Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021.

People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.

Chronic kidney disease and diabetes in the national health service: a cross-sectional survey of the U.K. national diabetes audit.

AIMS: We investigated the prevalence of chronic kidney disease and attainment of therapeutic targets for HbA1c and blood pressure in a large U.K.-based diabetes population. METHODS: The U.K. National Diabetes Audit provided data from 1 January 2007 to 31 March 2008. Inclusion criteria were a documented urinary albumin:creatinine ratio and serum creatinine. Patients were stratified according to chronic kidney disease stage and albuminuria status. Chronic kidney disease was defined as an estimated glomerular filtration rate < 60 ml min(-1) 1.73 m(-2) , albuminuria or both. The proportions of patients achieving nationally defined glycaemic and systolic blood pressure targets were determined. RESULTS: The cohort comprised 1,423,669 patients, of whom 868,616 (61%) met inclusion criteria. Of the patients analysed, 92.2% had Type 2 diabetes. A higher proportion of people with Type 2 diabetes (42.3%) had renal dysfunction compared with those with Type 1 diabetes (32.4%). Achievement of systolic blood pressure and HbA1c targets was poor. Among people with Type 1 diabetes, 67.8% failed to achieve an HbA1c < 58 mmol/mol (7.5%). Of all people with diabetes, 37.8% failed to achieve a systolic blood pressure < 140 mmHg. Blood pressure control was poor in advanced chronic kidney disease. For example, mean (standard deviation) systolic blood pressure rose from 128.6 (15.4) mmHg among people with Type 1 diabetes and normal renal function to 141.0 (23.6) mmHg in those with chronic kidney disease stage 5 and macroalbuminuria. CONCLUSIONS: The high prevalence of chronic kidney disease and poor attainment of treatment targets highlights a large subset of the diabetes population at increased risk of cardiovascular mortality or progressive kidney disease.

Survival in dialysis patients is different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition.

AIMS/HYPOTHESIS: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients. METHODS: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients. RESULTS: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results. CONCLUSIONS/INTERPRETATION: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

Obesity and kidney disease in type 1 and 2 diabetes: an analysis of the National Diabetes Audit.

BACKGROUND: Obesity is increasingly prevalent in many countries. Obesity is a major risk factor for the development of type 2 diabetes but its relationship with diabetic kidney disease (DKD) remains unclear. Some studies have suggested that the metabolic syndrome (including obesity) may be associated with DKD in type 1 diabetes. AIM: To investigate the association between obesity and DKD. DESIGN: Retrospective cross-sectional study. METHODS: National Diabetes Audit data were available for the 2007-08 cycle. Type 1 and 2 diabetes patients with both a valid serum creatinine and urinary albumin:creatinine ratio were included. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), albuminuria or both. Logistic regression was used to analyse associations of obesity (body mass index ≥30 kg/m(2)) and other variables including year of birth, year of diagnosis, ethnicity and stage of kidney disease. RESULTS: A total of 58 791 type 1 and 733 769 type 2 diabetes patients were included in the analysis. After adjustment, when compared with type 1 diabetes patients with normal renal function those with DKD were up to twice as likely to be obese. Type 2 DKD patients were also more likely to be obese. For example, type 2 diabetes patients with an eGFR <15 ml/min/1.73 m(2) and normoalbuminuria, microalbuminuria or macroalbuminuria were all more likely to be obese; odds ratios (95% CI) 1.65 (1.3-2.1), 1.56 (1.28-1.92) and 1.27 (1.05-1.54), respectively. CONCLUSION: This study has highlighted a strong association between obesity and kidney disease in type 1 diabetes and confirmed their association in type 2 diabetes.

Changing trends in end-stage renal disease due to diabetes in the United kingdom.

