Jesse D. Schold

Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.

Acute rejection is known to have a strong impact on graft survival. Many studies suggest that very low acute rejection rates can be achieved with current immunosuppressive protocols. We wanted to investigate how acute rejection rates have evolved on a national level in the U.S. and how this has impacted graft survival in the most recent era of kidney transplantation. For this purpose, we analyzed data provided by the Scientific Registry of Transplant Recipients regarding all adult first renal transplants between 1995 and 2000.

Long‐Term Renal Allograft Survival: Have we Made Significant Progress or is it Time to Rethink our Analytic and Therapeutic Strategies?

Impressive renal allograft survival improvement between 1988 and 1995 has been described using projections of half‐lives based on limited actual follow up. We aimed, now with sufficient follow up available to calculate real half‐lives.

Acute Kidney Injury Is Associated With Increased Long-Term Mortality After Cardiothoracic Surgery

Background— Long-term survival after acute kidney injury (AKI) is poorly studied. We report the relationship between long-term mortality and AKI with small changes in serum creatinine during hospitalization after various cardiothoracic surgery procedures. Methods and Results— This was a retrospective study of 2973 patients with no history of chronic kidney disease who were discharged from the hospital after cardiothoracic surgery between 1992 and 2002. AKI was defined by the RIFLE classification (Risk, Injury, Failure, Loss, and End stage), which requires at least a 50% increase in serum creatinine and stratifies patients into 3 grades of AKI: Risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed with a risk-adjusted Cox proportional hazards regression model. Survival was worse among patients with AKI and was proportional to its severity, with an adjusted hazard ratio of 1.23 (95% CI 1.06 to 1.42) for the least severe RIFLE risk class and 2.14 (95% CI 1.73 to 2.66) for the RIFLE failure class compared with patients without AKI. Survival was worse among all subgroups of cardiothoracic surgery with AKI except for valve surgery. Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.28 (95% CI 1.11 to 1.48) compared with patients without AKI. Conclusions— The risk of death associated with AKI after cardiothoracic surgery remains high for 10 years regardless of other risk factors, even for those patients with complete renal recovery. Improved renal protection and closer postdischarge follow-up of renal function may be warranted.

Long-term risk of mortality and acute kidney injury during hospitalization after major surgery.

Objective:To determine the relationship between long-term mortality and acute kidney injury (AKI) during hospitalization after major surgery. Summary Background Data:AKI is associated with a risk of short-term mortality that is proportional to its severity; however the long-term survival of patients with AKI is poorly studied. Methods:This is a retrospective cohort study of 10,518 patients with no history of chronic kidney disease who were discharged after a major surgery between 1992 and 2002. AKI was defined by the RIFLE (Risk, Injury, Failure, Loss, and End-stage Kidney) classification, which requires at least a 50% increase in serum creatinine (sCr) and stratifies patients into 3 severity stages: risk, injury, and failure. Patient survival was determined through the National Social Security Death Index. Long-term survival was analyzed using a risk-adjusted Cox proportional hazards regression model. Results:In the risk-adjusted model, survival was worse among patients with AKI and was proportional to its severity with an adjusted hazard ratio of 1.18 (95% confidence interval [CI], 1.08–1.29) for the RIFLE-Risk class and 1.57 (95% CI, 1.40–1.75) for the RIFLE-Failure class, compared with patients without AKI (P < 0.001). Patients with complete renal recovery after AKI still had an increased adjusted hazard ratio for death of 1.20 (95% CI, 1.10–1.31) compared with patients without AKI (P < 0.001). Conclusions:In a large single-center cohort of patients discharged after major surgery, AKI with even small changes in sCr level during hospitalization was associated with an independent long-term risk of death.

Kidney Transplantation Halts Cardiovascular Disease Progression in Patients with End-Stage Renal Disease

Morbidity and mortality from cardiovascular disease have a devastating impact on patients with chronic kidney disease (CKD) and end‐stage renal disease. Renal function decline in itself is thought to be a strong risk factor for cardiovascular disease (CVD). In this study, we investigated the hypothesis that the elevated CV mortality in kidney transplant patients is due to the preexisting CVD burden and that restoring renal function by a kidney transplant might over time lower the risk for CVD. We analyzed 60 141 first‐kidney‐transplant patients registered in the USRDS from 1995 to 2000 for the primary endpoint of cardiac death by transplant vintage and compared these rates to all 66813 adult kidney wait listed patients by wait listing vintage, covering the same time period. The CVD rates peaked during the first 3 months following transplantation and decreased subsequently by transplant vintage when censoring for transplant loss. This trend could be shown in living and deceased donor transplants and even in patients with end‐stage renal disease secondary to diabetes. In contrast, the CVD rates on the transplant waiting list increased sharply and progressively by wait listing vintage. Despite the many mechanisms that may be in play, the enduring theme underlying rapid progression of atherosclerosis and cardiovascular disease in renal failure is the loss of renal function. The data presented in this paper thus suggest that the development or progression of these lesions could be ameliorated by restoring renal function with a transplant.

