Sirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy.

All patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified.

Successful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure.

eGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.

Proteinuria is common in kidney transplant recipients and has been established as a risk factor for graft-loss and mortality. In the general population, proteinuria has also been tied to a higher risk of cardiovascular disease. There is limited data exploring the association between changes in proteinuria over time and cardiovascular disease in kidney transplant recipients.

In this retrospective cohort study we evaluated proteinuria as a time-varying covariate using urine dipstick protein values at 6 month intervals post-transplant. The primary outcome was the occurrence a major cardiovascular event (MACE). Univariate and multivariate time varying Cox model was used.

579 patients were included in the final cohort. 120 episodes of MACE were documented in 98 patients. Time varying proteinuria was associated with MACE by univariate and multivariate analysis (HR 2.63, 95% CI 1.76-3.93, p < 0.001) and (HR 2.33, 95% CI 1.53-3.54, p < 0.001). Reduction of proteinuria to normal was associated with reduced risk of MACE compared with active proteinuria (HR 0.44, 95% CI 0.28-0.69, p < 0.001) and (HR 0.47, 95% CI 0.3-0.76, p = 0.002) for univariate and multivariate analyses. Exposure to proteinuria for more than 1 year was significantly associated with an increased risk of MACE for univariate and multivariate analysis (HR 2.33, 95% CI 1.48-3.68, p < 0.001) and (HR 2.18, 95% CI 1.37-3.45, p = 0.002) respectively, in comparison to exposure of less than 1 year.

These findings may suggest that we should consider applying clinical interventions that are known to reduce cardiovascular morbidity in these patients.

24-hour proteinuria (24h-P) has been the most widespread test for clinical follow-up of proteinuria after kidney transplantation (KT), but urine collection is often not properly collected. Spot protein-creatinine ratio (P/Cr) has become the alternative to 24h-P for proteinuria evaluation in many KT units. However, its reliability, equivalence to 24h-P, and prognostic value regarding allograft outcome remain unknown. Therefore, the aim of this study was to evaluate the correlation and agreement between both methods for assessing proteinuria and to analyze which of them is a better predictor of graft survival.

We collected proteinuria measurements from KT patients in our center. 24h-P was adjusted for body surface area. Pearson correlation test and the Bland-Altman method were used to analyze correlation and agreement. Survival analysis was performed with the use of the Kaplan-Meier method and multivariate Cox proportional hazard model.

A total of 8,549 urine samples were analyzed from 472 patients in whom 24h-P and P/Cr were simultaneously measured. A significant correlation was observed between 24h-P and P/Cr (r = .76; P < .001); however, the agreement between methods showed that P/Cr overestimated proteinuria compared with 24h-P, particularly when the latter was >1 g/24 h. The Cox regression multivariate model showed an increased risk of graft loss associated with proteinuria when assessed by either 24h-P (hazard ratio [HR] 6.53, 95% confidence interval [CI] 2.49-17.1) or P/Cr (HR 3.34, 95% CI 1.04-10.7).

P/Cr is an method interchangeable with 24h-P for detecting proteinuria after KT. When proteinuria increases, the P/Cr overestimates 24h-P, even though it also has a significant and similar prognostic value for predicting graft survival.

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for-cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression.

Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients (RTRs) remain at an increased risk of fatal and non-fatal cardiovascular (CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease (CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Non-traditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.

Recent studies have demonstrated a relationship between low-grade proteinuria and worse graft survival, but this has not been fully studied in expanded criteria donor (ECD) kidney transplant recipients.

The aim of this study was to assess whether the combination of early low-grade proteinuria (<1 g/d) and allograft dysfunction at the third month post-transplantation predicts outcomes in terms of survival in ECD kidney transplant recipients.

We studied a cohort of 269 ECD kidney transplant recipients subdivided into 4 groups according to clinically relevant proteinuria (300 mg/d) and median creatinine (Cr; 1.7 mg/dL; interquartile range, 1.4-2.1 mg/dL) at the third month post-transplantation: Group A (Cr <1.7 mg/dL and proteinuria <300 mg/24 h; n = 97), Group B (Cr <1.7 mg/dL and proteinuria ≥300 mg/24 h; n = 38), Group C (Cr ≥1.7 mg/dL and proteinuria <300 mg/24 h; n = 79), and Group D (Cr ≥1.7 mg/dL and proteinuria ≥300 mg/24 h; n = 55).

Death-censored graft survival was significantly lower in Group D compared with the rest (P < .007). Multivariate Cox regression analysis using fixed covariates showed that the combination of low-grade proteinuria and a lower estimated glomerular filtration rate (eGFR) as associated with graft failure (hazard rate [HR] 2.5, 95% confidence interval [CI], 1.09-5.97; P = .03).

The early association of low-grade proteinuria and allograft dysfunction represents an important risk factor for graft loss in ECD kidney transplant recipients. Strategies to optimize renal function could improve the outcome in this specific population.