Kidney transplantation: state of the art.

Despite ever-improving health care and new advances in medical technology, the number of Americans who develop end-stage renal disease continues to increase. Diabetes remains the leading cause of new cases, followed by hypertension and glomerulonephritis. More than 200,000 patients require dialysis and more than 40,000 are awaiting kidneys for transplantation. Kidney transplantation has been extremely successful with 1-year patient and graft survival rates at 95% and 90%, respectively. The advantages of kidney transplantation are reversal of many of the pathophysiologic changes associated with renal failure as normal kidney function is restored, elimination of dependence on dialysis and the associated dietary restrictions, the opportunity to return to normal life activities, and lower medical costs than dialysis after the first year. The shortage of donor kidneys is the major limiting factor. Because of the supply and demand discrepancy, maximum use of donors from all sources, appropriate recipient selection, and equitable allocation are critical.

Issues surrounding xenotransplantation.

Currently there is a shortage of cadaver organs that can be transplanted from one human being to another. In response to this shortage, scientists and medical researchers have developed techniques for transplanting animal organs into humans, a procedure known as xenotransplantation. This may address the shortage of organs for patients in need; however, it raises other concerns related to cross-species disease transmission, consent issues, ethical issues of sacrificing animals for their organs, psychological issues of receiving organs from an animal, religious concerns, and economic factors. These medical, ethical, and philosophical issues need to be thoroughly addressed before xenotransplantation becomes a reality.

Azathioprine monotherapy in HLA-identical live donor kidney transplant recipients.

The high success rate of HLA-identical sibling transplants and our previous experience with steroid-free immunosuppressive regimens and cyclosporine withdrawal prompted us to evaluate the safety and efficacy of monotherapy with azathioprine in 12 HLA-identical kidney transplant recipients with a serum creatinine concentration less than 176.8 mumol/L, a 1-way stimulatory index less than 2.0 in a post-transplant mixed lymphocyte culture, and a demonstrated tolerance of a minimum azathioprine dose of 1.0 mg/kg per day without leukopenia. Eleven of 12 patients were successfully converted to azathioprine monotherapy without a significant change in serum creatinine concentration for as long as 76 months. Benefits of steroid and cyclosporine withdrawal included a significant reduction in mean systolic and diastolic blood pressure, number of blood pressure medications, total serum cholesterol, and glycohemoglobin in diabetic subjects. Our results suggest that azathioprine monotherapy is safe and effective in a select group of HLA-identical sibling transplants, but these benefits must be carefully balanced against an associated risk of precipitating acute allograft rejection.

Issues in cyclosporine drug substitution: implications for patient management.

Substantial improvements in short-term and long-term outcomes for kidney transplant recipients have resulted from better use of existing immunosuppressive agents and newer treatment options. Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) remain the foundation of immunosuppressive therapy. These agents are considered critical-dose drugs because of their narrow therapeutic range, variable pharmacokinetics, formulation-dependent bioavailability, and negative clinical consequences of underdosing or overdosing. With the recent introduction of a new cyclosporine formulation, concern exists that current bioequivalence guidelines for generic approval may not provide adequate assessment of the safety and efficacy of critical-dose drugs. Transplant experts at 2 recent conferences recommended more rigorous criteria for bioequivalence testing of critical-dose drugs and adoption of consistent drug substitution practices. Additional recommendations included specifying the intended formulation and instituting appropriate monitoring whenever formulations are switched. A summary of the outcomes of these conferences and practice implications for transplant coordinators is discussed.

Benefits of pre-emptive dose reduction for Sandimmune to Neoral conversion in stable renal transplant recipients.

In an effort to minimize nephrotoxicity resulting from greater exposure to cyclosporine after Sandimmune to Neoral conversion, we compared two conversion regimens using different dosing ratios. Serial serum creatinine concentrations and trough cyclosporine levels were measured in 26 patients converted from Sandimmune to Neoral using a 1:0.8 dosing ratio (Group 1) and compared to those of 26 patients converted using a 1:1 dosing ratio (Group 2). The percentage change in peak serum creatinine concentration after conversion was greater in Group 2. However, at last follow-up, the dose reductions in each group were comparable. Following conversion, patients in Group 1 required fewer dose adjustments and follow-up blood tests. Compared to conversion using a 1:1 dosing ratio, conversion from Sandimmune to Neoral using a 1:0.8 ratio results in comparable dose reductions and less short-term nephrotoxicity, while requiring less frequent laboratory monitoring.

Resolution of hepatitis B viremia in a renal transplant recipient treated with alpha-2b interferon.

A renal transplant patient developed symptomatic hepatitis after withdrawal from corticosteroids. Tests for hepatitis B e antigen and hepatitis B viral DNA were both positive prior to treatment with 1 million units alpha interferon three times weekly for 3 weeks followed by an increase to 3 million units alpha interferon three times weekly for a total of 16 weeks. At the end of treatment, hepatitis had clinically resolved with conversion to a hepatitis B e antibody positive and hepatitis B e antigen and viral DNA negative state. The renal allograft function remained excellent throughout the course of therapy with interferon.

Conversion from Sandimmune to Neoral in organ transplant recipients.

The pharmacokinetic profiles of Sandimmune and Neoral vary considerably among transplant recipients. Cyclosporine exposure is far more consistent with Neoral than it is with Sandimmune. Because intrapatient variability of drug exposure has been demonstrated to be a risk factor for chronic rejection, this difference becomes important. Neoral also has a linear dose response and a stronger correlation between trough level and drug exposure. Dose linearity greatly facilitates accurate dose titration. Results of controlled studies in which kidney, liver, and heart transplant recipients were converted from Sandimmune to Neoral have shown that conversion on a 1:1 mg basis results in more predictable bioavailability and often in reductions in cyclosporine dose. Carefully monitored conversion has not been associated with increased side effects, and any side effects that do emerge can usually be managed by taking Neoral with food, changing the dose from every 12 hours to every 8 hours, or through dose reduction.

Effects of fluvastatin on hyperlipidemia after renal transplantation: influence of steroid therapy.

OBJECTIVE: To assess the efficacy and safety of fluvastatin in hypercholesterolemic, cyclosporine-treated, renal transplant recipients, and to determine whether concomitant steroid therapy in such patients alters the lipid-lowering effects of fluvastatin. DESIGN: An open-label, prospective, parallel study was performed in 20 cyclosporine-treated renal transplant recipients with hypercholesterolemia defined by a low-density lipoprotein (LDL) concentration greater than 160 mg/dL or a total cholesterol/high-density lipoprotein (HDL) concentration ratio greater than 5.0. Lipid profiles were measured before and 1 month after treatment with fluvastatin 20 mg/d. Lipid profiles in a group of patients receiving concomitant therapy with prednisone (n = 12) were compared with those of patients who had not received steroids for at least 6 months (n = 8). SETTING: The Renal Transplant Clinic at University Hospitals of Cleveland. MAIN OUTCOME MEASURES: The main outcome measures were serum concentrations of total cholesterol, LDL, HDL, and triglycerides. Treatment failure was defined by LDL concentrations persistently above 160 mg/dL after 1 month of fluvastatin therapy. Safety was assessed clinically and by serial measurements of liver enzymes and creatine phosphokinase. RESULTS: LDL concentrations decreased significantly in both the steroid-treated and steroid-free groups after 1 month of fluvastatin therapy. There was no significant change in HDL concentrations or serum triglycerides in either group. Treatment failure was more common in patients receiving steroids (4/12 patients) than in steroid-free patients (1/8 patients). After 1 month of therapy, LDL cholesterol was significantly lower in the steroid-free group (126 +/- 18 mg/dL) than in the steroid-treated group (147 +/- 23 mg/dL) (p < 0.05). There was no clinical or laboratory evidence of myonecrosis in either group. CONCLUSIONS: Low dosages of fluvastatin appear to be safe in cyclosporine-treated renal transplant recipients. Steroid-free patients exhibit a response to fluvastatin that is qualitatively similar to that of steroid-treated patients, consisting of a significant decrease in LDL concentrations and no change in HDL or serum triglyceride concentrations.

Relationship between pretransplant noncompliance and posttransplant outcomes in renal transplant recipients.

Approximately 5% to 18% of kidney transplant recipients do not comply with their posttransplant medical treatment. This study examined the relationship between pretransplant noncompliance and posttransplant outcomes. Using a longitudinal retrospective chart audit, pretransplant and posttransplant data were collected for 126 kidney transplant recipients over a 3-year period. Sixty-one percent of those identified as noncompliant before transplant lost their graft or died after transplant. Significant relationships between pretransplant noncompliance and graft loss and between pre- and posttransplant noncompliance were found. Clinicians must identify those with pretransplant noncompliance, as they are at risk for poor outcomes and might benefit from an intensive posttransplant follow-up regimen.

Determinants of long-term allograft function following steroid withdrawal in renal transplant recipients.

We retrospectively measured changes in serum creatinine concentration as estimates of changes in renal function in 96 renal transplant recipients who were withdrawn from steroid therapy, maintained on cyclosporine and azathioprine, and followed for 1 to 5 years. Multivariate analyses were used to assess the influence of cyclosporine dose and blood levels, azathioprine dose, age, sex, race, diabetes, HLA match and mismatch, PRA, and history of rejection following steroid withdrawal on long-term allograft function. Results indicate that acute rejection and cyclosporine dose are the major factors influencing long-term renal function after steroid withdrawal. In this setting, there is an inverse relationship between cyclosporine dose and serum creatinine concentration for up to 5 years. Optimal renal function is achieved in patients receiving more than 5.5 mg/kg of cyclosporine per day at the time of steroid withdrawal.

Combined kidney and pancreas transplantation.

Diabetes is the leading cause of end-stage renal disease in the United States. Combined kidney and pancreas transplantation is a safe and effective treatment option for diabetic nephropathy. During the past decade, pancreas transplants had improved outcomes as a result of improvements in pancreas recovery and preservation, the surgical procedure, immunosuppressive regimens, and immunologic monitoring. Current 1-year patient and graft survival rates are 90% and 80%, respectively, and evidence is accumulating that improvements occur in microvascular and neuropathic complications as well. Successful outcomes of kidney and pancreas transplantation are due in large part to careful nursing assessment, diagnosis, intervention, teaching, and discharge planning.

Factors influencing vertebral bone density after renal transplantation.

In an effort to determine the influence of immunosuppressive therapy and other clinical variables on posttransplant osteopenia, vertebral bone density was measured at least 6 months after transplantation in 65 adult primary renal transplant recipients receiving a variety of immunosuppressive regimens. Fifteen of the 65 patients (23%) had vertebral bone densities below a fracture threshold of 1.0 g hydroxyapatite/cm2. Multivariate analyses indicated that cumulative steroid dose and female gender were the major independent predictors of low vertebral bone density. In women, postmenopausal status also was associated with osteopenia. There was no correlation between cumulative cyclosporine dose and bone density. Results of this study indicate that posttransplant osteopenia is common in renal transplant recipients, including those treated with CsA. Although CsA has allowed the use of lower cumulative doses of steroids, concomitant steroid therapy remains the preeminent factor accounting for loss of bone density.

The effects of steroid withdrawal on the lipoprotein profiles of cyclosporine-treated kidney and kidney-pancreas transplant recipients.

Lipoprotein profiles were measured before and two months after complete withdrawal of prednisone in 34 kidney and 9 kidney-pancreas transplant recipients subsequently maintained on cyclosporine and azathioprine. Withdrawal of steroid therapy was accompanied by a 17% reduction in total serum cholesterol levels. However, there was a parallel reduction in all other measured lipoprotein concentrations, including an 18% reduction in high-density lipoprotein cholesterol levels. In diabetic recipients of a kidney or kidney-pancreas transplant, the ratio of total to high-density lipoprotein cholesterol was unchanged after steroid withdrawal. In nondiabetic kidney transplant recipients, this ratio actually increased significantly following withdrawal of prednisone. These observations suggest that it is premature to presume that withdrawal of steroid therapy will reduce the cardiovascular risk related to hyperlipidemia in cyclosporine-treated kidney or kidney-pancreas transplant recipients.

Kidney-pancreas transplantation: a treatment option for ESRD and type I diabetes.

Combined kidney-pancreas transplantation is a safe and effective treatment option for patients with end stage renal disease (ESRD) resulting from type I diabetes. Current 1 year graft survival rates are nearing 80% and evidence is accumulating that improvement occurs in microvascular and neuropathic complications of diabetes after transplantation. This article is a detailed overview based on the current literature and our experience at The University Hospitals of Cleveland of the challenges and benefits of kidney-pancreas transplantation and the nursing care required to prepare the patient for home.

Variable effects of steroid withdrawal on blood pressure reduction in cyclosporine-treated renal transplant recipients.

The effects of complete withdrawal of steroid therapy on blood pressure and other clinical variables were studied in 58 renal transplant recipients subsequently maintained on azathioprine and cyclosporine; 76% of the patients were hypertensive prior to withdrawal of steroids. Cessation of steroids was accompanied by a significant decrease in mean arterial blood pressure and by a reduction in the number of required antihypertensive medications; however, changes in blood pressure were variable among individual patients. Previously normotensive patients exhibited little further decline in blood pressure. Multivariate analysis of the entire cohort of patients showed that the reduction in blood pressure accompanying steroid withdrawal was directly related to the prior severity of hypertension and inversely related to the dose of cyclosporine. We conclude that steroids play an important role in the pathogenesis of posttransplant hypertension in the majority of renal transplant recipients. Withdrawal of steroids generally is accompanied by reduction in blood pressure, but the benefit is greatest in previously hypertensive patients receiving relatively low doses of cyclosporine.

Withdrawal of steroids after renal transplantation--clinical predictors of outcome.

Withdrawal of steroid therapy in renal transplant recipients is associated with a risk of acute allograft rejection. To define clinical risk factors for rejection associated with steroid withdrawal, we analyzed the clinical characteristics of 107 patients with drawn from steroid therapy at various times after transplantation. Both univariate and multivariate analyses suggested that the timing of steroid withdrawal is an important predictor of steroid withdrawal failure. Withdrawal of steroids was successful in only 13 of 32 patients (41%) in whom prednisone was discontinued shortly after transplantation. In contrast, steroid withdrawal has been successful in 59 of 75 patients (79%) in whom prednisone was discontinued at least 6 months after transplantation. Black race and donor-recipient racial mismatch also were significant predictors of rejection associated with steroid withdrawal. In patients undergoing steroid withdrawal at least 6 months posttransplant, serum creatinine concentration also correlated independently with the risk of rejection. Neither age, sex, HLA match, pretransplant PRA, source of the allograft (cadaver vs. living relative), acute tubular necrosis, nor the presence of diabetes was predictive of the outcome of steroid withdrawal.

Effects of steroid withdrawal on posttransplant diabetes mellitus in cyclosporine-treated renal transplant recipients.

Posttransplant diabetes mellitus (PTDM) traditionally has been attributed to therapy with steroids--however, several lines of evidence suggest that cyclosporine also is diabetogenic. A retrospective review revealed that PTDM developed in 9 of 70 previously nondiabetic kidney transplant recipients (12.9%) maintained on prednisone, azathioprine, and CsA compared with 8 of 83 nondiabetics (9.6%) maintained on azathioprine and prednisone alone in an earlier era (P = NS). Among patients maintained on triple-drug therapy, complete withdrawal of prednisone was attempted in 7 renal transplant recipients with PTDM and in 1 recipient of a combined kidney-pancreas transplant who exhibited evidence of type II diabetes mellitus. Seven of the 8 patients were able to discontinue insulin or oral hypoglycemic agents within 4 months of discontinuing steroids. Mean glycohemoglobin level declined from 10.6 +/- 3.6% prior to steroid withdrawal to 6.0 +/- 1.3% within 1 month of steroid cessation, while mean CsA dose and trough CsA blood levels remained unchanged. In 2 patients, mild rejection episodes prompted a return to steroid therapy. Although CsA may be diabetogenic, evidence from this study suggests that withdrawal of steroid therapy is a safe and effective approach to the management of PTDM in patients subsequently maintained on CsA and azathioprine.