A randomized and double-blind comparison of isradipine and spirapril as monotherapy and in combination on the decline in renal function in patients with chronic renal failure and hypertension.

AIMS: Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function. Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment, but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs. The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination. METHODS: Sixty patients with chronic renal failure and hypertension were enrolled in the study. After enrollment, patients were followed prospectively for 6 months in the outpatient clinic on their usual antihypertensive medication, and then randomized to a double-blinded comparison of either spirapril 6 mg daily, isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily. After randomization, patients were followed for 21 months or until the need for dialysis. Every 3 months before and 3.5 months after randomization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid. RESULTS: Blood pressure and the decline in glomerular filtration rate did not differ between the groups before randomization. After randomization, the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2) in the spirapril group, -0.58 ml/(min x month x 1.73 m2) in the isradipine group and -0.14 ml/(min x month x 1.73 m2) in the combination group (p = 0.38). Twelve patients, 4 in each group, reached end-stage renal failure. No significant difference was found with respect to diastolic (p = 0.10) or systolic blood pressure (p = 0.08) during the treatment period, but a trend towards a better blood pressure control in the combination group was present. During treatment, the rate of decline in renal plasma flow did not differ significantly between the groups (p = 0.09), neither did the changes in filtration fraction (FF) (p = 0.58) nor the mean FF (p = 0.22) during the treatment. CONCLUSIONS: Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control, but the differences where insignificant. Thus, the treatments might differ, but we were unable to confirm this because of large variation in GFR and small sample size.

Growth hormone, insulin-like growth factors and their binding proteins in adult hemodialysis patients treated with recombinant human growth hormone.

BACKGROUND: Growth deficiency and malnutrition in uremic children are often caused by malfunction of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis and can be corrected by treatment with GH. The purpose of this study was to evaluate the levels of GH, IGF-I and II and their binding proteins compared to changes in body composition in adult, enfeebled, uremic patients in chronic hemodialysis (HD), treated for 6 months with recombinant human growth hormone (rhGH). METHODS: 31 patients were included in a controlled, randomized, double-blinded study using either 4 IU/m2/day of rhGH or placebo injected subcutaneously every evening for 6 months. RESULTS: Fasting levels of GH were normal at start and increased significantly from 2.2 to 13.5 microg/l (p = 0.01) within the first 4 months of rhGH treatment. Before treatment IGF-I was at the upper limit of normal range (130 to 220 microg/l) in both groups, and it increased significantly from 213 to 348 microg/l (p = 0.01) during rhGH treatment. IGF-II was above the normal range in both groups, and remained unchanged throughout. IGFBP-1 decreased in the rhGH-treated group from 53.1 to 24.7 microg/l (p = 0.004), while IGFBP-3 increased from 5620 to 7100 microg/l (p = 0.004). The molar ratio of IGF-I/IGFBP-3 increased significantly from 14 to 25% (p = 0.01), while the ratio decreased in the placebo group (p = 0.01). During the treatment with rhGH the patients increased their lean body mass (= muscle mass) by a median of 3.18 kg (range 0.82 to 5.12 kg) (p = 0.0001) while their fat mass decreased by a median of 3.33 kg (range 0.18 to 5.82 kg) (p = 0.004). Total body mass (= weight) remained stable. No significant changes were observed in the placebo group. CONCLUSION: The baseline GH and IGF-I concentrations were normal in malnourished HD patients. When treated with rhGH in a dosage as used in growth-retarded uremic children, IGF-I increased to the levels seen in acromegalic persons. IGF-I increased more than IGFBP-3 whereby its biological activity obviously improved. This was reflected in an increased muscle mass and a decreased fat mass. The rhGH treatment was well tolerated.

Glomerular filtration rate estimated from the uptake phase of 99mTc-DTPA renography in chronic renal failure.

BACKGROUND: The purpose of the study was to compare the estimation of glomerular filtration rate (GFR) from 99mTc-DTPA renography with that estimated from the renal clearance of 51Cr-EDTA, creatinine and urea. METHODS: Fifty patients with reduced renal function (serum creatinine between 150 and 600 micromol/l) were enrolled in the study. GFR was estimated from the uptake phase of 99mTc-DTPA renography (GFR(DTPA)). The renal clearance of 51Cr-EDTA (GFR(EDTA)) was used as the reference method. Creatinine clearance (C(Cr)), urea clearance (C(Ur)) and the mean of urea and creatinine clearance (C(Cr+Ur)/2) were also calculated from urine collected during a period of 24 h. Limits of agreement were used for method comparison. RESULTS: The limit of agreement between GFR(DTPA) and GFR(EDTA) was 2 +/- 17 ml/min. The mean difference did not deviate significantly from zero. The other clearance techniques had larger limits of agreement and a mean difference significantly different from zero. Furthermore, C(Ur) and C(Cr+Ur)/2 had systematic deviations of the differences, indicating that C(Ur) and C(Cr+Ur)/2 are poor estimates of GFR. CONCLUSION: The limit of agreement between GFR(DTPA) and GFR(EDTA) are acceptable and, therefore, GFR estimated from 99mTc-DTPA renography is acceptable for clinical use in patients with reduced renal function. Furthermore, the method is simple and less time consuming compared with renal clearance techniques.

Dialysis catheter-related septicaemia--focus on Staphylococcus aureus septicaemia.

BACKGROUND: Dialysis catheters are a common cause of nosocomial septicaemia in haemodialysis units usually due to staphylococci, of which Staphylococcus aureus is the most pathogenic. In this study, the epidemiology and pathogenesis of dialysis catheter-related infections were studied, and methods to identify patients with these infections were evaluated. METHODS: A one-year prospective study of 67 catheters in 43 haemodialysis patients was performed. Details about patients and catheters were obtained successively during the catheter period, and biochemical parameters expected to be related to infection were measured. After catheter insertion, all patients were screened for nasal carriage of S. aureus, and a culture was taken from the skin overlying the catheter insertion site. Once a week, cultures were taken from the insertion site and from the hub, and aerobic and anaerobic blood cultures were drawn from the catheter. If clinical signs of septicaemia occurred, peripheral blood cultures were also performed, when it was possible. RESULTS: The incidence of septicaemia was 49% (21/43) in patients, and 56% of all cases were caused by S. aureus. The mortality was 14% (3/21) and the incidence of severe secondary complications to septicaemia was 24% (5/31). In all, 80% of all severe complications and 75% of all deaths from septicaemia were due to S. aureus. With respect to S. aureus septicaemia, the predictive values of positive (P) and negative (N) S. aureus cultures were as follows: nasal culture, P=36% (10/28), N=90% (35/39); culture from the insertion site, P=72% (13/18), N=98% (48/49); and culture from the hub, P=75% (3/4), N=83% (52/63). The risk ratio for S. aureus septicaemia was 26.2 (6.1-113), P=0.0001, according to the presence of S. aureus at the insertion site, and 3.3 (0.74-15.1), P=0.12 according to nasal carriage of S. aureus. The frequency of S. aureus phage-type Group 2 (43%) was much higher than the general frequency of this phage-type in Denmark, which is about 23%. Catheter blood cultures were positive although there were no clinical signs of septicaemia in 34% (23/67) of all catheter periods--84% of these were due to coagulase-negative staphylococci. CONCLUSIONS: Dialysis catheter-related S. aureus septicaemia was highly unlikely if the patient had not been carrying S. aureus in the nose or at the insertion site during the time the catheter was in place. The best predictor of dialysis catheter-related S. aureus septicaemia was a positive S. aureus culture from the insertion site. Positive catheter blood cultures unrelated to any clinical signs of septicaemia occurred in one-third of all catheter periods, and 84% of these were due to coagulase-negative staphylococci.

The pulsatility index and the resistive index in renal arteries. Associations with long-term progression in chronic renal failure.

BACKGROUND: The pulsatility index (PI) and the resistive index (RI) are used as pulsed-wave Doppler measurements of downstream renal artery resistance. PI and RI have been found to correlate with renal vascular resistance, filtration fraction and effective renal plasma flow in chronic renal failure. The aim of the present study was to evaluate the potential relationship between these indices and the rate of decline in renal function, as reflected by changes in different parameters of renal function in patients with chronic renal failure. METHODS: Twenty-one patients (8 females; 13 males, mean age 58 years (36-75)) with chronic renal failure were enrolled in the study. Doppler examinations were performed in the segmental arteries by an Acuson 128XP. The PI and the RI was calculated from the blood flow velocities. Parameters of renal function were measured every 3 1/2 months, and all patients were followed for 18-21 months. Progression of renal dysfunction was estimated by linear regression of parameters of renal function versus time. RESULTS: In a multiple regression analysis both PI and RI correlated significantly to the rate of decline in reciprocal serum creatinine (PI: r = -0.48, P = 0.03; RI: r = -0.52, P = 0.02). Furthermore, when separating the patients in two groups by the median RI value, there was a significant difference between the groups in rate of decline in reciprocal serum creatinine (P = 0.02). For PI this distinction was also present (P = 0.04). CONCLUSION: PI and RI correlated to the severity of the renal disease, as reflected by the rate of decline in reciprocal serum creatinine during antihypertensive treatment. The median RI or PI value could separate the patients into groups one of slow and another of fast progression.

[The influence of antihypertensive treatment on progression of chronic nepropathy]. / Antihypertensiv behandlings indflydelse på progressionen af kronisk nefropati.

This article describes the influence of antihypertensive treatment on the kidneys, both the acute and the long-term effects, especially with regard to the progression of chronic non-diabetic renal failure. Our knowledge about the different antihypertensive drugs is still limited, but some studies indicate that especially ACE-inhibition and perhaps calcium antagonism may have the potential to postpone renal failure.

Parathyroid hormone secretion in chronic renal failure.

The aim of study was to introduce and evaluate a method for quantifying the parathyroid hormone (PTH) secretion during hemodialysis in secondary hyperparathyroidism due to end-stage renal failure. We developed a method suitable for inducing sequential hypocalcemia and hypercalcemia during hemodialysis. During the development of the method we found significantly different results of blood ionized calcium and serum PTH concentration when obtained from the arterial blood line on the dialysis unit or from peripheral venous blood. However, when corrected for the calculated recirculation of 3 to 25%, the result obtained from arterial blood was comparable to the result from venous blood. Furthermore, the results obtained from venous blood were comparable to the results of sequential citrate and calcium clamping performed on a non-dialysis day. From our data of venous blood during hemodialysis, blood PTH/ionized calcium curves were constructed, and a mean calcium set-point of 1.16 mmol/liter was estimated compared to the normal mean of about 1.13 mmol/liter. In conclusion, we demonstrate that it is important to use a standardized method to evaluate parathyroid hormone dynamics in chronic renal failure. By the use of a standardized method we show that the calcium set-point is normal or slightly elevated, indicating normal parathyroid reactivity to calcium in chronic renal failure.

Anticardiolipin antibodies and lipoprotein (a) levels in patients with chronic renal failure treated with dialysis: associations with atherothrombotic disease.

The present study evaluated the importance of anticardiolipin antibodies (ACA) and lipoprotein (a) (Lp(a)) as markers of atherothrombotic disease in a retrospective study of patients on maintenance hemodialysis (HD) or peritoneal dialysis (PD). ACA and Lp(a) were measured in 22 patients on PD, and 64 on HD. Three patients were ACA IgM seropositive, whereas none were ACA IgG seropositive. The mean number of previous atherothrombotic events was 2.0 (1-3) in ACA seropositive patients, as compared to 0.7 (0-4) in ACA seronegative patients. The mean Lp(a) level was 56.7 mg/dl (3.0-217.7) in PD patients and 38.8 mg/dl (2.0-255.6) in HD patients (n.s.). Levels of Lp(a) greater than 30 mg/dl were not significantly associated with a history of atherothrombotic events, but all patients who had suffered a myocardial infarction or cerebrovascular insult had Lp(a) levels above 30 mg/dl. We conclude that ACA seropositivity is rare. All ACA seropositive patients had suffered atherothrombotic disease in the current study, whereas all patients with myocardial infarction or cerebrovascular insult had Lp(a) levels above 30 mg/dl.

MR velocity mapping measurement of renal artery blood flow in patients with impaired kidney function.

Renal blood flow (RBF) was measured in 9 patients with chronic impaired kidney function using MR velocity mapping and compared to PAH clearance and 99mTc-DTPA scintigraphy. An image plane suitable for flow measurement perpendicular to the renal arteries was chosen from 2-dimensional MR angiography. MR velocity mapping was performed in both renal arteries using an ECG-triggered gradient echo pulse sequence previously validated in normal volunteers. Effective renal plasma flow was calculated from the clearance rate of PAH during constant infusion and the split of renal function was evaluated by 99mTc-DTPA scintigraphy. A reduction of RBF was found, and there was a significant correlation between PAH clearance multiplied by 1/(1-hematocrit) and RBF determined by MR velocity mapping. Furthermore, a significant correlation between the distribution of renal function and the percent distribution of RBF was found.

The pulsatility index and the resistive index in renal arteries in patients with hypertension and chronic renal failure.

BACKGROUND: The pulsatility index (PI) and the resistive index (RI) are used as pulsed-wave Doppler measurement of downstream renal artery resistance. Little information is available on their value in chronic renal failure and their correlation to parameters of renal function and haemodynamics. The aim was to compare PI and RI of renal arteries in healthy volunteers and in patients with hypertension and chronic renal failure, and furthermore to study the correlation of these indices to measurements of renal haemodynamics and function by standard methods in patients with renal failure and hypertension. METHODS: Twenty-five hypertensive patients (10 females, 15 males, mean age 52 years (24-74) with a glomerular filtration rate (GFR) less than 50 ml/min and an arterial blood pressure above 140 mmHg systolic and 95 mmHg diastolic were included in the study. Ten healthy, normotensive volunteers (4 females and 6 males, mean age 43 years (30-62)) served as controls in the Doppler examinations. Doppler examinations were performed in segmental arteries by an Acuson 128. The PI and the RI was calculated from the blood flow velocities. RESULTS: Both the PI and the RI were significantly higher in the patient group (P) than in the control group (C) (PI, P 1.65 (1.31-1.86), C 1.19 (0.93-1.25), P = 0.003; RI, P 0.76 (0.69-0.81), C 0.67 (0.64-0.70), P = 0.003). Both PI and RI correlated significantly with effective renal plasma flow (PI: r = -0.5, P = 0.02; RI: r = -0.5, P = 0.006), renal vascular resistance (PI: r = 0.4, P = 0.05; r = 0.5, P = 0.02), filtration fraction (PI: r = 0.6, P = 0.005; RI: r = 0.5, P = 0.01) and clearance of creatinine (PI: r = -0.6, P = 0.008; RI: r = -0.6, P = 0.006). Only RI correlated significantly to GFR (r = -0.5, P = 0.02). The indices did not correlate to serum creatinine, or mean arterial blood pressure. CONCLUSION: PI and RI seems to be closely related to parameters of renal haemodynamics and clearance of creatinine in patients with chronic renal failure and hypertension.

Expression of the intercellular adhesion molecule-3 (ICAM-3) in human renal tissue with relation to kidney transplants and various inflammatory diseases.

Adhesion molecules are important for immune regulatory mechanisms concerning antigen presentation, lymphocyte activation, localisation and migration as well as effector-target cell interactions in inflammatory processes. The immunohistochemical expression of ICAM-3, a recently cloned new member of the immunoglobulin family which also binds leucocyte function antigen 1 (LFA-1), was examined in 80 needle core biopsies from 35 renal allografts, 7 patients with mesangioproliferative glomerulonephritis, 5 patients with extracapillary glomerulonephritis, 4 patients with interstitial nephritis and 5 patients with diabetic nephropathy and 20 normal kidneys. In all types of lesions ICAM-3 was constitutively expressed on the majority of infiltrating leucocytes without detectable upregulation or presentation on possible target structures during inflammation indicating its possible role to be mainly in initiation of the inflammatory response.

[Carbamide kinetics in the evaluation of the therapeutic quality of hemodialysis]. / Carbamidkinetik til vurdering af behandlingskvalitet ved haemodialyse.

A urea kinetic analysis, (the Sargent and Gotch model), was applied to 62 haemodialysis patients. The protein catabolic rate was below 1 g/kg/day in 56.5% of the patients and 66.3% had a KT/V (Clearance x Time/Volume) below 1. The median KT/V was 0.90 and the median normalized protein catabolic rate was 0.95 g/kg/day. KT/V was strongly correlated to protein intake (normalized protein catabolic rate). It is concluded that urea kinetic modelling is a practical tool for assessing the dialysis adequacy and nutritional status of haemodialyzed patients.

Pharmacokinetics of 1 alpha-hydroxycholecalciferol after intraperitoneal, intravenous and oral administration in patients undergoing peritoneal dialysis.

Intravenous (i.v.) injection of vitamin D3 has a well known suppressive effect on the release of parathyroid hormone. However, the i.v. route is inconvenient in patients undergoing peritoneal dialysis. Moreover, no study has been published on the pharmacokinetics of 1 alpha-hydroxycholecalciferol (1 alpha-OHD3) after intraperitoneal (IP), i.v. and oral administration. Therefore, the appearance of 1,25-(OH)2D3 after administration of 1 alpha-OHD3 was studied in 8 peritoneal dialysis patients. Open, prospective, randomized cross-over design with single doses of 1 alpha-OHD3 (80 ng/kg BW) given on 3 separate occasions either IP, i.v. or oral was applied. After the administration of 1 alpha-OHD3, blood was collected at baseline and 0.5, 1, 2, 3, 4, 6, 12 and 24 h for measurement of circulating 1,25-(OH)2D3. A one compartment model with first order absorption and elimination (Cpl = Be-ke*t-Ae-ka*t) was fitted to the concentrations following i.v. administration. Following IP and oral administration the concentrations did not reach maximum levels within the time of blood sampling. In all cases, the 24 h area under the time/concentration curve for 1,25-(OH)2D3 (AUC24) was calculated using the trapezoidal method. Residual areas were calculated using the terminal slope from i.v. administration, and added to AUC24 giving AUC0-->infinity. After i.v. administration A, ka, B, ke, t1/2, AUC24 and AUC0-->infinity were (mean +/- SD) 62.9 +/- 16.4 pg/ml, 0.76 +/- 0.30 h-1, 71.6 +/- 14.7 pg/ml, 0.017 +/- 0.015 h-1, 109.4 +/- 129.5 h, 1315.8 +/- 236.9 pg/ml x h and 10322.2 +/- 11473.7 pg/ml x h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel blockers in kidney transplantation.

PURPOSE: To review the question as to whether treatment with a calcium channel blocker (CCB) influences the course and outcome of cadaveric renal transplantation in recipients treated with cyclosporin A. METHODS: Computer-assisted search (Medline) and manual search of the literature. Odds ratio, Mantel-Haenszel test, Fischer's test and Chi 2 test. RESULTS: Two Randomised, placebo-controlled studies, 12 randomised, open studies, 3 retrospective studies, 1 study using a historic control group and 3 studies only reported in abstract form were identified. In the randomised, open studies treatment with CCB reduced the rate of delayed graft function but had no effect on the rate of rejection and graft survival. The effect on graft function was equivocal. In the blind, placebo-controlled studies no beneficial effects of treatment with CCB were found. Treatment with CCB reduced the dose of CyA needed to reach target whole blood level of CyA in nearly all studies. CONCLUSION: Results are conflicting. Further studies are needed.

Tertiary hyperparathyroidism treated by ultrasonically guided percutaneous fine-needle ethanol injection.

Advanced renal failure is often accompanied by secondary and tertiary hyperparathyroidism. In tertiary hyperparathyroidism it is necessary to reduce the gland mass. The present study describes the response to treatment with percutanous injection of ethanol of enlarged parathyroid nodules in 9 uremic patients. All had hypercalcemia, severely elevated serum levels of parathyroid hormone and ultrasonically detectable enlarged parathyroid glands. Three patients did not respond to the treatment. In the remaining 6 patients, serum values of total and ionized calcium were normalized and the serum values of parathyroid hormone were reduced at least 30% after 18 months. Seven of the patients experienced an improvement of symptoms. No complications were seen. We conclude that treatment with ethanol injection can be used as an alternative to conventional parathyroidectomy to improve parathyroid status in selected patients.

Acute effect of oral, intraperitoneal, and intravenous 1 alpha-hydroxycholecalciferol on markers of bone metabolism.

OBJECTIVE: To study the acute effect of 1 alpha-hydroxycholecalciferol (1 alpha-OHD3) on serum levels of alkaline phosphatase, Ca2+, osteocalcin, parathyroid hormone (PTH), phosphate and type I and III procollagens (PICP and PIIINP respectively) in patients undergoing peritoneal dialysis. Also, 1,25-(OH)2D3 was measured. DESIGN: Single doses of 1 alpha-OHD3 (80 ng/kg body wt) were given in randomized cross-over fashion, orally, intraperitoneally (i.p.) and intravenously (i.v.) on three occasions. Blood was sampled at 0, 1, 6, 12, and 24 h after administration of 1 alpha-OHD3. MAIN RESULTS: Following oral administration of 1 alpha-OHD3, a decrease in serum alkaline phosphatase was seen when levels at 1 and 6 h were compared to baseline (P < 0.05). Oral and i.v. drug administrations resulted in an increasing trend in serum Ca2+ throughout the study (P < 0.05). Moreover, a difference in serum Ca2+ was found when 24-h levels after oral 1 alpha-OHD3 dose was compared to baseline (P < 0.05). Serum osteocalcin at 12 and 24 h after oral 1 alpha-OHD3 compared to baseline were increased (P < 0.05). Intact PTH followed a circadian rhythm after all three routes of drug delivery. After 24 h, significant decreases of intact PTH were observed in the oral and i.v. group. No changes in serum phosphate and serum PICP levels were observed over time after oral, i.p., and i.v. delivery of 1 alpha-OHD3. However, serum PIIINP following oral and i.p. administration of 1 alpha-OHD3 decreased at 1 and 6 h (P < 0.05). CONCLUSION: Oral and i.v. administration of 1 alpha-OHD3 does influence serum levels of osteocalcin, PTH, and PIIINP: Noticeable is the significant increase in serum osteocalcin after oral administration of 1 alpha-OHD3, the remarkable increase (22.6%) in osteocalcin 24 h after i.v. 1 alpha-OHD3, though not statistically significant, the increase in serum PTH levels 12 h following oral and i.v. doses of 1 alpha-OHD3 and the moderate effect on serum Ca2+ levels.

Influence of diltiazem on renal function and rejection in renal allograft recipients receiving triple-drug immunosuppression: a randomized, double-blind, placebo-controlled study.

In a prospective, randomized and placebo-controlled study we evaluated the influence of treatment with the calcium-channel blocker diltiazem on the course and results of cadaveric kidney transplantation in 39 graft recipients. The grafts were reperfused with Euro-Collins solution containing diltiazem 20 mg/l. All recipients except those in chronic treatment with a calcium-channel blocker received preoperatively a bolus of diltiazem or placebo 0.3 mg/kg and in all an infusion of diltiazem or placebo 3 mg/kg/24 h was started preoperatively. After that, diltiazem or placebo was given orally for 3 months. Donors were not treated. Immunosuppressive therapy consisted of prednisone, azathioprine and CsA. There were no significant differences between the groups concerning donor or recipient characteristics, HLA-mismatching, and ischaemic time. Thrombosis leading to graft loss occurred in 3 recipients (diltiazem:2, placebo:1) and one graft was lost due to septicaemia (diltiazem). For the remaining 35 grafts no beneficial effect of treatment with diltiazem was found for the rate of delayed graft function, the rate of rejections, time to first rejection, whole blood CsA concentration, or graft function. The CsA dose needed to reach target whole blood concentration was significantly less in the diltiazem group. In conclusion, our results do not indicate any beneficial effects of treatment with diltiazem in cadaveric kidney transplantation, except a reduction of costs because of a significant reduction of the CsA dosage.

Acute kidney graft rejection. A morphological and immunohistological study on "zero-hour" and follow-up biopsies with special emphasis on cellular infiltrates and adhesion molecules.

Serial biopsies from 41 consecutive renal allotransplanted patients were evaluated in order to obtain pretransplant data as well as information on well-functioning and acutely rejecting grafts. Each patient served as his own control. Thirty-five patients were followed according to the schedule which included biopsy prior to transplantation, shortly after opening of reanastomosis, at least once postoperatively (days 7-10), and furthermore whenever clinically indicated. The morphological evaluation was in each case combined with immunofluorescence (to detect immunoglobulins and complement fractions) and immunohistochemistry with a wide panel of monoclonal antibodies for T cells (CD2, CD3, CD4, CD8, gamma delta), B cells (CD20, CD22), macrophages (CD68, MAC387) NK cells (leu-7, CD16), activation markers (IL-2-R, Ki-67, transferrin-R), MHC antigens (HLA-ABC, HLA-DR), adhesion molecules (ICAM-1, VCAM-1, ELAM-1, PADGEM, VLA-4, LFA-1 alpha/beta), and growth factors (EGF, TGF-alpha, EGF-R). When 132 biopsies and 10 failed allografts were examined, no specific morphological or immunohistological parameter predictive of rejection or graft outcome could be found. Morphology in follow-up biopsies from non-rejecting and rejecting patients revealed a continuum of inflammatory changes, and several non-rejecting cases demonstrated cellular inflammatory infiltrates which could not be discriminated from those seen in acute rejection. Of the patients 44% had acute rejection accompanied by increased infiltration of T cells and macrophages showing enhanced IL-2-R expression, increased tubular and endothelial staining for MHC class II, ICAM-1, and VCAM-1, and strong leukocytic expression of VLA-4 and LFA-1 alpha/beta.

[Loop diuretics. Rational pharmacotherapy]. / Slyngediuretika. Rationel farmakoterapi.

UNLABELLED: The pharmacodynamics and -kinetics as well as rational pharmacotherapy of furosemide and bumetanide is reviewed. In renal insufficiency, a reduced response to diuretics is due to altered pharmacokinetics. The optimum dose can be determined within three to four hours by titration and the effect is measured by the amount of excreted sodium. In nephrotic syndrome, both pharmaco-kinetics and--dynamics are altered. The optimum dose is established as above. Starting and ceiling doses are given in tables for both drugs in renal insufficiency and nephrotic syndrome. In congestive heart failure, the difference is greater between oral and intravenous doses than apparent from the bioavailability of the drugs. If potent diuretics are without effect, the heart failure must be treated more vigorously or a combination with thiazides tried out. Potent diuretics are seldom used in the treatment of liver cirrhosis, but, if used, large doses are necessary. Non-steroidal antiinflammatory drugs are usually considered contra-indicated in patients with severe renal insufficiency, since the pharmacodynamics of the diuretics are altered. CONCLUSION: The general strategy when using potent diuretics is titration to an effective dose and then using this dose as frequently as needed in order to obtain the desired response.