Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group.

BACKGROUND: Cytomegalovirus (CMV) disease is a major complication of organ transplantation. We hypothesized that prophylactic treatment with valacyclovir would reduce the risk of CMV disease. METHODS: A total of 208 CMV-negative recipients of a kidney from a seropositive donor and 408 CMV-positive recipients were randomly assigned to receive either 2 g of valacyclovir or placebo orally four times daily for 90 days after transplantation, with the dose adjusted according to renal function. The primary end point was laboratory-confirmed CMV disease in the first six months after transplantation. RESULTS: Treatment with valacyclovir reduced the incidence or delayed the onset of CMV disease in both the seronegative patients (P<0.001) and the seropositive patients (P=0.03). Among the seronegative patients, the incidence of CMV disease 90 days after transplantation was 45 percent among placebo recipients and 3 percent among valacyclovir recipients. Among the seropositive patients, the respective values were 6 percent and 0 percent. At six months, the incidence of CMV disease was 45 percent among seronegative recipients of placebo and 16 percent among seronegative recipients of valacyclovir; it was 6 percent among seropositive placebo recipients and 1 percent among seropositive valacyclovir recipients. At six months, the rate of biopsy-confirmed acute graft rejection in the seronegative group was 52 percent among placebo recipients and 26 percent among valacyclovir recipients (P=0.001). Treatment with valacyclovir also decreased the rates of CMV viremia and viruria, herpes simplex virus disease, and the use of inpatient medical resources. Hallucinations and confusion were more common with valacyclovir treatment, but these events were not severe or treatment-limiting. The rates of other adverse events were similar among the groups. CONCLUSIONS: Prophylactic treatment with valacyclovir is a safe and effective way to prevent CMV disease after renal transplantation.

Evolving strategies in immunosuppressive therapy: the Emory experience.

We have reviewed our experience with various immunosuppression regimens over the past 11 years in 2,065 renal transplant recipients. Patients received triple-drug maintenance therapy with CsA, imuran and prednisone following either no induction therapy or treatment with polyclonal (PCA) or monoclonal (MCA) antibody. The most recent immunosuppressive regimen has included CsA, MMF, and prednisone without induction therapy. We observed that those patients receiving PCA had a better graft survival 5 years after transplantation than recipients with MCA induction or those receiving standard triple drug therapy without induction. Patients receiving MMF experienced superior one-year graft survival compared with those receiving induction with PCA, MCA or standard triple drug therapy. A similar one-year graft survival rate for both Black and White recipients was observed in the MMF group and raises the possibility of achieving improved long-term graft survival in Black recipients with a MMF-based immunosuppression strategy. Our experience indicates that excellent short-term graft survival can be achieved with an immunosuppressive protocol of MMF, CsA and prednisone without induction. Graft survival in MMF-treated recipients was equal to or superior to that which we previously achieved with induction therapy.

Hyponatremia and ultramarathon running.

Two ultramarathon runners were hospitalized with hyponatremic encephalopathy after completing 80 and 100 km (50 and 62 miles), respectively, of the 1983 American Medical Joggers Association ultramarathon race in Chicago. The two runners consumed such large quantities of free water during the race that apparent water intoxication developed. Both recovered satisfactorily after treatment with intravenous saline. The hyponatremia was caused primarily by increased intake and retention of dilute fluids and contributed to by excessive sweat sodium loss. A possible explanation for the postrace onset of symptoms might be the sudden absorption of fluid in the gastrointestinal tract after exercise ceased, with subsequent further dilution of the plasma sodium. Hyponatremia, which has not been commonly associated with exercise, should be considered as a possible consequence of ultraendurance events.

Bioequivalence of a slow-release potassium tablet and a liquid potassium supplement.

The rate and extent of potassium absorption from a slow-release potassium chloride tablet and a 10% potassium chloride solution were compared in 12 healthy male volunteers, 18-25 years old. A single 48 mEq potassium dose of the tablet released potassium 30 min slower than the same dose of potassium chloride solution. Potassium was completely absorbed from both preparations within 24 h. Complete absorption was confirmed by quantitative determination of fecal potassium excretion. Gastrointestinal tolerance was good with both preparations, although the incidence of adverse experiences was slightly higher with the liquid preparation. "Bad taste" was not associated with the slow-release tablet; 92% of the subjects reported "bad taste" with the potassium chloride solution.

