Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses.

OBJECTIVES: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cydosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses. SUBJECTS AND METHODS: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg/kg/day) were studied in a double-blind, double-dummy, randomized, parallel-group multicenter trial in 44 stable kidney graft recipients. RESULTS: The median area under the curve [AUC(0-24)] of pravastatin was 249 microg x hr/L (range, 104 to 1026 microg x hr/L) after a single dose (day 1) and 241 microg x hr/L (114 to 969 microg x hr/L) after multiple doses (day 28) and was fivefold higher than values reported in the absence of cyclosporine. The median AUC(0-24) of lovastatin was 243 microg x hr/L (105 to 858 microg x hr/L) on day 1 and 459 microg x hr/L (140 to 1508 microg x hr/L) on day 28. Besides a significant accumulation during the study period (p < 0.001), the lovastatin AUC(0-24) values were twentyfold higher than values reported without cyclosporine. Coadministration of pravastatin or lovastatin did not alter cyclosporine pharmacokinetics. In this study, 20 mg/day doses of both drugs resulted in a significant improvement of the lipid profile and were well tolerated. CONCLUSIONS: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.

Apolipoprotein A-I and apolipoprotein B containing lipoprotein particles in coronary patients treated with extracorporal low density lipoprotein precipitation (HELP).

Evidence for chemical and biological heterogeneity of human plasma lipoprotein density classes has been steadily accumulating over the last 15 years. Furthermore, several recent reports have indicated potential clinical significance of certain lipoprotein subspecies as either atherogenic or antiatherogenic. It is generally accepted that lipid lowering treatments can retard or even reverse development of atherosclerotic lesions. However, very little is known about effects of various lipid lowering treatments on specific lipoprotein particles. The purpose of this study was to explore the effects of heparin induced extracorporal low density lipoprotein precipitation (HELP) on various subspecies of plasma lipoprotein particles defined primarily by their apolipoprotein composition. Using particle specific enzyme immunoassays, the immediate changes in lipoprotein particle profiles were analyzed after a single HELP treatment in 12 patients with angiographically documented coronary artery disease. In a separate group of 6 patients, particles were repeatedly measured over a period of 96 h following a HELP treatment. Single HELP treatment caused an immediate and highly significant decrease (67%) in the concentration of simple lipoprotein particles containing apolipoprotein B (apo B) as a sole apolipoprotein (LP-B). Various subspecies of complex particles containing apo B and other apolipoproteins (Lp-B-complex) were also decreased although to a lesser degree (44-53%). HELP treatment caused an insignificant, 3% decrease of lipoprotein particles containing apo A-I but no apo A-II (Lp-A-I) and a 6% decrease in the concentration of particles containing both apo A-I and apo A-II (Lp-A-I:A-II). During the 96-h period following HELP treatment various apo B containing particles recovered at different rates in different patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Low atrial natriuretic peptide plasma concentrations in 100 patients with essential hypertension.

Although atrial natriuretic peptide (ANP) plays a key role in electrolyte and volume regulation and causes direct vasorelaxation, controversial results have been reported in hypertensive patients. We studied 58 men and 42 women, aged 19 to 78 years, with essential hypertension (blood pressure: 150 to 210/95 to 110 mm Hg) using 24 h blood pressure recording, treadmill exercise and x-ray of the chest. In 70 patients ANP plasma concentrations were found to be completely within the normal range of healthy controls (17 to 38 fmol/mL; n = 50) and 52% were detected within the lower third or even below the normal range. In mild to moderate essential hypertension a diminished secretion of ANP may be responsible for an elevated blood pressure in these patients.

Quantitative assessment of carnitine loss during hemodialysis and hemofiltration.

Carnitine deficiency has been claimed to be responsible for the myo- and cardio-myopathy observed in dialysis patients and has been attributed to the loss of carnitine during dialysis. To quantitate carnitine loss, we determined the carnitine concentrations in 29 patients on chronic hemodialysis, 10 patients on chronic hemofiltration, and 8 patients on CAPD. Mean plasma carnitine levels in hemodialysis and hemofiltration patients (39.8 +/- 2.7 mumoles/liter; N = 39) were significantly lower (P less than 0.01) than in controls (49.8 +/- 2.0 mumoles/liter; N = 43). Hemodialysis or hemofiltration led to a further reduction (33.2 +/- 3.5 mumoles/liter; P less than 0.001). There was no significant difference in the mean plasma carnitine level between CAPD patients (40.0 +/- 5.7 mumoles/liter) and controls. Hemofiltration treatment resulted in a weekly loss of 795 +/- 84 mumoles of carnitine. This was significantly lower (P less than 0.0001) than the urinary carnitine excretion in healthy controls (1534 +/- 134 mumoles per week; N = 27) and the carnitine elimination in the dialysate of CAPD patients (1905 +/- 236.6 mumoles per week; N = 8). It is concluded that carnitine deficiency in dialysis patients cannot be explained by loss into dialysate or filtrate. Because intestinal reabsorption of carnitine does not seem to be impaired, decreased endogenous carnitine synthesis is considered as the most plausible explanation for the moderate degree of carnitine deficiency observed in dialysis patients.

