Reduced platelet thromboxane formation in uremia. Evidence for a functional cyclooxygenase defect.

A qualitative platelet abnormality and a bleeding tendency are frequently associated with renal failure and uremia. We demonstrated previously that uremic patients display an abnormal platelet aggregation to arachidonic acid and reduced malondialdehyde production in response to thrombin and arachidonic acid. The objectives of this investigation were: (a) to compare platelet prostaglandin (PG) and thromboxane (TX) production in whole blood and in platelet-rich plasma (PRP) of 21 uremic patients and 22 healthy subjects; (b) to evaluate the concentration and activity of platelet PG- and TX-forming enzymes; (c) to assess the functional responsiveness of the platelet TXA(2)/PGH(2) receptor; (d) to explore the hemostatic consequences of partially reduced TXA(2) production.Platelet immunoreactive TXB(2) production during whole blood clotting was significantly reduced, by approximately 60%, in uremic patients as compared to age- and sex-matched controls. Exogenous thrombin (5-30 IU/ml) failed to restore normal TXB(2) production in uremic platelets. Uremic PRP produced comparable or slightly higher amounts of TXB(2) than normal PRP at arachidonate concentrations 0.25-1 mM. However, when exposed to substrate concentrations >2 mM, uremic PRP produced significantly less TXB(2) than normal PRP. To discriminate between reduced arachidonic acid oxygenation and altered endoperoxide metabolism, the time course of immunoreactive TXB(2) and PGE(2) production was measured during whole blood clotting. The synthesis and release of both cyclooxygenase-derived products was slower and significantly reduced, at all time intervals considered. Furthermore, PGI(2) production in whole blood, as reflected by serum immunoreactive 6-keto-PGF(1alpha) concentrations, was significantly reduced in uremic patients as compared with healthy subjects. PGH synthase levels, as determined by an immunoradiometric assay, were not significantly different in platelets from uremic patients as compared to control platelets. A single 40-mg dose of aspirin given to five healthy volunteers reduced their serum TXB(2) to levels found in uremic patients. This was associated with a significant increase of threshold aggregating concentrations of ADP and arachidonic acid and prolongation of bleeding time. Substantially similar threshold concentrations of U46619, a TXA(2) agonist, induced aggregation of normal and uremic platelets. Prostacyclin induced a significant elevation of uremic platelet cyclic AMP, which was suppressed by U46619, further suggesting normal responsiveness of the TXA(2)/PGH(2) receptor. WE CONCLUDE THAT: (a) an abnormality of platelet arachidonic acid metabolism exists in uremia, leading to a reduced TXA(2) production; (b) the characteristics of this abnormality are consistent with a functional cyclooxygenase defect; (c) reduced TXA(2) production may partially explain the previously described abnormality of platelet function in uremia.

Social/economic costs and health-related quality of life in patients with juvenile idiopathic arthritis in Europe.

OBJECTIVE: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with juvenile idiopathic arthritis (JIA) in Europe. METHODS: We conducted a cross-sectional study of patients with JIA from Germany, Italy, Spain, France, the United Kingdom, Bulgaria, and Sweden. Data on demographic characteristics, healthcare resource utilization, informal care, labor productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D-5L) questionnaire. RESULTS: A total of 162 patients (67 Germany, 34 Sweden, 33 Italy, 23 United Kingdom, 4 France, and 1 Bulgaria) completed the questionnaire. Excluding Bulgarian results, due to small sample size, country-specific annual health care costs ranged from €18,913 to €36,396 (reference year: 2012). Estimated direct healthcare costs ranged from €11,068 to €22,138; direct non-healthcare costs ranged from €7837 to €14,155 and labor productivity losses ranged from €0 to €8715. Costs are also shown to differ between children and adults. The mean EQ-5D index score for JIA patients was estimated at between 0.44 and 0.88, and the mean EQ-5D visual analogue scale score was estimated at between 62 and 79. CONCLUSIONS: JIA patients incur considerable societal costs and experience substantial deterioration in HRQOL in some countries. Compared with previous studies, our results show a remarkable increase in annual healthcare costs for JIA patients. Reasons for the increase are the inclusion of non-professional caregiver costs, a wider use of biologics, and longer hospital stays.

Platelet function in patients on maintenance hemodialysis: depressed or enhanced?

Uremic patients on long-term hemodialysis show a paradoxical association of hemorrhages on the one hand and thrombotic complications or atherosclerosis on the other. Platelet function has been found to be depressed in some cases but enhanced in others. In 19 patients, both platelet aggregation and prostaglandin formation appeared to be significantly enhanced in response to low concentrations of arachidonic acid but significantly reduced with high concentrations. It is suggested that this double functional abnormality of uremic platelets may contribute to the complex vascular disturbances of hemodialyzed patients.

Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is the most common form of nephrotic syndrome in adults. The disease shows a benign or indolent course in the majority of patients, with a rate of spontaneous complete or partial remission of nephrotic syndrome as high as 30% or more. Despite this, 30-40% of patients progress toward end-stage renal failure (ESRF) within 5-15 years. OBJECTIVES: To assess the benefits and harms of immunosuppressive treatment for IMN in adults. SEARCH STRATEGY: We searched the Cochrane Renal Group Specialised Register (December 2003), The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4, 2003), MEDLINE and Pre-MEDLINE (1966 - December 2003), EMBASE (1980 - December 2003), reference lists of nephrology textbooks, review articles, prospective trial registers, relevant trials and abstracts from nephrology scientific meetings and the internet without language restriction. We also contacted principal investigators of controlled studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive interventions for the treatment of IMN in adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed and extracted information. Information was collected on method, participants, interventions and outcomes (death, ESRF, proteinuria, serum creatinine, GRF, remission, adverse events). MAIN RESULTS: A total of 18 trials with 1025 patients were included. No differences were found when we combined data of all treatment categories as a group and compared them with placebo or no treatment. Oral glucocorticoids. No beneficial effect on any of the end points chosen for efficacy was observed. Alkylating agents showed a significant beneficial effect on complete remission (RR 2.37, 95%CI 1.32 to 4.25, P = 0.004) but not on partial remission (RR 1.22, 95%CI 0.63 to 2.35, P = 0.56) or complete or partial remission (RR 1.55, 95%CI 0.72 to 3.34, P = 0.27). Cyclophosphamide treatment resulted in significantly lower rate of discontinuations due to adverse events as compared to chlorambucil (RR 2.34, 95%CI 1.25 to 4.39, P = 0.008). There was no evidence of clinically relevant differences in favour of cyclosporin and there was insufficient data on anti-proliferative agents. REVIEWERS' CONCLUSIONS: This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil.

Proteinuria and its consequences in renal disease.

UNLABELLED: Chronic renal diseases that involve proteinuria are typically characterized by an inexorable progression to end-stage renal failure. Many studies suggest that this progression may be the result of factors, such as intraglomerular hypertension and glomerular hypertrophy, that are unrelated to the initial disease. This paper reviews the mechanisms of progression of chronic renal diseases and discusses therapeutic strategies that should prevent or minimize further renal damage and the applicability of these strategies to patients with the rare X-linked lysosomal storage disorder Fabry disease. Renal involvement is a major feature of Fabry disease, which is characterized by vacuolated epithelial cells in the glomerulus and distal tubules, resulting from lipid inclusions within these cells. Although enzyme replacement therapy is the key strategy to halt the progression of Fabry disease, additional therapeutic options include blood pressure control, reduction of proteinuria, lipid control and inhibition of the renin-angiotensin system. CONCLUSION: A range of therapeutic options, used in conjunction with enzyme replacement therapy, may have beneficial effects on the renal manifestations of Fabry disease.

Takayasu's arteritis: A study of 104 Italian patients.

OBJECTIVE: Takayasu's arteritis (TA) is a rare vasculitis. The Italian Takayasu's Arteritis study group was established with the aim to describe a large cohort of patients. METHODS: Data were collected by means of an ad hoc form. Demographic information, clinical history, vascular findings, treatment, risk factors, and comorbidities were analyzed. RESULTS: Data of 104 patients were collected. The median delay in diagnosis was 15.5 months (range 0-325 months). Age at onset <15 years was associated with a higher probability, whereas elevated erythrocyte sedimentation rate with a lower probability, of a delay in diagnosis. The majority of patients experienced nonspecific signs and symptoms indicative of an inflammatory disease in the early phase. Among vascular involvement, stenosis was the most frequent lesion, being present in 93% of patients, followed by occlusion (57%), dilatation (16%), and aneurysm (7%). Glucocorticoids were the mainstay of treatment in our series; however, treatment with cytotoxic agents was required in about half of the patients. Fifty-two patients underwent at least 1 surgical procedure. The main indications for intervention were renal vascular hypertension, cerebral hypoperfusion, and limb claudication. CONCLUSION: As with many rare diseases, delay in diagnosis is an important issue for patients with TA. The increasing occurrence of vascular lesions along with the disease progression put to question the long-term effectiveness of contemporary treatment. These data may be helpful in increasing physicians' awareness to prevent diagnosis delay, update guidelines, and plan future research projects.

Modulating the profit motive to meet needs of the less-developed world.

The success, despite the problems, of academic/industrial collaborations over the past decade owes much to the profit motive. However, market-driven research and development has little to offer patients in the less-developed world. Some flexibility has already been demonstrated on drugs for orphan (rare or under-researched) diseases. Many diseases in less-developed countries are not rare. Academic researchers should be encouraging the establishment of funding for basic and clinical research that is directed at patients' needs in the less-developed world and that is independent of a commercial ethos.

Recent developments in the management of membranous nephropathy.

Idiopathic membranous nephropathy is one of the most commonly encountered forms of nephrotic syndrome in adults. The natural history of the disease, observed in a small sample of untreated patients, reveals that a large proportion of patients experience spontaneous remission, whereas approximately one third of them progress towards renal insufficiency, and thus require dialysis. Hence, several attempts to treat this condition have been investigated and several protocols, based on different combinations of corticosteroids and/or immunosuppressive agents, have been proposed. However, none of these protocols has been uniformly adopted by renal physicians, either because of no or limited efficacy of most of them, or due to the potential of short- and long-term untoward effects. In this review, we examine the available data on the natural course of the disease and the possibility of identifying clinical and laboratory characteristics that could help to predict the course of membranous nephropathy. We also summarise the results of the most relevant clinical trials, and offer an updated meta-analysis of treatment studies, including the latest data on cyclosporin.

Treatment of idiopathic membranous glomerulopathy.

The treatment of membranous nephropathy, the most common form of glomerular diseases causing nephrotic syndrome in adults, is still debated. A considerable percentage of patients have a spontaneous remission of the disease and reduction of urinary protein excretion with time. Studies in the past have indicated that prednisone may have beneficial effects, but this has not been confirmed by more recent investigation. Others have studied the association of methylprednisolone with cyclophosphamide or chlorambucil, but results are conflicting. The main reasons for the conflicting data are the variety of clinical presentations of the disease and the different study populations. Most trials performed so far have not included enough patients in each category to adequately detect differences between treatment groups and placebo groups. Several studies with few numbers of patients reported that cyclosporine effectively reduced proteinuria and may have less long-term toxicity than more conventional immunosuppressants. This finding, however, must be verified by appropriate clinical trials.

Progression, remission, regression of chronic renal diseases.

The prevalence of chronic renal disease is increasing worldwide. Most chronic nephropathies lack a specific treatment and progress relentlessly to end-stage renal disease. However, research in animals and people has helped our understanding of the mechanisms of this progression and has indicated possible preventive methods. The notion of renoprotection is developing into a combined approach to renal diseases, the main measures being pharmacological control of blood pressure and reduction of proteinuria. Lowering of blood lipids, smoking cessation, and tight glucose control for diabetes also form part of the multimodal protocol for management of renal patients. With available treatments, dialysis can be postponed for many patients with chronic nephropathies, but the real goal has to be less dialysis-in other words remission of disease and regression of structural damage to the kidney. Experimental and clinical data lend support to the notion that less dialysis (and maybe none for some patients) is at least possible.

Mycophenolate mofetil for the treatment of Takayasu arteritis: report of three cases.

BACKGROUND: Takayasu arteritis is a rare form of chronic inflammatory disease of the large arterial vessels. Some patients do not respond to steroids or immunosuppressant drugs. OBJECTIVE: To evaluate the effect of mycophenolate mofetil in patients with severe Takayasu arteritis. DESIGN: Case series. SETTING: Clinical Research Center for Rare Diseases in Bergamo, Italy. PATIENTS: Three patients with Takayasu arteritis. INTERVENTION: Mycophenolate mofetil (2 g/d) given orally in two divided doses. MEASUREMENTS: Clinical evaluation and assessment of leukocyte counts were done weekly. Vascular lesions were assessed by using Doppler ultrasonography. RESULTS: All patients showed clinical benefit, and two resumed work after months of inactivity. Patients were also able to taper and discontinue steroid use. Mycophenolate mofetil was well tolerated, and no signs of toxicity were observed. CONCLUSIONS: Mycophenolate mofetil may be an alternative to steroids and cytotoxic agents in patients with Takayasu arteritis. Before results of controlled trials become available, mycophenolate mofetil should be considered only for patients who do not improve or stabilize with conventional therapy.

Angiotensin-converting enzyme inhibition ameliorates the defect in glomerular size selectivity in hyponatremic hypertensive syndrome.

The glomerular size-selective properties in a patient with "hyponatremic hypertensive syndrome" were investigated before and after administration of the angiotensin-converting enzyme inhibitor enalapril. Hyponatremic hypertensive syndrome is a rare condition of renovascular hypertension characterized by electrolyte abnormalities (hyponatremia, hypokalemia), polyuria, and high renin activity. In this patient a marked increase in urinary protein excretion was observed. Treatment with enalapril normalized BP, corrected electrolyte abnormalities, and reduced proteinuria. Glomerular filtration rate (GFR), renal plasma flow (RPF), and the clearance of neutral dextrans of graded sizes were measured before and after 6 months of enalapril (20 mg/d) administration. Theoretical analysis of dextran and inulin clearance data with a model of glomerular size selectivity were adopted to separate effects of hemodynamic changes on macromolecule filtration from changes of intrinsic membrane selective properties. After enalapril urinary protein excretion decreased, GFR was unchanged and RPF almost doubled. Fractional clearance values of dextran molecules were markedly elevated in comparison with the corresponding values measured in a group of normal controls and were normalized by enalapril. Theoretical calculation of membrane pore characteristics showed that enalapril treatment reduced the radius of all membrane pores by approximately 1 nm. Altogether these results indicate that enalapril normalized glomerular filtration of neutral macromolecules and circulating proteins in a human condition of angiotensin II-induced proteinuria. Enalapril effectively restored glomerular size-selective function, reducing dimensions of membrane pores, independently of its effect on renal hemodynamics.

Effect of extracellular acidosis on 45Ca uptake in isolated hypoxic proximal tubules.

