The renin-angiotensin system in kidney development: role of COX-2 and adrenal steroids.

Recent data from studies in rodents with targeted gene disruption and pharmacological antagonists have shown that the renin-angiotensin-aldosterone system (RAAS) and cyclooxygenase type-2 (COX-2) are necessary for late stages of kidney development. The present review summarizes data on the developmental changes of RAAS and COX-2 and the pathways by which they are activated; their possible interplay and the mechanisms by which they affect kidney development. Intrarenal and circulating renin and angiotensin II (ANG II) are stimulated at birth in most mammals. In rats, renin and ANG II stay significantly elevated in the suckling period while aldosterone stabilizes at an adult level. COX-2 is stimulated in thick ascending limb of Henle's loop in the suckling period at a time when urine concentrating ability is not developed. Data suggest that this induction is mediated by combined low plasma glucocorticoid concentration and by a low NaCl intake. Studies with selective inhibitors of COX-2 and COX-2 null mice show that COX-2 activity stimulates renin secretion from JG-cells during postnatal kidney development and that lack of COX-2 activity leads to pathological change in cortical architecture and eventually to renal failure. In the postnatal period, ANG II initiates and maintains pelvic and ureteric contractions necessary for urine flow. Lack of ANG II in the neonatal period is thought to cause injury by a chronic increase of renal pelvic pressure. Aldosterone is crucial for survival and growth in the neonatal period through its effects on sodium reabsorption and the intrarenal sensitivity to aldosterone is increased in the postnatal period. Final maturation of the kidney occurs through an intimate interplay between a low dietary sodium intake and a non-responsive HPA-axis which stimulates cortical COX-2 activity. COX-2 supports increased activity of the RAAS and may contribute to a low concentrating ability.

Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients.

BACKGROUND: The oral formulation of cyclosporin A (CsA)-Sandimmun-has a highly variable absorption. The development of a CsA microemulsion-Sandimmun Neoral-resulted in increased bioavailability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with numerous other drugs and grapefruit juice. Several of these interactions might be explained by decreased pre-systemic metabolism by a cytochrome-enzyme (e.g. CYP3A4) located in the enteral mucosa, and/or via the P-glycoprotein-mediated decreased transport of CsA back from enterocytes into the gut lumen. The purpose of this pharmacokinetic study was to investigate the interaction between Sandimmun Neoral and grapefruit juice. METHOD: Eight stable renal transplant recipients were studied during two 8-h sessions in a randomized cross-over design with 4 weeks interval. Following an overnight fast the patients ingested their habitual morning dose of Neoral either with water or with grapefruit juice. During the 8-h study period 10 blood samples were taken for determination of CsA concentration. These results formed the basis for calculation of area under curve (AUC), and half-life (t(1/2)). Maximum concentration (C(max)) and time until C(max) (t(max)) were obtained from the concentration-time profile. RESULTS: The median AUC increased by 38% (12-194%) (P<0.05) following co-administration of Neoral with grapefruit juice. There were no significant changes in C(max), t(max), and t((1/2)). CONCLUSION: Co-administration of Sandimmun Neoral with grapefruit juice resulted in an increased bioavailability of CsA, indicating unchanged pre-systemic enterocyte first-pass metabolism as compared to Sandimmun. There was no impact of an oral grapefruit juice load on systemic clearance of CsA. It seems prudent to advise renal allograft recipients treated with Sandimmun Neoral not to ingest their medication with grapefruit juice.

Changes in cardiac muscle mass and function in hemodialysis patients during growth hormone treatment.

BACKGROUND: Adult patients with chronic renal failure (CRF) often show symptoms as fatigue, wasting, and reduced working capacity with concomitant findings of reduced cardiac performance and muscle mass. This state may in part be caused by an imbalance in the somatostatin/somatomedine axis resulting in increased catabolism. During an attempt to correct this catabolic state by administration of exogenous growth hormone, cardiac muscle mass and performance were studied. METHODS: In a double-blind, placebo-controlled 6-month study comprising 20 adult enfeebled hemodialysis patients, 9 patients were treated with a single daily subcutaneous injection of recombinant human growth hormone (rhGH) 4 IU/m2 and 11 with placebo injections. Left ventricular muscle mass (LVM) and ejection fraction (EF) were evaluated by echocardiography and the maximal working capacity (MWC) was measured by a bicycle exercise test performed before and after the treatment period. Supplementary electrocardiography (ECG) was performed before and after 6-month treatment. RESULTS: Median LVM increased significantly from 172 to 220 g (p = 0.03) in the rhGH-treated group, while an insignificant decrease was observed in the placebo group from 281 to 200 g (p = 0.3). The EF showed no significant changes in the two groups. MWC showed a slight, insignificant decrease in both groups. From ECG no significant ST deviations were found and no significant changes regarding B-Hb, blood pressure or pulse were observed in the two groups. Irregular heart rhythm aggravated in one patient during the first month of treatment with rhGH, but was overcome by a -blocking agent. CONCLUSION: The treatment with rhGH of adult chronic hemodialysis patients for 6 months increased the left ventricular mass significantly, but without any effect on ejection fraction or maximal working capacity. No electrocardiographic signs of ischemia were associated with the increasing muscle mass and only one patient developed symptoms that might relate to ischemia. No changes in B-Hb, blood pressure or pulse were observed during the treatment period.

