John D. Whelchel

Inhibition of Angiotensin-Converting Enzyme in Renal-Transplant Recipients with Hypertension

HYPERTENSION has a high prevalence among recipients of renal allografts.1 , 2 Such post-transplantation hypertension may contribute3 , 4 to the high mortality from atherosclerotic vascular disease ...

Treatment of secondary hyperparathyroidism in patients with chronic renal failure by total parathyroidectomy and parathyroid autograft.

Sixty-one patients with chronic renal failure and secondary hyperparathyroidism underwent total parathyroidectomy and parathyroid autograft. Symptoms relieved by parathyroidectomy included bone pain, pruritus, soft tissue calcification, muscle weakness and healing of fractures. Serum parathormone levels measured before and after operation in 48 patients returned to normal in all but two patients. Serum alkaline phosphatase levels also returned toward normal after operation, except in one patient with a retained parathyroid gland. Complete radiographic studies before and after operation were available in 30 of 61 patients. Twenty-three of 24 patients with osteitis fibrosa had evidence of healing, and in one patient no change occurred. Osteosclerosis noticed in 23 patients improved slightly in eight patients, did not change in 14 and became worse in one. Pathologic examinations revealed 45 patients to have diffuse hyperplasia and 16 nodular hyperplasia. There were two early postoperative deaths, in the first 30 days, and 16 late postoperative deaths, from four months to four years afterward. In no case did the operation contribute to the death. Some patients required the administration of supplemental calcium after operation, but in no instance did profound hypocalcemia occur. No patient developed recurrent hyperparathyroidism.

Pharmacology, tolerance, and antiviral activity of vidarabine monophosphate in humans.

Vidarabine (adenine arabinoside) is a purine nucleoside useful in humans for therapy of herpes simplex virus encephalitis and herpes zoster virus infections in immunocompromised patients. However, the potential usefulness of vidaribine is limited by its poor solubility, which requires continuous infusion in relatively large volumes of intravenous fluid. Vidarabine 5′-monophosphate is highly soluble and has the advantage that it can be administered intermittently intramuscularly or intravenously. In a clinical, pharmacokinetic study, plasma levels and urinary excretion of vidarabine 5′-monophosphate were determined after intravenous and intramuscular administration in 29 immunosuppressed patients with herpes simplex or zoster virus infections at dosages of 15 to 30 mg/kg per day administered for 5 days. As determined by high-pressure liquid chromatography, vidarabine 5′-monophosphate was metabolized in a fashion comparable to the metabolism of vidarabine and its major metabolite in plasma was arabinosyl hypoxanthine. After administration, 40 to 50% of the vidarabine 5′-monophosphate was recovered from the urine as arabinosyl hypoxanthine, and 3 to 4% was recovered as vidarabine. Determinations of areas under the curve for arabinosyl hypoxanthine were not statistically different by dosage for intramuscular or intravenous routes of administration. At all dosages studied, viral clearance appeared to occur with therapy. The advantage of increased solubility will lead to controlled clinical investigations in which vidarabine 5′-monophosphate is administered by intramuscular or intravenous routes against targeted human herpesvirus infections.

Mucocutaneous herpes simplex virus infections in immunocompromised patients: A model for evaluation of topical antiviral agents☆

Forty-three immunocompromised patients with progressive cutaneous herpes simplex virus infections were studied in a double-blind, placebo-controlled evaluation of topically applied acyclovir. Patients were randomized and 22 received acyclovir and 21 placebo; medications were applied four times daily for 10 days. Both study populations were balanced for all demographic characteristics. Acyclovir therapy resulted in no median differences in time to total healing compared with placebo responses, p = 0.13. However, those patients who received the acyclovir ceased shedding virus more rapidly, p less than 0.001, and lost pain more readily, p = 0.04, than placebo counterparts. Neither group experienced adverse effects. Because of the protracted nature of mucocutaneous herpes simplex infections in these patients, the immunocompromised host provides a good model for evaluation of topical antiviral therapy.

Aggressive therapy of infants with renal failure

Nine infants, who presented with renal failure within the first 3 months of life, were treated with continuous ambulatory peritoneal dialysis (CAPD). Seven infants survived to an age of 12–15 months, when they received transplants. Two patients died while on CAPD. Six infants are alive with a functioning renal allograft, at an average age of 35.5 months and an average of 22 months post-transplant. Neurological development is normal in four of the six infants tested. The mean current height of the six transplant recipients is just below 2 SD from the mean.

Effect of primary and recurrent cytomegalovirus infections upon graft and patient survival after renal transplantation.

