Melanocortin 1 receptor agonists reduce proteinuria.

Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats (P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients.

The effects of adrenocorticotrophic hormone and an equivalent dose of cortisol on the serum concentrations of lipids, lipoproteins, and apolipoproteins.

Previous studies have shown a strong lipid-lowering effect of adrenocorticotrophic hormone (ACTH) in healthy individuals and in patients with different kinds of dyslipoproteinemia. The mechanism behind this effect has not been established and its direct ACTH-specific nature has been questioned. Therefore, the present study was performed. Thirty healthy young males were randomized into 3 groups of equal size: one group received ACTH1-24 1 mg IM, daily for 4 days, another group was treated with cortisol 150 mg ID (50 mg tid) daily for 4 days, whereas a control group was observed for 4 days. Fasting blood samples were collected before and after treatment or observation. The serum concentrations of cholesterol (12%, P < .05), low-density lipoprotein cholesterol (24%, P < .01), and apolipoprotein (apo) B (31%, P < .01) decreased significantly in the ACTH group but not in the cortisol and control groups. The statistical workup confirmed that only ACTH had a lowering effect on the apo B-containing lipoproteins. In contrast, the results indicated conformity between the treatment groups with respect to increases in the serum apo E concentrations. There were inconsistent changes in the serum concentrations of the triglycerides, high-density lipoprotein cholesterol, apo A, and lipoprotein(a). The main results were clear: the lowering effect of ACTH on the serum concentration of apo B-containing lipoproteins could not be ascribed to cortisol. These, in combination with previous in vitro results, indicated an ACTH-specific effect.

Effects of different doses of adrenocorticotrophic hormone on the serum lipoprotein profile in healthy subjects.

Adrenocorticotrophic hormone (ACTH) at pharmacological dosage has marked lipid-lowering effects that may have therapeutic implications. The rationale behind the present investigation was the possible use of ACTH as a lipid-lowering replacement for steroids. Thirty-two healthy individuals were randomly divided into four groups of 8 each. Three ACTH groups received different doses of ACTH(1-24) intramuscularly (0.1 mg, 0.5 mg and 1.0 mg daily for four days) and the control group received NaCl 0.9% 1 ml intramuscularly daily for four days. Moreover, 8 healthy subjects were given ACTH(1-24) 1.0 mg intramuscularly five times at an interval of four days. Blood and urine samples were collected at regular intervals. ACTH treatment at the dose of 1.0 mg daily lowered the serum concentrations of low density lipoprotein (LDL) cholesterol and apolipoprotein B by 28% and 22%, respectively, which is similar to previous observations. ACTH treatment at the doses of 0.5 mg and 0.1 mg gave smaller reductions (17% and 12%, and 9% and 8%, respectively) resulting in near linear dose-response relationships. There were no changes in the control group. Only the ACTH dose of 1.0 mg resulted in significant changes when compared with the control group. During the ACTH administration at four-days intervals, the serum concentrations of LDL cholesterol and apolipoprotein B reached the lowest values at 48 hr after an injection, remained there at 72 hr but were rising again at 96 hr. For effective lipid reduction, an ACTH dose of about 1 mg is needed and it should be given more often than every fourth day, probably every second or third day. With regard to the cortisol exposure, the results should be viewed in the light of calculations, presented in the paper, that 1 mg of ACTH is equivalent to 90 mg of cortisol administered parenterally.

Severe, very early onset pre-eclampsia associated with liquorice consumption.

BACKGROUND: We present the case of very early onset pre-eclampsia, possibly aggravated by liquorice consumption. CASE: An 18-year-old healthy primigravida presented with high blood pressure and proteinuria at 18 weeks gestation. She had a strong family history of pre-eclampsia and was consuming considerable amounts of liquorice. A diagnosis of severe pre-eclampsia/hemolysis, elevated liver enzymes, and low platelet count was confirmed. The pregnancy was terminated. Extensive investigation ruled out underlying diseases and autopsy revealed a normal fetus. In three consequtive pregnancies, she developed milder forms of pre-eclampsia. CONCLUSION: In healthy women with a familial/genetic susceptibility for pre-eclampsia, liquorice consumption may aggravate the course of the disease.

Encapsulating peritoneal sclerosis following a peritoneal foreign body reaction to Dacron fibres-a case report.

The aetiological factors and the pathophysiological mechanisms of encapsulating peritoneal sclerosis (EPS) have not been fully elucidated. We present a patient on continuous ambulatory peritoneal dialysis whose peritoneal catheter was exchanged due to repeated episodes of bacterial peritonitis. Immediately afterwards, he experienced severe abdominal pain, nausea and fever. Peritoneal biopsy, taken 12 days after the operation, revealed fibrotic thickening of the peritoneum and a foreign body inflammatory reaction to particles manifesting striking similarity to the Dacron fibres of the catheter cuff. Shedding of Dacron fibres into the peritoneum may have elicited the acute fulminant phase of the EPS diagnosed in this case.