Recent in vitro studies have suggested that the presence of extracellular acidosis is protective against the development of oxygen-deprivation injury in several tissues. Because cellular Ca accumulation after renal ischemia may represent a major pathogenic event leading to cellular damage, the purpose of the present study was to examine the effect of extracellular acidosis on 45Ca uptake and desaturation in normal and hypoxic isolated rat proximal tubules. At pH 7.4, an increase in 45Ca uptake was observed in proximal tubules after 30 min of hypoxia. In addition, 45Ca desaturation was increased significantly in hypoxic tubules at pH 7.4. The alterations in 45Ca uptake and desaturation in hypoxic tubules at pH 7.4 were accompanied by significant signs of cellular injury as assessed by the amount of lactate dehydrogenase (LDH) released by the tubules at the end of the hypoxic period (22.5% above control tubules, P less than 0.01) as well as in morphological changes consistent with hypoxic cell injury. In contrast, when maintained at pH 6.9 throughout the study, no difference in 45Ca uptake or desaturation was observed between the control and hypoxic tubules; the hypoxic proximal tubules exhibited a smaller increase in LDH release (12.7% above control tubules) and did not develop the morphological changes observed at pH 7.4. Thus, during hypoxia and reoxygenation at pH 7.4, the increased 45Ca uptake may contribute in part to cellular injury in rat proximal tubules.

Effect of renal ischemia on cortical microsomal calcium accumulation.

Mitochondrial respiration, Ca2+ content, and Ca2+ kinetics have been found to be profoundly altered in ischemic acute renal failure (ARF). The effect of clamping the bilateral renal artery for 50 and 90 min on microsomal Ca2+ uptake was therefore examined in the rat. The 50-min clamping produced a reversible model of nonoliguric ARF, and the 90-min clamping produced a model of nonreversible oliguric ARF. In the 50-min nonoliguric model, ATP-dependent Ca2+ uptake by microsomes from renal cortex (nmol X mg protein-1 X 30 min-1) was significantly impaired immediately before release of the clamp and before return of renal blood flow (reflow) (191 +/- 11 vs. 83 +/- 11, P less than 0.005). However, in this nonoliguric model of ischemic ARF, microsomal uptake returned completely to normal after 1 h of reflow (sham 189 +/- 11 vs. 167 +/- 14 at 1 h, NS) and persisted at this normal level at 24 h (sham 166 +/- 14 vs. 150 +/- 13 at 24 h, NS). In the oliguric model of ARF the microsomal Ca2+ uptake also was impaired immediately after the clamp release (sham 191 +/- 11 vs. 93 +/- 11, P less than 0.001) as well as after 1 h of reflow (sham 189 +/- 11 vs. 129 +/- 12, P less than 0.005) but not at 24 h (sham 166 +/- 14 vs. 173 +/- 13, NS). The results indicate that impaired microsomal Ca2+ uptake occurs early in both oliguric and nonoliguric ARF and persists after 1 h of reflow in the oliguric model.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis by fast atom bombardment mass spectrometry of phospholipids from tubuli, glomeruli, and urine of normal rats and rats with acute renal failure.

Fast atom bombardment mass spectrometry was used to characterize phospholipids from tubuli and glomeruli of normal rats and rats with acute renal failure. It was possible to assess the molecular species of the principal phospholipidic classes. In all of them, the most abundant species contained a residue of arachidonic acid. The phospholipids of urine were also analyzed, showing the presence of the major molecular species of several phospholipid classes. Excretion of phospholipids was greater in urine from rats with acute renal failure.

The first clinical and epidemiological programme on renal disease in Bolivia: a model for prevention and early diagnosis of renal diseases in the developing countries.

