Nicolae Mircea Panduru

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Clinical management of concurrent diabetes and tuberculosis and the implications for patient services

Diabetes triples the risk for active tuberculosis, thus the increasing burden of type 2 diabetes will help to sustain the present tuberculosis epidemic. Recommendations have been made for bidirectional screening, but evidence is scarce about the performance of specific tuberculosis tests in individuals with diabetes, specific diabetes tests in patients with tuberculosis, and screening and preventive therapy for latent tuberculosis infections in individuals with diabetes. Clinical management of patients with both diseases can be difficult. Tuberculosis patients with diabetes have a lower concentration of tuberculosis drugs and a higher risk of drug toxicity than tuberculosis patients without diabetes. Good glycaemic control, which reduces long-term diabetes complications and could also improve tuberculosis treatment outcomes, is hampered by chronic inflammation, drug-drug interactions, suboptimum adherence to drug treatments, and other factors. Besides drug treatments for tuberculosis and diabetes, other interventions, such as education, intensive monitoring, and lifestyle interventions, might be needed, especially for patients with newly diagnosed diabetes or those who need insulin. From a health systems point of view, delivery of optimum care and integration of services for tuberculosis and diabetes is a huge challenge in many countries. Experience from the combined tuberculosis and HIV/AIDS epidemic could serve as an example, but more studies are needed that include economic assessments of recommended screening and systems to manage concurrent tuberculosis and diabetes.

Urinary Liver-Type Fatty Acid-Binding Protein and Progression of Diabetic Nephropathy in Type 1 Diabetes

OBJECTIVE Diabetic nephropathy (DN) has mainly been considered a glomerular disease, although tubular dysfunction may also play a role. This study assessed the predictive value for progression of a tubular marker, urinary liver-type fatty acid–binding protein (L-FABP), at all stages of DN. RESEARCH DESIGN AND METHODS At baseline, 1,549 patients with type 1 diabetes had an albumin excretion rate (AER) within normal reference ranges, 334 had microalbuminuria, and 363 had macroalbuminuria. Patients were monitored for a median of 5.8 years (95% CI 5.7–5.9). In addition, 208 nondiabetic subjects were studied. L-FABP was measured by ELISA and normalized with urinary creatinine. Different Cox proportional hazard models for the progression at every stage of DN were used to evaluate the predictive value of L-FABP. The potential benefit of using L-FABP alone or together with AER was assessed by receiver operating characteristic curve analyses. RESULTS L-FABP was an independent predictor of progression at all stages of DN. As would be expected, receiver operating characteristic curves for the prediction of progression were significantly larger for AER than for L-FABP, except for patients with baseline macroalbuminuria, in whom the areas were similar. Adding L-FABP to AER in the models did not significantly improve risk prediction of progression in favor of the combination of L-FABP plus AER compared with AER alone. CONCLUSIONS L-FABP is an independent predictor of progression of DN irrespective of disease stage. L-FABP used alone or together with AER may not improve the risk prediction of DN progression in patients with type 1 diabetes, but further studies are needed in this regard.

Osteopontin Is a Strong Predictor of Incipient Diabetic Nephropathy, Cardiovascular Disease, and All-Cause Mortality in Patients With Type 1 Diabetes

OBJECTIVE Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. RESEARCH DESIGN AND METHODS Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9–11.8) years. RESULTS Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. CONCLUSIONS Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D.

Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins

ABSTRACT Upon the invasion of the host by microorganisms, innate immunity is triggered through pathogen recognition by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are the best-studied class of PRRs, and they recognize specific pathogen-associated molecular patterns (PAMPs) from various microorganisms. A large number of studies have shown that genetic variation in TLRs may influence susceptibility to infections. We assessed the genetic variation of TLR2, which encodes one of the most important TLRs, in various populations around the globe and correlated it with changes in the function of the molecule. The three best-known nonsynonymous TLR2 polymorphisms (1892C>A, 2029C>T, and 2258G>A) were assessed in different populations from the main continental masses: Romanians, Vlax-Roma, Dutch (European populations), Han Chinese (East Asia), Dogon, Fulani (Africa), and Trio Indians (America). The 2029C>T polymorphism was absent in both European and non-European populations, with the exception of the Vlax-Roma, suggesting that this polymorphism most likely arose in Indo-Aryan people after migration into South Asia. The 1892C>A polymorphism that was found exclusively in European populations, but not in Asian, African, or American volunteers, probably occurred in proto-Indo-Europeans. Interestingly, 2258G>A was present only in Europeans, including Vlax-Roma, but at a very low frequency. The differential pattern of the TLR2 polymorphisms in various populations may explain some of the differences in susceptibility to infections between these populations.

Kidney Injury Molecule-1 and the Loss of Kidney Function in Diabetic Nephropathy: A Likely Causal Link in Patients With Type 1 Diabetes

OBJECTIVE We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (eGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 was measured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or eGFR. In multiple regressions, KIM-1 was associated with lower eGFR independently of diabetes duration (β = −4.066; P < 0.0001) but not of AER. In our GWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = −0.51; P = 6.5 × 10−38). In the MR, KIM-1 was associated with lower eGFR, independently of diabetes duration and AER (β = −5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower eGFR is likely to represent a causal link.

Urinary Adiponectin Is an Independent Predictor of Progression to End-Stage Renal Disease in Patients With Type 1 Diabetes and Diabetic Nephropathy

OBJECTIVE We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. RESEARCH DESIGN AND METHODS uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4–6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. RESULTS uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. CONCLUSIONS uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes.

Insulin resistance is associated with all chronic complications in type 1 diabetes.

Insulin resistance (IR) is present in type 1 diabetes mellitus (T1DM) and is suggested to be related to chronic diabetic complications. The primary aim of our study was to assess IR in T1DM patients with and without chronic complications. A secondary aim was to evaluate the possible association between IR and chronic diabetic complications.

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Aims/hypothesisDiabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.MethodsWe exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).ResultsFive genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case–control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno.Conclusions/interpretationThis study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Considerations on glycaemic control in older and/or frail individuals with diabetes and advanced kidney disease

The increasing prevalence of chronic kidney disease (CKD) and diabetes over the last decade has resulted in increasing numbers of frail older patients with a combination of these conditions. Current treatment guidelines may not necessarily be relevant for such patients, who are mostly excluded from the trials upon which these recommendations are based. There is a paucity of data upon which to base the management of older patients with CKD. Nearly all current guidelines recommend less-tight glycaemic control for the older population, citing the lack of proven medium-term benefits and concerns about the high short-term risk of hypoglycaemia. However, reports from large landmark trials have shown potential benefits for both microvascular and macrovascular complications, though the relevance of these findings to this specific population is uncertain. The trials have also highlighted potential alternative explanations for the hazards of intensive glycaemic control. These include depression, low endogenous insulin reserve, low body mass index and side effects of the medication. Over the last few years, newer classes of hypoglycaemic drugs with a lower risk of hypoglycaemia have emerged. This article aims to present a balanced view of advantages and disadvantages of intense glycaemic control in this group of patients, which we hope will help the clinician and patient to come to an individualized management approach.