Prescription medications and their influence on acute kidney injury presentation and outcomes.

BACKGROUND: Acute kidney injury (AKI) is a common clinical problem. An increase in the severity of AKI is associated with increased mortality and worse prognosis. Many patients presenting with AKI also take long-term medications that may potentially exacerbate or precipitate AKI. However, no study has examined the role of such medications on AKI outcomes. AIM: Our aim was to analyse use of chronic prescription medications by patients presenting with AKI and their impact on outcomes. METHODS: A retrospective study of discharge data identified 172 patients admitted to a tertiary level metropolitan hospital with a primary diagnosis of AKI over a 2-year period. Patient characteristics, medications that could precipitate or exacerbate AKI, and outcomes based on mortality, need for renal replacement therapy (RRT) and intensive care unit admission were analysed. RESULTS: Patients taking medications (69.2%) were older (P = 0.04) with more comorbidities such as: congestive cardiac failure (P < 0.001), chronic kidney disease (P < 0.001) and diabetes (P = 0.004) than patients not consuming any. Patients taking medications were less likely to be admitted with severe AKI (P = 0.01) or require RRT (P = 0.04). Multivariate logistic regression analysis did not show a significant impact of medications on outcomes. CONCLUSION: Prescription medication use in patients presenting with AKI is common. Despite being used in older patients with more comorbidities, these medications had no detrimental effect on need for RRT, intensive care unit admission or mortality, and were associated with a decrease in the incidence of severe AKI.

Efficacy of once-weekly epoetin alfa.

BACKGROUND: Patients with end-stage renal disease requiring hemodialysis are frequently treated with epoetin alfa (recombinant human erythropoietin, rHuEPO) for anemia. The aim of this study was to determine whether successful management of anemia could be maintained by changing the dosing schedule of epoetin alfa from 2 or 3 times per week to once-weekly administration via not only the subcutaneous (s.c.) but also the intravenous (i.v.) route. METHODS: Patients included in the study had hemodialysis for > 12 months, treatment with epoetin for > or = 6 months and adequate iron stores. The study consisted of a pre-study period (12 weeks), Phase I (4 weeks, patients continued prestudy regimen), Phase II (12 weeks, once-weekly i.v. or s.c. regimen with dose adjustments permitted to maintain target hemoglobin (Hb) concentrations) and Phase III (4 weeks, once-weekly i.v. or s.c. regimen without dose adjustments). RESULTS: The study was completed by 203 patients (per-protocol population: i.v. group, n = 115, s.c. group, n = 88). In the majority of patients (69.4% overall: i.v. group, 67.0%, s.c. group, 72.7%), the individual Phase I Hb concentrations were maintained within +/-1.0 g/dl (+/-10 g/l) during Phase III. In 79.3% of the patients (i.v. group, 75.7%, s.c. group, 84.1%), a stable Hb concentration (decrease of < or = 1 g/dl (< or = 10 g/l)) was maintained without statistically significant dose adjustments (82.4+/-33.8 - 86.8+/-42.1 IU/kg body weight/week). Hb concentrations decreased from 11.57+/-0.83 g/dl(115.7+/-8.3 g/l) in Phase I to 11.39+/-1.09 g/dl (113.9+/-10.9 g/l) in Phase III (p < 0.05) in the entire group. The weekly dose of epoetin alfa required to maintain the individual target Hb concentrations changed from 85.1+/-34.6 IU/kg in Phase I to 92.1+/-45.1 IU/kg in Phase III in the entire population (p <0.05). CONCLUSIONS: With once-weekly administration of epoetin alfa, Hb concentrations can be maintained in the majority of stable hemodialysis patients, and only minimal dose adjustments are required.

Advanced donor-origin melanoma in a renal transplant recipient: immunotherapy, cure, and retransplantation.

BACKGROUND: A kidney transplant recipient inadvertently contracted donor-origin melanoma, which was found to be very advanced at presentation. Withdrawal of immunosuppression failed to induce rejection, and interferon-alpha was required. When florid allograft rejection was in progress, the allograft was removed, before it was recognized that the transplanted melanoma was not being simultaneously rejected. METHODS: Subsequent immunotherapy was required, which largely recapitulated treatment of recognized value in autologous melanoma and included interferon-alpha, use of cultured melanoma cells as tumor vaccine, pooled allogeneic cell vaccination, and adoptive immunotherapy using lymphokine-activated killer cells. RESULTS: Prolonged immunotherapy eradicated the widespread malignancy, and the patient went on to a successful second renal transplant, with follow-up of over 24 months. CONCLUSIONS: This unique case demonstrates the successful cure of advanced transplanted melanoma through the use of immunotherapy, which did not require sophisticated tumor vaccine technology, and successful retransplantation.

Effect of OKT3 in steroid-resistant renal transplant rejection.