Vitamin D Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Observational Studies and Randomized Controlled Trials

BACKGROUND AND OBJECTIVES Vitamin D deficiency is highly prevalent among patients with chronic kidney disease (CKD). The benefits and harms of vitamin D supplementation (ergocalciferol or cholecalciferol) were assessed in patients with nondialysis-dependent CKD, dialysis-dependent CKD, and renal transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS MEDLINE (1966 to September 2009), SCOPUS (September 2009), and nephrology conference proceedings were searched for relevant observational and randomized controlled trials (RCTs). Treatment effects were summarized as mean differences (MDs) with 95% confidence intervals (CIs) using a random effects model. Separate analyses were conducted for observational studies and RCTs. RESULTS Twenty-two studies (17 observational and 5 RCTs) were included. There was a significant improvement in 25-hydroxyvitamin D (MD 24.1 ng/ml, 95% CI 19.6 to 28.6) and an associated decline in parathyroid hormone (PTH) levels (MD -41.7 pg/ml, 95% CI -55.8 to -27.7) among observational studies. PTH reduction was higher in dialysis patients. Among RCTs, there was a significant improvement in 25-hydroxyvitamin D (MD 14 ng/ml, 95% CI 5.6 to 22.4) and an associated decline in PTH levels (MD -31.5 pg/ml, 95% CI -57 to -6.1). A low incidence of hypercalcemia and hyperphosphatemia was reported with vitamin D supplementation. Cardiovascular and skeletal effects of vitamin D supplementation have not been studied. Included studies were mostly of low to moderate quality. CONCLUSIONS Available evidence from low-to-moderate quality observational studies and fewer RCTs suggests that vitamin D supplementation improves biochemical endpoints. However, whether such improvements translate into clinically significant outcomes is yet to be determined.

Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response

Background:Excessive fructose intake causes metabolic syndrome in animals and can be partially prevented by lowering the uric acid level. We tested the hypothesis that fructose might induce features of metabolic syndrome in adult men and whether this is protected by allopurinol.Methods:A randomized, controlled trial of 74 adult men who were administered 200 g fructose daily for 2 weeks with or without allopurinol. Primary measures included changes in ambulatory blood pressure (BP), fasting lipids, glucose and insulin, homeostatic model assessment (HOMA) index, body mass index and criteria for metabolic syndrome.Results:The ingestion of fructose resulted in an increase in ambulatory BP (7±2 and 5±2 mm Hg for systolic (SBP) and diastolic BP (DBP), P<0.004 and P<0.007, respectively). Mean fasting triglycerides increased by 0.62±0.23 mmol l−1 (55±20 mg per 100 ml), whereas high-density lipoprotein cholesterol decreased by 0.06±0.02 mmol l−1 (2.5±0.7 mg per 100 ml), P<0.002 and P<0.001, respectively. Fasting insulin and HOMA indices increased significantly, whereas plasma glucose level did not change. All liver function tests showed an increase in values. The metabolic syndrome increased by 25–33% depending on the criteria. Allopurinol lowered the serum uric acid level (P<0.0001) and prevented the increase in 24-h ambulatory DBP and daytime SBP and DBP. Allopurinol treatment did not reduce HOMA or fasting plasma triglyceride levels, but lowered low-density lipoprotein cholesterol relative to control (P<0.02) and also prevented the increase in newly diagnosed metabolic syndrome (0–2%, P=0.009).Conclusions:High doses of fructose raise the BP and cause the features of metabolic syndrome. Lowering the uric acid level prevents the increase in mean arterial blood pressure. Excessive intake of fructose may have a role in the current epidemics of obesity and diabetes.

The Broad Spectrum of Quality in Deceased Donor Kidneys

The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy.

Are We Frozen in Time? Analysis of the Utilization and Efficacy of Pulsatile Perfusion in Renal Transplantation

Preservation techniques are crucial to deceased donor kidney transplantation (DDTx), but the efficacy of pulsatile perfusion (PP) versus cold storage (CS) remains uncertain. We describe patterns of PP use and explore four fundamental questions. What kidneys are selected for PP? How does PP affect utilization of donated kidneys? What effect does PP have on outcomes? When does PP appear to be most efficacious? We examined rates of PP in DDTx in the United States from 1994 to 2003. We generated models for organ utilization, delayed graft function (DGF) and for the use of PP. We analyzed the long‐term effect of PP with multivariate Cox models. The utilization rates for non‐expanded criteria donors (ECDs) were similar by storage type, but for ECDs there was a significantly higher utilization rate with PP (70% with PP vs. 59% with CS, p < 0.001). Use of PP was widely variable across transplant centers. DGF rates were significantly lower with PP (27.6% vs. 19.6%). PP was associated with a mild benefit on death censored graft survival (adjusted hazard ratio = 0.88, 95% CI 0.85–0.91). Reduced DGF and significantly lower discard rates of ECDs associated with PP suggest an important utility of PP in renal transplantation. Additional evidence of improvement in graft survival, particularly in more recent years, provides further encouraging evidence for the use of PP.

Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL.