Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.

Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.     

Measurement of serum amyloid A protein concentrations as test of renal allograft rejection in patients with initially non-functioning grafts.

Serum amyloid A protein concentrations were monitored in 10 renal transplant recipients who required dialysis after transplantation because of an initially non-functioning graft. Fifteen rejection episodes were identified by repeated fine needle aspiration biopsies of the grafts. All rejections were characterised by pronounced increases in serum amyloid A concentrations, the mean peak value being 363 (SE 57) mg/1 as compared with a mean preoperative concentration of 14 (5) mg/1. The rise in concentrations preceded the start of anti-rejection treatment by an average of 2.5 days in eight of the rejection episodes, in five episodes it occurred the same day, and in two episodes it occurred the next day. With exclusion of the predictable surgery induced rise in values, which peaked on the second postoperative day, there were 17 increases in amyloid A concentrations peaking at greater than or equal to 100 mg/1; in two cases they were not related to documented rejection. These findings show that measurements of serum amyloid A concentration provide a valuable non-invasive aid in identifying acute renal allograft rejection, including that in patients whose graft does not function initially.     

Detection of renal allograft rejection by computer.

A computer program incorporating an adaptation of a statistical method, the multiprocess Kalman filter, was used to detect changes in trends of plasma creatinine and urea concentrations. In 28 recipients of renal allografts a definite deterioration in renal function was identified retrospectively on 32 occasions by an experienced renal physician independently of the statistical analysis. The computer identified 31 of these 32 episodes using creatinine and urea results, and 29 using creatinine alone. Dysfunction was identified by the computer significantly earlier (p less than 0.05) than by the clinician and a median of one day earlier (p less than 0.02) than treatment was actually initiated. The computer identified dysfunction on 11 out of 1259 days when the clinician did not suspect rejection. These 11 episodes may have had a pathological importance, though no clinical diagnosis was made. This computer method is useful for immediate analysis of incoming results and for timing events either prospectively or retrospectively.     

Plasma creatinine and urea: creatinine ratio in patients with raised plasma urea.

We examined the plasma urea and creatinine concentrations and the ratio between them according to diagnosis in 100 unselected and 31 selected adult hospital patients with a plasma urea concentration greater than or equal to 10 mmol/l (60mg/100ml). We also examined plasma urea and creatinine concentrations in 350 unselected consecutive patients, but found no useful relation between the two values. Congestive heart failure was the most common identifiable cause of a raised plasma urea concentration in the 100 unselected patients (36%). Among these 100 patinets the plasma creatinine concentration was a more useful discriminant between prerenal uraemia and intrinsic renal failure than was the urea:creatinine ratio or the plasma urea concentration. A plasma creatinine concentration greater than 250 mumol/1 (2-8 mg/100ml) indicated intrinsic renal failure with a 90% probability.     

Beta 2-microglobulinaemia: a sensitive index of diminishing renal function in diabetics.

A sensitive single measure of diminishing renal function is of importance in attempts to modify the progression of diabetic nephropathy. In 12 insulin-dependent diabetics with proteinuria plasma concentrations of beta 2-microglobulin were found to correlate more closely than plasma creatinine concentrations or creatinine clearance with glomerular function as measured by clearance of 52Cr-EDTA. The plasma beta 2-microglobulin concentration was raised in all patients with diminished glomerular filtration rate (below 80 ml/min/1.73 m2). By contrast, in two of these patients plasma creatinine concentration was normal. Plasma beta 2-microglobulin concentrations were stable throughout the day and not affected by food intake, unlike plasma creatinine concentrations, which rose in the afternoon and evening and after a meat meal. Plasma beta 2-microglobulin concentrations were the same in venous and capillary blood, the capillary blood being readily self-collected. Concentrations of beta 2-microglobulin were stable for up to 24 hours when whole blood was stored at 4 degrees C; adding aprotinin inhibited loss of beta 2-microglobulin for up to seven days. The results of this study suggest, therefore, that measuring beta 2-microglobulin concentrations is a simple and accurate method of detecting minor degrees of renal impairment and monitoring the effects of treatment.     

Cyclosporin treatment of IgA nephropathy: a short term controlled trial.

Cyclosporin''s known regulatory effects on the immune system suggest that it may be useful in treating patients with IgA nephropathy. A randomised prospective single blind study of 19 patients with IgA nephropathy and proteinuria (greater than 1.5 g/day) was conducted to determine the therapeutic value of cyclosporin. The patients were divided into two groups: nine patients were given oral cyclosporin (5 mg/kg/day) for 12 weeks and 10 patients a placebo. The two groups were comparable in age of presentation, ratio of men to women, plasma creatinine and serum IgA concentrations, creatinine clearance, daily urinary protein excretion, severity of renal histopathological changes, and prevalence of hypertension. A significant reduction of proteinuria and an increase of plasma albumin concentration was observed with treatment with cyclosporin. Nevertheless, a significant rise of plasma creatinine concentration and a fall in creatinine clearance was found in patients after six weeks'' treatment with cyclosporin, although the plasma cyclosporin concentrations were maintained within a narrow therapeutic range. Serum IgA concentrations were reduced in seven patients. Renal function improved within eight weeks after treatment was stopped. Three months after treatment was stopped proteinuria remained less than half of the pretreatment values in three patients. No similar biochemical changes were observed in the controls. Short term cyclosporin therapy may be beneficial in reducing proteinuria in some patients with IgA nephropathy. As transient renal impairment was seen, despite cyclosporin concentrations being maintained within a narrow therapeutic range, indiscriminate use of cyclosporin in glomerulonephritis should be discouraged.     

Interrelationships between progesterone, 13,14-dihydro-15-keto PGF-2 alpha (PGFM) and LH in cyclic and early pregnant cows

Plasma progesterone and LH secretion patterns were examined in 18 mature dairy cows during the oestrous cycle and after insemination. Blood samples were collected every 15 min for 8 h per day on Days 3, 5, 6, 7, 8, 9, 10, 12, 14, 16, 17, 18, 19, 20 and 21 of the oestrous cycle, then, in the same cows, at the same times during early pregnancy. PGF-2 alpha secretion rates (as determined by plasma PGFM concentrations) were also monitored on Days 14, 16 and the day of, or equivalent to, luteal regression. Mean daily plasma progesterone concentrations were similar until Day 16 in cyclic and pregnant cows, after which values in non-pregnant animals declined. Regression analysis indicated that progesterone concentrations were best described by a quadratic expression with fitted maximum values on Day 13 in non-pregnant animals but values increased linearly over the whole period to Day 21 in pregnant cows. The frequency, amplitude and area under the curve of LH episodes showed no significant differences between cyclic and pregnant animals. In pregnant cows, the amplitude and area under the curve of progesterone episodes increased linearly between Days 8 and 21, although no such increase occurred in cyclic cows. Low-level PGFM episodes were present in cyclic and pregnant cows on Days 14 and 16 after oestrus, and high amplitude episodes occurred in non-pregnant cows during luteal regression. Pregnant cows showed a significant depression of the amplitude, but not the frequency of episodes at the expected time of luteal regression. These results confirm that the corpus luteum of pregnancy secretes an increasing amount of progesterone per se and per unit of LH until at least Day 21 after mating. They further suggest that the corpus luteum of the cyclic cow may experience small episodes of PGF-2 alpha and be subjected to initial degenerative changes by Day 14 after oestrus, some time before the onset of definitive luteolysis.     

Renal function after long-term treatment with lithium.

Daily urine volumes, plasma creatinine concentrations, and creatinine clearance were measured in 106 patients with unipolar and bipolar affective disorders attending a "lithium" clinic. Urine volumes exceeded 3.51 in only six patients, plasma creatinine concentrations exceeded 150 mumol/1 (1.7 mg/100 ml) in only five, and creatinine clearance was below 50 ml/min in 16. Renal function was assessed by measuring creatinine clearance and renal tubular function, including response to 20 hours of water deprivation, in a representative sample of 30 patients from the lithium clinic and 30 psychiatric patients matched for age and sex who were taking other psychotropic drugs. Creatinine clearance and tubular function, including urine osmolality after water deprivation, were not significantly different between the two groups. Urinary excretion of arginine vasopressin (AVP), however, was much greater in the lithium-treated patients, who therefore had a diminished tubular responsiveness to AVP. The findings do not support suggestions that long-term lithium treatment results in seriously impaired renal function, renal damage, and polyuria. Compared with other series, however, the patients were being maintained with low serum lithium concentrations, which apparently area as effective prophylactically as higher concentrations.     

Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients.

Prazosin was used in combination with other antihypertensive drugs in the successful management of hypertension in seven patients with chronic renal failure and six renal transplant recipients, also with chronic renal failure. The addition of small doses of prazosin (mean 3 mg/day) to the antihypertensive regimen produced significant falls in systolic and diastolic blood pressures in both the lying and standing positions. The standing blood pressures were significantly lower than the lying blood pressures during prazosin treatment. Neither the mean blood urea concentrations nor the mean plasma creatinine concentrations changed significantly during prazosin administration. Chromium-51 edetic acid clearances did not change significantly during prazosin treatment in the seven patients in whom it was measured. Severe symptomatic postural hypotension occurred in one patient a week after starting prazosin 3 mg/day. This hypotensive episode was associated with a transient and reversible deterioration in renal function. Another patient developed a rash while on prazosin but it was probably related to propranolol rather than prazosin. Prazosin is thus an effective antihypertensive drug in patients with chronic renal failure, and it may be used with a variety of other drugs. It should be used cautiously, however, since patients with chronic renal failure may respond to small doses, and significant postural falls in blood pressure may result. There was no evidence that the use of prazosin resulted in progressive deterioration in the residual renal function of the patients with chronic renal failure.     

Role of the kidney in regulating plasma immunoreactive beta-melanocyte-stimulating hormone.

An analysis of the factors that influence the increase in plasma immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) concentration in chronic renal failure showed that: (a) the increase correlated with the increase in serum creatinine concentrations; (b) beta-MSH was not cleared from the plasma by haemodialysis; (c) beta-MSH concentrations increased with length of time on dialysis and increased further after bilateral nephrectomy but there was no further increase with time; (d) beta-MSH levels decreased to normal after renal transplantation; and (e) beta-MSH was excreted in urine only when plasma levels rose to well above those of chronic renal failure (in Nelson''s syndrome). These findings suggest that the kidney regulated plasma beta-MSH by a non-excretory mechanism and is the major site of beta-MSH metabolism.     

Dosing time-dependent nephrotoxicity of cyclosporin A during 21-day administration to Wistar rats

The incidence of cyclosporine A (CsA) nephrotoxicity with reference to the temporal stage of administration was studied during a chronic 21-day treatment in male Wistar rats. Oral administration (20 mg/kg/day) was given at four different times: 1, 7, 13, or 19 hours after light onset (HALO). Plasma creatinine and blood urea nitrogen (BUN) levels were determined at regular intervals over the 24 h: before treatment (day 0); 7, 14, and 21 days after the beginning of treatment (days 7, 14, and 21); and 7 and 14 days after CsA withdrawal (days 28 and 35). At the same times, creatinine clearance and g-glutamyl transferase urinary excretion were determined in the groups of animals treated at 7 and 19 HALO. Residual concentrations of CsA in the renal tissue were measured at the end of the treatment period (day 21) in all groups. Nephrotoxicity of CsA was dependent on the temporal stage of administration. The renal vasoconstriction showed by the increase in plasma creatinine and BUN levels and the decrease in creatinine clearance was maximal when the CsA was given at 7 and 19 HALO and was correlated to the tissue concentrations of CsA. Tubular injury seems to occur earlier and the return to normal function less rapidly in animals treated at 19 HALO compared with animals treated at 7 HALO.     

Diurnal variations in plasma testosterone concentrations in the male lesser mouse lemur (Microcebus murinus)

In 6 isolated adult male lesser mouse lemurs, concentrations of testosterone in plasma were determinated at 6-h intervals over a 24-h period. Blood samples were collected at monthly intervals and for a period of 12 months under natural photoperiod. In this nocturnal prosimian, there were no apparent diurnal changes in testosterone concentrations during the non-breeding season (autumn). During seasonal sexual activity (January-August), diurnal changes in testosterone concentrations were characterized by a significant rise during the light phase. The daily testosterone peak occurred about 8.5 h after sunrise from February to July, but at the beginning (January) or at the end (August) of the breeding season, the daily testosterone peak was displaced to the morning. A circannual testosterone rhythm occurred with the highest testosterone values in May/June and the lowest values 6 months later. The dramatic fall in testosterone concentrations after the summer solstice may be associated with a change in the peripheral metabolism of testosterone.     

Copper deficiency and tissue glutathione concentration in the rat

Copper deficiency in rats increased renal vein and arterial (heart) plasma GSH concentration by approximately 50%. There was no change in plasma GSSG concentration. Renal vein plasma GSSG/GSH ratio was decreased in copper deficiency, which is consistent with previous reports showing a copper-dependent thiol oxidase activity in the renal basement membrane. No change occurred in arterial plasma GSSG/GSH ratio. Hepatic GSH concentrations were also elevated by 50% in copper deficiency, GSSG concentrations were unaffected, but GSSG/GSH ratio was depressed. Renal and cardiac tissue GSH and GSSG were unaffected by copper deficiency. The decreased SOD activity and GSH-Px activity observed in copper deficiency may contribute to increased hepatic and plasma GSH concentrations.     

Influence of Medetomidine on Acid-base Balance and Urine Excretion in Goats

Seven goats were given medetomidine 5 μg/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion.     

Abnormal renal response to twenty-four-hour dehydration and fasting in Nagase analbuminemic rats.

We assessed renal function in fasting adult Nagase analbuminemic rats (NAR). Sodium output in male and female NAR was 68% and 46%, respectively, of the output of age- and sex-matched normal Sprague-Dawley (SD) rats. Potassium excretion was significantly greater in female NAR but there was no difference between male NAR and SD rats. The renal clearances of urea and creatinine were reduced in NAR with corresponding increases in plasma concentrations; however, the urea and creatinine concentrations were not different in plasma samples taken from normally fed and hydrated SD and NAR rats. Exchangeable body sodium and sodium space was significantly larger in normally fed and hydrated NAR than in SD but there were no differences in plasma sodium concentrations or plasma volumes. Although plasma concentrations of albumin in NAR were only about 0.07% of the concentration in SD rats, the renal clearance of albumin in NAR was threefold greater. Kidney weights in NAR were 10 to 16% less than in SD rats but liver weights were 22 to 42% greater. Clearly, renal function was markedly abnormal in Nagase rats during a 24-hour fast.     

Rapid accumulation of plasma acid-stable trypsin inhibitor in experimental acute renal injury.

Acid-stable trypsin inhibitor (ASTI) activity was measured during experimental acute renal tubular dysfunction and glomerulonephritis in rats. A marked elevation of ASTI activity occurred at a very early stage of acute renal tubular damage, and the changes were observed prior to histological abnormalities or elevation of blood creatinine. No alteration in ASTI activity was observed at an early stage of experimental glomerulonephritis. The data obtained confirm that ASTI is excreted through the renal tubules and that the plasma ASTI concentration is very sensitive to renal tubular dysfunction.     

Acute biochemical responses to moderate beer drinking.

The consequences of drinking six pints of beer (3.31) over three hours were investigated in six healthy men. The expected rise in plasma osmolality, fall in plasma vasopressin concentration, and increase in free water clearance occurred; these variables had returned to normal by nine hours. There was a small but significant fall in plasma concentrations of urea and creatinine accompanied by a rise in plasma potassium concentration. Serum activities of alkaline phosphatase, gamma-glutamyl transferase, creatinine kinase, and lactate dehydrogenase did not change, and there was no alcohol-induced hypoglycaemia. All subjects had a slight hangover, but none was fluid depleted. It is concluded that, apart from inducing changes in water balance, alcohol in this form causes remarkably little metabolic disturbance.     

Polyamine concentrations in red cells and urine of patients with chronic renal failure

Spermidine and spermine concentrations were measured in 6 healthy subjects, 18 patients with chronic renal failure and 6 patients undergoing maintenance hemodialysis. In nondialyzed patients with advanced renal failure (serum creatinine levels greater than 6 mg %), red cell spermidine concentrations were significantly higher than in normal subjects (54.8±14.5 vs. 24.8±63 SD nmoles/ml packed cells). However red cell spermine concentrations were unchanged as compared to normal subjects (18.7±7.3 vs. 12.4±3.4 nmoles/ml packed cells). In patients with serum creatinine levels below 6 mg%, neither red cell spermidine or spermine concentrations were significantly different from normal subjects. There was a significant correlation between red cell spermidine values and both serum urea and serum creatinine levels, but no correlations were observed for red cell spermine. Red cell spermidine values were also significantly higher in patients undergoing maintenance hemodialysis than in normal subjects. In each patient, red cell spermidine concentrations were no different after a hemodialysis treatment than immediately prior to dialysis. In urine, excretion rates of polyamines as well as the precursor diamine, putrescine, were lower in patients with chronic renal failure than in normal subjects. Hence in renal failure, one factor contributing to the accumulation of spermidine in red cells would appear to be a decrease in the urinary excretion of polyamines.     

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 (Oat1-/-) and OAT3 (Oat3-/-). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1-/- (-0.03 ± 0.10 μg/min; -3 ± 18%) and Oat3-/- (0.01 ± 0.06 μg/min; -6 ± 19%), with greater variability in Oat1-/-. Expression of OAT3 protein in the renal membranes of Oat1-/- mice was reduced to ～6% of WT levels, and that of OAT1 in Oat3-/- mice to ～60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3-/- were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.