Heparin extracorporeal LDL precipitation (HELP): an effective apheresis procedure for lowering Lp(a) levels.

Heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) is based on the precipitation of apolipoprotein B (apo B) containing lipoproteins with heparin at low pH (4.85). In in vitro experiments we could show that Lp(a) is quantitatively (> 99%) precipitated from plasma by heparin in the pH range 4.6-5.2. The acute changes in Lp(a) after a single HELP-LDL apheresis were investigated in twelve patients with Lp(a) concentrations > 30 mg/dl. A single treatment caused a highly significant decrease (62%) in the concentration of Lp(a), similar to the decrease (60%) observed for LDL-cholesterol. Analysis of the data from ten patients with different apo(a) phenotypes indicated that Lp(a) is eliminated with almost 100% efficiency in the extracorporeal circulation, irrespective of apo(a) phenotype and plasma concentration. The mean rate of recovery of Lp(a) following HELP-LDL apheresis was slightly slower than that of LDL-cholesterol. Plasma Lp(a) concentrations were monitored in seven patients over 2 years. Mean Lp(a) concentrations after 2 years were lower than pre-treatment levels, indicating that repeated elimination of the lipoprotein does not lead to an induction in its synthesis. HELP-LDL apheresis should be particularly suitable for treatment of patients with elevated LDL-cholesterol levels who are also at increased coronary risk because of high Lp(a) concentrations.

[Maximal therapy of hypercholesterolemia in coronary heart disease]. / Maximaltherapie der Hypercholesterinämie bei koronarer Herzerkrankung.

Extracorporeal procedures to eliminate LDL from plasma now allow us to drastically lower the plasma LDL-concentrations to virtually every desired level. In a new therapeutic approach the combination of HMG-CoA reductase inhibitors with an LDL/fibrinogen apheresis procedure (the HELP-system) was evaluated in hypercholesterolemic CAD-patients. HELP treatment alone can lower the mean plasma LDL-cholesterol by about 50-60%, HMG-CoA reductase inhibitor therapy reduces the LDL-cholesterol by about 40%. The combination of both treatments resulted in a lowering of mean LDL-cholesterol to about 80% of baseline values. Improvement of blood rheology by lowering plasma viscosity and inhibiting erythrocyte aggregation became apparent. No relevant adverse effects were noted over a period of two years. This therapeutic strategy for maximal LDL-cholesterol lowering may be useful in secondary prevention of coronary heart disease in hypercholesterolemic patients if plasma LDL-C cannot be reduced by diet and drug treatment to desirable plasma levels (LDL-cholesterol less than 120 mg/dl). Preliminary data show an improvement in the symptoms of our CAD-patients treated with this combined therapy. Furthermore, within the near future a combined HELP and dialysis unit will be available for patients with terminal renal insufficiency and progressive atherosclerosis.

Increase of glomerular filtration rate and renal plasma flow by insulin-like growth factor-I during euglycaemic clamping in anaesthetized rats.

Renal function was studied in anaesthetized rats receiving i.v. infusions of recombinant human insulin-like growth factor-I (IGF-I) under euglycaemic clamp conditions. IGF-I increased glomerular filtration rate up to 35% and renal plasma flow up to 100%, this increase being dose dependent with half-maximal stimulation at serum IGF-I concentrations of about 24 pmol ml-1. Renal vascular resistance was reduced up to 50%, filtration fraction decreased up to 30% and urine flow increased up to three fold while arterial blood pressure was unchanged. Renal haemodynamics were affected at serum IGF-I concentrations that did not stimulate total body glucose disposal during euglycaemic clamping. IGF-I seemed to regulate renal function through IGF-I receptors apparently independent of acute changes of glucose metabolism.