Between January 1, 1982, and November 1, 1986, 169 cadaver renal graft transplantations were performed at this hospital with CsA as induction therapy. OKT3 was not available in this period. Of these grafts, 15.9% were lost within 6 months, 10.7% from acute rejection (AR). Between November 1, 1986, and October 1, 1992, 483 cadaver renal graft transplantation were performed. Induction therapy included CsA and OKT3 was available. Of these grafts, 8.7% were lost inside 6 months, 3.1% from AR. Of these last 483 grafts, 113 received 125 courses of OKT3. Ten courses were prophylactic, and 115 courses in 103 patients were for rejection resistant to steroid therapy (biopsy proven in all but 2 cases. Ninety-three percent of rejection episodes treated with OKT3 responded, at least initially. Graft survival in OKT3-treated patients was 81%, 77%, and 76% at 6 months, 1 year, and 2 years, respectively. In contrast, graft survival in steroid-resistant rejection during the first period (without OKT3) was 59%, 57%, and 57% at these intervals. There were 8 infective deaths within 6 months in the 113 OKT3-treated patients, compared with 2 in the 343 who did not receive OKT3 (P < 0.001). There were 7 viral deaths in the OKT3 group compared with none in those not receiving OKT3 (P < 0.001). Prophylaxis with oral acyclovir and cotrimoxazole was instituted in October 1990 in OKT3-treated patients and ganciclovir use was increased. Since this change, no further viral deaths have occurred. OKT3 is a very effective antirejection agent, but its use is associated with an increased mortality from viral infections. With appropriate prophylaxis and treatment, however, this mortality can be reduced.

Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans.

To investigate the possible role of cytokines in the mediation of glomerular injury in the nephrotic syndrome, the levels of interleukin (IL)-1 beta, IL-2, interferon (IFN)-alpha, IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha) were measured in patients with primary nephrotic syndrome. These patients had minimal change nephropathy (MCN), focal and segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN) on biopsy. Cytokine levels were assessed by immunoradiometric assays, and specimens consisted of plasma, urine, and the culture supernate of mitogen-stimulated peripheral blood mononuclear cells (PBMC). Only TNF-alpha was found to be significantly elevated, in the plasma and urine of patients with FSGS and MN, above that found in healthy control subjects and patients with MCN. The elevation of TNF-alpha could not be shown to correlate with the length or severity of the nephrotic syndrome or with loss of body mass. IL-1 beta, IL-2, IFN-alpha, and IFN-gamma levels were not elevated. In culture, mitogen-stimulated PBMC from all three groups of nephrotic subjects released an excess of TNF-alpha compared with controls, a response not consistently observed for the other cytokines measured. The findings of this survey of cytokine levels in nephrotic patients support the possibility that TNF-alpha may play a pathogenic role in the induction or maintenance of glomerular barrier dysfunction in humans.

Lymphocyte adhesion molecules in T cell-mediated lysis of human kidney cells.

The complementary adhesion molecules LFA-1 (CD11a, 18)/ICAM-1 (CD54) and LFA-2 (CD2)/LFA-3 (CD58) have been shown to be important in T cell interaction with lymphoid target cells. The role of these ligand pairs in cytotoxicity against somatic cells is less well established. While LFA-3 is expressed by all cells in the kidney, ICAM-1 expression is low in normal kidneys but is increased in allograft rejection. An in vitro cytotoxicity assay was used to examine the relative importance of the two adhesion ligands in immune damage against kidney cells in rejection. HLA-A2 specific cytotoxic T lymphocyte (CTL) recognition of cultured human kidney cells (HKC), of predominantly renal tubular cell origin, was studied. Immunofluorescence studies showed that both induced and uninduced HKC target cells expressed ICAM-1, MHC class I and LFA-3, but only MHC class I and class II antigens and ICAM-1 were significantly upregulated by cytokine induction. Effector cells expressed LFA-1 and LFA-2 but little or no ICAM-1 and LFA-3. Cytokine induction of ICAM-1 expression on HKC target cells increased their susceptibility to lysis. Monoclonal antibody against ICAM-1 or LFA-1 produced the greatest inhibition of HKC lysis, and their effects were not additive. Antibody against LFA-2 (CD2) or LFA-3 also produced significant inhibition, but to a lesser degree, and no additive effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Current status of renal transplantation.

The success rate of renal transplantation has improved considerably during the past decade, with substantial improvements in both graft and patient survival. The quality of graft function, however, and not graft survival alone is increasingly determining the standards by which transplantation outcome is being judged. As the demand for kidney transplants continues to rise and transplants are being offered to an ever-increasing number of patients, organs are being sought from new supply pools and efforts are being made to use current resources more efficiently. Improvements in clinical management have allowed short-term complications such as infection and rejection to be better prevented or better diagnosed and treated. Fundamental advances in the understanding of the immunologic processes underlying both allograft rejection and acceptance and the introduction of new immunosuppressive agents have allowed a better use of drug therapy and have moved the goal of acquired transplant tolerance closer to attainment. With improved initial transplant success rates, the long-term transplantation outcome is becoming more important. The role of tissue matching in preventing chronic rejection is becoming more appreciated, and the long-term risks of malignancy, arteriosclerosis, and chronic rejection are being better recognized and managed.

Immunomodulation of human fetal cells by the fungal metabolite gliotoxin.

Gliotoxin (GT) is a fungal metabolite that reduces the ability of murine macrophages to react immunologically in vitro. It is also capable of modulating the immunogenicity of murine bone marrow cells, so that the onset of graft-versus-host disease in fully allogeneic bone marrow chimeras is delayed. The present study examines the effect of GT on human fetal cells, both in terms of reduction of immunogenicity and toxicity. GT (10 micrograms/ml) significantly decreased the responsiveness in mixed lymphocyte cultures of cells derived from human fetal pancreas, spleen, liver and bone marrow. This concentration of GT was, however, mildly toxic to explants of the pancreas, with a significant reduction in insulin secretion from this tissue during the first day of its organ culture, but not thereafter. GT-treated pancreatic explants were lighter and contained less insulin than the untreated controls 3 months after the tissue had been implanted beneath the renal capsule of nude mice. This difference was not apparent 3 weeks after transplantation into these animals. It is hypothesized that the immunomodulating effect of GT (at a concentration less than 10 micrograms/ml) may be of benefit in treating allografted human fetal pancreas before it is transplanted, as it has for murine adult bone marrow cells.

Expression of HLA antigens on renal tubular cells in culture. I. Evidence that mixed lymphocyte culture supernatants and gamma interferon increase both class I and class II HLA antigens.

The altered expression of HLA antigens on tissues during rejection is of potential importance to both the initiation and effector arms of the alloimmune response. Associated with rejection episodes, renal tubular cell expression of HLA DR (class II) antigens has been observed to be markedly increased. In this study an in vitro assay using cultured renal tubular cells from normal human kidneys was developed. Monoclonal antibodies to detect HLA DR and HLA A,B,C (class I) molecules were used to identify these antigens on cultured tubular cells either by indirect immunofluorescence stains and flow cytometric analysis or by immunoperoxidase stains with cytological analysis. With these techniques normal cultured cells had little membrane or cytoplasmic HLA DR but did have membrane HLA A,B,C. Culture of renal tubular cells with either supernatants from mixed lymphocyte cultures or purified gamma interferon induced expression of HLA DR, with maximum expression occurring between day 4 and day 6. Increased HLA A,B,C expression was also observed. This increased expression of HLA antigens was shown not to be dependent upon increased cell division of the cultured cells, and removal of gamma interferon from the cultures resulted in a decay in both HLA DR and A,B,C expression within days. HLA expression was inhibited by addition of protein synthesis inhibitor cycloheximide, but not by the addition of puromycin, mitomycin C, or actinomycin D--which suggested that tubular cells had transcribed m RNA for both HLA DR and A,B,C antigens. Expression of HLA antigens was not inhibited by cyclosporine, corticosteroids, or azathioprine. These studies demonstrate that the increased expression of HLA antigens seen in renal allografts at the time of rejection episodes can be explained by the release of lymphokines, especially gamma interferon, by infiltrating cells, and that reduced HLA DR expression of transplanted kidneys in patients treated with cyclosporine is not due to the drug directly inhibiting HLA expression by graft cells.

Effects of verapamil in the prevention of warm ischaemia induced acute renal failure in dogs.

Acute renal failure in the immediate postoperative period remains a significant complication of renal transplantation. A major factor in the pathogenesis may be warm ischaemia (WI). Recent evidence implicates a calcium mediated mechanism as a final common pathway in certain models of acute renal failure. This study was undertaken to evaluate the effects of Verapamil, a calcium antagonist, in the prevention of warm ischaemia-induced acute renal failure following renal autotransplantation in the dog. Twenty-one mongrel dogs were randomly allocated to three groups. Group 1 (control, 8 dogs) received 20 ml normal saline before a standardized 60 min warm ischaemic insult to the left kidney. Group 2 (6 dogs) received Verapamil (0.3 mg/kg) by intravenous injection and Group 3 (7 dogs) received Verapamil (0.3 mg/kg) by intra-arterial injection into the left renal artery prior to the same ischaemic insult. The left kidney was heterotopically grafted to the right iliac fossa in the warm ischaemic period. Contralateral nephrectomy was performed. The dogs were followed up to 7 days after operation by serial creatinine estimation. Histological examination of some autografts was performed. Of the eight controls, six showed marked renal impairment (serum creatinine greater than 800, or death in renal failure). Three of the six dogs given intravenous Verapamil showed marked renal impairment. None of the seven dogs receiving intra-arterial Verapamil showed marked renal impairment (P = 0.013, chi 2 test). The mean rate of serum creatinine rise for each group was analysed by multivariate analyses of variance.(ABSTRACT TRUNCATED AT 250 WORDS)