Body composition and circulating estradiol are the main bone density predictors in healthy young and middle-aged men.

PURPOSE: Current fracture risk assessment options in men call for improved evaluation strategies. Recent research directed towards non-classic bone mass determinants have often yielded scarce and conflicting results. We aimed at investigating the impact of novel potential bone mass regulators together with classic determinants of bone status in healthy young and middle-aged men. METHODS: Anthropometric measurements, all-site bone mineral density (BMD) and body composition parameters assessed by dual-energy X-ray absorptiometry and also serum concentrations of (1) the adipokines leptin and resistin, (2) vitamin D and parathormone (PTH), (3) sex hormone binding globulin (SHBG), total testosterone and estradiol (free testosterone was also calculated) and (4) C-terminal telopeptide of type I collagen (CTx) were obtained from 30 apparently healthy male volunteers aged 20-65 years enrolled in this cross-sectional study. RESULTS: Only lean mass (LM) and total estradiol independently predicted BMD in men in multiple regression analysis, together explaining 49% (p ≤ 0.001) of whole-body BMD variance. Hierarchical regression analysis with whole-body BMD as outcome variable demonstrated that the body mass index (BMI) beta coefficient became nonsignificant when LM was added to the model. Adipokines, fat parameters, testosterone (total and free), SHBG, PTH and vitamin D were not independently associated with BMD or CTx. CONCLUSIONS: The present study shows that LM and sex hormones-namely estradiol-are the main determinants of bone mass in young and middle-aged men. The effects of BMI upon BMD seem to be largely mediated by LM. Lifestyle interventions should focus on preserving LM in men for improved bone outcomes.

Calibrating the impact of dual RAAS blockade on the heart and the kidney - balancing risks and benefits.

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.

The EVOLVE study is negative, so what does this 'bitter pill' of disappointment mean now for renal patients?

The extremely high morbidity and mortality experienced by subjects with chronic kidney disease (CKD) has often been described and reviewed, but this familiarity should not breed indifference to the huge burden of premature cardiovascular disease ­ something which becomes more obvious, but increasingly challenging to treat, as GFR declines, or proteinuria increases. The health outcomes for a middle-aged person entering renal replacement therapy are as bad as those seen with a major solid organ malignancy; while there has been modest progress in improving outcomes over the last two decades, the diagnosis of significant or progressive CKD should and thus still does continue to cast a shadow over patients, carers and healthcare professionals alike.

Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex.

PURPOSE: Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Although, SEGAs are slow-growing glioneuronal tumors, they represent a significant cause of morbidity and mortality due to the risk of sudden death from acute hydrocephalus. Neurosurgical resection has been the mainstay of therapy, since radiotherapy and chemotherapy were proved inefficient in those tumors. Recent studies support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis and suggest it might represent a disease-modifying treatment for other aspects of tuberous sclerosis. METHODS: We describe the clinical and radiological progression of three pediatric patients with definitive diagnosis of TSC and SEGA, which have been treated with everolimus. RESULTS: Up to 34 % sustained SEGA decrease was observed in the three cases. All three patients have experienced seizure control and two of them have showed cognitive and behavioral improvement. Everolimus has been well tolerated by all. No severe adverse events have been observed to date. CONCLUSION: Everolimus offers significant promise in treating SEGAs. Studies are required to explore optimal therapy duration and management upon discontinuing therapy.

Surgical management of renal hyperparathyroidism: a preliminary series report.

BACKGROUND: Renal hyperparathyroidism (RHPT) is a frequent complication of uremic patients on hemodialysis and despite various advances in medical therapy parathyroidectomy is necessary in a semnificative number of cases. PATIENTS AND METHODS: We reviewed our experience (first in Romania) regarding fortythree patients with RHPT operated on in our clinic between 1994 and 2009 evaluating the diagnosis methods, surgical indications, techniques and results together with the evolution of our own therapeutical concept. The study included 22 men and 21 women of median age of 48 (range 15-67) years, performing hemodialysis (n=41) or peritoneal dialysis (n=2) from 7,7 (range 3-13) years respectively. Three patients received an unsuccessful renal graft. The diagnosis was established by anamnesis, clinical complaints (mainly osteoarticular pains, osteoporosis, fractures and skeletal deformities, muscle weakness, severe itching and mental troubles), completed by abnormal values of calcemia, phosphatemia alkaline phosphatasis and intact PTH. Ultrasonography and parathyroid scan were useful in "adenomised" parathyroids and coexistent thyroid pathology. RESULTS: All the patients were operated on. Twentyfour sub-total parathyroidectomies and 19 total parathyroidectomies (6 with autotransplantation), were performed (two video-assisted). There were no deaths and the operative morbidity was 20,9% (vocal cord hemiparesis and postoperative bleeding--each one case, mild transitory hypocalcemia three cases and recurrences four cases). Pathology revealed that RHTP was due to four gland diffuse hyperplasia (n = 23) or nodular hyperplasia (n = 19). One parathyroid carcinoma (in the fourth parathyroid gland), one thymoma and two papillary thyroid microcarcinoma was identified. Clinical and biochemical cure was achieved at median term control of 38 (range 6-165) months in 79.0% (n = 34) of cases. CONCLUSION: Parathyroidectomy is effective for long intervals as symptomatic therapy in cases of RHPT appearing in uremic patients on hemodialysis or after renal transplant but the optimal technique must be individualized on each case and still to be debated.

Renin-angiotensin system and cancer: epidemiology, cell signaling, genetics and epigenetics.

Day by day, the health and economical burden of cancer increases globally. Indeed it can be considered that there is ''cancer pandemic''. Blocking the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors (ACEI) or angiotensin-receptor blockers (ARB) are widely used measures to treat hypertension and heart failure. It has been recently suggested the activation and blocking of RAS has been associated with various types of cancer in epidemiological and experimental studies. Various studies have shown that RAS blockage is protective in some cancers. However, although fewer, contradictory data also showed that RAS blockage is either not related or adversely related to cancer. Although the reasons for these findings are not exactly known, different types of receptors and effectors in RAS may account for these findings. In the current review, we summarize the different RAS receptors and cancer development with regard to epidemiology, and pathogenesis including cell signaling pathways, apoptosis, genetic and epigenetic factors.

Burden of disease - prevalence and incidence of ESRD in selected European regions and populations.

Rates of renal replacement therapy (RRT) vary markedly between Eastern and Western European countries. This review aims to establish the characteristics of healthcare systems and renal services that are independently associated with rates of initiation of RRT in these countries. The incidence of RRT varied from 12 to 455 per million populations (pmp); the only general population indicator independently associated with RRT incidence was aged 65+. Economic and financial conditions could also play an important role. Gross Domestic Product (GDP) per capita and the proportion of GDP spent on healthcare independently predicted RRT incidence. Each increase in hemodialysis (HD) facilities and competition between providers is associated with higher RRT incidence. In this context, macroeconomic and potentially modifiable renal service organizational factors appear more important determinants of provision of RRT than measurable medical factors. The economic, financial or medical conditions could also play an important role in treatment strategy. The proportion of patients receiving HD, peritoneal dialysis (PD) or transplantation shows marked variation in Europe. The East Europeans use more HD and less RTx as compared to West Europeans; the use of PD is similar. Treatment of anemia and mineral metabolism disorders also varies from one region to another. The mean baseline hemoglobin level and the prevalence of patients reaching this value are higher in West Europeans. Regarding mineral metabolism, the percent of patients achieving all four parameters (Ca, P, CaxP and PTH) was also higher in Western Europe. The adherence to EBPG (European Best Practice Guidelines) was also higher in these countries.

Association of +35A/C (intron3/exon3) polymorphism in SOD1-gene with diabetic nephropathy in type 1 diabetes.

Diabetic nephropathy is a major complication of type 1 diabetes whose pathogenesis is insufficiently known, but oxidative stress and genetic susceptibility seem to be involved. The purpose of this study is to assess the possible association of +35A/C (rs2234694) polymorphism in SOD1-gene with advanced stages of diabetic nephropathy in patients with type 1 diabetes in Romania. There have been enrolled 238 unrelated patients, having type 1 diabetes, divided into group A (106 patients) with diabetic nephropathy - macroalbuminuria or ESRD (End Stage Renal Disease) and group B (132 patients) without diabetic nephropathy. The genomic DNA was extracted from the peripheral venous blood and the genotyping of +35A/C (rs2234694) polymorphism has been made using the PCR-RFLP technique. The statistical analysis has been made using De Finetti's program. There has not been a significant deviation from the Hardy-Weinberg equilibrium for any group (p=0.229 and p=0.894, respectively). The data analysis revealed that the presence of a C-allele confers a significant risk (p=0.008) for the advanced diabetes nephropathy (OR=4.940, 95% C.I.=1.341-18.198), and the CA-genotype (p=0.015) confers a little lower risk (OR=4.491, 95% C.I.=1.203-16.766). This study shows the association of a mutant C-allele of rs2234694 polymorphism in SOD1-gene with the advanced stages of diabetic nephropathy in patients with type 1 diabetes in Romania, suggesting the involvement of the defense against oxidative stress, as an important link in the pathogeny of diabetic nephropathy.

