Jan Carstens

Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans

The effect of a continuous infusion of human brain natriuretic peptide (BNP) was studied in 48 healthy men. The study was randomized, placebo controlled, and single blind. BNP was given in doses of 1, 2, or 4 pmol ⋅ kg-1 ⋅ min-1for 60 min, and peak values of BNP in plasma were 38, 85, and 199 pmol/l, giving increments in plasma as seen in heart or renal failure. BNP infusion increased the urinary flow rate and the excretion of sodium in a dose-dependent way. The maximal effects were +65 and +156%, respectively. GFR increased and RPF decreased, the latter in a dose-dependent manner. Blood pressure, heart rate, angiotensin II, and aldosterone were all unaffected by infusion of BNP, whereas a direct inhibition of renin secretion was seen. With the use of the lithium clearance technique, we concluded that the tubular site of action is in both the proximal and distal segments, and the major effect on sodium handling is in the distal parts of the nephron.The effect of a continuous infusion of human brain natriuretic peptide (BNP) was studied in 48 healthy men. The study was randomized, placebo controlled, and single blind. BNP was given in doses of 1, 2, or 4 pmol.kg-1.min-1 for 60 min, and peak values of BNP in plasma were 38, 85, and 199 pmol/l, giving increments in plasma as seen in heart or renal failure. BNP infusion increased the urinary flow rate and the excretion of sodium in a dose-dependent way. The maximal effects were +65 and +156%, respectively. GFR increased and RPF decreased, the latter in a dose-dependent manner. Blood pressure, heart rate, angiotensin II, and aldosterone were all unaffected by infusion of BNP, whereas a direct inhibition of renin secretion was seen. With the use of the lithium clearance technique, we concluded that the tubular site of action is in both the proximal and distal segments, and the major effect on sodium handling is in the distal parts of the nephron.

Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells

BACKGROUND AND PURPOSE Introducing the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) decrease survival rates.

Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity. WHAT THIS STUDY ADDS This is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses of ciclosporin and tacrolimus. We document that both drugs acutely increase insulin sensitivity, while first phase and pulsatile insulin secretion remain unaffected. This study demonstrates that ciclosporin and tacrolimus have similar acute effects on glucose metabolism in healthy humans. AIM The introduction of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. METHODS Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following methods: a hyperinsulinaemic-euglycemic clamp, an intravenous glucose tolerance test (i.v.GTT), glucose-stimulated insulin concentration-time series and indirect calorimetry. RESULTS Clamp derived insulin sensitivity was increased by 25% during CsA (P < 0.0001) and 13% during Tac administration (P = 0.047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l(-1) for CsA and 12.8 ± 0.5 µg l(-1) for Tac. CONCLUSIONS Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin sensitivity, without any effect on first phase or pulsatile insulin secretion.

Effects of urodilatin on natriuresis in cirrhosis patients with sodium retention

BackgroundSodium retention and ascites are serious clinical problems in cirrhosis. Urodilatin (URO) is a peptide with paracrine effects in decreasing sodium reabsorption in the distal nephron. Our aim was to investigate the renal potency of synthetic URO on urine sodium excretion in cirrhosis patients with sodium retention and ascites.MethodsSeven cirrhosis patients with diuretics-resistant sodium retention received a short-term (90 min) infusion of URO in a single-blind, placebo-controlled cross-over study. In the basal state after rehydration the patients had urine sodium excretion < 50 mmol/24 h.ResultsURO transiently increased urine sodium excretion from 22 ± 16 μmol/min (mean ± SD) to 78 ± 41 μmol/min (P < 0.05) and there was no effect of placebo (29 ± 14 to 44 ± 32). The increase of UROs second messenger after the receptor, cGMP, was normal. URO had no effect on urine flow or on blood pressure. Most of the patients had highly elevated plasma levels of renin, angiotensin II and aldosterone and URO did not change these.ConclusionThe short-term low-dose URO infusion increased the sodium excretion of the patients. The increase was small but systematic and potentially clinically important for such patients. The small response contrasts the preserved responsiveness of the URO receptors. The markedly activated systemic pressor hormones in cirrhosis evidently antagonized the local tubular effects of URO.

Metabolism and action of urodilatin infusion in healthy volunteers

The objective of this investigation was to study both the pharmacokinetics and renal pharmacodynamic properties of intravenously infused urodilatin in human beings.

The impact of calcineurin inhibitors on insulin sensitivity and insulin secretion: a randomized crossover trial in uraemic patients.

The calcineurin inhibitors cyclosporine and tacrolimus are implicated in post‐transplant complications such as new‐onset diabetes after transplantation. The relative contribution of each calcineurin inhibitor to new‐onset diabetes after transplantation remains unclear. We sought to compare the impact of cyclosporine and tacrolimus on glucose metabolism in humans.

Three-years experience with Neoral C2 monitoring adjusted to a target range of 500–600 ng/ml in long-term renal transplant recipients receiving dual immunosuppressive therapy

Objective. There is little knowledge about the optimal 2-h post-dose concentration (C2 level) of cyclosporin A (CsA) in renal transplant recipients beyond 1 year post-transplant. The aim of this study was to investigate the effects of C2-CsA monitoring on Neoral® dose, renal graft function and systemic blood pressure in long-term renal transplant recipients, who had previously been monitored by means of trough levels (C0). Material and methods. Eighty-six patients treated with CsA+prednisolone were reviewed retrospectively during a follow-up period after switching to C2-CsA monitoring. Results. The patients were 6.0 years (3.4, 9.0 years) [median (25% quartile, 75% quartile)] post-transplant at the time of conversion to C2-CsA monitoring. They were studied for 3.7 years (3.3, 3.8 years). Baseline C0-CsA level was 161 ng/ml (131, 208 ng/ml). The Neoral dose was reduced in 95% of the recipients. The median C2 level was reduced by 40% to 585 ng/ml (484, 670 ng/ml) and, accordingly, the Neoral dose was reduced by 30% to 2.8 mg/kg/day (2.3, 3.8 mg/kg/day). Overall, plasma creatinine remained stable during the follow-up period. In 48/86 patients (56%), the plasma creatinine level was lower at the end of the study compared to baseline, declining from 163 µmol/l (124, 189 µmol/l) in 2001 to 147 µmol/l (106, 172) in 2005. Three patients (3.5%) had late acute rejections, 14 (16.3%) discontinued CsA, five (5.8%) commenced dialysis and seven (8.1%) died. Conclusion. Adoption of C2-CsA monitoring resulted in a substantial reduction in Neoral dose, while the overall renal graft function remained stable.