Cerebral Microvascular Disease Predicts Renal Failure in Type 2 Diabetes

Abnormalities in small renal vessels may increase the risk of developing impaired renal function, but methods to assess these vessels are extremely limited. We hypothesized that the presence of small vessel disease in the brain, which manifests as silent cerebral infarction (SCI), may predict the progression of kidney disease in patients with type 2 diabetes. We recruited 608 patients with type 2 diabetes without apparent cerebrovascular or cardiovascular disease or overt nephropathy and followed them for a mean of 7.5 years. At baseline, 177 of 608 patients had SCI, diagnosed by cerebral magnetic resonance imaging. The risk for the primary outcome of ESRD or death was significantly higher for patients with SCI than for patients without SCI [hazard ratio, 2.44; 95% confidence interval (CI) 1.36 to 4.38]. The risk for the secondary renal end point of any dialysis or doubling of the serum creatinine concentration was also significantly higher for patients with SCI (hazard ratio, 4.79; 95% CI 2.72 to 8.46). The estimated GFR declined more in patients with SCI than in those without SCI; however, the presence of SCI did not increase the risk for progression of albuminuria. In conclusion, independent of microalbuminuria, cerebral microvascular disease predicted renal morbidity among patients with type 2 diabetes.Diabetes is estimated to increase the risk of ESRD by approximately 12-fold,¹ and 20% to 45% of patients with ESRD in most developed countries have type 2 diabetes mellitus.² Furthermore, the presence of nephropathy is known to seriously affect the prognosis of diabetes by increasing the likelihood of cardiovascular death.³ An association has also been reported between elevated urinary albumin excretion rate and diabetic nephropathy,³ and patients with microalbuminuria are defined as having incipient nephropathy.⁴ Nephropathy in type 2 diabetes progresses from microalbuminuria to macroalbuminuria, and from macroalbuminuria to an elevated serum creatinine (Cr) concentration or the need for renal replacement therapy. However, recent clinical studies have shown that renal insufficiency in the absence of microalbuminuria is relatively common in patients with type 2 diabetes.⁵ In addition, GFR was reported to be negatively correlated with the resistive index (RI) of the interlobular renal arteries ⁶ in patients with type 2 diabetes. These results have led to the suggestion that glomerular lesions and arteriosclerosis in the kidney independently play important roles in the development of ESRD in type 2 diabetes.Although small vessel diseases in the kidney may increase the risk of developing impaired renal function, there is still no established method to assess small vessel disease in the kidney. A linear relationship was observed between the RI and renal vascular resistance.⁷ However, RI is also affected by renal interstitial pressure, indicating that RI is increased in patients with increased interstitial fibrosis,^7,8 which occurs in various conditions such as chronic pyelonephritis, glomerulosclerosis, and ureteral obstruction. The vascular beds of the kidney and brain have similar hemodynamic properties⁹; therefore, silent cerebral infarction (SCI), small vessel disease in the brain, may be indicative of the presence of small vessel disease in the kidney.It is therefore possible that the presence of small artery diseases in the brain could indicate an increased risk for worsening kidney function. Accordingly, the goal of the study presented here was to investigate the association between the presence of SCI and renal prognosis in patients with type 2 diabetes.     

Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software

Introduction

High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method.

C-peptide Predicts the Remission of Type 2 Diabetes After Bariatric Surgery

Background  

C-peptide is a surrogate of the pancreatic beta cell mass. However, the clinical significance of C-peptide in a diabetic patient after bariatric surgery has not been studied clearly.     

Bone Mineral Density of the Radius Predicts All-Cause Mortality in Patients With Type 2 Diabetes: Diabetes Heart Study

This study aimed to determine the association between areal and volumetric bone mineral density (BMD) with all-cause mortality in patients with type 2 diabetes (T2D). Associations between BMD and all-cause mortality were examined in 576 women and 517 men with T2D in the Diabetes Heart Study. Volumetric BMD in the thoracic and lumbar spine was measured with quantitative computed tomography. Areal BMD (aBMD) in the lumbar spine, total hip, femoral neck, ultradistal radius, mid radius, and whole body was measured using dual X-ray absorptiometry. Association of BMD with all-cause mortality was determined using sequential models, stratified by sex: (1) unadjusted; (2) adjusted for age, race, smoking, alcohol, estrogen use; (3) model 2 plus history of cardiovascular disease, hypertension, and coronary artery calcification; (4) model 3 plus lean mass; and (5) model 3 plus fat mass. At baseline, mean age was 61.2 years for women and 62.7 years for men. At mean 11.0?±?3.7 years' follow-up, 221 (36.4%) women and 238 (43.6%) men were deceased. In women, BMD at all skeletal sites (except spine aBMD and whole body aBMD) was inversely associated with all-cause mortality in the unadjusted model. These associations remained significant in the mid radius (hazard ratio per standard deviation ?=?0.79; p?=?0.0057) and distal radius (hazard ratio per standard deviation ?=?0.76; p?=?0.0056) after adjusting for all covariates, including lean mass. In men, volumetric BMD measurements but not aBMD were inversely associated with mortality and only in the unadjusted model. In this longitudinal study, lower baseline aBMD in the radius was associated with increased all-cause mortality in women with T2D, but not men, independent of other risk factors for death.     

Genetic Variant at the GLUL Locus Predicts All-Cause Mortality in Patients With Type 2 Diabetes

Single nucleotide polymorphism (SNP) rs10911021 at the glutamate-ammonia ligase (GLUL) locus has been associated with an increased risk of coronary heart disease in individuals with type 2 diabetes. The effect of this SNP on mortality was investigated among 1,242 white subjects with type 2 diabetes from the Joslin Kidney Study (JKS) (n = 416) and the Gargano Mortality Study (GMS) (n = 826). During a mean follow-up of 12.8 ± 5.8 and 7.5 ± 2.2 years, respectively, a total of 215 and 164 deaths were observed in the two studies. In both cohorts, the all-cause mortality rate significantly increased with the number of rs10911021 risk alleles, with allelic hazard ratios (HRs) of 1.32 (95% CI 1.07–1.64, P = 0.01), 1.30 (1.10–1.69, P = 0.04), and 1.32 (1.12–1.55, P = 0.0011), respectively, in the JKS, the GMS, and the two studies combined. These associations were not affected by adjustment for possible confounders. In the JKS, for which data on causes of death were available, the HR for cardiovascular mortality was 1.51 (1.12–2.04, P = 0.0077) as opposed to 1.15 (0.84–1.55, P = 0.39) for mortality from noncardiovascular causes. These findings point to SNP rs10911021 as an independent modulator of mortality in patients with type 2 diabetes and, together with the previous observation, suggest that this results from an effect of this variant on cardiovascular risk.     

Association of Adiponectin Gene Polymorphisms With Type 2 Diabetes in an African American Population Enriched for Nephropathy

OBJECTIVE—Polymorphisms in the adiponectin gene (ADIPOQ) have been associated with type 2 diabetes and diabetic nephropathy in type 1 diabetes, in mostly European-derived populations.RESEARCH DESIGN AND METHODS—A comprehensive association analysis of 24 single-nucleotide polymorphisms (SNPs) in the adiponectin gene was performed for type 2 diabetes and diabetic nephropathy in African Americans.RESULTS—The minor allele (A) in a single SNP in intron 1 (rs182052) was associated with diabetic nephropathy (P = 0.0015, odds ratio [OR] 1.37, CI 1.13–1.67, dominant model) in an African American sample of 851 case subjects with diabetic nephropathy and 871 nondiabetic control subjects in analyses incorporating adjustment for varying levels of racial admixture. This association remained significant after adjustment of the data for BMI, age, and sex (P = 0.0013–0.0004). We further tested this SNP for association with longstanding type 2 diabetes without nephropathy (n = 317), and evidence of association was also significant (P = 0.0054, OR 1.46, CI 1.12–1.91, dominant model) when compared with the same set of 871 nondiabetic control subjects. Combining the type 2 diabetes and diabetic nephropathy samples into a single group of case subjects (n = 1,168) resulted in the most significant evidence of association (P = 0.0003, OR 1.40, CI 1.17–1.67, dominant model). Association tests between age at onset of type 2 diabetes and the rs182052 genotypes also revealed significant association between the presence of the minor allele (A/A or A/G) and earlier onset of type 2 diabetes.CONCLUSIONS—The SNP rs182052 in intron 1 of the adiponectin gene is associated with type 2 diabetes in African Americans.Type 2 diabetes and diabetic nephropathy are more prevalent among African Americans than European Americans, even when taking into consideration ethnic differences in socioeconomic status, prevalence and severity of hypertension, and access to adequate health care (1–3). Studies of African American families with type 2 diabetes (4) or diabetic nephropathy (5) have revealed clustering of both diseases, indicating a genetic component to susceptibility. Genome scans in families have supported a genetic contribution to susceptibility to type 2 diabetes and diabetic nephropathy in African Americans (4,6).Plasma adiponectin levels are inversely correlated with diabetes and insulin resistance (7,8). In contrast, plasma adiponectin has been shown to be increased in patients with kidney disease (9), and studies suggest that increased adiponectin concentration is a predictor of subsequent kidney disease (10).Adiponectin gene (ADIPOQ) polymorphisms have been implicated in type 2 diabetes (11) and type 1 diabetic nephropathy (12,13). Few studies have addressed genetic variants in adiponectin and association with diabetes in Africans (14) or African Americans (15). This second report in African Americans noted several differences between European-derived samples and African Americans regarding associations between ADIPOQ polymorphisms and body composition and lipid phenotypes highlighting potential ethnic differences in the adiponectin gene and the importance of investigating variants in this gene in African Americans.Given the paucity of studies on adiponectin gene polymorphisms and type 2 diabetes or diabetic nephropathy in African Americans and the high risk of these diseases in this population, a thorough interrogation of this gene in African Americans was warranted. We tested 24 single-nucleotide polymorphisms (SNPs) in the adiponectin gene for association with type 2 diabetes and diabetic nephropathy in a large collection of African Americans residing in the southeastern U.S.     

Recognition of Posttranslationally Modified GAD65 Epitopes in Subjects With Type 1 Diabetes

Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease. Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes. Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance. We show that citrullination and transglutamination of peptides can enhance their binding to DRB1*04:01, a diabetes-susceptible HLA allele. These and corresponding modifications to amino acids at T-cell contact positions modulated the recognition of multiple GAD65 peptides by self-reactive T cells. Using class II tetramers, we verified that memory T cells specific for these modified epitopes were detectable directly ex vivo in the peripheral blood of subjects with type 1 diabetes at significantly higher frequencies than healthy controls. Furthermore, T cells that recognize these modified epitopes were either less responsive or nonresponsive to their unmodified counterparts. Our findings suggest that PTM contributes to the progression of autoimmune diabetes by eliciting T-cell responses to new epitope specificities that are present primarily in the periphery, thereby circumventing tolerance mechanisms.     

Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes

Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes–affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity.     

Normal Q-angle in an Adult Nigerian Population

The Q-angle has been studied among the adult Caucasian population with the establishment of reference values. Scientists are beginning to accept the concept of different human races. Physical variability exists between various African ethnic groups and Caucasians as exemplified by differences in anatomic features such as a flat nose compared with a pointed nose, wide rather than narrow faces, and straight rather than curly hair. Therefore, we cannot assume the same Q-angle values will be applicable to Africans and Caucasians. We established a baseline reference value for normal Q-angles among asymptomatic Nigerian adults. The Q-angles of the left and right knees were measured using a goniometer in 477 Nigerian adults (354 males; 123 females) in the supine and standing positions. The mean Q-angles for men were 10.7° ± 2.2° in the supine position and 12.3° ± 2.2° in the standing position in the right knee. The left knee Q-angles in men were 10.5° ± 2.6° in the supine position and 11.7° ± 2.8° in the standing position. In women, the mean Q-angles for the right knee were 21° ± 4.8° in the supine position and 22.8° ± 4.7° in the standing position. The mean Q-angles for the left knee in women were 20.9° ± 4.6° in the supine position and 22.7° ± 4.6° in the standing position. We observed a difference in Q-angles in the supine and standing positions for all participants. The Q-angle in adult Nigerian men is comparable to that of adult Caucasian men, but the Q-angle of Nigerian women is greater than that of their Caucasian counterparts. Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his or her institution has approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.     

Preoperative Fasting C-Peptide Predicts Type 2 Diabetes Mellitus Remission in Low-BMI Chinese Patients After Roux-en-Y Gastric Bypass

Objective

This study investigated the role of preoperative fasting C-peptide (FCP) levels in predicting diabetic outcomes in low-BMI Chinese patients following Roux-en-Y gastric bypass (RYGB) by comparing the metabolic outcomes of patients with FCP >?1 ng/ml versus FCP ≤?1 ng/ml.

Methods

The study sample included 78 type 2 diabetes mellitus patients with an average BMI <?30 kg/m² at baseline. Patients’ parameters were analyzed before and after surgery, with a 2-year follow-up. A univariate logistic regression analysis and multivariate analysis of variance between the remission and improvement group were performed to determine factors that were associated with type 2 diabetes remission after RYGB. Linear correlation analyses between FCP and metabolic parameters were performed. Patients were divided into two groups: FCP >?1 ng/ml and FCP ≤?1 ng/ml, with measured parameters compared between the groups.

Results

Patients’ fasting plasma glucose, 2-h postprandial plasma glucose, FCP, and HbA1c improved significantly after surgery (p?<?0.05). Factors associated with type 2 diabetes remission were BMI, 2hINS, and FCP at the univariate logistic regression analysis (p <?0.05). Multivariate logistic regression analysis was performed then showed the results were more related to FCP (OR = 2.39). FCP showed a significant linear correlation with fasting insulin and BMI (p?<?0.05). There was a significant difference in remission rate between the FCP >?1 ng/ml and FCP ≤?1 ng/ml groups (p?=?0.01). The parameters of patients with FCP >?1 ng/ml, including BMI, plasma glucose, HbA1c, and plasma insulin, decreased markedly after surgery (p?<?0.05).

Conclusion

FCP level is a significant predictor of diabetes outcomes after RYGB in low-BMI Chinese patients. An FCP level of 1 ng/ml may be a useful threshold for predicting surgical prognosis, with FCP >?1 ng/ml predicting better clinical outcomes following RYGB.

     

Lean Mass Predicts Hip Geometry in Men and Women With Non–Insulin-Requiring Type 2 Diabetes Mellitus

Persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture despite normal bone mineral density (BMD). The contribution of body composition to hip geometry, a measure of hip strength, has not been studied in T2DM. We hypothesized that lean mass would predict hip geometry. Subjects (n = 134) for this cross-sectional analysis were men and women aged 56 ± 6 yr with non–insulin-requiring T2DM. Fat and lean mass were measured with dual-energy X-ray absorptiometry (DXA). Abdominal fat was measured with magnetic resonance imaging. Hip geometry parameters including section modulus, cross-sectional area, and buckling ratio were estimated from DXA using validated formulae. Subjects had normal BMD, elevated body mass indices (29–41 kg/m²), and controlled T2DM (hemoglobin A1c: 5.1–8.3%). In bivariate analysis, lean mass was positively associated with section modulus and cross-sectional area in both sexes (r = 0.36–0.55, p < 0.05). In multivariate analyses, lean mass remained a significant predictor of all hip strength estimates in both sexes. In women alone, fat mass predicted parameters of hip strength. These data demonstrate that lean mass is significantly associated with hip strength in subjects with non–insulin-requiring T2DM. Resistance exercises that build lean mass may be an intervention for hip fracture prevention in T2DM, although additional research is needed.     

A Variant in the KCNQ1 Gene Predicts Future Type 2 Diabetes and Mediates Impaired Insulin Secretion

OBJECTIVE

Two independent genome-wide association studies for type 2 diabetes in Japanese subjects have recently identified common variants in the KCNQ1 gene that are strongly associated with type 2 diabetes. Here we studied whether a common variant in KCNQ1 would influence BMI as well as insulin secretion and action and predict future type 2 diabetes in subjects from Sweden and Finland.

RESEARCH DESIGN AND METHODS

Risk of type 2 diabetes conferred by KCNQ1 rs2237895 was studied in 2,830 type 2 diabetic case subjects and 3,550 control subjects from Sweden (Malmö Case-Control) and prospectively in 16,061 individuals from the Malmö Preventive Project (MPP). Association between genotype and insulin secretion/action was assessed cross- sectionally in 3,298 nondiabetic subjects from the Prevalence, Prediction and Prevention of Diabetes (PPP)-Botnia Study and longitudinally in 2,328 nondiabetic subjects from the Botnia Prospective Study (BPS). KCNQ1 expression (n = 18) and glucose-stimulated insulin secretion (n = 19) were measured in human islets from nondiabetic cadaver donors.

RESULTS

The C-allele of KCNQ1 rs2237895 was associated with increased risk of type 2 diabetes in both the Malmö Case-Control (odds ratio 1.23 [95% CI 1.12–1.34]; P = 5.6 × 10⁻⁶) and the prospective (1.14 [1.06–1.22]; P = 4.8 × 10⁻⁴) studies. Furthermore, the C-allele was associated with decreased insulin secretion (corrected insulin response [CIR] P = 0.013; disposition index [DI] P = 0.013) in the PPP-Botnia Study and in the BPS at baseline (CIR P = 3.6 × 10⁻⁴; DI P = 0.0058) and after follow-up (CIR P = 0.0018; DI P = 0.0030). C-allele carriers showed reduced glucose-stimulated insulin secretion in human islets (P = 2.5 × 10⁻⁶).

CONCLUSIONS

A common variant in the KCNQ1 gene is associated with increased risk of future type 2 diabetes in Scandinavians, which partially can be explained by an effect on insulin secretion.Recently, two independent genome-wide association studies in Japanese subjects have shown that single nucleotide polymorphisms (SNPs) in the KCNQ1 gene (rs2074196, rs2237892, rs2237895, rs2283228, and rs2237897) are associated with type 2 diabetes (1,2). We have previously replicated association of rs2074196 and rs2237892 reported by Yasuda et al. (1) in Scandinavian subjects. Here we studied rs2237895, which is the only of the replicated variants by Unoki et al. (2) in a Danish population with a minor allele frequency >5% (43%). KCNQ1 encodes for a voltage-gated potassium channel that is highly expressed in cardiac muscle, pancreas, intestine, and kidney. Mutations in the KCNQ1 gene cause the long QT syndrome and deafness (3).Here we studied whether rs2237895 increases risk of type 2 diabetes and/or affects insulin secretion and action in several Swedish and Finnish cross-sectional and prospective cohorts including a total of 28,067 individuals.     

GAD65 Autoantibodies Detected by Electrochemiluminescence Assay Identify High Risk for Type 1 Diabetes

The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies.Islet autoantibodies play an essential role in the prediction of type 1 diabetes (T1D) (1–3). These autoantibodies can appear as early as 6–9 months of age and usually precede clinical diabetes by years. Accurate detection of islet autoantibodies is crucial for finding the environmental factors that may trigger islet autoimmunity and promote progression to T1D.In addition, islet autoantibodies are used extensively to stage diabetes risk and as the inclusion criteria for trials to prevent T1D. The risk of developing T1D is strongly associated with the number of islet autoantibodies among both first-degree relatives of patients with T1D and general population subjects. Children who have two or more persistent islet autoantibodies are at high risk; 70% of them will progress to diabetes in <10 years (4). In contrast, children with a single positive persistent autoantibody are at a much lower risk, with <10% progressing to diabetes in 10 years. Further stratification of these single autoantibodies for disease relevance by more-specific assays would greatly enhance staging of diabetes risk for clinical trials.We recently developed an electrochemiluminescence (ECL) insulin autoantibody (IAA) assay (5,6) that has been shown to be more sensitive and more specific for detecting diabetes than the standard micro-IAA radioassay. In the current study, we evaluated a similar ECL-GAD antibody (GADA) assay and compared its sensitivity and disease relevance among GADA-positive children by the standard GADA radioassay.     

Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A₂ receptor (anti-PLA₂R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m²) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0–145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA₂R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA₂R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA₂R antibody depletion. On average, 50% anti-PLA₂R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA₂R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.     

The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes

OBJECTIVES

This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS

The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type 1 diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland.

RESULTS

During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2–4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5–1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroalbuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death.

CONCLUSIONS

An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes.Despite modern therapeutics, type 1 diabetes continues to be associated with premature death. For example, mortality in individuals with type 1 diabetes from Finland is 3–4 times higher than in the general population (1). However, not all individuals with type 1 diabetes share this risk. In order to determine the current prognosis of any individual with type 1 diabetes and direct preventive interventions, it is important to identify those individuals at increased risk of death.Chronic kidney disease is a common complication of type 1 diabetes, affecting up to 30% of patients (2). Previous studies have identified chronic kidney disease as a risk factor for mortality in type 1 diabetes (3–6). However, many of these observations were made when current management paradigms, including intensified metabolic control and blockade of the renin angiotensin system, were not widely applied. In this article, we examine the incidence and predictors of all-cause mortality in a nationally representative cohort of adults with type 1 diabetes, showing that the presence and severity of chronic kidney disease remains the major determinant of excess mortality associated with type 1 diabetes.     

Prevalence of Antiphospholipid Antibody Positivity and Association of Pretransplant Lupus Anticoagulant Positivity With Early Allograft Dysfunction in Liver Transplantation

Background

Antiphospholipid antibodies (aPL), including anticardiolipin (aCL), anti-β₂-glycoprotein I (anti-β2GPI), and lupus anticoagulant (LA) antibodies, are frequently found in liver cirrhosis and associated with splanchnic vein thrombosis. Although the risk factors of early allograft dysfunction (EAD) are known, the association between EAD and aPL has been poorly investigated. We hypothesized that LA, potent aPL with thrombotic potential, may be associated with EAD development after living donor liver transplantation (LDLT).

Prevalence of Vitamin D Insufficiency in an Adult Normal Population

The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43° and 51° N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant ‘sun’ effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D values ≤ 30 nmol/l (12 ng/ml), which represents the lower limit (< 2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p < 0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.