Detection of fluid overload by plasma concentration of human atrial natriuretic peptide (h-ANP) in patients with renal failure.

There are no reliable parameters for the detection of fluid overload in anuric patients. In 70 patients on regular haemodialysis (HD) or haemofiltration (HF) treatment, plasma ANP IR concentrations were determined by radioimmunoassay and compared to 43 controls with normal renal function. ANP IR levels were markedly elevated immediately before HD or HF (m 82 fmol/ml) compared to ANP IR plasma concentrations after HD or HF (m 42 fmol/ml) and to ANP IR levels of healthy controls (m 19 fmol/ml). ANP IR was detected in haemofiltrates and found to be eliminated by HF. During isovolemic HF, ANP IR levels remained constant suggesting that ANP synthesis is much higher than elimination by HF and that the decrease in circulating volume at the end of HF or HD is the main stimulus for a lower secretion rate of ANP. Elevated ANP IR levels at the end of HD/HF were found to be associated with fluid overload even without clinical or radiographic symptoms. Consistent weight reduction was followed by a decrease of ANP IR levels.

[Hypertension after kidney transplantation: chronic rejection or arterial stenosis?]. / Hypertonus nach Nierentransplantation: chronische Abstossung oder Arterienstenose?

Chronic transplant rejection with diminished renal function and development of serious hypertension resistant to treatment occurred in a 36-year-old patient 3 years after kidney transplantation. Symptoms of vascular obstruction resulted in detection of advanced stenosis of the external iliac artery prior to branching of the transplant artery. Obstruction disappeared after percutaneous transluminal dilatation of the stenosis, renal function improved, and blood pressure returned to normal with reduced medication.

Anaphylactoid reactions during haemodialysis in sheep are associated with bradykinin release.

Anaphylactoid reactions have been observed in patients treated with AN69 dialysers and ACE inhibitors. Recently, it has been shown in vitro that AN69 membranes induce the release of high amounts of bradykinin in plasma. To verify the possible role of bradykinin in these shock-like reactions, six sheep were dialysed in a random fashion using AN69 or the new SPAN membrane with and without pretreatment with captopril. All animals were dialysed for 60 min via double-lumen Shaldon catheters. Blood samples were drawn at 0, 5, 10, 15, 30, and 60 min from the venous line. A total of 24 haemodialysis procedures was carried out: group A (n = 6), AN69 without captopril; group B (n = 6), SPAN without captopril; group C (n = 6), AN69 with captopril; group D (n = 6), SPAN with captopril. A significant bradykinin release was observed only in groups A and C, reaching peak values already after 5 min. Animals in group C showed the highest bradykinin values. In four of six animals in group C anaphylactoid reactions with severe hypotension were noted. From this animal model we conclude that dialysis with the AN69 membrane is associated with bradykinin release. Pretreatment with ACE inhibitors results in further increasing bradykinin levels, which lead to anaphylactoid reactions. In contrast, the new SPAN membrane was well tolerated without detectable changes in bradykinin concentrations.

Decrease in lipoprotein(a) after renal transplantation is related to the glucocorticoid dose.

Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) phenotypes were determined in 46 patients with end-stage renal disease both before as well as 1 week and 1, 3 and 6 months after renal transplantation. Immunosuppressive therapy consisted of cyclosporin A, prednisone and azathioprine. Before transplantation median Lp(a) levels did not differ between the patients and a healthy control group. A highly significant decrease (P < 0.001) in Lp(a) levels was observed in both male and female patients 1 week after transplantation. This marked reduction in Lp(a) occurred at a time when patients were receiving the highest doses of corticosteroids. As steroid doses were gradually tapered, Lp(a) concentrations subsequently increased, although at 6 months levels were still significantly reduced (P < 0.01) in women. No significant correlation was observed between Lp(a) and whole-blood cyclosporin levels, nor was there any correlation with the azathioprine dose. The reduction in Lp(a) concentrations was seen for all apo(a) phenotypes observed in the study.

Cyclosporin A trough levels correlate with serum lipoproteins and apolipoproteins: implications for therapeutic drug monitoring of cyclosporin A.

