Knut Joachim Berg

Fifteen years' experience with renal transplantation in systemic amyloidosis

Abstract. At our center 62 renal transplantations (31 living donor and 31 cadaveric donor grafts) have been performed in 58 patients with amyloid renal disease since 1974. The amyloidosis was secondary to rheumatic disease in 74 % of the patients. Predialytic transplantation was performed in 28% of the patients. Mean follow‐up time was 5.1 years (0.3–14.5 years). One‐year actuarial patient survival was 79%, decreasing to 65% after 5 years. First graft survival was 74 % at 1 year and 62 % at 5 years. Patient death with a functioning graft caused 16 out of 25 graft losses. Infections caused 11 out of 18 deaths (61 %), more than half of them within 3 months. Renal transplant amyloid was diagnosed in about 10% of the cases (6/ 62); however, only about 3% of the grafts (2/62) were lost. These long‐term results encourage transplantation in amyloid renal end‐stage disease.

Acute renal effects of sulindac and indomethacin in chronic renal failure

The effects of 2 days of oral dosing with sulindac (200 mg twice a day) or indomethacin (75 mg twice a day) on glomerular filtration rate, urinary excretion of prostaglandin E2, sodium homeostasis, and other renal function parameters were investigated in eight patients with chronic stable impaired renal function. Indomethacin reduced creatinine clearance (from 41.0 ± 7.9 to 30.3 ± 6.3 ml/min) and increased serum levels of creatinine and β2‐microglobulin. Sulindac had no effect on any of these parameters. Both drugs induced depression of urinary prostaglandin E2 excretion; this depression was greater after indomethacin. Urinary sodium excretion fell from 144.4 ± 18.7 to 85.5 ± 9.7 mmol/24 hr after indomethacin and from 131.7 ± 11.6 to 103.4 ± 13.3 mmol/24 hr after sulindac. Body weight increased 1.2 kg after indomethacin but was not changed by sulindac. Plasma renin activity was reduced from 2.3 ± 0.8 to 1.7 ± 0.6 nmol/L/hr by sulindac and from 2.8 ± 0.8 to 1.5 ± 0.5 nmol/L/hr by indomethacin. Urinary N‐acetyl‐β‐glucosaminidase and kallikrein excretion was not changed by either drug. Our data suggest that sulindac affects renal prostaglandin E2 synthesis and sodium excretion in patients with severe renal failure to a lesser extent than does indomethacin. Sulindac still seems to be the drug of choice in this group of patients, but glomerular filtration rate, body weight, and electrolyte balance should be carefully monitored.

Plasma ascorbic acid in patients undergoing chronic haemodialysis.

AbstractObjective: Patients with renal disease receiving dialysis therapy are susceptible to a deficit in ascorbic acid (AA) caused by loss during dialysis and a restricted dietary AA intake. In previous studies, in such patients, the methods generally used for AA determination are non-specific and insensitive, and control of the easily deteriorating AA in the samples is often disregarded. The purpose of this work was to study the AA plasma levels and dialyser clearances as well as the kinetics of administered AA in a group of dialysis patients, using selective and sensitive methodology and a procedure preserving the AA sample content. Methods: Using an analytical method based on high-performance liquid chromatography and electrochemical detection, we have examined the dialyser clearance of AA as well as the pre- and post dialysis plasma levels of AA in patients on chronic dialysis therapy. The plasma AA levels were further measured after single and multiple dose supplementation of 200 mg p.o. per day. Results: The majority of the patients (16 of 19) had pre-dialysis plasma levels below the normal range. The dialyser clearance of AA was 212 ml/min (median value). Following dialysis, the plasma AA concentrations were reduced by a median of 33%. AA supplementation significantly increased these levels; however, they dropped soon after supplementation was stopped. AA in uraemic whole blood and plasma was, on average, less stable than in samples from healthy subjects. Conclusion: This study, using selective analytical method with adequate stability control, confirms that AA is readily removed by conventional haemodialysis membranes. Patients on chronic haemodialysis have remarkably low plasma AA levels unless given AA supplementation.

