Specific management of anemia and hypertension in renal transplant recipients: influence of renin-angiotensin system blockade.

BACKGROUND: Renin-angiotensin system (RAS) inhibition has proven to be helpful in reducing cardiovascular and kidney disease progression in the general population; whether kidney transplant patients would derive similar benefits is unknown. RAS inhibition also reduces posttransplantation erythrocytosis in kidney transplant recipients, but its effect on hemoglobin (Hb) levels in patients without posttransplantation erythrocytosis is unclear. METHODS: The Specific Management of Anemia and Hypertension in Renal Transplant (SMAhRT) recipients study was designed to examine the cardiovascular benefits of RAS blockade with telmisartan 80 mg versus placebo, and Hb management with darbepoetin α in a randomized, double-blind, single-center controlled trial in 2,000 patients over 3 years. The primary efficacy variable was a composite of all-cause mortality, myocardial infarction or stroke. RESULTS: The SMAhRT study was stopped prematurely due to a lower than expected event rate. At that point, 136 patients were enrolled and were followed for a mean duration of 15 months. The use of RAS blockade was not associated with an increased risk of adverse events such as worsening anemia or hyperkalemia. Likewise, the correction of Hb with darbepoetin was not associated with any increase in thrombotic events. CONCLUSIONS: This study provides insight into the safety of RAS inhibition and Hb correction with an erythrocyte-stimulating agent in kidney transplant recipients.

Renal consequences of prostaglandin inhibition in heart failure.

Prostaglandins are products of intracellular arachidonate metabolism via the cyclooxygenase pathways. In the kidney, prostaglandins are modulators of afferent arteriole autoregulation. In diminished effective intravascular volume, vasodilatory prostaglandins reduce afferent arteriolar resistance, helping to maintain overall glomerular filtration. In subjects who have a low perfusion state, as in congestive heart failure, arthrosclerosis, hepatorenal syndrome, and cirrhosis, impaired renal autoregulation occurs, predisposing to kidney injury. Adverse effects of prostaglandin inhibition include acute kidney injury, hyperkalemia, hypertension, and edema. Hypertension and edema can occur because prostaglandins play an important role in renal regulation of salt and water balance. This review summarizes the renal consequences of using prostaglandin inhibitors in subjects who have congestive heart failure.

COX-2 inhibitors and cardiovascular risk.

The development of drugs that selectively inhibit cyclooxygenase-2 (COX-2) demonstrates translational research from bench to bedside based on underlying knowledge of micro-cellular structure and function. However, theoretical concerns about potentially prothrombotic effects of selective COX-2 inhibitors coupled with observations of increased cardiovascular risk have produced significant consternation and lead to the withdrawal of two of these agents from the market. A number of questions remain unanswered. It appears clear that both selective and non-selective COX inhibitors are associated with increases in blood pressure. In addition, blood pressure is often increased after starting nonsteroidal therapy, and we know that even small increases in blood pressure in subjects with pre-existing vascular disease are associated with substantial increases in the risk of cardiovascular morbidity. Given this line of reasoning, one might hypothesize that the observed increases in the risk of cardiovascular events associated with COX-inhibitors are largely due to increases in blood pressure in populations of subjects who are already at high risk. But can we generalize that the adverse cardiovascular effects observed for rofecoxib and valdecoxib are sufficient to indict the entire class of COX-2 inhibitors, or is this not a class effect, but dependent upon the degree of COX-2 selectivity? In either case, it seems prudent to recommend that subjects who are at higher risk for a cardiovascular event and receiving a COX-inhibitor should also be treated with low dose ASA with close follow up of blood pressure and efficacious use of anti-hypertensive medications. Finally, modest dietary salt restriction may help lessen the effects of COX-inhibitors on blood pressure.

Is RAS blockade routinely indicated in hypertensive kidney transplant patients?

There is a high incidence of hypertension after kidney transplantation, which has been associated with the development of left ventricular hypertrophy, an increased risk for acute rejection, lower graft survival, and increased mortality. The pathogenesis of post-transplant hypertension is multifactorial, and therefore optimum therapy for it is not clearly defined. Historically, use of renin-angiotensin system (RAS) blockade in post-transplant hypertension has been limited given concerns of inducing worsening allograft function. Recent data demonstrated that subjects with post-transplant hypertension can be treated effectively with RAS blockers, and that these agents may offer significant additional benefits beyond blood pressure control. Review of the literature suggests that RAS blockers should be considered as useful agents for treatment of post-transplant hypertension not due to transplant renal artery stenosis.

Survival benefit of recombinant human erythropoietin administration prior to onset of end-stage renal disease: variations across surrogates for quality of care and time.

BACKGROUND: Recombinant human erythropoietin (rHuEPO) is recommended pre-dialysis to correct the anemia of chronic kidney disease. This study evaluated the impact of pre-dialysis rHuEPO on mortality in incident end-stage renal disease (ESRD) patients with varying levels of pre-ESRD care. METHODS: The study included 15,807 individuals whose exposure to rHuEPO was determined from HCFA 2728 forms. RESULTS: Median follow-up after starting dialysis was 32.8 months. Pre-ESRD rHuEPO use occurred in only 3,994 (25.3%) subjects and was more common in individuals with insurance, currently employed, started on outpatient dialysis, and initiated on peritoneal dialysis. During the study, 8,608 (54.5%) patients died. The risk of death was lower for rHuEPO-treated patients versus non-treated (relative risk 0.87, 95% CI 0.82-0.92). The survival benefit with rHuEPO was greatest early after dialysis initiation (relative risk at 1 vs. 7 years post-dialysis 0.73, 95% CI 0.66-0.80 vs. 0.87, 95% CI 0.82-0.92, respectively), did not vary across several surrogates for quality of care, and was greatest in those with the highest achieved hematocrit pre-ESRD. CONCLUSION: Pre-dialysis rHuEPO confers a survival benefit that depends on achieved hematocrit and diminishes post-dialysis, but is independent of several surrogates for quality of care except for insurance status pre-ESRD.

Increasing resident research in a military internal medicine program.

The internal medicine residents from our training program rarely participated in scholarly activity prior to 1994. In an attempt to increase the quality and quantity of resident research, we initiated a research program that included: (1) a mandatory research project, (2) 2 months of dedicated research time, (3) appointment of a research director, (4) lectures on the critical appraisal of medical literature and research design, (5) technical support, (6) faculty mentoring, (7) a research meeting and competition involving five residency programs, and (8) military achievement awards. From 1994 to 1999, our house staff has had 134 research presentations and 21 manuscripts accepted for publication in peer-reviewed journals. Ninety percent of our residents presented at least one project at a scientific meeting by completion of their training between 1996 and 1999. Resident scholarly activity is significantly enhanced by a structured research program, an opportunity to present at a scientific meeting, and award recognition.