In a prospective study over 6 months, the relationship between serum lipid parameters and CsA whole blood trough concentrations was investigated in 39 renal transplant recipients receiving a triple immunosuppressive therapy with cyclosporin (CsA), azathioprine and prednisone. CsA trough concentrations were measured with a selective monoclonal immunoassay (Abbott TDx). Six months after transplantation, significant positive correlations were observed between the CsA trough concentration and serum concentrations of triglycerides (r = 0.448, p < 0.01), total cholesterol (r = 0.360, p < 0.05), and apoB (r = 0.418, p < 0.01). After exclusion of patients with over hypertriglyceridemia (> 400 mg/dl), however, the associations were no longer significant. HDL-cholesterol (HDL-C) and apo AI concentrations showed significant inverse correlations with the CsA trough level (HDL-C: r = -0.427, p < 0.01; apoAI: r = -0.350, p < 0.05); the correlations with the CsA trough level were still significant (HDL-C: r = -0.379, p < 0.05; apoAI: r = -0.354, p < 0.05) after exclusion of patients with triglyceride levels of > 400 mg/dl. As a result of these divergent effects on the plasma lipids and lipoproteins, there was a strong positive association (r = 0.633, p < 0.001) between the CsA trough concentration and the total cholesterol/HDL-C ratio. Consequently, elevated total cholesterol/HDL-C ratios that represent an increased atherogenic risk tended to be associated with higher CsA trough levels. In monitoring CsA therapy of renal transplant recipients on maintenance immunosuppressive therapy, it may well be advisable to adjust CsA dosages to obtain CsA trough levels within the lower therapeutic range for patients with an unfavorably high TC/HDL-C ratio.

Beneficial impact of aorto-coronary graft markers on post-operative angiography.

OBJECTIVE: When coronary and graft angiography is required for patients with prior coronary artery bypass (CAB) graft surgery, it is often difficult to localize the proximal aorto-coronary graft anastamosis. Our goal was to quantify the potential benefit during subsequent angiography if the proximal anastamosis is marked by an aorto-coronary graft marker at the time of CAB. METHODS: Retrospective review of 414 angiograms that were performed for patients with prior CAB. Cohorts with an without graft markers were compared. RESULTS: In the group with aorto-coronary graft markers and > or = 2 aorto-coronary grafts, there were significant reductions in fluoroscopy time (30.5%, p < 0.0001), contrast volume (21.7%, p < 0.0001), and numbers of angiographic catheters used (17.0%, p = 0.0001). If only one aorto-coronary graft was placed and marked, a trend toward reduced fluoroscopy time was observed (23.8%, p = 0.07). CONCLUSIONS: This study demonstrates the objective benefit supporting routine placement of circumferential aorto-coronary graft markers during CAB, particularly if > 1 graft is required.

Selective removal of low density lipoproteins (LDL) by precipitation at low pH: first clinical application of the HELP system.

The first clinical application of a new extracorporeal procedure (HELP) for the selective elimination of low-density lipoproteins by heparin precipitation at acid pH is described. Plasma, obtained by filtration of whole blood through a 0.2 mu filter, is continuously mixed with an equal volume of an acetate buffer (pH 4.85) containing heparin. After removal of the precipitated heparin complex by filtration, excess heparin is adsorbed to a specially developed filter and the clear plasma filtrate is subject to bicarbonate dialysis/ultrafiltration to restore physiologic pH and remove excess fluid. The calculated efficiency for the elimination of low-density lipoproteins from plasma by HELP is 100% and is therefore comparable to conventional plasmapheresis. The HELP system shows a high degree of specificity with over 80% of total protein being returned to the patient. Over 130 treatment procedures have now been performed. Patient compliance and acceptance have been excellent and no major complications have been observed.

[Modification of atrial natriuretic peptide (ANP) and cyclic GMP by hemofiltration and hemodialysis]. / Beeinflussung von atrialem natriuretischen Peptid (ANP) und zyklischem GMP durch Hämofiltration und Hämodialyse.

ANP and c-GMP concentrations in 7 patients with chronic renal failure (CRF) undergoing regular hemofiltration (HF) were determined. After switching to hemodialysis (HD) under identical ultrafiltration and treatment time no significant difference of the ANP and c-GMP profiles was detected, suggesting that the type of treatment does not affect ANP and c-GMP plasma levels. In both procedures a continuous decrease of ANP and c-GMP was observed. Head down tilting to compensate hypotension during HD was immediately followed by an increase in ANP and c-GMP during ultrafiltration. An acute onset of tachyarrhythmia absoluta during HD was also accompanied by a rise in ANP plasma concentrations. This demonstrates that ANP secretion is not altered in patients with CRF. Since ANP plasma levels closely correlate with intravascular volume, periodic determination of this hormone in HD/HF patients may provide diagnostic information to detect volume overload.

[Loss of renal functional reserve following kidney transplantation and in patients with advanced disorders of liver function]. / Verlust der renalen Funktionsreserve nach Nierentransplantation und bei Patienten mit fortgeschrittenen Leberfunktionsstörungen.

Renal functional reserve capacity was evaluated in healthy controls, kidney transplant recipients and patients with impaired liver function by simultaneous measurements of periodic clearances of inulin, PAH and creatinine every 30 minutes before, during and after infusion of an amino acid (AA) solution. During AA infusion glomerular filtration rate rose in 10 healthy controls to about 35% above basal values (inulin clearance from 107 +/- 6 to 144 +/- 7 ml/min, p less than or equal to 0.0005), renal plasma flow increased by 27% (PAH clearance from 530 +/- 25 to 675 +/- 40 ml/min, p less than or equal to 0.002). 8 renal transplant recipients with good and stable renal function (creatinine clearance above 65 ml/min) showed no rise in GFR and RPF, as did 10 patients with severe impairment of liver function and normal basal kidney function (creatinine clearance above 100 ml/min). The lack of renal functional reserve in kidney transplant recipients might indicate a hyperfiltration of the transplanted kidney. This could affect the longtime prognosis of these patients. The liver seems to play a role in the mediation of the amino acid-induced rise of GFR, supporting the hypothesis of a putative liver hormone regulating GFR after protein ingestion or AA infusion.

[Behavior of the renal functional reserve in type I diabetic patients: effect of ACE-inhibition]. / Verhalten der renalen Funktionsreserve von Typ I Diabetikern: Einfluss der Konversionshemmung.

Renal functional reserve capacity was evaluated in 19 normotensive type I diabetics without microalbuminuria. All patients had normal basal renal function as assessed by 24-hour creatinine clearances higher than 120 ml/min. PAH, inulin, and creatinine clearances were carried out every hour before, during, and after infusion of an amino acid (AA) solution. The same experiment was repeated after ACE inhibition with captopril (25 mg). Two groups of patients were found: Group A (responders) showed a significant rise in GFR after AA infusion (inulin clearances from 117 +/- 8 to 138 +/- 10 ml/min) (p less than 0.05), whereas in Group B (non-responders) no significant change in GFR was observed. Groups were comparable in age, duration of diabetes, metabolic control, and mean arterial blood pressure. Group B, however, had a significantly higher basal inulin clearance (167 +/- 17 ml/min) than Group A (117 +/- 8 ml/min). In Group A ACE inhibition completely blocked the AA-induced rise in GFR, while basal GFR in Group B was significantly reduced (167 +/- 17 to 148 +/- 8 ml/min) after captopril administration. In both groups renal plasma flow was enhanced by ACE inhibition. A rise in glucagon was observed in all patients during AA infusion. It is concluded that type I diabetics with normal basal renal function already have reduced (Group A) renal functional reserve capacity, which is completely abolished (Group B) when concomitant hyperfiltration occurs. ACE inhibition reduces hyperfiltration and is capable of blocking the AA-induced rise in GFR in these patients.

[Is the plasma ANP level an index of volume expansion in dialysis patients?]. / Ist der Plasma-ANP-Spiegel ein Index für die Volumenexpansion bei Dialysepatienten?

Fluid overload is a frequent complication in anuric patients undergoing hemodialysis (HD) or hemofiltration (HF). Elevated ANP plasma concentrations are associated with overhydration or congestive heart failure (CHF). After intensive ultrafiltration in 18 HD patients with high ANP levels at the end of HD, ANP values normalized (28 +/- 4 fmol/ml) in 11 patients (group A), suggesting previous volume overload, whereas ANP remained elevated (126 +/- 31 fmol/ml) in seven patients (group B). Left ventricular ejection fraction by radionuclide ventriculography (LVEF) was significantly (p less than 0.01) lower in group B (41 +/- 7%) as compared to normal values in group A (67 +/- 8%). M-mode echocardiography demonstrated left atrial enlargement (53 +/- 3 mm) and pathologic enddiastolic left ventricular diameters (58 +/- 4 mm) in group B, compared to normal dimensions of left atrial (43 +/- 1 mm) and left ventricular enddiastolic diameters (47 +/- 4 mm) in group A. Persisting high ANP concentrations after intensive ultrafiltration in HD patients indicate CHF and require further diagnostic evaluation.