Hemoglobin normalization trials in chronic kidney disease: what should we learn about quality of life as an end point?

This editorial review takes an in-depth look to the effect of hemoglobin (Hb) normalization with erythropoietin on quality of life (QoL) in chronic kidney disease (CKD). The analysis of the current available data shows major inhomogeneities in the tools used for assessment of QoL and in data reporting. Furthermore, the major trials on Hb normalization were generally not primarily designed to analyze QoL as a specific end-point. However, current data suggest that only partial correction of anemia with EPO may improve QoL, whereas correction of Hb to above 12 g/dL does not exert any positive effect. Finally, the authors provide recommendations on a more rigorous assessment of QoL in future trials in CKD patients.

ORAMA: a study to investigate EBPG impact on renal anaemia - design and baseline data.

BACKGROUND: It is of paramount importance not only to publish anaemia management guidelines for chronic kidney disease (CKD) but also to verify their implementation in clinical practice. The Optimal Renal Anaemia Management Assessment (ORAMA) is the first European study investigating the impact of adherence to the 2004 revised European Best Practice Guidelines (EBPG) and its impact on patient outcomes. METHODS: Participating centres were randomised into 2 groups: group A with, and group B without, access to an EBPG-based computerised clinical decision support (CDS) system after baseline. Patients with stage 2-5 CKD either anaemic (haemoglobin [Hb] <11 g/dL) or treated with erythropoiesis-stimulating agents (ESAs) and/or iron supplementation were enrolled. Primary end points are based on achievement of anaemia-related guideline targets. Here, baseline data are reported descriptively. RESULTS: Fifty-three centres in 8 countries included 739 patients, 81% of whom have received dialysis. Mean baseline Hb was 11.2 g/dL, and 52% of all patients met the EBPG target of >11 g/dL Hb at baseline. However, only 37% of patients had their Hb values >11 g/dL throughout a 3-month prestudy period. Serum ferritin and transferrin saturation were above the guideline target in circa 80% of patients. The vast majority of patients (96%) received ESA therapy at baseline. CONCLUSIONS: In line with findings from previous studies ORAMA baseline data show that achievement of EBPG is suboptimal across European countries. Final results promise an insight into the impact of guideline-based CDS tools on clinical practice and target attainment.

Kidney transplantation in Romania: two transplant centers experience.

PURPOSE: Kidney graft survival rates improved from decade to decade, but data about factors that affect patient and graft survival remain challenging and even controversial. METHODS: We analyzed retrospectively data from kidney transplanted patients followed in two Romanian transplant centers (Iasi and Bucharest)-new programmes specifically developed after 1989 to cover transplantation requirements for two-thirds of Romania. We used a composite survival outcome defined as 50% reduction in estimated glomerular filtration rate (eGFR), return to dialysis or death. Survival analysis was performed using uni- and multivariable Cox regression with baseline and time-updated covariates. RESULTS: From the entire cohort of 365 patients, 243 had the outcome of interest. In the univariable Cox survival analysis, age, hemoglobin, eGFR, cholesterol, AST and transplant center were associated with the outcome. The multivariable Cox analysis reveals that only cholesterol (HR 0.97, 95% CI 0.94-0.99 per 10 mg/dL increase) and transplant center (HR 3.64, 95% CI 2.67-4.97) remain associated. For the time-updated Cox survival analysis we found that eGFR (HR 0.91, 95% CI 0.87-0.96 per 10 ml/min/1.73 m2 increase) and cholesterol are associated with the outcome in the univariable analysis and only eGFR and transplant center in the multivariable Cox survival analysis. CONCLUSIONS: Our study reports data from two distinct transplant centers from a developing country. Our results are similar to the current literature data, but also reveal that the approach of a center to the transplantation management is an independent factor associated with graft survival.

Biosimilars: recent developments.

Biopharmaceuticals are recombinant protein drugs which are produced by biotechnology. The availability of such molecules has revolutionised the way we treat many diseases. However, the patents for many originator biopharmaceuticals are expiring, and a new generation of follow-on molecules, termed "biosimilars", are under development. Health care providers perceive biosimilars to be cheap replacements for originator drugs such as recombinant human erythropoietin and human growth hormone. However, concerns have been raised about the comparability of biosimilars with originator products especially in light of the complex manufacturing process required to produce biopharmaceuticals. The complexity of protein molecules renders it impossible to produce identical copies; this in turn raises questions on the safety of follow-on biosimilar products, particularly with respect to immunogenicity. This review briefly outlines the process of biopharmaceutical production, potential problems that can arise from their long-term use in patients, and the issues facing regulatory bodies as they look to institute guidelines for new biosimilar molecules.

Diabetic nephropathy: What does the future hold?

The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era.

Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients.

BACKGROUND: Increased aortic stiffness markers - aortic pulse wave velocity (PWV) and augmentation index (AIx) - are powerful predictors of survival in ESRD patients - well-recognized for the high prevalence of coronary artery disease (CAD) and unusually high PWV and AIx. Recently, decreased aortic compliance has been shown to be predictive of primary coronary events in hypertensive patients with normal renal function. We aimed to explore relationships between arterial stiffness and CAD in cohorts of patients with chronic kidney disease (CKD). METHODS AND RESULTS: 46 patients with chronic kidney disease (33 males, aged 55.7+/- 13.2 years, 20 on dialysis, 18 post renal transplantation, and 8 with glomerular filtration rate (GFR) between 10 and 25 ml/min) underwent coronary angiography for the assessment of CAD. PWV and aortic AIx were determined from pulse waveform analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCortm device. The atherosclerosis burden score was calculated by adding the percentage luminal reduction of the most severe lesion in each artery. Patients with normal angiograms had significantly less arterial stiffness (as reflected by both a lower PWV=8.42+/-1.53 m/s and a lower AIx=17.9+/-5.55 %) compared with the 35 subjects with evidence of obstructive coronary disease at angiography (PWV=9.21+/-1.15 m/s and AIx=23.4+/-5.4 %, P<0.05 for both). Moreover, as more coronary vessels were affected, PWV and AIx increased proportionally. Based on receiver operating characteristics (ROC) curve analysis mean PWV levels showed an optimal cut-off point at 8.35 m/s (sensitivity=0.77; specificity=0.60), while mean AIx levels showed an optimal cut-off point at 17% (sensitivity=0.87; specificity=0.70). There was a statistically significant linear relationship between the atherosclerosis burden and both measures of arterial stiffness: PWV (r=0.31, p=0.007) and AIx (r=0.46, p=0.003). Independent predictors for the arterial stiffness parameters in this CKD population (multiple stepwise regression analysis) were age (r=0.69 for PWV and r=0.62 for AIx), and mean arterial pressure (MAP) (for AIx, p<0.0001). CONCLUSION: This study provides the first direct evidence in a cross-sectional investigation that PWV and AIx are related to the extent of coronary obstruction in CKD patients.

POSTOPERATIVE ARTERIAL RELAXATION AND INTRAOPERATIVE VENOUS DILATION AS INTERCONNECTED PROGNOSTIC FACTORS FOR THE MATURATION OF ARTERIOVENOUS FISTULAS.

AIM: To investigate if immediate arterial distention can be used as a predictive factor for the development of a good fistula. MATERIAL AND METHODS: Over a 5-months period (January- May 2015) all the patients who underwent an arteriovenous fistula between the radial artery and the cephalic vein of the forearm at the Second Surgical Clinic of the Iasi Regional Cancer Institute and were willing to participate were enrolled in the study. The diameters of the vessels were measured 1 hour and 8 weeks after surgery. RESULTS: We found statistically significant differences for all measured diameter variations between the calcified artery and normal artery groups (p < 0.001 for the arterial distention at 1 hour and 8 weeks after surgery and p = 0.002 for the venous distention 8 weeks after surgery). A linear regression also showed that the degree of arterial distention immediately after surgery and the venous distention 8 weeks after surgery were statistically correlated. CONCLUSIONS: Arterial distention immediately after surgery and therefore the lack of it due to the presence of arterial calcifications can be used to predict whether or not a good fistula can be achieved at a 1% statistical significance level.

Successful renal transplantation decreases aortic stiffness and increases vascular reactivity in dialysis patients.

BACKGROUND: Patients with end-stage renal disease on dialysis have among the highest cardiovascular event rates documented. Abnormal nitric oxide (NO)-dependent endothelial reactivity and increased arterial stiffness are commonly described in hemodialysis (HD) patients. Measures of aortic stiffness--aortic pulse wave velocity (PWV) and augmentation index (AGI)--have been shown to be powerful predictors of survival on hemodialysis. It is not known how these parameters interfere with successful renal transplantation. METHODS: PWV and aortic AGI (difference between the first and second systolic peak on the aortic pressure waveform divided by the pulse wave height) were determined from contour analysis of arterial waveforms recorded by applanation tonometry using a SphygmoCor device in 41 HD patients (20 men; age, 41.8 years) and in a control group of 20 patients with essential hypertension (HTA) (10 men; age, 43.6 years). Twenty of the HD patients (10 men; age, 39.7 years) received live-related renal transplants (RTx) and were restudied (3 months after RTx, normal serum creatinine). NO-dependent and NO-independent vascular reactivity were assessed by changes in AGI after challenges with inhaled salbutamol (SAL) and sublingual nitroglycerin (NTG), respectively. RESULTS: AGI values were significantly lower in RTx patients compared with subjects on hemodialysis (15.9 +/- 13.9% vs. 27.9 +/- 11.9%, P<0.05), but similar to essential HTA controls (16.5 +/- 17%). Serial AGI measurements showed that successful renal transplantation is associated with a decrease in AGI in all cases, from a mean of 25.1 +/- 7.8% while on dialysis to 15.9 +/- 7.0% 3 months after transplantation (P<0.0001). The responsiveness to both endothelium-dependent stimuli (inhaled SAL) and endothelium-independent stimuli (sublingual NTG) was greater in transplant patients than in hemodialysis patients (SAL-induced decrease in AGI -82.3 +/- 65.7% vs. 45 +/- 72.3%, P<0.01; and NTG-induced decrease in AGI 197 +/- 108 vs. -129.0 +/- 215.5%, P<0.01). PWV values in dialysis patients (7.19 +/- 1.88 m/sec) were significantly higher than those measured in essential HTA patients (6.34 +/- 1.32 m/sec, P<0.05) with normal renal function (despite similar blood pressure levels). PWV after RTx was 6.59 +/- 1.62 m/sec, significantly different from pretransplantation (dialysis) values (P<0.05 for comparison) but similar to the control group of essential HTA patients. CONCLUSIONS: Renal transplantation is associated with marked improvements in vascular structure and function to a profile comparable to essential HTA patients.

Reduced blood pressure diurnal variability as a risk factor for progressive left ventricular dilatation in hemodialysis patients.

Cardiovascular mortality places a considerable burden on chronic renal replacement therapy programs. Left ventricular hypertrophy (LVH) increases the risk for cardiovascular mortality. Risk factors for LVH in the dialysis population are numerous and include arterial distensibility, hypertension, anemia, arteriovenous fistula, and hyperparathyroidism. An important factor to consider in the diagnosis and evaluation of hypertension in this clinical setting is blood pressure (BP) level variation, only accessible using ambulatory BP monitoring (ABPM). In uremic patients, a relative elevation of BP during sleep periods leading to an increased 24-hour BP load is frequently described. Whether this additional BP burden is pathophysiologically significant has not been resolved. This study is designed to examine the effect on echocardiographically derived measurements of the left ventricle in 60 stable chronic hemodialysis patients of abnormal (reduced) diurnal BP variability, measuring ambulatory BP on three occasions and performing echocardiography twice over a 12-month period. First, we found that most dialysis patients (76%) had consistent diurnal BP rhythms over a 12-month period, and second, those patients with persistently reduced diurnal BP rhythm tended to develop a dilated left ventricle and left atrium in the absence of other known and/or relevant risk factors (persistently increased sleep BP group; n = 36; LV end-diastolic diameter, 38.2 +/- 2.5 mm/m(2) versus persistently normal sleep BP group; n = 10; LV end-diastolic diameter, 30.6 +/- 3. 3 mm/m(2); P < 0.05). These results suggest that persistent abnormal BP variability is a risk factor for a dilated heart on dialysis, independent of the BP level.

A family-based strategy to identify genes for diabetic nephropathy.

