James F. Burke

Long-Term Efficacy and Safety of Cyclosporine in Renal-Transplant Recipients

BACKGROUND AND METHODSnThe safety of long-term immunosuppression with cyclosporine in renal-transplant recipients is not well understood. This drug may cause a progressive toxic nephropathy, but it also preserves renal function because it prevents rejection. To determine the effect of cyclosporine on renal function and graft rejection, we conducted a retrospective analysis of data on 1663 renal-transplant recipients at six centers.nnnRESULTSnThe rate of graft survival was 78 percent (median follow-up, 36 months). Grafts were was lost in 279 patients (17 percent), mostly because of acute rejection (68 patients) or chronic graft dysfunction that was unresponsive to a reduction in the dose of cyclosporine (125 patients); 92 patients died with functioning grafts. The median change in the serum creatinine concentration in all patients after transplantation was less than 0.001 mg per deciliter per month (< 0.09 mumol per liter per month). Patients who had episodes of rejection had decreased rates of long-term graft function and survival. Eight percent of patients with functioning grafts at one year had first episodes of rejection more than one year after transplantation. These late first rejections were associated with noncompliance with therapy (in 34 percent), blood cyclosporine concentrations that were marginally lower than those of patients who had no episodes of rejection, and a low rate of successful reversal of rejection (77 percent, vs. 97 percent in patients with rejection during the first year; P < 0.001).nnnCONCLUSIONSnThe majority of renal-transplant patients tolerate long-term cyclosporine therapy without evidence of progressive toxic nephropathy. Graft failure is most often due to rejection.

Biochemical Profile of Uremic Breath

We attempted to define the substances that contribute to the characteristic uremic breath of patients with end-stage renal disease. Breath samples from nine patients underwent direct analysis before and after hemodialysis with use of gas chromatography and confirmation by mass spectrometry, and indirectly assessment by an organoleptic panel. Concentrations of secondary and tertiary amines, dimethylamine and trimethylamine were increased, with subsequent reduction after hemodialysis (dimethylamine from 2.00 +/- 0.19 [S.E.M.] to 0.88 +/- 0.12 microng per 30 minutes, P less than 0.001, and trimethylamine from 0.79 +/- 0.22 to 0.44 +/- 0.15 microng per 30 minutes, P less than 0.003). Treatment with nonabsorbable antibiotics in two patients reduced both serum and breath amine levels without dialysis. Loss of nitrogen via the breath was not quantitatively important. We conclude that uremic breath reflects the systemic accumulation of potentially toxic volatile metabolites, among which dimethylamine and trimethylamine have been positively identified and correlated with the classic fishy odor.

Accelerated atherosclerosis in chronic-dialysis patients--another look.

Actuarial statistics of 53 dialysis patients treated between 1965 and 1976 are reviewed. It is suggested that dialysis did not accelerate atherosclerosis over the observed time period. It appears as though a fundamental change in the dialysis population has occurred and there are too few long-term dialysis patients available to establish whether dialysis does accelerate atherosclerosis.

A 6-month study of low-dose recombinant human erythropoietin alone and in combination with androgens for the treatment of anemia in chronic hemodialysis patients

Two previous short-term studies (12 weeks and up to 16 weeks) that used androgens to supplement recombinant human erythropoietin (rHuEPO) for the treatment of the anemia associated with end-stage renal disease showed divergent results. Both studies were limited by their brief duration, since the hematopoietic effect of androgens does not peak until 5 months. Therefore, we conducted a 6-month, prospective, randomized trial comparing low-dose rHuEPO alone and in combination with androgens for the treatment of the anemia of end-stage renal failure. Nineteen anemic chronic hemodialysis patients were randomized into two groups. Group A (n = 10) received 1,500 U rHuEPO intravenously three times a week for 26 weeks. Group B (n = 9) received the same dose of rHuEPO plus nandrolone decanoate 100 mg intramuscularly weekly. Baseline transferrin saturation, serum ferritin, intact serum parathyroid hormone, plasma aluminum, and hematocrit levels were not significantly different between the groups. At study completion, both groups showed a significant increase in mean hematocrit compared with baseline (group A: 24.8% +/- 1.4% to 28.3% +/- 2.8%, P = 0.003; group B: 25.1% +/- 1.5% to 33.2% +/- 4.5%, P = 0.001). The increase in hematocrit in the rHuEPO plus androgen-treated group was statistically greater than in the rHuEPO-alone group (8.2% +/- 4.4% v 3.5% +/- 2.8%; P = 0.012). With the exception of mild discomfort at the injection site, there were no significant side effects from nandrolone. We conclude that the combination of low-dose rHuEPO and nandrolone decanoate is effective treatment for the anemia of end-stage renal failure.

National transplantation pregnancy registry: Report on outcomes in cyclosporine-treated female kidney transplant recipients with an interval from transplant to pregnancy of greater than five years

Successful renal transplantation enables previously infertile females to conceive and carry a pregnancy. Much of the reported data on posttransplantation pregnancy accrued before the advent of cyclosporine, when steroids and azathioprine were the mainstays of maintenance immunosuppression. One factor affecting pregnancy outcome in kidney recipients is the length of time from transplantation to conception or transplant interval. It has been recommended that patients wait at least 2 years posttransplantation to conceive, as transplant intervals of shorter duration have had less favorable outcomes. Some have suggested that extended transplant intervals (> 5 years) paradoxically result in adverse outcomes. We have extracted data on cyclosporine-treated recipients with transplant intervals longer than 5 years from the National Transplantation Pregnancy Registry, and report 17 pregnancies from 15 recipients (transplant interval, 5.9 +/- 0.9 years). There were 13 live births (76.5%) and four spontaneous abortions (23.5%). The mean gestational age was 37.7 +/- 2.04 weeks and mean birth weight was 2,753 +/- 679 g. Prematurity occurred in 30.8%, low birth weight in 15.4%, very low birth weight in 7.7%, and neonatal complications in 15.4%. There were no maternal or neonatal deaths. The mean serum creatinine before pregnancy was 1.31 mg/dL, and there was no significant change during or after pregnancy. There were no rejections during or up to 3 months postpartum. Graft survival at 2 years was 100%. We conclude that most pregnancy outcomes in cyclosporine-treated recipients with transplant intervals greater than 5 years are favorable for the newborn, recipient, and graft.

Ranitidine-Induced Acute Interstitial Nephritis With Epithelial Cell Foot Process Fusion

Although acute interstitial nephritis has been well described with the histamine H2-receptor antagonist cimetidine, we found only one previous case report of ranitidine-induced interstitial nephritis in the literature. We describe an additional patient who developed acute interstitial nephritis after taking ranitidine. Electron microscopy showed focal fusion of the epithelial cell foot processes that was not described in the previous report of ranitidine-induced interstitial nephritis.

Successful living donor renal transplantation despite ABO incompatibility and a positive crossmatch.

Abstract:u2002 Potential live kidney donors have been rejected when the prospective recipients are blood type or crossmatch incompatible. By utilizing plasmapheresis combined with intravenous immune globulin (PP/IVIg) prior to surgery, donor‐specific antibodies against blood group or human leukocyte antigens (HLA) have been removed, thereby allowing successful renal transplantation. A 26‐yr‐old male with a panel reactive antibody level of 100% and repeated positive crossmatches against deceased donor kidney offers, including zero HLA mismatched donors, successfully underwent ABO‐incompatible kidney transplantation from his HLA‐identical but nevertheless crossmatch‐incompatible sister. The initial anti‐A blood group isoagglutinin titers were 128, 256, and 1024 at room temperature, 37°C, and 37°C anti‐IgG enhanced, respectively. With an individualized PP/IVIg regimen based on donor‐specific antibody titer, however, the relevant antibodies were adequately reduced and hyperacute rejection avoided. Subsequent antibody‐mediated rejection, likely directed against a minor histocompatibility antigen, was diagnosed on postoperative day 7 and successfully treated. Neither ABO, or crossmatch incompatibility, or both in combination prohibit kidney transplantation.

Suppression of Secondary Hyperparathyroidism by Propranolol in Renal Failure Patients

Renal osteodystrophy in part due to secondary hyperparathyroidism, is one of the major unresolved problems affecting patients on chronic hemodialysis. In addition, evidence has shown that parathyroid hormone (PTH) is toxic to other organ systems besides bone. The results of a prospective study on the effect of propranolol in reducing PTH levels in chronic renal failure patients on hemodialysis are reported. Propranolol administration reduced PTH levels by over 50-75%. The levels of calcium, phosphorus, alkaline phosphatase and hematocrit were variable, but patients with severe derangements in these measurements also seemed to benefit from propranolol. It should now be determined by larger and longer studies whether these biochemical improvements can be translated into clinical benefits.

Association of IgA nephropathy with Clostridium difficile colitis

Immunoglobulin A (IgA) nephropathy, the most common cause of glomerulonephritis worldwide, is usually idiopathic in origin and renal limited. Secondary IgA nephropathy has been associated with systemic disease, including such gastrointestinal tract disturbances as celiac sprue and inflammatory bowel disease. We describe gross hematuria and reversible acute renal failure from IgA nephropathy in a patient with cephalosporin-induced Clostridium difficile colitis. In addition to mesangial IgA and C3 deposition, renal histological examination showed glomerular bleeding, intratubular red blood cell casts, and acute tubular necrosis. To the best of our knowledge, this is the first report of an association between IgA nephropathy and C difficile colitis.