[Acute flank pain syndrome: a common presentation of acute renal failure in young men in Iceland]. / Brátt síðuheilkenni: algeng birtingarmynd bráðrar nýrnabilunar hjá ungum mönnum á Íslandi.

OBJECTIVES: The purpose of the study was to calculate the incidence of the acute flank pain syndrome in Iceland and to describe the case series. MATERIAL AND METHODS: The hospital records of those who fulfilled the following criteria were studied: age 18-41 years, acute renal failure, and a visit to Landspitali University Hospital in 1998-2007. The acute flank pain syndrome was defined as severe flank pain in combination with acute renal failure, unexplained except for the possible consumption of NSAIDs, ethanol or both. Information was collected about the sales of NSAIDs. RESULTS: One hundred and six patients had acute renal failure. Of those, 21 had the acute flank pain syndrome (20%). The annual incidence of the acute flank pain syndrome increased threefold during the study period. The average incidence was 3.2/100.000/year (relative to the population of the Reykjavik area) and 2.0/100.000/year (relative to the population of Iceland). 18 patients were male and the median age was 26 (19-35) years. The symptoms regressed spontaneously during a few days or weeks. There was history of NSAID intake in 15, ethanol consumption in 15, either in 20, and both in nine patients. The sales figures of NSAIDs were high and they increased during the study period, especially those of the over-the-counter sales of ibuprofen. CONCLUSIONS: The incidence of the acute flank pain syndrome was high. The paper describes the largest case series that has been published since the withdrawal of suprofen in 1987. Young people should be warned about consuming NSAIDs during or directly after binge drinking.

Incidence and outcome of acute phosphate nephropathy in Iceland.

BACKGROUND: Oral sodium phosphate solutions (OSPS) are widely used for bowel cleansing prior to colonoscopy and other procedures. Cases of renal failure due to acute phosphate nephropathy following OSPS ingestion have been documented in recent years, questioning the safety of OSPS. However, the magnitude of the problem remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population based, retrospective analysis of medical records and biopsies of all cases of acute phosphate nephropathy that were diagnosed in our country in the period from January 2005 to October 2008. Utilizing the complete official sales figures of OSPS, we calculated the incidence of acute phosphate nephropathy in our country. Fifteen cases of acute phosphate nephropathy were diagnosed per 17,651 sold doses of OSPS (0.085%). Nine (60%) were women and mean age 69 years (range 56-75 years). Thirteen patients had a history of hypertension (87%) all of whom were treated with either ACE-I or ARB and/or diuretics. One patient had underlying DM type I and an active colitis and one patient had no risk factor for the development of acute phosphate nephropathy. Average baseline creatinine was 81.7 µmol/L and 180.1 at the discovery of acute renal failure, mean 4.2 months after OSPS ingestion. No patient had a full recovery of renal function, and at the end of follow-up, 26.6 months after the OSPS ingestion, the average creatinine was 184.2 µmol/L. The average eGFR declined from 73.5 ml/min/1.73 m(2) at baseline to 37.3 ml/min/1.73 m(2) at the end of follow-up. One patient reached end-stage renal disease and one patient died with progressive renal failure. CONCLUSION/SIGNIFICANCE: Acute phosphate nephropathy developed in almost one out of thousand sold doses of OSPS. The consequences for kidney function were detrimental. This information can be used in other populations to estimate the impact of OSPS. Our data suggest that acute phosphate nephropathy may be greatly underreported worldwide.

[Encapsulating peritoneal sclerosis]. / Umlykjandi lífhimnuhersli--tvö tilfelli og yfirlit yfir sjúkdóminn.

The incidence of encapsulating peritoneal sclerosis in patients on peritoneal dialysis seems to be increasing worldwide. In Iceland, two cases of encapsulating peritoneal sclerosis have recently been diagnosed (cumulative incidence 1.6%). The patients followed a similar course; the disease was diagnosed in the wake of a bacterial peritonitis, steroid treatment was effective during the acute phase but eventually surgical treatment was needed and a successful enterolysis performed.

The effects of adrenocorticotrophic hormone and cortisol on homocysteine and vitamin B concentrations.

BACKGROUND: Homocysteine metabolism is mainly governed by serum concentrations of folate and vitamin B(12), renal function and genetic factors. It is also well documented that endocrinological disturbances influence homocysteine metabolism. However, studies on the hormones of the hypothalamic-pituitary-adrenal axis have given conflicting results. METHODS: A total of 30 healthy young males were randomised into three groups of equal size; one group received adrenocorticotrophic hormone (ACTH)(1-24) 1 mg i.m. daily for 4 days, another group was treated with cortisol 50 mg i.m. t.i.d. for 4 days, while a control group was observed for 4 days. Fasting blood samples were collected before and after treatment or observation. RESULTS: The pattern of changes was the same for the ACTH and cortisol groups; there were significant decreases in serum concentrations of folate (23% and 24%) and cobalamines (13% and 19%) and decreases in plasma total homocysteine concentrations that did not reach significance. There were no changes in the control group. CONCLUSIONS: The virtually identical pattern of changes in both treatment groups suggests that the effects were mediated by cortisol. The reductions in serum concentrations of folate and cobalamines call for further research.

2,8-dihydroxyadeninuria: are there no cases in Scandinavia?

Homozygosity or mixed heterozygosity for mutations in the adenine phosphoribosyltransferase gene cause enzyme deficiency directing adenine through an alternative metabolic pathway. This results in the production of 2,8-dihydroxyadenine, which is actively secreted into the urine. 2,8-dihydroxyadenine is insoluble at physiological urinary pH but as marked supersaturation is possible the manifestations differ: there may be minimal consequences, there may be infiltration of the tubulointerstitial tissue with acute or chronic damage or there may be stone formation in the urinary tract. Effective treatment can be offered and therefore the prognosis depends upon the renal function at diagnosis. Treatment consists of adequate fluid intake, a low-purine diet and administration of allopurinol. Urinary 2,8-dihydroxyadenine crystals are easily recognized under a microscope. The diagnosis of 2,8-dihydroxyadeninuria can be confirmed by estimation of adenine phosphoribosyltransferase activity in erythrocyte lysates. More than 300 cases of 2,8-dihydroxyadeninuria have been diagnosed worldwide, most of them in Japan, France and Iceland. One case has been reported in Finland but there have been no reports from the Scandinavian peninsula or from Denmark. The relevant mutations may be very rare in these countries but underdiagnosis is also possible.

The postdialytic rise in the plasma total homocysteine concentration is delayed.

BACKGROUND/AIMS: The mechanism behind the uremic hyperhomocysteinemia has not been elucidated. Possibly, dialyzable uremic toxins play a role, e.g. as enzyme inhibitors. If so, the conditions for enzymatic removal would be expected to improve after dialysis. Therefore, we studied the postdialytic pattern of the plasma total homocysteine (tHcy) concentration. METHODS: We collected blood samples from 19 stable, vitamin-supplemented hemodialysis patients before and at 5, 60, as well as at 480 min after a dialysis session. The patients were studied after dialysis with a low-flux dialyzer (Polyflux 6L) and a high-flux dialyzer (Polyflux 14S). RESULTS: The mean predialytic plasma tHcy concentration was 13.3 micromol/l which is considerably lower than the concentrations observed in our previous studies. In all patients, the plasma tHcy concentration fell during treatment with both types of dialyzers (average decrease 28 +/- 7%, p < 0.0001, and 31 +/- 8%, p < 0.0001, respectively). No postdialytic change in the plasma tHcy concentration was observed at 60 min after low-flux dialysis, however, after high-flux dialysis, the plasma tHcy concentration was significantly lower at 60 min postdialysis than at 5 min (3 +/- 8%, p < 0.05). At 480 min after dialysis, a significant postdialytic increase in the plasma tHcy concentration was found (6 +/- 9%, p < 0.01, and 11 +/- 5%, p < 0.0001, respectively) both in the case of low-flux and high-flux treatment. CONCLUSION: In the postdialytic phase, we observed a short-lived stability in the plasma tHcy concentration, and in the case of high-flux dialysis, even a slight decrease in the plasma tHcy concentration. The results support the hypothesis that dialyzable substances interfere with homocysteine removal.

Renal function exerts only a minor influence on high plasma homocysteine concentrations in patients with acute coronary syndromes.

It has been suggested that hyperhomocysteinemia observed in patients with occlusive vascular disease is caused by reduced renal function secondary to renovascular disease. We have therefore used serum cystatin C, a new sensitive marker for glomerular filtration, in 59 patients with acute coronary syndromes and high plasma homocysteine (tHcy) concentration to measure renal function. Samples were also obtained from 34 patients with low-normal plasma tHcy and 50 control subjects. The patients with low-normal plasma tHcy concentration showed decreased concentrations of serum cystatin C and serum creatinine and increased concentrations of blood folate and serum cobalamin compared to the controls and to the patients with high plasma tHcy. There was a large overlap in cystatin C concentrations between patients with high and low-normal plasma tHcy. None of the parameters investigated except plasma tHcy were significantly different in the group of patients with high plasma tHcy concentration compared to the control group. In order to further demonstrate the importance of renal impairment, a subgroup of the patients with high plasma tHcy was supplemented daily with folic acid 5 mg, pyridoxine 40 mg and cyancobalamin 1 mg for 3 months. Vitamin therapy reduced plasma tHcy from 18.3+/-4.6 pmol/l to 9.6+/-2.2 pmol/l (p<0.0001). However, vitamin treatment did not strengthen the correlation between cystatin C and plasma tHcy concentrations. These findings do not support the hypothesis that subtle renal dysfunction is an important cause of high plasma tHcy concentration in patients with acute coronary syndromes.