Acute physiological changes in canine kidneys following exposure to extracorporeal shock waves.

Nine anesthetized dogs were studied for four to five hours after administration of extracorporeal shock waves to one kidney, the contralateral organ serving as control. Urinary excretion of electrolytes, N-acetyl-beta-glucosaminidase (NAG) and kallikrein, clearances of creatinine, inulin and para-amino-hippuric acid (PAH), serum aldosterone level and plasma renin activity (PRA) were determined. On the exposed side there was a significant increase in urinary flow and urinary NAG excretion, and a significant fall in urinary osmolality. Effective renal plasma flow (ERPF) was reduced and glomerular filtration rate (GFR) unchanged, thus filtration fraction (FF) was increased. Extraction of PAH was significantly reduced compared with the control kidney. On the control side there was a significant increase in urinary flow and excretion of electrolytes, and a significant fall in urinary osmolality. GFR was increased and ERPF unchanged. FF therefore increased also on this side. The mean rise of PRA in the exposed kidney was higher than in the control kidney, the difference being not significant (p = 0.09). Our results may indicate a triggering of the renin-angiotensin system, and an effect on proximal tubular function following exposure of extracorporeal shock waves.

The use of elderly living donors in renal transplantation

Abstract. The safety and the results of using living donors above the age of 60 years were studied. In 235 consecutive donors the complications were not different in elderly (n= 70) compared to younger donors. Graft survival and function were studied in 232 consecutive 1‐HLA‐haplotype mismatched grafts. Graft survival at 1 year was equivalent (87% vs. 92%), but after 2–6 years graft survival was inferior in recipients of older grafts (n= 62). The recipients of older grafts were 10 years older, and patient death with functioning graft was a more frequent cause of graft loss. Up to 4 years serum creatinine levels were significantly higher, but stable, in recipients of older grafts; at 5 years the difference was not significant. It is concluded that the use of elderly living donors is safe. Taking recipient age into consideration, graft survival is not different in the two groups. Graft function in older grafts is some what inferior, but stable.

Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients.

OBJECTIVE The aim of the present study was to investigate the effect of grapefruit juice on the pharmacokinetics of cyclosporin A (CsA), as Sandimmun Neoral, and its main metabolites, M1, M9 and M4N, in renal transplant recipients. METHODS Ten renal transplant recipients, on CsA-based immunosuppressive therapy, were included in this open, randomized crossover study. Patients were given their individualized morning dose of CsA, administered with either 250 ml water or 250 ml grapefruit juice and 12-hour CsA pharmacokinetic investigations were performed. The 2 investigation days were separated by at least 7 days. RESULTS Administration of CsA with grapefruit juice compared with water significantly increased the area under the whole blood concentration versus time curve in the interval from 0-12 hours (AUC(0-12)) of CsA, by an average of 25 +/- 19% (p = 0.002). Intake of grapefruit juice did not have any significant influence on maximum whole blood concentration (Cmax) or time to Cmax (tmax) of CsA. AUC(0-12) and Cmax of M9 decreased significantly with intake of grapefruit juice, on average 22 +/- 11% (p = 0.0007) and 36 +/- 6% (p = 0.0001), respectively. AUC(0-12) of M1, however, was on average 13 +/- 14% (p = 0.02) higher upon co-administration of CsA with grapefruit juice as compared with water. The level of M4N was below the limit of quantification in most samples, and an effect of co-administration of CsA with grapefruit juice could not be determined for this metabolite. CONCLUSION The present study shows that co-administration of grapefruit juice with CsA compared with water affects the formation and/or elimination of the 2 metabolites M1 and M9 differently. In addition, administration of CsA with grapefruit juice compared with water induced a moderate, but significant increase in systemic exposure of CsA in renal transplant recipients.

