Early Pulse Pressure and Low-Grade Proteinuria as Independent Long-Term Risk Factors for New-Onset Diabetes Mellitus After Kidney Transplantation

Risk factors for new-onset diabetes after transplantation (NODAT) need to be assessed in large cohorts.
We retrospectively evaluated the impact of early (3 and 6 months after transplantation) proteinuria, urinary albumin excretion (UAE) and arterial pressure on NODAT in 828 Causasian renal transplant recipients (median follow-up: 5.3 years; 5832 patient-years).
The 10- and 20-year incidence of NODAT was 15.0% and 22.0%, respectively. Low-grade (<1 g/day) (HR: 2.04 [1.25–3.33], p = 0.0042) and very low-grade (<0.3 g/day) (HR: 2.21 [1.32–3.70], p = 0.0025) proteinuria were independent risk factors for NODAT. There was a dose-dependent relationship across UAE categories (increasing risk from normoalbuminuria to macroalbuminuria) with NODAT. Tacrolimus, sirolimus and beta-blockers (HR: 1.86 [1.07–3.22], p = 0.0277) were significantly associated with NODAT even after multiple adjustments, but not diuretics, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Systolic arterial pressure (HR per 10 mmHg: 1.16 [1.03–1.29], p = 0.0126) and pulse pressure (HR: 1.26 [1.12–1.43], p = 0.0002) were associated with NODAT. Only pulse pressure remained significant after adjustments. Patients at highest risks had early proteinuria and pulse pressure >60 mmHg.
Early low-grade proteinuria and pulse pressure (in addition to beta-blockers) constitute independent risk factors for NODAT; they may be markers of the metabolic syndrome and/or vascular damage in renal transplant recipients.     

Proteinuria After Kidney Transplantation, Relationship to Allograft Histology and Survival

Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria >150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In >84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria >1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p < 0.0001) and higher protein excretion (378 + 997 vs. 955 + 1986 mg/day, p < 0.0001). Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria >500. Thus, proteinuria, usually at low levels (<500 mg/day), is present in 45% of recipients at 1 year. However, and even low levels of proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.     

Twenty Years of Renal Transplantation in Children

Two hundred and sixty–eight renal transplant operations were done in 244 children over the past 20 years. The donors were parents in 229 cases, living relatives in another 1 3 eases, and cadavers in the remaining 26 cases. There were 242 first grafts, 22 second grafts, and 4 third grafts. The initial 130 grafts were carried out with conventional immunosuppressive regimens and the subsequent 1 38 were done using immunosuppression including cyclosporin–A. In lanuary 19′)5, 186 recipients (76.2%) were alive with functioning grafts, 33 (1 3.5%) were alive on dialyses, and 25 (10.2%) were dead. The management results in terms of patient and graft survival, as well as the causes of graft failure and patient death are described.     

Respective Predictive Role of Urinary Albumin Excretion and Nonalbumin Proteinuria on Graft Loss and Death in Renal Transplant Recipients

Proteinuria is constituted by urinary albumin (UAE) and nonalbumin proteins (NAP). UAE was shown to predict ESRD and death. Whether NAP predicts graft or patient outcome is unknown in renal transplantation. We retrospectively analyzed the impact of UAE and NAP respectively on end-stage renal disease (ESRD) and death in 616 renal transplant recipients. In subjects with proteinuria <0.25 g/day, 76% of urine proteins were NAP; in those with >1 g/day, 44% of the urine proteins were NAP. Determinants of UAE and NAP were partly different: fasting glucose, body weight, donor cause of death and cyclosporine were significantly associated with NAP (but not UAE); panel reactive antibodies (PRA) and rapamycine were significantly associated with UAE (but not with NAP). NAP expressed as a continuous (HR: per g/day: 4.00 [2.85-5.63], p < 0.0001) or a categorical (presence vs. absence, HR = 29.09[8.80-96.20], p < 0.0001) parameter and UAE (per g/day, HR = 1.86 [1.24-2.78], p < 0.0001) were risk factors for graft loss in univariate analyses. NAP remained significant even after adjustment on UAE. The presence of NAP (HR: 5.37 [2.55-11.34], p < 0.0001) and macroalbuminuria (HR: 4.12 [1.65-10.29], p = 0.0024) were risk factors for death. Proteinuria is made of various proportions of UAE and NAP in renal transplantation; these two parameters provide different information on graft/patient survival.     

Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study

Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3–1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0–3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis.     

Rapid Resolution of Proteinuria of Native Kidney Origin Following Live Donor Renal Transplantation

To assess the contribution of the protein content of urine from the native kidneys to post-transplant proteinuria, we prospectively studied 14 live donor transplant recipients with a pre-transplant random urine protein to creatinine ratio (UPr:Cr) >0.5. Seven patients received preemptive transplants, and seven patients were on dialysis pre-transplant (with residual urine output). Resolution of proteinuria was defined as UPr:Cr < 0.2. Immunosuppression consisted of tacrolimus, mycophenolate mofetil and corticosteroids. Anti-hypertensive drugs that might reduce proteinuria were avoided during the study. The serum creatinine was 8.7 +/- 0.7 mg/dL pre-transplant, and the nadir post-transplant serum creatinine was 1.4 +/- 0.1 mg/dL. The pre-transplant UPr:Cr ranged between 0.5 and 9.2 (mean = 2.9 +/- 0.6). The UPr:Cr decreased to <0.2 in all 14 patients at a mean of 4.5 weeks post-transplant (range 1-10 weeks). In conclusion, in live donor renal transplant recipients with immediate graft function, proteinuria of native kidney origin resolves in the early post-transplant period. After the immediate post-transplant period, proteinuria cannot be attributed to the native kidneys, and work up for proteinuria should focus on the allograft.     

Obesity is Associated with Worsening Cardiovascular Risk Factor Profiles and Proteinuria Progression in Renal Transplant Recipients

Obesity is associated with adverse cardiovascular (CV) parameters and may be involved in the pathogenesis of allograft dysfunction in renal transplant recipients (RTR). We sought the spectrum of body mass index (BMI) and the relationships between BMI, CV parameters and allograft function in prevalent RTR. Data were collected at baseline and 2 years on 90 RTR (mean age 51 years, 53% male, median transplant duration 7 years), categorized by BMI (normal, BMI < or = 24.9 kg/m2; pre-obese, BMI 25-29.9 kg/m2; obese, BMI > or = 30 kg/m2). Proteinuria and glomerular filtration rate (eGFR(MDRD)) were determined. Nine percent RTR were obese pre-transplantation compared to 30% at baseline (p < 0.001) and follow-up (25 +/- 2 months). As BMI increased, prevalence of metabolic syndrome and central obesity increased (12 vs 48 vs 85%, p < 0.001 and 3 vs 42 vs 96%, p < 0.001, respectively). Systolic blood pressure, fasting blood glucose and lipid parameters changed significantly with BMI category and over time. Proteinuria progression occurred in 65% obese RTR (23 (13-59 g/mol creatinine) to 59 (25-120 g/mol creatinine)). BMI was independently associated with proteinuria progression (beta 0.01, p = 0.008) but not with changing eGFR(MDRD.) In conclusion, obesity is common in RTR and is associated with worsening CV parameters and proteinuria progression.     

Development of Proteinuria After Switch to Sirolimus-Based Immunosuppression in Long-Term Cardiac Transplant Patients

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil ± steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0–5.7) preswitch to 0.23 g/day (0–9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.     

Improved Long-Term Outcomes After Renal Transplantation Associated with Blood Pressure Control

Hypertension has a negative impact on long-term outcomes after renal transplantation. We investigated the effect of a recent decline in blood pressure among renal transplant patients in the Collaborative Transplant Study (CTS) database on long-term graft and patient survival. CTS data were used to evaluate transplant outcomes in relation to recipient systolic blood pressure (SBP) for 24,404 first cadaver kidney recipients transplanted between 1987 and 2000. Patients whose SBP was > 140 mmHg at 1 year posttransplantation but controlled to < or = 140 mmHg by 3 years had significantly improved long-term graft outcome compared with patients with sustained high SBP to 3 years (RR 0.79; CI 0.73-0.86; p < 0.001). Additional examination at 5 years showed that SBP lowering after year 3 was associated with improved 10-year graft survival (RR 0.83; CI 0.72-0.96; p = 0.01), whereas even a temporary increase in SBP at 3 years was associated with worse survival (RR 1.37; CI 1.19-1.58; p < 0.001). Changes in SBP were paralleled by changes in the incidence of cardiovascular death among recipients younger than 50 but not in older recipients. Lowering SBP, even after several years of posttransplantation hypertension, is associated with improved graft and patient survival in renal allograft recipients.     

Early Graft Loss After Kidney Transplantation: Risk Factors and Consequences

Early graft loss (EGL) after kidney transplantation is a catastrophic outcome that is assumed to be more likely after the use of kidneys from suboptimal donors. We therefore examined its incidence, risk factors and consequences in our center in relation to different donor types. Of 801 recipients who received a kidney‐only transplant from deceased donors, 50 (6.2%) suffered EGL within 30 days of transplantation. Significant risks factors for EGL were donation after circulatory death (DCD) (odds ratio [OR] 2.88; p = 0.006), expanded criteria donor (ECD) transplantation (OR 4.22; p = 0.010), donor age (OR 1.03; p = 0.044) and recipient past history of thrombosis (OR 4.91; p = 0.001). Recipients with EGL had 12.28 times increased risk of death within the first year, but long‐term survival was worse for patients remaining on the waiting list. In comparison with patients on the waiting list but not transplanted, and with all patients on the waiting list, the risk of death after EGL decreased to baseline 4 and 23 months after transplantation, respectively. Our findings suggest that DCD and ECD transplantation are significant risk factors for EGL, which is a major risk factor for recipient death. However, long‐term mortality is even greater for those remaining on the waiting list.     

Effect of Donor Factors on Early Graft Survival in Adult Cadaveric Renal Transplantation

Previous studies of the effect of donor factors on renal transplant outcomes have not tested the role of recipient body mass index, donor/recipient weight ratios and age matching, and other factors. We analyzed 20,309 adult (age 16 or older) recipients having solitary cadaveric renal transplants from adult donors from 1 July 1994 to 30 June 1998 in an historical cohort study (the 2000 United States Renal Data System) of death censored graft loss by the Cox proportional hazards models, which corrected for characteristics thought to affect outcomes. The only independently significant findings in Cox Regression analysis were a high donor/ recipient age ratio (> or = 1.10, e.g. a 55-year-old donor given to a recipient age 50years or younger, adjusted hazard ratio (AHR) 3.22, 95% confidence interval (CI) 2.36-4.39) and African American donor kidneys (AHR 1.64, 95% CI, 1.24-2.17). African American recipients and older donors were not at independently increased risk of graft failure in this model. Among donor factors, older donor kidneys given to younger recipients and donor African American kidneys were independently associated with graft loss in recipients of cadaver kidneys. The task for the transplant community should be to find the best means for managing all donor organs without discouraging organ donation.     

Early Assessment of Renal Resistance Index and Long-Term Renal Function in Renal Transplant Recipients

Background. The effect of the intrarenal arterial resistance index (RI) on long-term renal functions is not well known. We examined the predictive value of intrarenal RI on long-term allograft outcomes. Methods. We retrospectively investigated 121 stable renal transplant recipients, followed for a mean of 63.21?±?19.9 months after renal transplant. Patients with complications during the first six months after transplant were not included. Color Doppler ultrasonography was done to calculate the intrarenal RI within the first four weeks after transplant. Results. Older recipient age, high pulse pressure, active smoking, and proteinuria were associated with a higher intrarenal RI. Multivariate analyses revealed that renal RI and donor age were independent predictors of allograft outcome. Kaplan-Meier estimates of cumulative graft survival were significantly worse in patients who had an RI of 0.7 or more than they were in patients who had an RI of less than 0.7 (p?=?.005). Development of chronic allograft nephropathy (CAN) was significantly higher in patients who had an RI of 0.7 or more (p?=?.02). Conclusions. Renal RI determined within the first month after renal transplant predicts long-term allograft function and development of CAN in renal transplant recipients.     

Renal transplantation in Slovenia after joining Eurotransplant.

BACKGROUND: This report presents data on renal transplantation in Slovenia before and after joining Eurotransplant (ET). METHODS: Slovenia (population: 2 million) has one renal transplant centre. The establishment of an appropriate national transplantation organization resulted in an increase in transplantations and the acceptance of Slovenia into ET at the beginning of 2000. Current immunosuppression is composed of cyclosporin (Neoral), mycophenolate mofetil, methylprednisolone and anti-interleukin-2 receptor monoclonal antibodies. RESULTS: By the end of 2004, 607 renal transplantations had been performed. From 1970 to 1998, 124 patients were given living related donor kidneys. From 1986 to 1999, 239 patients received renal grafts from deceased donors. From 2000 to 2004, 244 patients were transplanted from deceased donors. In 2004, 55 renal transplantations were carried out. One hundred and forty one (57.8%) renal grafts were shipped from other ET countries. The HLA-antigen mismatch of 2.8+/-1.1 was not significantly different from what it was before 2000. Up to 31 December 2004, the 1- and 3-year patient survival rates were 98.3% and 96.0%, respectively. The concomitant graft survival rates were 95.8% and 93.5%, respectively. CONCLUSIONS: In the ET era, the number of deceased donor renal transplants per year was 2.8 times higher than in the 14 years before. In 2004, we reached the average number of deceased donor renal transplants per million population of ET. Although tissue compatibility in these recipients was not significantly better than it was before the ET era, it would have been much worse had we not joined ET. Short- and medium-term results in the ET era have been entirely comparable to those in large reports.     