BACKGROUND: In some countries, diabetic kidney disease (DKD) is responsible for half of all new patients requiring renal replacement therapy (RRT). Understanding the relationship between early and later stages of DKD is important as it is a preventable cause of renal failure. This review aims to establish the trends in end-stage renal disease (ESRD) due to diabetes in the United Kingdom as the first step in this understanding. METHODS: Using annual reports from the UK Renal Registry, we summarise the presentation, incidence, prevalence and survival of ESRD patients with diabetes over the last 10-15 years. RESULTS: Between 1995 and 2009, initiation of RRT in diabetes patients increased from 12.3 to 27.6 patients per million population (pmp). These rates are approximately five times less than those of Caucasians in the United States suggesting fundamental differences in early DKD management. Survival of diabetic patients on dialysis has improved such that prevalent numbers on RRT increased from 47 to 117 pmp in a 12-year period. A longer time to prepare patients for RRT is strongly related with better outcomes. In 2002, 23% of all patients with diabetic nephropathy were referred late, within 90 days of RRT start; by 2009, this figure had fallen to 11.2%. Access to renal transplantation, the best form of RRT, has improved with almost 12.5% of new transplants occurring in patients with diabetes compared to 8.3% in 1997. CONCLUSIONS: End Stage DKD is more extensively and better treated now than in the late 1990 s and coincides with a time of rapid expansion of UK renal services. More diabetes patients start RRT, patients are referred earlier and survive longer. The prevalence of end-stage DKD is 2.5 times what it was just over 10 years ago. However, across the United Kingdom, there still exists variation in the incidence and outcomes of end-stage DKD. That these figures have grown so much but are still dwarfed by other countries' burden of DKD merits further research. Further prevention of DKD is achievable for the United Kingdom and particularly critical for developing nations who can least afford the expensive 'option' of RRT.

Identifying additional patients with diabetic nephropathy using the UK primary care initiative.

AIMS: The aim of this study was to use general practice data to estimate the prevalence of diabetic nephropathy within the registered diabetes patients and examine variation in practice prevalence and management performance since introduction of this initiative. METHODS: Reported quality indicators from the Northern Ireland General Practice Quality and Outcomes Framework were analysed for diabetes and diabetic nephropathy prevalence and management in the period 2004-2008. Variation in prevalence at practice level was assessed using multiple linear regression adjusting for age, practice size, deprivation and glycaemic control. RESULTS: In 2006-2007, 57,454 (4.1%) adult diabetic patients were registered in the denominator population of 1.4 million compared with 51,923 (3.8%) in 2004-2005 (mean practice range 0.5-7.7%). Diabetic nephropathy prevalence was 15.1 and 11.5%, respectively (8688 and 5955 patients). Documented diabetic nephropathy prevalence showed marked variation across practices (range 0-100%) and was significantly negatively correlated with diabetes list size, albumin creatinine ratio testing rates and renin-angiotensin-aldosterone system blockade use and positively correlated with exception reporting rates. Specifically, for every increase in 100 diabetic patients to a register, documented diabetic nephropathy prevalence reduced by 40% (P=0.003). On the positive side, median albumin-creatinine ratio testing rates doubled to 82% compared with figures in the pre-Framework era. CONCLUSIONS: Implementation of the Northern Ireland General Practice Quality and Outcomes Framework has positively benefitted testing for diabetic nephropathy and increased numbers of detected patients in a short space of time. Large variation in diabetic nephropathy prevalence remains and is associated with diabetes registry size, screening and treatment practices, suggesting that understanding this variation may help detect and better manage diabetic nephropathy.

Meta-analysis of the effects of lithium usage on serum creatinine levels.

There is conflicting evidence concerning lithium's effect on renal function. The aim is to clarify whether lithium affects kidney function and at what stage of treatment any effect may occur. Systematic review identified 23 studies split into three groups on which meta-analysis was performed to identify the following: A) lithium's effect on renal function in cross-sectional case-control studies, B) studies of renal function before and after commencement on lithium, C) studies of longer term effect in those already established on lithium therapy. Group A showed a statistically significant increase of 5.7 µmol/L in creatinine in the study population compared with controls. Group B showed a non-statistically significant rise in creatinine (2.9 µmol/L) after a mean follow-up of 86 months. Group C showed a statistically significant increase in creatinine of 7.0 µmol/L over a mean duration of 64 months. An increase in creatinine of an average of 1.6 µmol/L/year on lithium was also identified in this group. Any lithium-associated increase in serum creatinine is quantitatively small and of questionable clinical significance. However, routine renal function monitoring of patients on lithium is essential.

Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis.

AIMS/HYPOTHESIS: Glomerular hyperfiltration is a well-established phenomenon occurring early in some patients with type 1 diabetes. However, there is no consistent answer regarding whether hyperfiltration predicts later development of nephropathy. We performed a systematic review and meta-analysis of observational studies that compared the risk of developing diabetic nephropathy in patients with and without glomerular hyperfiltration and also explored the impact of baseline GFR. METHODS: A systematic review and meta-analysis was carried out. Cohort studies in type 1 diabetic participants were included if they contained data on the development of incipient or overt nephropathy with baseline measurement of GFR and presence or absence of hyperfiltration. RESULTS: We included ten cohort studies following 780 patients. After a study median follow-up of 11.2 years, 130 patients had developed nephropathy. Using a random effects model, the pooled odds of progression to a minimum of microalbuminuria in patients with hyperfiltration was 2.71 (95% CI 1.20-6.11) times that of patients with normofiltration. There was moderate heterogeneity (heterogeneity test p = 0.05, measure of degree of inconsistency = 48%) and some evidence of funnel plot asymmetry, possibly due to publication bias. The pooled weighted mean difference in baseline GFR was 13.8 ml min(-1) 1.73 m(-2) (95% CI 5.0-22.7) greater in the group progressing to nephropathy than in those not progressing (heterogeneity test p < 0.01). CONCLUSIONS/INTERPRETATION: In published studies, individuals with glomerular hyperfiltration were at increased risk of progression to diabetic nephropathy using study level data. Further larger studies are required to explore this relationship and the role of potential confounding variables.

Influence of prolonged hospitalization on overall bed occupancy: a five-year single-centre study.

BACKGROUND: Effective bed use is crucial to an efficient NHS. Current targets suggest a decrease in mean occupancy as the most appropriate method of improving overall efficiency. The elderly and those suffering from complex medical problems are thought to account for a high proportion of overall bed occupancy. AIM: To assess the effect of prolonged hospital stay (>100 days) on overall bed occupancy in a modern teaching hospital. DESIGN: Retrospective analysis. METHODS: Analysis of all admission episodes (n = 117,178) over a five-year period in a large teaching hospital in a single UK region, serving a population of approximately 200,000. A logistic regression multi-factorial model was used to assess the effect of demographic and diagnostic variables on duration of stay. RESULTS: A prolonged stay (>100 days) was seen in 648 admission episodes (0.6%). These accounted for 11% of the overall bed occupancy over the 5-year period. Excluding all prolonged admission episodes from our analysis made no difference to the overall median length of stay. DISCUSSION: Prolonged hospitalizations have a significant impact on bed occupancy. Targeting these very long (>100 days) hospital stays may better improve overall efficiency, compared to targeting mean or median length of stay.

The challenge of patients' unmet palliative care needs in the final stages of chronic illness.

BACKGROUND: There is consensus in the literature that the end of life care for patients with chronic illness is suboptimal, but research on the specific needs of this population is limited. AIM: This study aimed to use a mixed methodology and case study approach to explore the palliative care needs of patients with a non-cancer diagnosis from the perspectives of the patient, their significant other and the clinical team responsible for their care. Patients (n = 18) had a diagnosis of either end-stage heart failure, renal failure or respiratory disease. METHODS: The Short Form 36 and Hospital and Anxiety and Depression Questionnaire were completed by all patients. Unstructured interviews were (n = 35) were conducted separately with each patient and then their significant other. These were followed by a focus group discussion (n = 18) with the multiprofessional clinical team. Quantitative data were analysed using simple descriptive statistics and simple descriptive statistics. All qualitative data were taped, transcribed and analysed using Colaizzi's approach to qualitative analysis. FINDINGS: Deteriorating health status was the central theme derived from this analysis. It led to decreased independence, social isolation and family burden. These problems were mitigated by the limited resources at the individual's disposal and the availability of support from hospital and community services. Generally resources and support were perceived as lacking. All participants in this study expressed concerns regarding the patients' future and some patients described feelings of depression or acceptance of the inevitability of imminent death. CONCLUSION: Patients dying from chronic illness in this study had many concerns and unmet clinical needs. Care teams were frustrated by the lack of resources available to them and admitted they were ill-equipped to provide for the individual's holistic needs. Some clinicians described difficulty in talking openly with the patient and family regarding the palliative nature of their treatment. An earlier and more effective implementation of the palliative care approach is necessary if the needs of patients in the final stages of chronic illness are to be adequately addressed.

A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes.

The main hallmark of diabetic nephropathy is elevation in urinary albumin excretion. We performed a genome-wide linkage scan in 63 extended families with multiple members with type II diabetes. Urinary albumin excretion, measured as the albumin-to-creatinine ratio (ACR), was determined in 426 diabetic and 431 nondiabetic relatives who were genotyped for 383 markers. The data were analyzed using variance components linkage analysis. Heritability (h2) of ACR was significant in diabetic (h2=0.23, P=0.0007), and nondiabetic (h2=0.39, P=0.0001) relatives. There was no significant difference in genetic variance of ACR between diabetic and nondiabetic relatives (P=0.16), and the genetic correlation (rG=0.64) for ACR between these two groups was not different from 1 (P=0.12). These results suggested that similar genes contribute to variation in ACR in diabetic and nondiabetic relatives. This hypothesis was supported further by the linkage results. Support for linkage to ACR was suggestive in diabetic relatives and became significant in all relatives for chromosome 22q (logarithm of odds, LOD=3.7) and chromosome 7q (LOD=3.1). When analyses were restricted to 59 Caucasian families, support for linkage in all relatives increased and became significant for 5q (LOD=3.4). In conclusion, genes on chromosomes 22q, 5q and 7q may contribute to variation in urinary albumin excretion in diabetic and nondiabetic individuals.

Investigation of the C242T polymorphism of NAD(P)H oxidase p22 phox gene and ischaemic heart disease using family-based association methods.

Ischaemic heart disease is a complex phenotype arising from the interaction of genetic and environmental factors. Excessive production of reactive oxygen species leading to endothelial dysfunction is believed to be important in the pathogenesis of ischaemic heart disease. The NAD(P)H oxidase system generates superoxide anions in vascular cells; however, the role of the C242T polymorphism of the NAD(P)H oxidase p22 phox gene in ischaemic heart disease is unclear due to contradictory results from case-control studies. Consequently, we applied family-based association tests to investigate the role of this polymorphism in ischaemic heart disease in a well-defined Irish population. A total of 1023 individuals from 388 families (discordant sibships and parent/child trios) were recruited. Linkage disequilibrium between the polymorphism and ischaemic heart disease was tested using the combined transmission disequilibrium test (TDT)/sib-TDT (cTDT) and pedigree disequilibrium test (PDT). Both cTDT and PDT analyses found no statistically significant excess transmission of either allele to affected individuals (P =0.30 and P =0.28, respectively). Using robust family-based association tests specifically designed for the study of complex diseases, we found no evidence that the C242T polymorphism of the p22 phox gene has a significant role in the development of ischaemic heart disease in our population.

Angiotensin receptor-like immunoreactivity in adult brain white matter astrocytes and oligodendrocytes.

Most of the physiological effects of brain angiotensins are currently believed to be mediated by angiotensin receptors located principally on neurons. However, numerous studies in vitro have demonstrated the presence of functional angiotensin receptors on brain astrocytes, raising the possibility that glial cells may also participate in mediating the effects of the central renin-angiotensin system. Nevertheless, it is uncertain whether these cells in situ express angiotensin receptors, raising questions about the physiological significance of results observed in cell cultures. We have examined the distribution of angiotensin receptor-like immunoreactivity in glial cells in white matter tracts in the adult CNS, using a panel of antisera to the AT1 and AT2 angiotensin receptors. Antiserum preadsorption and/or Western blot demonstrated the specificity of the antisera in brain tissue. In immunohistochemical experiments, the AT1 antisera selectively labeled AT1-expressing neurons in the piriform cortex, whereas the AT2 antiserum stained cells in the trigeminal motor nucleus, these being nuclei known to express AT1 and AT2 receptors, respectively. Using double-label immunohistochemistry, we observed AT1- and AT2-immunoreactive astrocytes and oligodendrocytes in white matter tracts, which include the rat cerebellar white matter, periventricular white matter, and optic nerve, in addition to the bovine corpus callosum and human subcortical white matter. In contrast, astrocytes in the gray matter region of the cerebral cortex were not found to be angiotensin receptor-like immunoreactive. These results demonstrate the presence of AT1 and/or AT2 angiotensin receptor-like immunoreactivity in brain white matter macroglial cells in situ and support the idea that glial cells may play a more important role in the central renin-angiotensin system than previously thought.