Iodixanol vs iopamidol in intravenous DSA of the abdominal aorta and lower extremity arteries: a comparative phase-III trial.

Iodixanol (visipaque, 320 mgI/ml) was compared with iopamidol (Solutrast, 370 mfI/ml) in a double-blind, randomized, parallel group, intravenous DSA phase-III trial for evaluation of safety and efficacy. A total of 117 patients received iodixanol (n = 60) or iopamidol (n = 57). Diagnostic efficacy was evaluated using categoric and visual analogue scales. Discomfort and adverse evenets were recorded. A total of 39 patients collected urine up to 72 h after the examination for analysis. Diagnostic efficacy and radiographic density were similar in both groups. Discomfort was milder with iodixanol. The difference between the frequency of adverse events between both groups (iodixanol = 7, iopamidol = 2) was without statistical significance. Creatinine clearance was slightly more affected by iodixanol, whereas the increase in renal excretion ofN-acetyl-beta-glucosaminidase (NAG) in the first 24 h collection period after the examination was significantly higher (p < 0.01) with iopamidol. Iodixanol was of equal diagnostic efficacy compared with iopamidol despite its reduced iodine content. Both contrast media are well suited for IV DSA.

Acute changes in renal function following extracorporeal shock wave lithotripsy in patients with a solitary functioning kidney

Twelve consecutive patients with a solitary functioning kidney were treated for renal stone by extracorporeal shock wave lithotripsy (ESWL*) with the modified Dornier HM3 lithotriptor and studied for 3 days after treatment. Urinary excretion of electrolytes, N-acetyl-beta-glucosaminidase (NAG), alkaline phosphatase, kallikrein, glycosaminoglycans, albumin and beta 2-microglobulin, and clearances of creatinine, inulin and para-aminohippuric acid were determined, as were serum levels of creatinine, urea, beta 2-microglobulin and aldosterone, and plasma renin activity. Urinary flow rate, free water clearance, and urinary excretion of NAG, kallikrein and beta 2-microglobulin were significantly increased 0 to 24 hours after ESWL. The urinary excretions of alkaline phosphatase, albumin and glycosaminoglycans were unchanged. Glomerular filtration rate was significantly decreased and effective renal plasma flow was unchanged. Filtration fraction was stable. Serum lactic dehydrogenase increased significantly after ESWL and remained high through the period of observation. Serum levels of creatinine, beta 2-microglobulin and aldosterone were unaltered. A decrease in plasma renin activity immediately after treatment is explained by the water immersion and the extracellular volume expansion during treatment.

Renal replacement therapy in elderly patients

The results of renal replacement therapy (RRT) in elderly patients in Norway were evaluated. During the 5-year period between 1981 and 1985, 368 patients at least 60 years of age (mean, 66.7 years) at the start of RRT were included and followed until 15 February 1987. Transplantation was planned for 249 patients; of these 127 were not grafted. The actuarial survival in this group was 64%, 44%, and 7% at 6, 12, and 48 months, respectively. Survival in 122 grafted patients was 93%, 87%, and 62%, respectively, and the corresponding graft survival was 70%, 67%, and 48%. The remaining 119 patients were allocated to long-term dialysis, with a survival of 63%, 48%, and 13%, respectively. Our results describe the outcome of a treatment program available to the entire elderly population accepted for RRT. In two-thirds of the patients transplantation was planned, and one-third of all patients were actually grafted, with good patient and graft survival. The results suggest that transplantation is the treatment of choice for most elderly patients.

Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients

AbstractObjective: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (MA, M1, M2). Methods: Nine CsA-treated renal transplant patients were treated with diltiazem, 90–120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites. Results: Diltiazem treatment resulted in a significant mean increase in the area under the concentration–time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (Cmax) of 34(8)% (P < 0.05), without altering time to peak concentration (tmax). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M1 and M2) tended to be increased. Conclusions: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics.