Karl Wagner

Prevention of posttransplant acute tubular necrosis by the calcium antagonist diltiazem: a prospective randomized study.

In a prospective randomized trial we evaluated the influence of the calcium antagonist diltiazem (Dil) on the development of acute tubular necrosis (ATN) in cadaveric kidney transplantation. Dil was added to Eurocollins solution (20 mg/l) at donor nephrectomy. The graft recipient received a preoperative bolus injection of Dil (0.28 mg/kg) which was followed by an infusion of Dil (0.0022 mg/min/kg) for 2 days. Thereafter, Dil was applied orally. Immunosuppressive therapy consisted of ciclosporin (CS) and low-dose steroids. There were no significant differences between the groups with respect to donor characteristics, HLA matching and ischemic periods. In the control group (n = 22), 9 patients (41%) developed ATN compared to 2 patients (10%) in the Dil group (p less than 0.05). In the control group, 3.5 +/- 0.4 HD per patient were necessary compared to 0.6 +/- 0.2 in the Dil group (p less than 0.05). Although CS blood levels were significantly higher in the Dil group (1st week 1,150 vs. 728 ng/ml; p less than 0.01), the GFR of grafts with primary function was significantly higher in the Dil group (day 7:39 vs. 24 ml/min; p less than 0.05). A significant reduction of the CS dose by 30% (p less than 0.01) led to comparable CS levels. In the Dil group, significantly fewer rejection episodes occurred during the first month. Our data indicate that the application of the calcium antagonist Dil lowered the incidence of posttransplant ATN. In addition, there is a possibility that Dil not only ameliorates ischemic damage in the kidney, but also reduces CS nephrotoxicity.

Effect of nitrendipine on renal function in renal-transplant patients treated with cyclosporin: a randomised trial

BACKGROUND Calcium antagonists such as nitrendipine reduce the effects of cyclosporin on renal haemodynamics, however, their long-term efficacy has not been established. We did a randomised trial to investigate the effects of nitrendipine on renal function in renal-transplant patients treated with cyclosporin. METHODS 253 renal-transplant patients were recruited: 52 normotensive patients (diastolic blood pressure <90 mm Hg) were assigned placebo and 57 nitrendipine 5 mg twice daily; 71 hypertensive patients (diastolic blood pressure >90 to <115 mm Hg) were assigned placebo and 73 nitrendipine 10 mg twice daily. Nitrendipine was increased to 20 mg twice daily if the target diastolic blood pressure (<90 mm Hg) was not achieved. The patients were seen once a month for 24 months; blood pressure and serum creatinine concentration were recorded at each visit. Analysis was by intention to treat. FINDINGS 63 patients were withdrawn (35 nitrendipine, 28 placebo). The mean serum creatinine concentration at baseline was slightly higher in the nitrendipine group (146.7 micromol/L [SE 4.42]) than in the placebo group (137.0 micromol/L [3.54]. At the 24-month endpoint or at dropout, serum creatinine concentration was significantly higher in the 123 patients in the placebo group than the 130 patients in the nitrendipine group (160.8 [7.1] vs 148.5 [5.3], p for effect of treatment=0.025, analysis of covariance in a two-way classification; 95% CI for difference -1.77 to -22.98). At study entry, the blood pressures of the placebo and the nitrendipine groups were almost identical. At 24 months, blood pressure was higher in the normotensive patients given a placebo than in those patients given nitrendipine. By contrast, blood-pressure values were similar in those hypertensive patients given a placebo and those given nitrendipine at the end of treatment. INTERPRETATION The calcium antagonist nitrendipine has no adverse effects on kidney function in renal-transplant patients with cyclosporin. The drug has a small but significant nephroprotective effect, that is independent of the drugs antihypertensive action.

Prevention of delayed graft function in cadaver kidney transplants by diltiazem: outcome of two prospective, randomized clinical trials.

Calcium entry blockers have a protective effect on experimental postischemic acute renal failure (ARF). Since delayed graft function (DGF) in cadaver kidney transplants is in part due to an ischemic damage to the kidney, we initiated two prospective, randomized clinical trials of human kidney transplants. Study I (control: n = 22; diltiazem: n = 20): Diltiazem (D) was added to Eurocollins solution at a dose of 20 mg/l. If the donor had been treated with D, the graft recipient got a bolus injection of 0.28 mg/kg D and a continuous infusion of 0.002 mg/min/kg D for the first two days. A dose of 60 mg D was then given orally twice daily. Study II (control: n = 11; diltiazem: n = 10): We used the same regimen without donor pretreatment. All patients had immunosuppression with cyclosporine A (CsA) and low-dose steroids. Primary graft function (PGF) was defined as vital kidney function without hemodialysis (HD) during the first week. In both studies the incidence of PGF was higher in the D groups (I: 90% vs. 59%, p less than 0.05; II: 70% vs. 55%). In the control groups, 3.6 +/- 0.4 (I) and 4.9 +/- 0.7 (II) HD per patient was necessary, compared to 0.6 +/- 0.2 (I), p less than 0.05) and 1.9 +/- 0.4 (II) HD in the treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of long-term infusion of the calcium antagonist diltiazem on postischemic acute renal failure in conscious dogs

SummaryThe influence of long-term infusion of the calcium-entry blocker diltiazem on postischemic acute renal failure was investigated in conscious dogs monitored by implanted instruments. In 18 uninephrectomized beagle dogs on a salt-rich diet, an electromagnetic flow probe and an inflatable plastic cuff were placed around the renal artery. Acute renal failure was induced by inflating the cuff for 180 min in the conscious animal. Group A (n=5, control) received an intraaortic injection of 0.9% NaCl (5 ml/day) from the 3rd day before until the 7th day after ischemia and group B (n=6, posttreatment) an intra-aortic injection of diltizem (5 µg·min−1·kg−1) beginning at the end of ischemia until the 7th day. Group C (n=7, pre- and posttreatment) received diltiazem from the 3rd day before until the 7th day after ischemia. In group A, renal blood flow dropped from 149±16 (preischemic) to 129±29 ml·min−1 on the 1st day after ischemia. In contrast, renal blood flow increased on the 1st postischemic day in both treatment groups by 29±15% (group B,P 0.05) and 14±13% (group C). In the following days, there was no significant difference in renal blood flow between groups A, B and C. In group B, the reduction of the glomerular filtration rate was similar to that in the control group. In group C, the glomerular filtration rate was significantly less reduced than in group A (34±1.8 preischemically to 17±5.4 on day 1,P 0.05 and 20±4.1 ml·min−1 on day 7,P 0.05). Plasma renin activity increased in both diltiazem groups, more pronounced so in group B (from 3.7±1.0 on day 1 to 16.2±7.9 ng ATI·ml−1·h−1 on day 7,P 0.05). In contrast to groups A and B, the increase in fractional sodium excretion was less pronounced in group C. Likewise, the decrease in free water-reabsorption was less marked than in groups A or B. It was apparent that diltiazem, when administered pre- and post-ischemically, preserved glomerular filtration rate and renal blood flow. When diltizem was given solely postischemically there was an improvement in renal blood flow, but no significant influence on glomerular filtration rate. We therefore conclude that mainly tubular factors, in addition to the attenuation of postischemic vasoconstriction, are involved in the protective effect of diltiazem on postischemic acute renal failure in conscious dogs.

Prostaglandin E2 Promotes Hypotension on Low-Sodium Hemodialysis

The influence of low-sodium dialysate (126 mmol/l) on plasma levels of prostaglandin E2 (PGE2) and PGF2 alpha, plasma renin activity (PRA) and arterial blood pressure was investigated in 16 patients on maintenance hemodialysis. PGE2 rose more than tenfold and there was a significant increase in PGF2 alpha and PRA. Mean arterial pressure dropped by 30 mm Hg causing discomfort in several patients. By contrast, conventional hemodialysis against 140 mmol/l of sodium was followed by less pronounced changes in plasma prostaglandins, and reduction of blood pressure was moderate (13 mm Hg). It is suggested that vasodilating prostaglandins may contribute to dialysis hypotension. Their origin may not be confined to the kidneys but rather extend to the lungs and circulating blood cells. The in vitro generation of prostaglandins was demonstrated when donor blood was circulated in an extracorporeal dialysis system.

Membrane plasma exchange in Goodpasture's syndrome.

We report two cases with Goodpastures 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 Goodpastures 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.

Elimination kinetics of plasma exchange

SummaryInterest in the therapeutic use of plasma exchange for various diseases is growing. The two different effects of plasma exchange are elimination and activation. The kinetics are linear for elimination by plasma exchange, but not for activation. Plasma exchange is performed intermittently and can be described by intermittent kinetics. According to intermittent kinetics, plasma exchange removes 50% to 75% of a substance in plasma within 1–2 h, corresponding to an elimination half-life of 30–40 min. Hybrid kinetics, a mixture of actually intermittent but theoretically continuous elimination by plasma exchange, can however also be applied. Hybrid kinetics are more convenient and more reliable than intermittent kinetics. This is because hybrid kinetics are based solely on the concentrations before each plasma exchange; hybrid kinetics also reflect removal from the entire body and not just from the plasma compartment. According to hybrid kinetics, the amount of a substance in the body removed within 3–4 days is 50% of the difference between the initial and the final plasma concentration, depending on the intensity of plasma exchange. The intensity may well contribute at least in part to the beneficial effect of plasma exchange in various diseases.

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. Peaks and troughs were significantly lower in the 23 patients who did not respond than in the 27 patients who responded to antibiotic treatment (54%). Ototoxicity developed in three of 18 investigated patients (17%). Thus, efficacy and toxicity of aminoglycosides in patients undergoing hemodialysis are comparable with those of patients with normal renal function, and the dosage can be derived from one‐compartment pharmacokinetics.

CC Chemokine Ligand 18 in ANCA-Associated Crescentic GN

ANCA-associated vasculitis is the most frequent cause of crescentic GN. To define new molecular and/or cellular biomarkers of this disease in the kidney, we performed microarray analyses of renal biopsy samples from patients with ANCA-associated crescentic GN. Expression profiles were correlated with clinical data in a prospective study of patients with renal ANCA disease. CC chemokine ligand 18 (CCL18), acting through CC chemokine receptor 8 (CCR8) on mononuclear cells, was identified as the most upregulated chemotactic cytokine in patients with newly diagnosed ANCA-associated crescentic GN. Macrophages and myeloid dendritic cells in the kidney were detected as CCL18-producing cells. The density of CCL18(+) cells correlated with crescent formation, interstitial inflammation, and impairment of renal function. CCL18 protein levels were higher in sera of patients with renal ANCA disease compared with those in sera of patients with other forms of crescentic GN. CCL18 serum levels were higher in patients who suffered from ANCA-associated renal relapses compared with those in patients who remained in remission. Using a murine model of crescentic GN, we explored the effects of the CCL18 murine functional analog CCL8 and its receptor CCR8 on kidney function and morphology. Compared with wild-type mice, Ccr8(-/-) mice had significantly less infiltration of pathogenic mononuclear phagocytes. Furthermore, Ccr8(-/-) mice maintained renal function better and had reduced renal tissue injury. In summary, our data indicate that CCL18 drives renal inflammation through CCR8-expressing cells and could serve as a biomarker for disease activity and renal relapse in ANCA-associated crescentic GN.

Beneficial Effects of Long-Term Prostaglandin E2 Infusion on the Course of Postischemic Acute Renal Failure

The effect of a continuous intra-aortal infusion of prostaglandin E2 (PGE2) (0.03 microgram . min-1 . kg-1) on the course of postischemic renal failure (180 min cessation of blood flow by inflation of a pneumatic cuff) has been investigated in 11 conscious sodium-replete dogs. The glomerular filtration rate (51Cr-EDTA: endogenous creatinine clearance) was less decreased in the PGE2 group (group B, n = 6) than in the control group (group A, n = 5; 13 ml . min-1 vs. 22 ml . min-1; p less than 0.05). Renal blood flow (electromagnetic flow probe) was markedly lower in the control group (82 ml . min-1) than in the PGE2 group (130 ml . min-1; p less than 0.05), even exceeding baseline levels in the latter group. Accordingly, the excessive rise in renal vascular resistance in the control group (+277%) was abolished in the PGE2 group (-20%) (p less than 0.05). Nitrogen retention was also markedly improved. Plasma renin activity, which was markedly raised initially (25.8 ng angiotensin I . ml-1 . h-1) was not significantly further increased during the subsequent 7 days. Urinary excretion of PGE2 was diminished in the control group and elevated following PGE2 infusion. It is suggested that the beneficial effects of PGE2 are mediated by preservation of renal perfusion. Additional effects of prostanoids on the ultrafiltration coefficient (KF) and cytoprotection by reduction of intracellular calcium accumulation must also be taken into consideration.