BACKGROUND: The prevalence and incidence of renal diseases in developing countries are not known. This lack of knowledge is an obstacle to the adoption of preventive measures which may be of great value in a social and economic environment where treatment options for end-stage renal failure are simply not available to the vast majority of the population. Urinalysis, a simple and inexpensive test, remains a cornerstone in the evaluation of the kidney and may also be easily employed in mass screening for renal abnormalities in a developing country. METHODS: An educational campaign on renal diseases was conducted in three selected areas of Bolivia. Urine samples were collected and sent to one of 21 participating clinical centers. Fresh urine specimens were screened using a dipstick for chemical analysis and by microscopic urinalysis after centrifugation. In those patients in whom urinary abnormalities were found, further investigations were carried out in order to define the diagnosis; these patients were enrolled in a 3-year follow-up program. RESULTS: Apparently healthy subjects (n = 14,082) were referred to the First Clinical and Epidemiological Program of Renal Diseases from rural and metropolitan areas in Bolivia. Urinary abnormalities were detected in 4261 subjects at first screening. The most common form of urinary abnormality was hematuria, which was found in 2010 (47% of positively screened subjects). Other renal abnormalities were leukocyturia (41%) and proteinuria (11%). Confirmatory tests and further clinical studies were then carried out in 1019 people. On a second screening 35% of the subjects had no urinary abnormalities; in the remaining people the following diagnosis were made: asymptomatic urinary-tract infection (48.4%), isolated benign hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%). Other diagnosis were: renal stones 1.3%, diabetic nephropathy 1% and polycystic kidney diseases 1.9%. CONCLUSIONS: This study helped define for the first time the frequency of asymptomatic renal diseases in Bolivia. It shows that it is possible to screen a large population of patients at relatively low cost, providing the framework for further action that may help in the prevention and timely diagnosis of renal diseases.

Prognosis of untreated patients with idiopathic membranous nephropathy.

BACKGROUND: Defining the most appropriate treatment for patients with idiopathic membranous nephropathy is a matter of controversy. The course of the disorder is often benign, and the immunosuppressive regimens used in some patients have uncertain benefits and substantial risks. We studied the natural history of idiopathic membranous nephropathy in patients who received only symptomatic therapy. METHODS: We prospectively studied 100 consecutive patients (68 men and 32 women; mean [+/- SD] age, 51 +/- 17 years) with biopsy-proved idiopathic membranous nephropathy. The patients received diuretic or antihypertensive drugs as needed, but no glucocorticoid or immunosuppressive drugs. We examined the patients and measured their urinary protein excretion and serum creatinine concentrations every 6 months for a mean of 52 months. RESULTS: Twenty-four (65 percent) of the 37 patients followed for at least five years had complete or partial remission of proteinuria; in 6 others (16 percent), end-stage renal disease developed, and they required dialysis. As calculated by the Kaplan-Meier method, the estimated probability (+/- the standard error of the estimate) of retaining adequate kidney function was 88 +/- 5 percent after five years and 73 +/- 7 percent after eight years. The prognosis was poorer in men and in patients over 50 years of age, but not in patients with the nephrotic syndrome, hypertension, or hypercholesterolemia. CONCLUSIONS: Most untreated patients with idiopathic membranous nephropathy maintain renal function for prolonged periods and are likely to have spontaneous remission. These results do not support the use of glucocorticoids and immunosuppressive drugs in patients with idiopathic membranous nephropathy.

Inhibition of human platelet aggregation by parathyroid hormone. Is cyclic AMP implicated?

Parathyroid hormone (PTH) is a polypeptide which in different in vitro systems raises intracellular cyclic AMP (cAMP) levels via adenyl cyclase activation and stimulates Ca2+ transport across cell membranes. We tested whether, on the basis of this mechanism, PTH would inhibit human platelet aggregation. The latter was tested in vitro by a photometric technique. Platelet aggregation induced by the calcium ionophore A 23187 was inhibited by PTH at concentrations (0.5-3 USP U/ml) similar to those effective in other in vitro systems. Higher concentrations of PTH were required to prevent aggregation initiated by adenosine-5'-diphosphate, arachidonic acid, or platelet-aggregating factor. The terminal synthetic fragment 1-34 b PTH was ineffective against all aggregation stimuli. The antiaggregating effect of PTH was potentiated by verapamil and theophylline and was additive to that of PGI2. However, PTH did not appear to increase platelet cAMP levels and was not counteracted by an inhibitor of platelet adenyl cyclase. It is therefore unlikely that PTH inhibits platelet aggregation through an adenyl cyclase stimulated increase of cAMP. Since PTH levels are markedly increased in uremic plasma, it might contribute to the defective platelet function and the bleeding tendency frequently occurring in uremic patients.