Effects of systematic methyl substitution of metal (III) tris(n-methyl-8-quinolinolato) chelates on material properties for optimum electroluminescence device performance.

We relate the chemical structure of a series of methyl (Me) substituted group III metal tris(8-quinolinolato) chelates (nMeq(3)M: n = 0, 3, 4, 5; M = Al(3+), Ga(3+)) to their photoluminescence (PL), electroluminescence, and thermal properties. Methylation of the 8-quinolinol ligand at the 3 or 4 position (pyridyl ring) results in a factor of 1.4 and 3.0 enhancement of PL quantum efficiency (phi(PL)), respectively, whereas methylation at the 5 position (phenoxide ring) results in a factor of approximately 3.0 decrease in phi(PL) relative to the unsubstituted analogue. Electroluminescent quantum efficiencies of undoped organic light-emitting devices using the aluminum tris(8-quinolinolato) chelates are 1, 0.45, 1.4, and 0.80% for unsubstituted 5-, 4-, and 3-methyl-8-quinolinol ligands, respectively. Devices made with the latter two ligands have a higher operating voltage to generate the same current density. Similar trends were observed for methylation of gallium tris(8-quinolinolato) chelates. We relate these results to the thermal properties of the compounds measured by simultaneous differential scanning calorimetry and thermal gravimetric analysis. The C-4 methylated derivatives exhibit approximately 60 degrees C lower crystalline melting points than all other derivatives, indicating the weakest cohesive forces between molecules. Unlike Alq(3), both the C-4 and C-5 methylated derivatives show no recrystallization of the glassy state below 500 degrees C and exhibit approximately 20-25 degrees C higher glass transition temperatures. We infer that methylation of the 8-quinolinol ligand reduces intermolecular interactions and consequently impedes charge transport through the film.

KA1-like kainate receptor subunit immunoreactivity in neurons and glia using a novel anti-peptide antibody.

Functional kainate receptors can be formed by various combinations of subunits with low (GluR5, GluR6 and GluR7) or high affinity (KA1 and KA2) for kainate. The precise contribution of each subunit to native receptors, as well as their distribution within the central nervous system (CNS) is still unclear. Here, we describe the presence of KA1-like immunoreactivity in both neurons and glial cells of the CNS, using a newly developed antiserum to a specific carboxy terminus epitope of the KA1 subunit. Intense immunoreactivity was observed in the CA3 area of the rat hippocampus. Electron microscopy revealed that immunostaining was present in dendritic structures postsynaptic to commissural-associational fibers, rather than in those contacted by mossy fiber terminals. We also observed immunostaining of CA1 pyramidal cell apical dendrites. In the cerebral cortex, KA1-like immunostaining was observed in many pyramidal neuron somata, mainly in layer V, and along their apical dendrites. A subset of gamma-amino-butyric acidic cells were also intensely stained. In the cerebellum, the antiserum selectively stained Purkinje cell somata and their dendrites as well as Bergmann glial processes. Other types of macroglia were also labeled by the KA1 antiserum. Thus, optic nerve oligodendrocytes both in vitro and in situ and cultured astrocytes were densely stained. Our results indicate that KA1-type subunits are more widely distributed throughout the CNS than previously thought. This newly developed antiserum may help to clarify the properties of kainate receptors containing KA1 or KA1-type subunits within the normal and pathological brain.

Segregation analysis of urinary albumin excretion in families with type 2 diabetes.

Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE measured as the urinary albumin-to-creatinine ratio (ACR). This included 630 subjects with type 2 diabetes and 639 subjects without diabetes. A significant correlation (Spearman's correlation 0.34, P < 0.001) was found between the median ACR values determined separately in nondiabetic and diabetic members of the same family. To determine whether this familial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation analyses were performed. In these analyses, ACR was modeled as a continuous trait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Akaike's information criterion was used to determine the most parsimonious models. The Mendelian model with multifactorial inheritance was supported more strongly than Mendelian inheritance alone. These analyses suggested that the best model for ACR levels was multifactorial with evidence for a common major gene. When the analyses were repeated for diabetic subjects only, the evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. The results from the current study suggest that levels of UAE are determined by a mixture of genes with large and small effects as well as other measured covariates, such as diabetes.

Effect of edrophonium and neostigmine on the pharmacokinetics and neuromuscular effects of mivacurium.

BACKGROUND: Previous studies demonstrated that both edrophonium and neostigmine affect mivacurium's pharmacokinetics, thereby potentially affecting its recovery profile. However, those studies were not clinically relevant because mivacurium was still infused after the antagonists were given. In the present study, the authors gave antagonists (or placebo) after discontinuing a mivacurium infusion, thereby obtaining data that are more clinically relevant. METHODS: In 18 patients, mivacurium was infused at 10 microg kg(-1) x min(-1) for 40 min, the infusion was discontinued for 15 min and then restarted at the same rate for another 40 min. Patients were randomized to receive 500 microg/kg edrophonium, 50 microg/kg neostigmine, or saline at discontinuation of the second infusion; all subjects received 1 mg atropine. Plasma was sampled during the final 10 min of each infusion to determine steady state mivacurium concentrations and for 15 min after each infusion. Twitch tension was recorded. Mivacurium concentrations after each of the two infusions were compared. RESULTS: After discontinuation of the second infusion, mivacurium concentrations were larger than those after the first infusion at 2 min with edrophonium and at 2, 4, and 7 min with neostigmine. With both neostigmine and edrophonium, twitch tension recovered after infusion #2 more rapidly than after infusion #1; however, the magnitude of this effect was small CONCLUSION: Edrophonium transiently slows the rate at which mivacurium concentrations decrease; this is consistent with our previous findings. Neostigmine has a similar, although longer, effect. Despite altering mivacurium's elimination characteristics, both drugs facilitate neuromuscular recovery, although their benefit is small.

Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure.

UNLABELLED: Urinary albumin excretion in families with type 2 diabetes is heritable and genetically correlated to blood pressure. BACKGROUND: Levels of urinary albumin excretion (UAE) are used to define both the diagnosis of diabetic nephropathy and its progression. Predisposition to high blood pressure is also a risk factor for susceptibility to nephropathy, but its relationship with UAE in type 2 diabetes remains unclear. In this study, we have estimated heritabilities of UAE and blood pressure and their correlation attributable to genetic effects using 96 large families ascertained for type 2 diabetes. METHODS: In these families, 630 individuals with type 2 diabetes and 639 individuals with normoglycemia were examined. All of them had a determination of UAE as the urinary albumin creatinine ratio (ACR), a convenient index of UAE, together with blood pressure and other variables, such as age, sex, and body mass index. A variance components approach was used to estimate heritability and genetic correlations for ACR and systolic and diastolic blood pressures (SBP and DBP) after adjustment for relevant covariates. RESULTS: In the 96 pedigrees, 6481 usable pairs of relatives were identified. In the total collection of pairs, heritability for ACR (h2 = 0.27, P < 0.001) was similar to that for blood pressure. When only pairs of diabetic relatives were analyzed (N = 1732), the estimates of heritability increased slightly for ACR (h2 = 0.31), SBP (h2 = 0.33), and DBP (h2 = 0.23). A significant genetic correlation was found between ACR and SBP (rg 0.27) and DBP (rg 0.26) in all pairs of relatives (P < 0.001). In pairs of diabetic relatives, these values were higher for SBP and DBP, 0.38 and 0.52, respectively. CONCLUSION: In families with type 2 diabetes, UAE is a heritable trait, with a heritability similar to that for blood pressure. A significant genetic correlation between UAE and blood pressure, particularly in the presence of diabetes, indicates that these traits share common genetic determinants.