CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine.

The CYP3A5*1 allele has been linked to high expression of CYP3A5 and metabolism of cyclosporine. We evaluated the role of CYP3A5*1 for long-term survival in renal transplant patients in a cohort of 399 patients who underwent cadaveric or living donor kidney allograft transplantation. All patients were treated with a similar cyclosporine-based immunosuppressive maintenance therapy protocol. The mean duration of follow-up was 8.6+/-3.7 years. In univariate survival analysis, the presence of the CYP3A5*1 allele in recipients significantly increased patient survival P=0.028 (log-rank), resulting in a hazard ratio (HR) of 0.52 (95% CI=0.29-0.94). When the presence of the CYP3A5*1 allele was included in multivariate Cox regression analyses accounting for major risk factors for patient death, CYP3A5*1 still conferred a protective effect. Further, haplotype analysis at the CYP3A5 locus confirmed that CYP3A5*1 might indeed be responsible for this survival benefit.

Pharmacokinetics of methylprednisolone and rejection episodes in kidney transplant patients.

Rejection crises after kidney transplantation could be associated with individual variability of pharmacokinetic parameters of steroids. We therefore investigated the individual pharmacokinetics of methylprednisolone on day 2 (60 mg intravenously) and day 4 (60 mg per os) in 40 patients after kidney transplantation. Methylprednisolone was determined in serum by HPLC. Within 6 months, all rejection episodes were recorded and confirmed by kidney transplant biopsy. Values are given as nonparametric medians with the 95% confidence interval (0.95 CI). The 7 patients with a rejection within the first 10 days had a methylprednisolone clearance of 437 ml/min (162-756) that was significantly higher than the 220 ml/min (121-604) in the 22 patients without a rejection episode (P = 0.04). In the complete group of 18 patients having a transplant rejection episode within 6 months, the methylprednisolone elimination half-life after oral dosage was 2.5 hr (1.6-3.9) and significantly shorter than 2.9 hr (1.7-4.0) in 22 patients without rejections (P = 0.03). No differences were seen for body weight, number of mismatches, cold ischemia time, immunosuppressive regimens, and other pharmacokinetic parameters of methylprednisolone (e.g. bioavailability, distribution volume, trough levels). We conclude that pharmacokinetic variability may contribute to the lack of immunosuppressive efficacy in patients with a short halflife of steroids. Therefore, a twice daily dose fraction might be useful for low-dose steroid regimens in kidney transplantation.

Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation.

Besides rejection-induced transplant glomerulopathy de novo membranous glomerulonephritis (MGN) is the most frequent cause of nephrotic syndrome after renal transplantation. We evaluated 1029 renal transplantations (271 without and 758 with cyclosporine treatment), performed on 848 patients between 1970 and 1992, which resulted in 872 functioning grafts. De novo MGN was seen in 30 biopsy specimens from 21 patients (about 2%), of whom 10 had received immunosuppressive treatment without and 11 with cyclosporine. Taking into account the longer periods of observation of patients without compared with those with cyclosporine treatment (88 +/- 60 vs. 41 +/- 31 mo., respectively, P = 0.001), the two treatment groups did not differ significantly in prevalence of de novo MGN (4.0% vs. 1.5%). De novo MGN was diagnosed by biopsy 62.7 +/- 44.4 mo. after transplantation; its incidence increased significantly with time (from 0% to 5.3% over 8 years; 95% confidential interval: 1.7-8%). Proteinuria (mean, 3.2 +/- 2.9 g/L) was first observed 47.5 +/- 51.3 mo. after transplantation. Thirteen of the 21 patients (62%) were nephrotic (proteinuria, over 1.5 g/L). Steroid pulses were given to 12 patients with de novo MGN and high proteinuria, which did not decline after treatment. Signs of chronic viral infection (hepatitis B antigen, hepatitis C antibody, or human immunodeficiency virus antibody) were found in 8 of the 21 patients (38%). Signs of vascular or interstitial rejection were seen in 17 and 12 of the 21 patients with de novo MGN, respectively, and cyclosporine arteriolopathy was diagnosed in four. Graft loss occurred in 14 of the 21 patients and was due to rejection in 13 and to de novo MGN in only one, who developed additional transplant vein thrombosis. Patients with de novo MGN did not differ significantly from the other 851 patients in graft survival (71.4 +/- 9.9% vs. 60.8 +/- 2.2% after 5 yr). De novo MGN is a late, often asymptomatic, complication of initially well tolerated grafts and is neither prevented by cyclosporine treatment nor reversed by further steroid medication. It is often associated with vascular changes caused by rejection or cyclosporine toxicity.

