Cardiovascular disease after renal transplantation

Cardiovascular disease (CVD) is common after renal transplantation. In the absence of controlled intervention trials, the strength of evidence that modifying a risk factor will reduce the incidence of CVD in renal transplant recipients must rest on: (1) evidence from studies in the general population, (2) observational studies linking the risk factor to CVD in renal transplant recipients, and (3) studies showing that the risk factor can be safely and effectively treated in transplant patients. Accordingly, the evidence is strong that hyperlipidemia should be treated after renal transplantation. Evidence is very suggestive that pretransplant screening for CVD, treatment of hypertension, the use of low-dose aspirin, and smoking cessation will also help to reduce the incidence of posttransplant CVD. Less compelling are data suggesting that intensive glucose control in diabetics will safely decrease the incidence of CVD. Although there is little evidence that treatment of erythrocytosis will reduce CVD, hematocrits above 55% to 60% should probably be treated to prevent venous thrombosis. Vitamins for reducing homocysteine, antioxidant vitamins, and prophylaxis for potentially atherogenic infections are therapies that warrant additional study. In summary, the best current approach to reducing the high incidence of posttransplant CVD is to aggressively identify, and then systematically treat modifiable risk factors.     

Serum C-reactive protein surge in renal transplant recipients: link with allograft survival

The restoration of kidney function by transplantation improves the common finding of chronic inflammation in patients with end-stage renal disease (ESRD). The C-reactive protein (CRP) level is a reliable marker of inflammation in renal transplant recipients. We analyzed the predictive value of posttransplant CRP surges on renal allograft survival among 141 ESRD patients who underwent renal transplantation between May 1999 and September 2001 at our institution. Twenty-seven cadaveric and 114 living donors were also studied. The subjects' demographic, clinical, and laboratory data were recorded. The renal transplant recipients were divided into three groups defined by the type of serum CRP surge: a normal, intermittently high, or consistently high serum CRP concentration. Renal allograft survival rates were 90.0% among recipients with normal serum CRP concentrations, 72.6% among those with intermittently high concentrations, and 11.1% in those with consistently high concentrations. A Cox regression analysis of factors that affect allograft survival showed that acute rejection, advanced recipient age, and consistently high serum CRP concentrations were associated with a high risk of renal allograft loss. Intermittent elevations in the serum CRP level were not associated with an increased risk of allograft loss, according to the Cox regression model. We concluded that consistently high serum CRP concentrations in renal allograft recipients showed a high negative predictive value for renal allograft survival. In recipients who exhibited ongoing inflammatory process in the 5-year posttransplant period, additional efforts are necessary to manage inflammation and therefore prolong renal allograft survival.     

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.     

Cardiovascular disease posttransplant

Renal transplantation is currently the preferred treatment modality for virtually all suitable candidates with end-stage renal disease. Compared with dialysis, kidney transplantation improves both patient survival and quality of life. Nonetheless, posttransplant cardiac complications are associated with increased morbidity and mortality after renal transplantation. When compared with the general population, cardiovascular mortality in transplant recipients is increased by nearly 10-fold among patients within the age range of 35 and 44 and at least doubled among those between the ages of 55 and 64. Although renal transplantation ameliorates cardiovascular disease risk factors by restoring renal function, it introduces new cardiovascular risks derived, in part, from immunosuppressive medications. We provide an overview of the literature on conventional and unconventional cardiovascular disease risk factors after renal transplantation, and discuss an approach to their medical management.     

Uric acid and transplantation

Hyperuricemia is a common complication in organ transplant recipients, and frequently is associated with chronic cyclosporine immunosuppressive therapy. Kidney and heart transplant recipients are prone to develop posttransplant hyperuricemia. Risk factors for hyperuricemia include decreased glomerular filtration rate (GFR), diuretic use, and preexistent history of hyperuricemia. The influence of hyperuricemia in patient and graft survival is unclear because uric acid is not usually considered a common risk factor for cardiovascular disease that affects graft and patient survival. However, there have been small studies that have suggested that control of uric acid levels contributes to recovery of renal function (in heart and liver transplant recipients) and in an improvement in GFR in renal transplant recipients. Despite controversies in the need for hyperuricemia treatment in transplant patients, strategies to decrease uric acid levels includes a decrease or avoidance of cyclosporine treatment, adequacy of antihypertension treatment, avoidance of diuretics, nutritional management, and use of uric acid-decreasing agents. In this article we review the incidence and risk factors for the development of posttransplant hyperuricemia, discuss the influence of different immunosuppressive agents on uric acid metabolism, and suggest some alternative treatments for posttransplant hyperuricemia. We also consider that uric acid should be considered as a potential risk factor for renal allograft nephropathy or for renal dysfunction in nonrenal transplant recipients, as well as a comorbid factor for a decrease in patient and graft survival.     

Risk factors for hospitalizations resulting from pulmonary embolism after renal transplantation in the United States.

BACKGROUND: Risk factors for pulmonary embolism (PE) have been identified in the general population but have not been studied in a national population of renal transplant recipients. METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System from 1 July 1994-30 June 1997 were analyzed in a historical cohort study of hospitalized PE (ICD9 Code 415.1x). HCFA form 2728 was used for comorbidities. RESULTS: Renal transplant recipients had an incidence of PE of 2.26 hospitalizations per 1000 patient years at risk. In multivariate analysis, polycystic kidney disease (adjusted odds ratio, 4.44, 95% confidence interval, 2.31-8.53), older recipient age, higher recipient weight, cadaveric donation, history of ischemic heart disease, and decreased serum albumin were associated with increased risk of PE. Body mass index and hemoglobin were not significant. Kidney-pancreas transplantation was also not significant. In Cox Regression analysis PE was associated with increased mortality (hazard ratio 2.06, 95% CI 1.34-3.18). CONCLUSIONS: The most important risk factors for PE in this population were polycystic kidney disease, advanced age and increased weight. The reasons for the increased risk of polycystic kidney disease remain to be determined but were independent of hematocrit level at initiation of end stage renal disease, and may result from venous compression. Prospective studies of anatomical and hemostatic changes after renal transplantation in recipients with polycystic kidney disease are warranted.     

Posttransplant bone disease

Kidney transplantation reverses some of the disturbances of mineral and bone metabolism. However, the reversal or degree of improvement is often incomplete. The well-documented bone loss, especially in the early posttransplant period, contributes to an increased incidence of fractures in kidney transplant recipients. To better understand the mechanism of bone loss posttransplant, we need to take in consideration both bone quantity (density) and quality (bone microarchitecture, turnover rate). In addition to bone density, which is a measure of bone quantity, there are other invasive and noninvasive tools that provide information about the bone architecture and turnover and may be helpful in evaluating kidney transplant recipients at risk of fractures. There are several factors that contribute to the development of bone loss in the posttransplant period. Among these, the use of glucocorticoids, as part of the posttransplant immunosuppressive regimen, remains the single most important risk factor for bone loss post–kidney transplant. Interventions for evaluation and management of bone disease posttransplant are described and discussed. Some of these measures have been shown to increase bone density, but so far, none have demonstrated an ability to reduce the fracture incidence.     

Metastatic renal cell carcinoma associated with acquired cystic kidney disease 15 years after successful renal transplantation

Renal cell carcinoma (RCC) is a relatively uncommon cancer in renal transplant patients. From 1968 to 1987, 101 cases of RCC of native kidneys have been reported to the Cincinnati Transplant Tumor Registry. We describe here a case of metastatic RCC associated with acquired cystic kidney disease (ACKD) 15 years after successful renal transplantation. The patient presented with a subcutaneous nodule, which led to discovery of a large primary tumor in the left kidney. ACKD was present in the atrophic right kidney. The reported cases of ACKD-associated RCC in renal transplant recipients were reviewed. Most of these cases are middle-aged men with a long posttransplant course, good graft function, and usage of azathioprine and prednisone as immunosuppressive agents. ACKD can develop or persist and progress to RCC many years after successful renal transplantation. Transplant patients with flank pain, hematuria, or other suspicious symptoms should have imaging studies of their native kidneys.     

Bimodal Distribution of Major Cardiovascular Events in Kidney Allograft Recipients

Cardiovascular disease (CVD) is the major cause of death after renal transplantation. We have retrospectively analyzed the incidence and the time of appearance of CVD among 870 consecutive cadaveric kidney transplant recipients, including 143 patients (16.5%) who experienced a fatal or nonfatal event after transplantation. Seventy-four recipients (54%) showed a fatal CVD. Studying the various manifestations, we observed a higher frequency of cardiac events (59% of ischemic heart disease), with 15% cerebrovascular disease and 22% peripheral vascular or aortic disease. In our group, CVDs were distributed in a bimodal manner, with a higher incidence in the first posttransplantation year and a late cluster of CVD at 8 years posttransplantation. The risk of death (hazard function) for CVD increased dramatically during the 8th year after transplantation. This trend of CVD after kidney transplantation may be explained by inadequate evaluation and management of CVD risk factors during waiting list time and, after transplantation, by the cumulative effects of traditional and nontraditional risk factors.     

