiovascular (39%) or infectious (24%) complications. As expected, patients with VC showed a higher age and a greater number of CVRF than those without VC. Overall mortality rate was also higher in VC group (19 vs. 9.5%; P = 0.0001), as well as cardiovascular mortality (9.5 vs. 3.1; P = 0.048). Multivariate Cox model showed that VC were predictor of overall mortality [relative risk (RR) 1.8; 95% CI 1.1–2.8; P = 0.015] and cardiovascular mortality (RR 2.6; 95%CI 1.1–6); P = 0.033), independently of other CVRF. An interaction between the presence of VC and diabetes was found. The effect of VC on mortality was evident in nondiabetic patients, that is, those with VC had a significantly higher mortality rate than patients without VC (21 vs. 9%; P = 0.0001). By contrast, these differences were not observed in diabetic patients (16.5 vs. 14.3%; P = 0.656). Conclusion VC evaluated by a simple and inexpensive plain radiography are an independent predictor of cardiovascular and all-cause mortality following RT. This finding may encourage the implementation of appropriate therapeutic strategies after RT.

Background. Prognostic indices that estimate long-term mortality are essential not only to compare different clinical studies and populations but also to perform the most appropriate therapeutic interventions. All-cause mortality is high after renal transplantation (RTx), but no prognostic index has focused on predicting mortality in RTx. We developed and tested a prognostic index for mortality in RTx after hospitalization. Methods. We retrospectively analyzed survival in 1,293 RTx recipients who were randomly assigned to two groups: a modeling population (n=646), used to create the new index, and a testing population (n=647), used to test this index. Patients were stratified into three risk groups (low, medium, and high) by combining peritransplant risk factors for mortality (β-coefficient), using a simple eight-point check list: age, pretransplant cardiovascular disease, renal dysfunction at discharge, cardiac hypertrophy, vascular calcification, diabetes, time on dialysis, and acute tubular necrosis. Results. Overall lower survival rates were observed with increasing risk classes in the testing population (log-rank test=18; P=0.0001). The 8-year survival rates ranged from 94% in the lowest-risk group to 59% in the highest-risk group. The area under the receiver operating characteristic curve was 0.63. Mortality risk (Cox analysis) significantly increased with increasing risk classes (medium risk: relative risk=3.8, 95% confidence interval=1.5–9.5, P=0.004; high risk: relative risk=6.3, 95% confidence interval=2.4–16.2, P=0.0001). Conclusions. This simple prognostic index applicable at the bedside may accurately predict survival in RTx recipients after discharge. Consequently, targeted treatment interventions may be indicated for minimizing mortality, especially in high-risk groups.