One hundred sixty-four patients were prospectively studied for evidence of cytomegalovirus (CMV) infection after renal transplantation to determine the effect of primary and recurrent CMV infection on early graft and patient survival. Primary infections occurred in 62% (21 of 34) of pretransplant seronegative recipients and recurrent infection in 93% (121 of 130) of seropositive recipients. Symptomatic infections occurred in 81% (17 of 21) of primarily infected and 31% (37 of 121) of recurrently infected recipients. CMV infections (determined by initial virus excretion) occurred in 86% of the primarily infected and 96% of the recurrently infected symptomatic recipients by the 9th post-transplant week. In contrast, only 53% of nonsymptomatic recipients excrete virus by the 9th week. Primarily infected recipients experienced a significantly lower graft survival at 6 months than uninfected seronegative or recurrently infected patients. However, there was no significant difference in patient or graft survival at 1 year. Recipients who developed recurrent symptomatic infections had a significantly lower graft and patient survival than those recipients who developed nonsymptomatic recurrent infections (P < 0.0002 patient survival and P < 0.001 graft survival at 12 months).

Hypertension after successful renal transplantation.

Thirty-three renal allograft recipients who had high blood pressure (mean arterial pressure more than 105 mm Hg) at least one year after their successful transplant operation were compared with 23 normotensive kidney transplant recipients (mean arterial pressure less than 105 mm Hg) at the General Clinical Research Center. The patients with higher blood pressure had markedly and significantly higher (96 percent) renal vascular resistance and significantly lower (41 percent) renal plasma flow. Responses to salt loading and restriction were suggestive of marked activity of the renin-angiotensin system as were plasma renin activity measurements. Subsequent follow-up has revealed chronic rejection or renal artery stenosis as a probable cause of hypertension for 11 of the 33 patients. The remaining 22 patients had increased renal vascular resistance and decreased renal plasma flow indistinguishable from that in the 11 patients in whom follow-up revealed a cause for their persistent hypertension; however, 21 of these 22 patients have their native kidneys in place.

Progressive Multifocal Leukoencephalopathy: Three Patients Diagnosed by Brain Biopsy, with Prolonged Survival in Two

Since 1980, three immunocompromised patients have been proved to have progressive multifocal leukoencephalopathy (PML) by brain biopsy at the University of Alabama at Birmingham. Two patients presented with focal neurological findings, and the third presented with dementia. Computed tomography (CT) revealed white matter low density lesions in areas appropriate to the neurological abnormalities. Brain biopsy of areas that were abnormal on CT produced diagnostic tissue in all three patients. No patient suffered ill effects from the biopsy. Neuropathological findings on light microscopy were compatible with PML in each case, although there was diversity within the group. Involvement of gray and white matter was present in all biopsy specimens; oligodendrocytes, astrocytes, and neurons were affected. Electron microscopic demonstration of particles compatible with polyoma virus confirmed the diagnosis in each case. Immunosuppressive medication was discontinued in two of the patients; these two have survived more than 2 years after diagnosis. One of these two has gradually improved and is independent in simple activities of daily life. Brain stem and cerebellar involvement and seizure disorders have been present in all reported cases. PML can be accurately and rapidly diagnosed by brain biopsy, enabling therapeutic manipulations that may prolong survival.

Efficacy of OKT3 monoclonal antibody therapy in steroid-resistant, predominantly vascular acute rejection: a report of three cases with morphologic and immunophenotypic evaluation

We describe three patients who became oliguric and uremic in the early posttransplantation period. Following treatment with pulse methylprednisolone, all had biopsy evidence of severe residual rejection that was predominantly vascular. T cells formed the bulk of the infiltrates. Subsequent treatment with the monoclonal antibody OKT3 was associated with an immediate diuresis and improvement in serum creatinine. Repeat renal biopsy, obtained in clinical remission, in two of the three patients, showed marked improvement in the vascular lesions. All three patients maintain normal renal function 9, 13, and 18 months later. We conclude that OKT3 was effective in reversing steroid-resistant rejection despite a predominantly vascular pattern of cellular infiltration not usually considered amenable to any antirejection therapy.

Mechanisms of Posttransplant Hypertension

Posttransplant hypertension is an important risk factor for cardiovascular mortality and graft function. We performed metabolic studies in 35 hypertensive patients with well-maintained graft function on maintenance immunosuppressive drugs and in 17 normotensive control transplant recipients. The group of hypertensive recipients were characterized by increased peripheral plasma renin activity, lack of change in blood pressure in response to salt loading and restriction, and by increased peripheral and renal resistance. In contrast, on the same protocol in a group of patients with essential hypertension, blood pressure fell significantly on a low-salt intake. Peripheral resistance in hypertensive transplant recipients fell in response to saline loading, in contrast to the effects in normotensive transplant recipients. Hypertensive patients with retained native kidneys as compared to those who had these removed prior to transplant, but were still hypertensive, differed only with regard to reduced renal plasma flow in the former group. These data are consistent with a predominantly renin-dependent hypertension in these renal transplant recipients. When bilateral nephrectomy or repair of graft renal artery stenosis is being considered, response to captopril may offer a means of selection; acute renal failure on captopril suggests functionally significant renal artery stenosis.