Renal Doppler resistance indices are associated with systemic atherosclerosis in kidney transplant recipients

BACKGROUND: In kidney transplant recipients, increased intrarenal resistance indices measured by duplex ultrasound are associated with poor subsequent allograft performance. It remains unclear whether high resistance indices rather reflect local renal damage or systemic vessel disease. We hypothesized that resistance indices are associated with cardiovascular risk factors and with subclinical systemic atherosclerosis in transplant recipients. METHODS: In 105 renal transplant recipients, categories of risk for coronary heart disease were determined by Framingham risk scoring. Intrarenal resistive index (RI) and pulsatility index (PI) were measured in segmental arteries at five representative locations. For assessment of subclinical atherosclerosis, common carotid intima-media thickness, and ankle-brachial blood pressure index (ABI) were determined. RESULTS: Transplant recipients with high coronary risk had higher intrarenal resistance indices than low-risk patients. Higher age, female gender, and lower body mass index were independently associated with increased resistance indices. Renal resistance indices were correlated with common carotid intima-media thickness [RI: r= 0.270 (P= 0.005); PI: r= 0.355 (P < 0.001)]. This association remained significant after adjusting for renal function. Renal resistance indices were increased in patients with pathologic ankle-brachial-indices compared to patients with physiologic ankle-brachial-indices [RI: 73.3 +/- 7.1 vs. 70.2 +/- 6.9 (P= 0.03); PI: 146.4 +/- 29.9 vs. 131.4 +/- 25.9 (P= 0.01)]. Renal resistance indices were neither significantly correlated with glomerular filtration rate (GFR), nor with donor age. CONCLUSION: Intrarenal resistance indices are a complex integration of arterial compliance, pulsatility, and peripheral resistance. They are associated with traditional cardiovascular risk factors as well as with subclinical atherosclerotic vessel damage and should thus not be considered specific markers of renal damage.     

The APOL1 Genotype of African American Kidney Transplant Recipients Does Not Impact 5‐Year Allograft Survival

Apolipoprotein L‐1 (APOL1) gene variants are associated with end‐stage renal disease in African Americans (AAs). Here we investigate the impact of recipient APOL1 gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 AA kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5‐year posttransplant for recipients with high‐risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation.     

Risk of lymphoma after renal transplantation varies with time: an analysis of the United States Renal Data System

BACKGROUND: Characterization of the incidence of posttransplant lymphoma over time may help guide the timing and intensity of posttransplant monitoring. We analyzed the United States Renal Data System to describe the occurrence of lymphoma following renal transplantation. METHODS: All end-stage renal disease patients placed on the transplant waiting list between January 1, 1990 and December 31, 1999 were considered. Survival analysis was used to estimate lymphoma risk in renal transplant patients. RESULTS: Of 89,260 eligible patients, a total of 556 lymphoma cases were identified with 357 in transplant patients. The overall rate of posttransplant lymphoma was 33.3/10,000 person-years in transplant patients. There was variation in the duration and magnitude of increased lymphoma risk by age. The highest rates of lymphoma were among transplanted patients in the first 12 months, after which the rate of lymphoma decreased. Among Caucasian transplant recipients less than 25 years of age, the adjusted relative risk of lymphoma ranged from 13.82 [95% CI: (3.96, 48.15)] within 6 months posttransplant to 3.46 [95% CI: (0.69, 17.44)] within months 30-36 posttransplant. Only patients under 25 years had a notably increased risk beyond the first 2 posttransplant years. The risk of lymphoma differed by race, with Caucasian patients at nearly double the risk of African-Americans. Gender was not associated with lymphoma incidence. CONCLUSIONS: We found and quantified a time-varying relationship between renal transplant and lymphoma risk. This information can be used in combination with knowledge of established risk factors to guide the schedule of posttransplant monitoring.     

Impact of obesity on renal transplant outcomes

Obesity is a frequent and important consideration to be taken into account when assessing patient suitability for renal transplantation. In addition, posttransplant obesity continues to represent a significant challenge to health care professionals caring for renal transplant recipients. Despite the vast amount of evidence that exists on the effect of pretransplant obesity on renal transplant outcomes, there are still conflicting views regarding whether obese renal transplant recipients have a worse outcome, in terms of short- and long-term graft survival and patient survival, compared with their non-obese counterparts. It is well established that any association of obesity with reduced patient survival in renal transplant recipients is mediated in part by its clustering with traditional cardiovascular risk factors such as hypertension, dyslipidaemia, insulin resistance and posttransplant diabetes mellitus, but what is not understood is what mediates the association of obesity with graft failure. Whether it is the higher incidence of cardiovascular comorbidities jeopardising the graft or factors specific to obesity, such as hyperfiltration and glomerulopathy, that might be implicated, currently remains unknown. It can be concluded, however, that pre- and posttransplant obesity should be targeted as aggressively as the more well-established cardiovascular risk factors in order to optimize long-term renal transplant outcomes.     

The Clinical Impact of an Early Decline in Kidney Function in Patients Following Heart Transplantation

Renal dysfunction is a well-known complication following heart transplantation. We examined an early decline in kidney function as a predictor of progression to end-stage renal disease and mortality in heart transplant recipients. We performed a retrospective cohort study of 233 patients who received a heart transplant between July 1985 and July 2004, and who survived >1 month. The decline in estimated creatinine clearance (CrCl) was used to predict the outcomes of need for chronic dialysis or mortality >1-year posttransplant. The earliest time to chronic dialysis was 484 days. A 30% decline in CrCl between 1 month and 12 months predicted the need for chronic dialysis (p = 0.01), all-cause mortality (p < 0.0001) and time to first CrCl ≤30 mL/min at >1-year posttransplant (p = 0.02). A 30% decline in CrCl between 1 month and 3 months also independently predicted the need for chronic dialysis (p = 0.04) and time to first CrCl ≤ 30 mL/min at >1-year posttransplant (p = 0.01). In conclusion, an early drop in CrCl within the first year is a strong predictor of chronic dialysis and death >1-year postheart transplantation. Future studies should focus on kidney function preservation in those identified at high risk for progression to end-stage kidney disease and mortality.     

Risk factors for changes in bone mineral density and the effect of antiosteoporosis management after renal transplantation

Using the pretransplant bone mineral density (BMD) data records of renal recipients, we retrospectively examined risk factors affecting posttransplant changes in BMD and the effect of antiosteoporosis management. For 294 kidney transplant recipients from January 1996 to September 2003, BMD values were expressed as spine and femur T-scores. Gender, age, pretransplant diabetes, blood type compatibility, mode and duration of dialysis, and previous transplantation were considered to be variables affecting BMD changes. T-test or ANOVA was used to compare risk factors. At the time of transplantation, mean spine T-scores were significantly lower among the retransplant group. Mean femur T-scores were significantly lower among the retransplant group, older patients (older than 45 years), and female recipients. Prolonged hemodialysis (>12 months) and retransplant were risk factors for BMD loss during the first year posttransplant. Early application of antiosteoporosis management was effective to ameliorate posttransplant BMD loss. However, antiosteoporosis management after 1 year posttransplant was relatively ineffective. Pretransplant evaluation of BMD and the possibility of significant BMD loss during the first posttransplant year should not be overlooked. Prophylaxis against bone loss and treatment should be started as soon as possible after transplantation for recipients with either normal or abnormal pretransplant BMD.     

Can the renal transplant patient be really considered as a patient with chronic renal insufficiency?

To assess if the renal transplant patient can really be considered as a patient with chronic renal insufficiency, disease progression and outcomes were compared in both groups. At the same stage of chronic kidney disease (CKD), the deterioration of renal function was slower and graft survival was longer in renal transplant patients. Despite slower rates of kidney function decline, overall patient survival was similar between the two groups. Interestingly, stage 3 adjusted mortality rates were greater in kidney transplant recipients, most likely because of the disease burden (history of end-stage renal disease in renal transplant recipients) and immunosuppression. The three major causes of mortality in transplant patients (cardiovascular, infectious and malignant) may present with specific characteristics in transplant patients. Renal transplantation is thus a specific form of CKD, controlled by 3 factors, a single kidney, immunosuppression and the burden of the disease. The general application of the KDOQI and KDIGO guidelines to kidney transplant recipients requires therefore further evaluation.     

Evaluation and management of bone disease and fractures post transplant

Bone disease is common in recipients of kidney, liver, heart, and lung transplants and results in fractures in 20–40% of patients, a rate much higher than expected for age. Fractures occur because of the presence of bone disease as well as other factors such as neuropathy, poor balance, inactivity, and low body or muscle mass. Major contributors to bone disease include both preexisting bone disease and bone loss post transplant, which is greatest in the first 6–12 months when steroid doses are highest. Bone disease in kidney transplant recipients should be considered different from that which occurs in other solid organ transplant recipients for several reasons including the presence of renal osteodystrophy, which contributes to low bone mineral density in these patients; the location of fractures (more common in the legs and feet in these patients than in spine and hips as in other solid organ recipients); and the potential danger in using bisphosphonate therapy, which may cause more harm than good in kidney transplant recipients with low bone turnover.Evaluation in all patients should preferably occur in the pretransplant period or early post transplant and should include assessment of fracture risk as well as metabolic factors that can contribute to bone disease. Bone mineral density measurement is recommended in all patients even if its predictive value for fracture risk in the transplant population is unproven.Management of bone disease should be directed toward decreasing fracture risk as well as improving bone density. Pharmacologic and nonpharmacologic treatment strategies are discussed in this review. Although there have been many studies describing a beneficial effect of bisphosphonates and vitamin D analogues on bone density, none have been powered to detect a decrease in fracture rate.     

Renal Dysfunction Is a Strong and Independent Risk Factor for Mortality and Cardiovascular Complications in Renal Transplantation

Renal transplant recipients (RTR) have shortened life expectancy, primarily due to premature cardiovascular disease (CVD). Traditional CVD risk factors are highly prevalent. In addition, several non-traditional risk factors may contribute to the high risk. The aim of the study was to evaluate the effects of renal dysfunction on mortality and cardiovascular complications in 1052 placebo-treated patients of the Assessment of LEscol in Renal Transplantation (ALERT) trial. Follow-up was 5-6 years and endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. The effects of serum creatinine at baseline on these endpoints were evaluated. Elevated serum creatinine in RTR was a strong and independent risk factor for MACE, cardiac, non-cardiovascular, and all-cause mortality, but not for stroke or non-fatal MI alone. Serum creatinine was associated with increased mortality and MACE, independent of established CVD risk factors. Graft loss resulted in increased incidences of non-cardiovascular death, all-cause mortality, MACE and non-fatal MI. In conclusion, elevated serum creatinine is a strong risk factor for all-cause, non-cardiovascular and cardiac mortality, and MACE, independent of traditional risk factors, but not for stroke or non-fatal MI alone.     

Management of chronic viral hepatitis before and after renal transplantation

Hepatitis C virus (HCV) infection is present in 2-50% of renal transplant recipients and patients receiving hemodialysis. Renal transplantation confers an overall survival benefit in HCV positive (HCV+) hemodialysis patients, with similar 5-year patient and graft survival to those without HCV infection. However, longer-term studies have reported increased liver-related mortality in HCV-infected recipients. Unfortunately, attempts to eradicate HCV infection before transplant have been disappointing. Interferon is poorly tolerated in-patients with end-stage renal disease and ribavirin is contraindicated because reduced renal clearance results in severe hemolysis. Antiviral therapy following renal transplantation is also poorly tolerated, because of interferon-induced rejection and graft loss. Although the prevalence of hepatitis B virus (HBV) infection has declined in hemodialysis patients and renal transplant recipients since the introduction of routine vaccination and other infection control measures, it remains high within countries with endemic HBV infection (especially Asia-Pacific and Africa). Renal transplantation is associated with reduced survival in HBsAg+ hemodialysis patients. Unlike interferon, lamivudine is a safe and effective antiviral HBV treatment both before and after renal transplantation. Lamivudine therapy commenced at transplantation should prevent early posttransplant reactivation and subsequent progression to cirrhosis and late liver failure. This preemptive therapy should also eradicate early liver failure from fibrosing cholestatic hepatitis. Because cessation of treatment may lead to severe lamivudine-withdrawal hepatitis, most patients require long-term therapy. The development of lamivudine-resistance will be accelerated by immunosuppression and may result in severe hepatitis flares with decompensation. Regular monitoring with liver function tests and HBV DNA measurements should enable early detection and rescue with adefovir. Chronic HCV and HBV infections are important causes of morbidity and mortality in renal transplant recipients. The best predictor for liver mortality is advanced liver disease at the time of transplant, and liver biopsy should be considered in all potential HBsAg+ or HCV+ renal transplant candidates without clinical or radiologic evidence of cirrhosis. Established cirrhosis with active viral infection should be considered a relative contraindication to isolated renal transplantation.