Improvement in Long-Term Renal Graft Survival due to CMV Prophylaxis with Oral Ganciclovir: Results of a Randomized Clinical Trial

Oral ganciclovir prophylaxis and intravenous preemptive therapy are competitive approaches to prevent cytomegalovirus (CMV) disease after renal transplantation. This trial compared efficacy, safety and long-term graft outcome in 148 renal graft recipients randomized to ganciclovir prophylaxis (N = 74) or preemptive therapy (N = 74). Hierarchical testing revealed (i) patients with CMV infection had more severe periods of impaired graft function (creatinine clearance_max-min 25.0 ± 14.2 mL/min vs. 18.1 ± 12.5 mL/min for patients without CMV infection; p = 0.02),(ii) prophylaxis reduced CMV infection by 65% (13 vs. 33 patients; p < 0.0001) but (iii) creatinine clearance at 12 months was comparable for both regimes (54.0 ± 24.9 vs. 53.1 ± 23.7 mL/min; p = 0.92). No major safety issues were observed, and patient survival at 12 months was similar in both groups (5 deaths [6.8%] vs. 4 [5.4%], p = 1.0000). Prophylaxis significantly increased long-term graft survival 4 years posttransplant (92.2% vs. 78.3%; p = 0.0425) with a number needed to treat of 7.19. Patients with donor +/recipient + CMV serostatus had the lowest rate of graft loss following prophylaxis (0.0% vs. 26.8%; p = 0.0035). In conclusion, it appears that routine oral prophylaxis may improve long-term graft survival for most renal transplant patients. Preemptive therapy can be considered in low risk patients in combination with adequate CMV monitoring.     

维持循环系统稳定性对肾移植的重要意义

本文报告肾移植57例。就末次血透时间对肾移植术中及术后早期血压的影响、血压波动范围与移植肾尿量及肌酐恢复的关系作了统计分析。结果表明:术前24h内加强透析的患者,术中及术后血压稳定,生命体征易管理,开放血流后绝大多数移植肾立即泌尿,术后ATN发生率低,透析次数少,肾功恢复恢。血压波动≤4kPa,对移植肾泌尿及其功能恢复有益。血压波动≥5kPa,ATN发生率高,肾功恢复慢,透析过程长。此外,本文就如何保持循环系统稳定性的具体措施作了介绍。强调术中止血彻底是保持血压稳定性之关键。     

The Effect of Everolimus Versus Mycophenolate Upon Proteinuria Following Kidney Transplant and Relationship to Graft Outcomes

Although mTOR inhibitor use has been associated with proteinuria in kidney transplant recipients, dose dependency and impact on allograft function are unknown. In a post hoc analysis, we compared rates of proteinuria 3 months posttransplant among everolimus (EVR) and mycophenolate (MPA) treatment arms and used a time‐dependent model to correlate the risk of proteinuria to EVR trough levels up to 24 months posttransplant. eGFR and graft loss was compared by proteinuria status at 3 months. Of 833 randomized patients, 24%, 36% and 19% of lower exposure EVR (1.5 mg/day), higher exposure EVR (3.0 mg/day) and MPA‐treated patients had proteinuria ≥ 300 mg/g Cr at 3 months, respectively. EVR 1.5 was not associated with an increase in risk of proteinuria (HR 1.20; p = 0.19) unlike EVR 3.0 (HR 1.84; p < 0.001) versus MPA. EVR trough levels >8 ng/mL were significantly associated with proteinuria compared to 3–8 ng/mL (HR 1.86; p < 0.001). Those patients with proteinuria at 3 months and those who developed proteinuria thereafter had lower eGFR and higher graft loss at 24 months, regardless of treatment arm. We identify a dose‐dependent effect of EVR with the risk of proteinuria; however, its independent impact upon eGFR and graft survival at 2 years was not evident.     

Renal transplantation outcomes: a comparative analysis between elderly and younger recipients

Renal transplantation is presently the best treatment for end-stage renal disease, although considered contraindicated for elderly patients. However, more investigation is needed due to higher life expectancy rates of the general population and the increasing number of over 60-yr-old patients with chronic renal failure dependent upon dialysis. This study aims to determine graft and patient survival rates of renal transplant patients 60 yr and older compared to a younger group (50-59 yr old). Relevant pre- and post-transplant clinical data related to graft and patient survival in both groups were also investigated. Three-hundred and twenty consecutive renal transplant patients were enrolled in this study and grouped based on age at the time of the transplantation: one-hundred and ten patients at or over 60 yr old (elderly group) and 210 patients ranging from 50 to 59 yr old (younger group). There were no statistical differences in either group regarding clinical characteristics and immunological risk factors. The incidence of acute rejection was higher in the younger group (37.6%) than in the elderly (22.7%) (p = 0.01). Censored to death graft survivals at five yr were respectively 86.7% for patients > or = 60 yr and 82.1% for patients 50-59 yr old (p = 0.49). Patient survival rates at five yr were respectively 76.2% for patients > or = 60 yr and 81.6% for patients 50-59 yr old (p = 0.33). Our data show that renal transplantation for elderly patients has similar results to those found in younger individuals, which does not make age, in and of itself, a contraindication for transplantation.