The basilic vein fistula for vascular access.

The basilic vein fistula provides reliable vascular access for chronic hemodialysis therapy. Early morbidity includes edema and mild pain. Ischemic complications have not developed in this series. Patency has been excellent in the initial period and no patient has yet developed infection, aneurysm or venous fibrosis, although longer follow-up is necessary. The use of the autogenous basilic vein fistula in patients unsuited for forearm arteriovenous fistulae is supported by these results. Long-term results which would support continued use of this modality would include an expected lower incidence of infection due to the absence of a foreign body and the inherent healing property of viable tissue, and improved long-term patency attributable to the absence of a venous anastomosis.

Single and multiple drug therapy in autologous immune complex nephritis in rats.

Autologous immune complex (AIC) nephritis is a form of chronic renal disease with remarkable similarities to idiopathic membranous nephropathy occurring in man. AIC nephritis was induced in 160 gram Lewis rats with a single footpad injection of tubular brush-border antigen (FxIA) in complete Freund's adjuvant. When killed at 8 weeks, 85 per cent of the rats demonstrated typical diffuse glomerular deposits of immunoglobulin G and B1C (C1/3 component of complement) by immunofluorescent microscopy, and subepithelial electron-dense deposits by electron microscopy. Both immune complex disease and significant proteinuria occurred in two-thirds of these animals. An attempt to modify the natural course of established AIC nephritis using large doses of potent glucocorticoids (methyl-prednisolone), anti-inflammatory agents (acetylsalicylic acid, indomethacin, and cyproheptadine), and immunosuppressive drugs (cyclophosphamide, azathioprine) was begun 4 weeks after initial immunization and continued for 4 more weeks. None of the single drug nor multiple drug protocols employed was of demonstrable benefit in ameliorating the immune events operating in AIC nephritis. Cyclophosphamide and indomethacin, when used singly, were associated with significant mortality in the animals studied. All combined drug protocols involving glucocorticoids and antimetabolites were associated with unacceptable mortality as well. Of interest, immune complexes could not be demonstrated in the vascular choroid plexus of any rat with AIC nephritis. This failure to modify the course of established renal disease (AIC) in an experimental animal with generally available pharmacologic agents, is similar to the usual results of such treatment in chronic renal disease (idiopathic membranous nephropathy) in man. It is possible that new and more potent anti-inflammatory agents employed singly or in various combinations, will permit more successful manipulation of the host's immunologic system to prevent or modify immune injury of the renal glomerulus.

The effect of chronic hypotonic volume expansion on the renal regulation of acid-base equilibrium.

Balance studies have been carried out to evaluate the influence of vasopressin-induced volume expansion on acid-base equilibrium in normal dogs and in dogs with steady-state metabolic acidosis induced by the administration of 5-7 mmoles/kg per day of hydrochloric acid.Hypotonic expansion in dogs with metabolic acidosis (mean plasma bicarbonate concentration 14 mEq/liter) produced a marked increase in renal acid excretion that restored plasma bicarbonate concentration to normal (20-21 mEq/liter) despite continued ingestion of acid. When water was restricted during the vasopressin period, and fluid retention thus prevented, no increase in acid excretion or plasma bicarbonate concentration occurred. From these findings we conclude that hypotonic expansion is a potent stimulus to renal hydrogen ion secretion and greatly facilitates the renal removal of an acid load. Normal dogs subjected to expansion demonstrated no change in net acid excretion or in plasma bicarbonate concentration even in the face of a marked diuresis of sodium and chloride and a reduction in plasma sodium concentration to approximately 110 mEq/liter. The animals did, however, regularly lose potassium, a finding that clearly indicates an acceleration of distal sodiumcation exchange. On the basis of these observations, and the findings in the expanded acidotic dogs, we suggest that in the expanded normal dogs acceleration of sodium-hydrogen exchange was responsible for preventing a bicarbonate diuresis and for stabilizing plasma bicarbonate concentration. These studies clearly demonstrate that chronic hypotonic expansion exerts a major influence on the renal regulation of acid-base equilibrium. The exact nature of the mechanism responsible for the increase in sodium-hydrogen exchange during hypotonic expansion remains to be determined.