Benign duodenocolic fistula. A case presenting with acidosis.

A case of benign duodenocolic fistula as a complication to peptic ulcer disease is presented, the case being interesting for the rarity of the diagnosis and by being complicated with acidosis. The etiology, clinical features, diagnosis, and treatment are reviewed.

[Antibiotic-induced hemorrhagic cystitis]. / Antibiotikaudløst haemoragisk cystitis.

Two cases of haemorrhagic cystitis following treatment with methicillin and penicillin G are presented. Two males, aged 24 and 45 years, presented identical symptoms including haematuria, dysuria and pollakisuria. The condition has in rare instances been described as caused by antibiotic treatment; in all cases a penicillin was involved. All symptoms promptly vanished when the antibiotic treatment was stopped, and the reactions were possibly allergic since cross-reactions between different penicillins have been described in earlier cases.

What are the clinical benefits of correcting the catabolic state in haemodialysis patients?

In a double-blind, placebo-controlled trial of recombinant human growth hormone (rhGH) comprising 20 chronic enfeebled haemodialysed patients, the clinical benefit of daily growth hormone treatment for six months was evaluated. Nine patients (five male, four female) were treated with rhGH 4 i.u./m2/day and eleven with placebo (seven male, four female). Their mean age was 46.5 years (range 18-68). No difference in mean age was found between the groups. A significant increase in insulin-like growth factor I (IGF-I) was observed in the rhGH-treated group (200 to 527ng/ml, p = 0.01), while a decrease was noticed in the placebo group (285 to 219ng/ml, p = 0.02). S-GH did not change significantly in either group, and there were no differences between the two groups in terms of weight, haemoglobin, s-albumin, -urea or -creatinine, which all remained unchanged during the trial. Patients' lean body mass, as measured by DXA-scanning, increased significantly in the rhGH-treated group (43.4 to 46.7kg, p = 0.004), while no change was observed in the placebo group (44.9 to 45.2kg, p = 0.76). The changes in lean body mass between the two groups were significant, p = 0.001. Left ventricular muscle mass increased significantly (227 to 286g, p = 0.03) in the rhGH-treated group, but not in the placebo group (292 to 253g, p = 0.3). The changes in left ventricular muscle mass between the two groups were significant (p = 0.02). The maximal working capacity decreased slightly and insignificantly in both groups, when measured by bicycle ergometry. Isometric muscle contraction force and endurance did not change significantly in either group. Patients' opinion about the influence of the treatment on their general well-being and working capacity, evaluated blindly on a subjective scale, improved significantly in the rhGH-treated group (9.7 to 12.6, p = 0.02), while no change was experienced in the placebo group (9.9 to 10.7, p = 0.2). No difference was however demonstrable between the two groups (p = 0.4). Thus we conclude that adult patients in long-term haemodialysis treated with rhGH experienced an increase in their lean body mass and left ventricular muscle mass. This increase in muscle mass did not, however, improve muscle contraction force or endurance when measured objectively. The rhGH-treated patients nevertheless had a subjective feeling of a slight improvement in their general wellbeing.

Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.

Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (P < 0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels.

[A short discharge letter with a copy to the patient--satisfactory for patients and practitioners]. / Kortfattet udskrivningsbrev med patientkopi--patienters og praktiserende laegers tilfredshed.

This study evaluated the introduction of a new type of discharge letter (DL). The new DL is hand-written by the discharging doctor on a form, and a copy is both given to the patient and sent immediately to the general practitioner (GP). Questionnaires were sent both to the receiving patients and GPs. One hundred and thirty-four patients (55%) and 157 GPs (87%) replied to the questionnaires. Half of the responding patients stated that the DL had helped them to understand what had happened during their hospital stay, as well as future plans for treatment. A majority of the responding GPs found the hospital stay, the patient's status at discharge and the planned after treatment to be satisfactorily described in the new DLs. Almost all GPs (90%) were pleased with the promptness with which they received the new DL. Compared to the traditional DL, 40% of the responding GPs found the new DL to be better and 29% found it to be worse.

[Electronic rectal temperature measurement. A clinical trial]. / Rektal elektronisk temperaturmåling. En klinisk undersøgelse.

Rectal measurement of body temperature with an electronic device (Ivac) was compared to measurement with mercury thermometers in 157 adult patients on a medical ward. The electronic thermometers were less accurate, giving 3.6 times as many febrile patients. This was reduced to 1.6 after thermometer calibration. It is necessary to make regular calibrations of Ivac thermometers.