Human immunodeficiency virus transmission by organ donation. Outcome in cornea and kidney recipients.

The human immunodeficiency virus (HIV) is reportedly transmitted by sexual contact, sharing of infected needles among intravenous drug abusers, blood and blood products, artificial insemination, and kidney transplantation. This study reports on cornea and kidney recipients of two HIV-infected donors. HIV was transmitted to two kidney recipients who developed symptoms of acute HIV infection (i.e., fever, leukopenia, mild thrombopenia, splenomegaly) starting 12 days after transplantation. These signs of acute infection ended with seroconversion of HIV antibodies on approximately the 56th day after transplantation. The three cornea recipients showed no signs of acute infection and no HIV antibodies were detected up to three years after transplantation. The nontransmission observed in our cases, however, may not be representative of cornea transplantations in general. HIV is neurotropic in the later stages of the disease, and transmission of other neurotropic viruses like rabies and Creutzfeldt-Jakob disease by cornea transplantation has been reported. All tissue and organ donors should be tested for anti-HIV prior to donation.

The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation--data on four cases and review of the literature.

Two women and two men were infected with the human immunodeficiency virus type 1 (HIV-1) transmitted by renal transplantation from i.v. drug-addicted donors in 1984. The four recipients were treated with cyclosporine and methylprednisolone (one patient only for three months because of early graft failure). Two patients died 66 and 74 months after transplantation, one of endocarditis and one of cerebral hemorrhage. Despite several infections including urinary tract infection (n = 8), peritonitis (n = 1), shunt infection (n = 1), bronchitis (n = 1), salmonellosis (n = 1), herpes stomatitis (n = 2), herpes zoster (n = 1), and cytomegalovirus (n = 1), and despite treatment of several rejection episodes (n = 8), none of them had or has infections typical of the acquired immunodeficiency syndrome (AIDS). However, two patients developed cervical lymphadenopathy and one autoimmune thrombocytopenia 15-20 months after HIV-1 infection. Their T helper cell counts (355/microliters to 75/microliters) and helper/suppressor T cell ratios (1.0-0.2) are distinctly lowered. One patient has membranous glomerulopathy with virus-like particles within and on the outside of the basement membrane and tubuloreticular inclusions in glomerular endothelial cells. We evaluated the case reports of 53 patients with HIV-infection caused by an infected transplant or by blood transfusions during or shortly after transplantation. The cumulative incidence of AIDS was significantly lower in 40 transplant patients with an immunosuppressive regimen including cyclosporine than in 13 transplant patients receiving immunosuppressive treatment without cyclosporine (5-year cumulative risk of AIDS: 31% versus 90%, P = 0.001).

Effects of diltiazem upon metabolism and immunosuppressive action of cyclosporine in kidney graft recipients.

It is widely believed that calcium antagonists such as diltiazem exert immunosuppressive effects in kidney graft recipients--however, the mechanism is unclear. In a randomized controlled trial, kidney graft recipients who received diltiazem during transplantation and for an average of 12 months thereafter experienced significantly fewer rejection episodes than patients treated with cyclosporine and steroids alone. Furthermore, 1-year (97% vs. 85%) and 4-year (80% vs. 70%) graft survival rates were higher in diltiazem-treated patients, but the difference was not statistically significant. In vitro, diltiazem had little immunosuppressive activity. Concentrations of diltiazem which blocked the proliferation of PHA-stimulated human peripheral blood mononuclear cells, or prevented activation-associated accumulation of interleukin-2 mRNA, or p50- and p70-IL-2 receptor mRNA exceeded pharmacological concentrations by more than 100-fold. Both, CsA and high doses of diltiazem caused an increase of IL-6 mRNA. In contrast to these findings, the IL-6 plasma concentrations were comparable in both groups, whereas the serum concentration of soluble IL-2 receptors was decreased in patients treated with diltiazem. Administration of diltiazem caused an alteration of CsA metabolism. The whole-blood concentration of CsA metabolite 17 was significantly increased in diltiazem-treated patients, resulting in a five-times-higher concentration of this metabolite in the cellular blood compartment compared with the parent drug. Changes in metabolites 1, 8, and 18 levels were less pronounced. Although direct immunosuppressive properties of diltiazem are unlikely, diltiazem could support immunosuppression by altering CsA metabolism, and promoting accumulation of certain metabolites.

Effect of plasma exchange on the steady-state kinetics of digoxin and digitoxin.

The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state kinetics of digoxin (5 patients) and digitoxin (9) was investigated. For digoxin, an unchanged elimination half-life (28 hours) and only slight increase in the total body clearance was found (from 203 to 204 ml/min). There was a more pronounced effect on the kinetics of digitoxin, where the elimination half-life decreased from 4.3 to 3.6 days, and the total body clearance increased from 4.4 to 4.7 ml/min. For digoxin there was no statistically significant difference between observed and predicted steady-state trough plasma concentrations. For digitoxin, the observed trough plasma concentrations at steady-state correlated well (p less than 0.05) with the predicted concentrations calculated from the amount removed or from extracorporeal clearance. The magnitude of the kinetic effect of plasma exchange is overestimated using the extracorporeal elimination rate constant; but the effect of extracorporeal elimination can be adequately evaluated from the amount of drug removed and from extracorporeal clearance. These later approaches can be considered model-independent. Thus, the influence of multiple plasma exchanges on the steady-state kinetics of digoxin and digitoxin will be limited and dosage adjustment is not required, if these drugs are given after - not before - the procedure and hypoalbuminaemia is corrected.

Familial hemolytic-uremic syndrome in three generations.

The hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are complex entities characterized by microangiopathic hemolytic anemia, thrombocytopenia, and variable impairment of renal function, occasionally complicated by neurological symptoms. In both syndromes, rare instances of familial forms have been reported. We present the case of a family in which signs and symptoms of HUS/TTP appeared in three generations. We also briefly review the literature on inherited forms of HUS/TTP and discuss the outcome of renal transplantation in adult patients with this syndrome.

Saturable first-pass kinetics of propranolol.

Reduced bioavailability (F) due to hepatic first-pass extraction of an oral dose (D) is a well-known pharmacokinetic phenomenon. An integrated solution for Michaelis-Menten kinetics of the first-pass effect is derived from the maximal metabolic rate (Vm), volume of distribution (Vd), first order absorption rate constant (ka), Michaelis constant (Km), and liver blood flow (Q). F = 1 - VmVd/kaD ln (1 + kaD/QKm) This equation for single dosage can also be extended to steady state kinetics after multiple dosing in which the amount of a drug present in the hepatic circulation is considered. According to the literature, the bioavailability of a single 80 mg oral dose of propranolol (F = 0.22) increases after multiple doses Fss = 0.36). Based on the first pass equations for single dosage and multiple dosing, the maximal metabolic rate (Vm = 0.043 mg l-1 h-1) corresponding to 310 mg per day and the Michaelis constant (Km = 0.10 mg/l) were calculated for propranolol. Incorporation of nonlinear plasma protein binding in this concept may explain the lack of threshold phenomenon for a single dose of less than 40 mg propranolol. Zero order absorption kinetics could explain why cumulation kinetics seem linear even at an excessive dosage of 960 mg propranolol per day. From these derivations it may be concluded that multiple dosing, increase in plasma protein binding, high absorption rate, and increased portal venous blood flow will increase bioavailability, whereas slow release formulations, fractional drug dosage, and saturable absorption kinetics will decrease bioavailability of first-pass drugs like propranolol.

Aminoglycoside dosage in hemodialysis patients.

Regulating aminoglycoside dosage in patients undergoing hemodialysis is difficult because its elimination depends entirely on renal function and because the therapeutic margin is narrow. Guidelines for aminoglycoside dosage were derived from published population-based kinetics and investigated in a prospective clinical study over a 12-month period in 50 consecutive patients undergoing hemodialysis with acute (70%) or chronic (30%) renal failure. Based on body weight, each patient received one loading dose (1.5 mg/kg) and a daily maintenance dose (0.5 mg/kg) of netilmicin. The dosage interval was 24 hours. On each hemodialysis day, the dose of netilmicin was given immediately after hemodialysis. Each posthemodialysis dose (1.3 mg/kg) was the sum of the daily maintenance dose plus a supplementary dose to replace the amount of the drug removed during hemodialysis. A blood sample was taken at the start and the end of each hemodialysis and one hour after the start of the posthemodialysis dosage. Netilmicin plasma concentrations were determined by substrate-labeled fluorescence immunoassay. The mean (+/- standard deviation) peak plasma concentration of the pooled data for all patients was 7.5 +/- 2.7 mg/L, and the mean trough level was 3.6 +/- 1.3 mg/L. The theoretically postulated range of therapeutic peak levels (5-10 mg/L) was the same as in patients with normal renal function, whereas the theoretically postulated range of therapeutic trough levels (2.2-5.0 mg/L) was considerably higher than in healthy persons. Peak and trough levels within the postulated range were achieved in 81% of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of 5,6-trans-25-hydroxycholecalciferol in relative vitamin D resistancy.

The relative vitamin D resistance in patients with chronic renal failure and in those with hypoparathyroidism is due to an impairment of 1-hydroxylation of cholecalciferol. 5,6-trans-25OHCC, which has a similar steric configuration as 1,25(OH)2CC was examined at a daily dose of 18,000 IU fro 14 days in both diseases. Intestinal 47calcium absorption as well as serum calcium level could be normalized in most patients with hypoparathyroidism. The improvement was less in patients with chronic renal failure, suggesting an additional depressing influence of uremia on calcium metabolism.

The effect of Solanum malacoxylon on rachitic bone lesions in the rat.

The plant Solanum malacoxylon (S.M.) is known to cause severe soft tissue calcifications in cattle and sheep and has recently become of special interest since it exerts biological actions which resemble those of vitamin D. In order to investigate whether S.M. is capable to improve the rachitic bone changes in vitamin D and phosphate deficient rats, a watery extract of 50, 100 and 200 mg S.M. was fed daily to these animals over a period of 10 days. The width of epiphyseal plates was compared after the time with those of rats treates with 0, 0.225, 0.45, and 0.9 IU of vitamin D3 daily. There was a dose related curative effect of S.M. on the epiphyseal lesions very similar to that of vitamin D3. The hypercalcemic and hyperphosphatemic effect of S.M. was identical to that of vitamin D3. The 25-hydroxy-vitamin D serum levels remained almost undetectable in the S.M. treated rats as well as in the vitamin D3 treated animals.

Long-term treatment and prognosis of rapidly progressive glomerulonephritis.

Short-term prognosis of rapidly progressive glomerulonephritis (RPGN) has improved since immunosuppressive therapy was introduced. The long-term course of the disease was investigated in 46 consecutive and unselected patients over a period of 15 years (1970-1986) with a mean observation time of five years (+/- 45 months). Most of the 46 patients had idiopathic RPGN (61%). Initially, hemodialysis needed 25 of the 46 patients (54%). Immunosuppressive therapy (plasma exchange, methylprednisolone pulses, steroids, cyclophosphamide, azathioprine) was administered in 36 of the 46 patients (78%). A remission was achieved in only 19 of the 36 patients who received immunosuppression (53%) and no spontaneous improvement was seen. Factors indicating poor prognosis were initial high serum creatinine, high percentage of crescents in glomeruli, glomerular sclerosis, and immunohistologic staining of the IgG at the tubuli. In 11 patients with remission, immunosuppression was discontinued and 6 had a relapse. Long-term immunosuppression was given to 8 patients with remission. Their renal function was not normal (creatinine 240 +/- 77 mumol/l), but none had a relapse (p = 0.01). It is concluded that the treatment of RPGN requires long-term attendance and repeated immunosuppression comparable to a systemic immune disease.

Fatal cytomegalovirus pneumonia after preemptive antiviral therapy in a renal transplant recipient.

Cytomegalovirus (CMV) infections occur with an incidence of up to 70% in renal transplant patients and mortality is low due to effective antiviral drugs. We report here the case of a patient who suffered from an uncommonly severe and therapy-resistant pulmonary CMV infection. During the disease course, CMV-PCR from alveolar cells and lung biopsy material was repeatedly negative despite high CMV pp65 antigenemia. CMV pneumonia was finally diagnosed from a biopsy obtained by open thoracotomy revealing positive CMV immunostaining of lung tissue. The patient died of respiratory failure though double-treatment using both ganciclovir and foscavir was administered. Post mortem, the clinically suspected resistance to both antiviral drugs, but not to cidofovir, could be proven by bioassay testing of in vitro growth responses using viral cultures. CMV pneumonia may thus not be diagnosed by standard PCR techniques in rare cases and may be resistant to the available antiviral therapy. Severe CMV pneumonia may benefit from novel antiviral drugs such as cidofovir, which is currently used in the treatment of CMV retinitis in HIV patients.

Characteristics and clinical course of hemodialysis patients with analgesic-associated nephropathy.

The knowledge of some characteristic findings on the personality of patients with analgesic-associated nephropathy (AAN) may facilitate diagnosis of the disease at an early stage. We therefore investigated the 144 patients at our hemodialysis center and compared the AAN patients (33%) with those having other kidney diseases (controls). Patients with AAN were older (60 +/- 10 vs 52 +/- 15 years, p less than 0.001) and predominantly women. Acetaminophen and metamizol metabolites were detected more frequently in blood from the AAN patients than in that from the controls (25% vs 3%, p = 0.002). More AAN patients were smokers, and they more frequently complained of vague symptoms (pain, sensitivity to changes in weather, insomnia) and also more frequently requested prescriptions for analgesics, hypnotics, laxatives, stomachics and antipruritics. Because they were older, AAN patients had fewer occupational and financial problems. The compliance of the AAN patients was significantly better with respect to important dialysis parameters such as weight gain between dialysis treatments (3.6 +/- 1.3 vs 4.0 +/- 1.3% body weight, p less than 0.05) and diastolic blood pressure (81 +/- 12 vs 86 +/- 12 mmHg, p = 0.025). Despite an older age and higher morbidity, the cumulative 17-year survival rate of the AAN patients did not differ from that of the controls. We conclude that AAN patients have characteristic personality traits. Their better compliance, adjustment to the hemodialysis situation and social conditions are responsible for their good survival on hemodialysis.

Failure to show a correlation between serum parathyroid hormone, nerve conduction velocity and serum lipids in hemodialysis patients.

The proposed role of parathyroid hormone as an important agent for the development of certain uremic complications could not be confirmed in studies correlating, in dialysis patients, the nerve conduction velocity and the serum lipids with four different immunochemically defined forms of circulating parathyroid hormone. To a certain extent the data invalidate suggestions which favor parathyroid hormone as a leading uremic toxin.

Membrane plasma exchange in Goodpasture's syndrome.

We report two cases with Goodpasture's syndrome successfully treated by membrane plasma exchange. In both patients, pulmonary infiltrations and hemoptysis had already resolved after the first pulse methylprednisolone dose (1000 mg IV). Following plasma exchange, renal function did not further deteriorate in one patient and returned to normal in the other patient. From the clinical course of our patients and a review of the literature, we conclude that membrane plasma exchange is effective in preventing deterioration of renal function in Goodpasture's syndrome. Analysis of the literature shows that patients who respond to plasma exchange have significantly fewer crescents and lower plasma creatinine, while non-responders are more often oliguric or anuric and require dialysis at the time of plasma exchange.

Kinetics of the redistribution phenomenon after extracorporeal elimination.

Evaluation of the efficiency of extracorporeal elimination is rendered difficult by the rebound phenomenon which may occur in plasma concentrations after hemodialysis, hemoperfusion, or plasma exchange. The term clearance, derived from the extraction rate, has the drawback that it is often based on the incompatible terms plasma concentration and blood flow. To avoid these difficulties, clearance may be calculated from kinetics of plasma concentrations. But this approach will lead to an overestimation of the eliminative efficiency, because plasma concentrations may decline faster than tissue levels, which will be indicated by the rebound phenomenon. The rebound is due to a redistribution from tissue into plasma and follows 2-compartment kinetics. However, the amount removed by extracorporeal elimination reflects the redistribution phenomenon and, simultaneously, can be used to evaluate the absolute efficiency. The amount removed can be derived from 1-compartment kinetics if redistribution can be neglected, and from 2-compartment kinetics if a redistribution takes place. The amount removed can also be evaluated using model- independent approaches, which may be applied even if sustained absorption or proliferation must be assumed. According to these approaches, the removed amount is given by graphic extrapolation, and it can be calculated from extracorporeal clearance and from concentrations in the removed fluid, or it can be eluted from the extracorporeal device.

Heparin-free hemodialysis with prophylactic change of dialyser and blood lines.

Heparinization during hemodialysis may cause severe bleeding complications in patients with high bleeding risk. Heparin-free hemodialyses (n = 208) were performed in 46 unselected patients with high bleeding risk after kidney transplantation (n = 25), after major surgery (n = 10), and with bleeding disorders (n = 11). Dialyser and blood lines were primed without heparin. In addition to the established measures (high blood flow, intermittent rinsing), system clotting was prevented by prophylactically changing the dialyser and blood lines in 107 of 208 dialyses (52 percent). Total system clotting with blood loss ranging from 100 to 250 ml occurred in six cases (3 percent). Mean hemodialysis time (+/- SD) was 4.1 hours (+/- 0.4), rising volume of the extracorporeal system 1.4 liters/hour (+/- 0.6), blood flow 244 ml/min (+/- 38), clotting time 12 min (+/- 4), and weight loss 2.5 kg (+/- 1.5). Mean hemodialysis creatinine clearance was 110 ml/min (+/- 34) and BUN clearance 138 ml/min (+/- 48). Heparin-free hemodialysis with prophylactic change of system is thus a safe and practical method of treatment for patients at high bleeding risk, but it is less effective, more expensive and the patient requires closer care.

The influence of the calcium/phosphorus ratio in the diet on human bone disease, the role of nutritive secondary hyperparathyroidism.

60 out of 100 patients suffering from severe periodontal disease received a daily calcium supplementation of 1,000 or 2,000 mg during a period of 9 or 12 months. Different investigations such as PTH and serum parameters were not influenced by this treatment. However, animal experiments, as well as acute studies in men involving an oral phosphorus load, suggest that parathyroid secretion might be increased by a lowered calcium/phosphorus ratio. Therefore it is possible that a diet too low in calcium could contribute to the pathogenesis of periodontal disease. The lacking effect of calcium therapy implies very strongly that other factors are more important for the development of this disorder.