Preserved incretin effect in type 1 diabetic patients with end-stage nephropathy treated by combined heterotopic pancreas and kidney transplantation.

Insulin secretion is stimulated better by oral than by intravenous glucose (incretin effect). The contribution of the autonomic nervous system to the incretin effect after oral glucose in humans is unclear. We therefore examined nine type 1 diabetic (insulin-dependent) patients with end-stage nephropathy, studied after combined heterotopic pancreas and kidney transplantation, and 7 non-diabetic kidney recipients (matched for creatinine clearance and immunosuppressive medication). The release of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) immunoreactivity and B cell secretory responses (IR insulin and C-peptide) to oral (50 g) and "isoglycaemic" intravenous glucose (identical glycaemic profile) were measured by radioimmunoassay. The difference in B cell responses between the two tests represents the contribution of the enteroinsular axis to the response after oral glucose (incretin effect). Insulin responses after the oral glucose challenge were similar in the two patient groups despite systemic venous drainage of the pancreas graft in the pancreas-kidney-transplanted group. In both groups GIP and GLP-1 increased after oral but not after intravenous glucose, and B cell secretory responses were significantly smaller (by 55.2 +/- 7.7% and 46.5 +/- 12.5%, respectively) with "isoglycaemic" intravenous glucose infusions. The lack of reduction in the incretin effect in pancreas-kidney-transplanted patients, whose functioning pancreas is denervated, indicates a lesser role for the nervous system and a more important contribution of circulating incretin hormones in mediating the enteroinsular axis in man.

Basal and nutrient-stimulated pancreatic and gastrointestinal hormone concentrations in type-1-diabetic patients after successful combined pancreas and kidney transplantation.

The secretion of pancreatic and gastrointestinal hormones in the basal state and after nutrient stimuli (50 g glucose, 50 g protein, or 30 g triglyceride administered on separate occasions) was assessed in ten previously type-1-diabetic patients after successful combined kidney and pancreas transplantation (systemic venous drainage). Fasting values were compared to matched non-diabetic kidney-transplanted patients and related to kidney function (endogenous creatinine clearance) and to the type and dosage of immunosuppressive medication. In the fasting state, only IR insulin concentrations were higher in pancreas-kidney-transplanted patients (by 88%; P = 0.001) than in the kidney graft recipients. There were significant inverse correlations of plasma C-peptide, GIP, and gastrin immunoreactivity to endogenous creatinine clearance (kidney function). In response to nutrients, insulin secretion (IR insulin, C-peptide) was significantly stimulated by glucose, and - to a lesser degree - also by protein. Pancreatic glucagon was suppressed by glucose and stimulated by protein ingestion. GIP was raised after glucose and triglyceride more than after protein (P = 0.0003). GLP-1 immunoreactivity was stimulated by all nutrients, with a tendency towards higher responses to protein and fat (P = 0.06). Gastrin was mainly raised by protein. In conclusion, the overall pattern of pancreatic and gastrointestinal hormone release is normal in patients after combined pancreas-kidney-transplantation, but there are some peculiarities due to (a) systemic venous drainage of the pancreas graft (elevated fasting IR insulin) and (b) impaired kidney function (negative correlation of fasting plasma values to endogenous creatinine clearance for C-peptide, GIP, and gastrin).(ABSTRACT TRUNCATED AT 250 WORDS)

Consequences of systemic venous drainage and denervation of heterotopic pancreatic transplants for insulin/C-peptide profiles in the basal state and after oral glucose.

