H. H. Neumayer

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.

Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease

SummaryThe measurement of plasma drug concentrations provides no insight into the relationship between the free and the plasma-protein-bound fractions of drugs. Plasma protein binding may decrease in renal disease due to uremia, hypoalbuminemia, or due to drug interactions. Decreased plasma protein binding leads to an increase in free plasma fraction causing an increase in volume of distribution and a shorter elimination half life. The increase in the apparent volume of distribution and the shorter elimination half life cause a decrease in total plasma concentration. Therefore, the free drug concentration is more reliable than the total plasma concentration for therapeutic drug monitoring. However, the free amount in plasma and in tissue and the tissue-bound amount remain unchanged under steady state conditions. Thus, a decrease in plasma protein binding in renal disease usually does not lead to increased drug toxicity, and alteration of drug dosage is not required, although the total plasma concentration may be found to be considerably lower than normal. In addition to plasma protein binding, alteration of tissue binding must also be considered for the determination of the appropriate dosage of some drugs in renal disease.

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.

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.

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.

Acute interstitial nephritis and non-oliguric renal failure after cefaclor treatment

SummaryA case of acute interstitial nephritis (AIN) developing after cefaclor treatment is reported. Diagnosis was proofed by kidney biopsy and lymphocyte transformation test. The clinical course of the patient with non-oliguric renal failure was favourable. Four weeks after discontinuation of cefaclor treatment the renal function was completely restored and remained stable over the ten-month follow-up period. It is concluded that cefaclor can cause hyperallergic AIN and acute renal failure.

Late conversion from steroids to azathioprine in cyclosporin-treated renal graft recipients

Abstract. In renal graft recipients primarily treated with cyclosporin and low‐dose methylprednisolone, withdrawal of the long‐term steroid medication increases the likelihood of developing rejection episodes. In order to determine the predictive value of clinical parameters and routine prewithdrawal graft biopsies for the risk of rejection, the authors studied 141 kidney recipients from whom steroids were withdrawn 7–9 months after transplantation in a clinically stable situation. Both the quality of the HLA‐match and the results of prospective graft biopsies were found to correlate significantly to the occurrence of acute rejection. In order to investigate the influence of additional azathioprine medication on the incidence of acute rejections in recipients not receiving steroids, immunosuppression was continued with cyclosporin monotherapy in 88 patients and with cyclosporin plus azathioprine in 53 patients. The risk of developing rejection episodes was significantly reduced from 48% after 1 year on monotherapy to 28% after the addition of azathioprine medication.

Einfluß von Diltiazem auf die Ciclosporin-Blutspiegel

SummaryThe simultaneous administration of the calcium channel blocker diltiazem and ciclosporin results in a significant increase of RIA ciclosporin blood levels. The HPLC ciclosporin levels are not influenced.The simultaneous administration of the calcium channel blocker diltiazem and cyclosporin results in a significant increase of RIA cyclosporin blood levels. The HPLC cyclosporin levels are not influenced.

Influence of Prostaglandin A1 on Renal Filtration, Hemodynamics and Excretion

The effect on renal function of a 210-min infusion of PGA1 into the aorta of 10 conscious beagle dogs has been investigated. In the sodium-replete group, PGA1 caused an increase in the glomerular filtration rate (GFR) (24%), renal blood flow (17%) and sodium excretion (20%). By contrast, in the sodium-depleted group, PGA1 caused a considerable reduction of GFR (25%) and sodium excretion (51%). In this group, baseline renal blood flow was lower, and there was no further reduction during PGA1 infusion. Fractional sodium excretion was unchanged in the sodium-replete dogs, but was reduced in the sodium-deplete state. Plasma renin activity was markedly elevated and further increased in the sodium-deplete group, but it was nearly unchanged in the sodium-replete group. This difference in renal response to exogenous PGA1 might be due to interaction with the renin-angiotensin system, which was markedly stimulated by sodium depletion and additionally by prostaglandin infusion.