Diabetic nephropathy (DN) clusters in families and specific ethnic groups, suggesting a genetic basis of disease transmission. Identification of DN susceptibility loci should reveal new therapeutic targets but requires accurate phenotyping. A powerful family-based strategy, which is novel to the pursuit of nephropathy genes in type 2 diabetes, is being used to collect a sample for candidate gene and genome scan analyses. Sib pairs that include DN index cases plus (1) sibs concordant for type 2 diabetes and DN (affected sib pairs [ASPs]) and (2) sibs concordant for type 2 diabetes but discordant for DN (discordant sib pairs [DSPs]) are targeted specifically for recruitment. Type 2 diabetes and DN phenotype criteria for index cases include diabetes onset after 38 years of age, duration 10 years or longer, no initial insulin treatment, diabetic retinopathy, end-stage renal disease (ESRD), and history of nephrotic proteinuria. ESRD patients were screened by questionnaire and medical record review (n = 2114). Of 666 patients with ESRD secondary to DN, 227 had a family history of ESRD, 150 had a living diabetic sib, and 124 families were enrolled. Sixty-five families, with 86 diabetic relative pairs (69 sibs, 17 children), have been completely phenotyped. If nephropathy in diabetic sibs is defined as albuminuria greater than 0.3 g/24 h, 31 ASPs and 26 DSPs (diabetic sib with albuminuria <0.3 g/24 h) were identified. Applying more stringent criteria, only 12 ASPs (sib with diabetes >10 years, diabetic retinopathy, and nephrotic proteinuria) and 9 DSPs (sib with diabetes >10 years and normal urine albumin excretion) were identified. Extrapolating from the number of subjects recruited using stringent phenotyping criteria, nearly 10,000 ESRD patients are required for screening to achieve adequate statistical power for linkage analysis (80% power to detect locus-specific relative risk of 2.2 at a lod score of 3.0). Careful phenotyping requires a large recruitment effort but is necessary to reduce population heterogeneity, a strategy that increases the likelihood of identifying DN loci.

Long-hours home haemodialysis--the best renal replacement therapy method?

Two hundred and eighty-six patients (190 males and 96 females) with end-stage renal failure (ESRD) started haemodialysis (HD) at Withington Hospital between 1 January 1968 and 31 December 1986. Of these, 152 (53.1%) were successfully transplanted, while 134 had only HD or one transplant lasting < 3 months (i.e. total HD interruption < 3 months). For the whole group, the probabilities of being alive on long-hours home HD at 10 and 20 years were 58.7% and 33.2%, respectively. Mean gross mortality 1968-1986 was 6.5 +/- 3.2% per year. The main causes of death were cardiovascular (36.6%), infection-related (19.2%) and malignancy (9.6%). Males and younger cohorts had a significantly (p < 0.05) higher probability of being alive on long-hours home HD than did females and older cohorts. Eighty-two patients (29% of the total group) survived more than 10 years, of whom 54 were still alive at 1 January 1996: 44 continuing on HD while the other ten had been successfully transplanted. In these 54 patients, mean 24-h ambulatory blood pressure recorded at the date of the study was 117.6/68.9 mmHg; mean BP for the last 5 years on HD was 136.4/81.2 mmHg. Only four (7.4%) were regularly taking antihypertensive medication. Left ventricular hypertrophy (LVH) (by ECG) was present in 64.8% of the 54 patients; its prevalence by echocardiography (LVM index > 130 g/m2 for men and > 110 g/m2 for women) was 77.5%. Only 10 (18.5%) had symptoms or clinical signs of ischaemic heart disease and/or peripheral vascular disease. None had cardiac failure symptoms NYHA class 3-4. Our data show a low incidence of all-cause and cardiovascular mortality, confirming those from the Tassin unit in France, and make a medical case for extended haemodialysis treatment hours.

Adenosine effects upon the spontaneous quantal transmitter release at the frog neuromuscular junction in the presence of protein kinase C-blocking and -activating agents.

This paper gives experimental evidence involving protein kinase C (PKC) in the inhibitory effects of adenosine (ADO) upon the spontaneous transmitter release at the frog neuromuscular junction. In the presence of two PKC inhibitors--polymyxin B (5 x 10(-6) mol/l) and H-7 (10(-5) mol/l), both adenosine (5 x 10(-5) mol/l) and its stable analogue 1-PIA (5 x 10(-8) mol/l), significantly increased the rate of the spontaneous release of acetylcholine quanta. Even when PKC was activated with OAG (5 x 10(-6) mol/l) or TPA (162 x 10(-9) mol/l) and quantal release was increased greatly, ADO still inhibited release. ADO deaminase increased the PKC-induced activation of the transmitter release significantly.