Plasma glucose, immunoreactive insulin and C-peptide concentrations were compared in nine pancreas-kidney-transplanted patients (systemic venous drainage) and in ten non-diabetic kidney-transplanted patients with similar kidney function. In the basal state, C-peptide (insulin secretion) was similar, but immunoreactive insulin was higher and glucose concentrations were slightly, but significantly lower in pancrease-transplanted patients. After 50 g oral glucose, the plasma glucose and IR-insulin profiles were similar in both groups. The circumvention of first-pass hepatic insulin extraction (decreased endogenous insulin clearance) was compensated for by a significant reduction in insulin secretion (C-peptide; p = 0.036). In conclusion, hyperinsulinaemia in pancreas-transplanted patients with systemic venous drainage is significant only in the basal state. Insulin delivered into the portal and peripheral circulation, when leading to similar insulin profiles, maintains comparable degrees of glucose tolerance.

[Clearance behavior of the kidney in relation to ANF in the autologous dog transplantation model]. / Clearanceverhalten der Niere gegenüber ANF im autologen Hundetransplantationsmodell.

ANF is totally filtrated by the kidney and is degradated in the brush border of the tubuli. In an experimental transplant model in dogs excretion of ANF is investigated after a cold ischemia period of 48 h and HTK-protection. The ANF-renin-antagonism was of interest respectively. The experiments demonstrated that the filtration in the glomeruli and the function of the endopeptidases in the brush border is normal after a cold ischemia period of 48 and HTK-protection. There is a linear correlation between the concentration of ANF in the renal vein and the aorta. An antagonism of ANF and renin could not be found. ANF is discussed as an additional ischemia parameter in renal transplantation.

Complications of plasma exchange in patients with neurological diseases.

Plasma exchange has proven to be effective in diseases of established or presumed autoimmune etiology as well as in hyperviscosity syndromes and some rare metabolic disorders. Its application is thought to be relatively safe; nevertheless, severe complications may occur. We therefore analyzed the complications of 291 exchanges in 39 patients with neurological diseases. Minor complications developed in 4.8% and major complications in 2.7% of procedures, including one death. Severe infections and technical problems have been the most serious side effects, sometimes followed by organ failure or even death.

[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.

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.

[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.

Binding sites of atrial natriuretic peptide in human renal tissue-quantification by in vitro receptor autoradiography.

Specific binding sites for atrial natriuretic peptide (99-126) in different areas of normal human renal tissue were quantified by in vitro autoradiography. Our data represent the first characterization of ANP binding sites in different structures of the human kidney. Characterization of ANP binding revealed by Scatchard plot analysis a single class of high affinity binding sites in the glomeruli (Kd 0.53 +/- 0.11 nM; BMax 74.4 +/- 17.86 fmol/mg protein), the vasculature (Kd 0.18 +/- 0.014 nM; BMax 91.6 +/- 25.02 fmol/mg protein), and the medulla (Kd 0.34 +/- 0.13 nM; BMax 106.0 +/- 30.61 fmol/mg protein). These sites may play a key role in the actions of the cardiac hormone in human kidney and in the ameliorating effects of ANP in the recovery from acute renal failure.

[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.

Isolation and structural analysis of the circulating human cardiodilatin (alpha ANP).

A new method was applied to isolate a polypeptide hormone from human blood. The polypeptides from 1,000 1 of hemofiltrate with a molecular weight lower than 20 kDaltons were adsorbed to 2.5 kg alginic acid, then eluted, precipitated, and desalted on a G-25 Sephadex column, thus obtaining a crude lyophilised plasma polypeptide extract. These polypeptides were further submitted to ion-exchange chromatography. Thereafter, two steps of HPLC were carried out to purify a distinct polypeptide which was the circulating form of cardiodilatin (CDD) in this case. The amino acid analysis, C-terminal enzymatic cleavage by carboxypeptidase A, and sequence analysis showed that the only form of circulating cardiodilatin is the 28 amino acid residue containing molecule, cardiodilatin-99-126 cleaved from the C-terminus of cardiodilatin-126 and identical with alpha-ANP (alpha atrial natriuretic polypeptide). Other bioactive molecular forms of the polypeptide hormones of the cardiodilatin family were not detected in the hemofiltrate. The isolation procedure was followed up by a bioassay using in vitro vascular smooth muscle relaxation.

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.