ADMA, SDMA and L-arginine/ADMA ratio but not DDAH genetic polymorphisms are reliable predictors of diabetic nephropathy progression as identified by competing risk analysis.

BACKGROUND/AIMS: Complex interplay of genetic and (patho)physiological factors influence availability of nitric oxide during the development and progression of diabetic complications. We assessed predictive value of commonly studied methylated asymmetric and symmetric dimethylarginines (ADMA and SDMA) and selected single nucleotide polymorphisms (SNPs) in dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes for the progression of diabetic nephropathy (DN). METHODS: A total of 341 type 1 and type 2 diabetes patients with variable degree of kidney disease were included at baseline. Plasma levels of ADMA, SDMA and L-arginine were measured and six tagging SNPs in DDAH1 and 2 were determined. Progression of DN was defined as a transition from any given stage to a more advanced stage of albuminuria. Competing risk analysis was applied. RESULTS: Plasma levels of ADMA and SDMA significantly correlated with GFR. No significant genotype-phenotype relationship was ascertained for ADMA and DDAH variants, but SNP rs805304 exhibited marginally significant association with DN. ADMA, SDMA and L-arginine/ADMA ratio standardised to GFR were identified as significant predictors of DN progression but not GFR decline using multivariate competing risk analysis. CONCLUSIONS: In our study we confirmed potentially significant role of ADMA and SDMA for the assessment of risk of DN progression in European diabetic population.

Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy.

BACKGROUND: Pentose phosphate pathway (PPP) represents a potentially 'protective' mechanism in hyperglycaemia due to shunting of glycolytic intermediates into PPP reactions. We hypothesized that thiamine status (plasma and erythrocyte levels of thiamine and its esters) together with genetic variability in key PPP enzymes-transketolase (TKT), transaldolase and TKT-like-might contribute to the progression of diabetic nephropathy (DN) and mortality of diabetics. METHODS: A total of 240 diabetic subjects with variable degree of kidney disease were included at baseline and were followed up for a median of 26 (IQR 21-50) months. Concentrations of thiamine in plasma and whole blood and TKT-catalysed reaction were determined by HPLC. Single-nucleotide polymorphisms (SNPs) (n = 14) were genotyped by means of PCR using TaqMan chemistry (Applied Biosystems, Foster City, CA, USA). RESULTS: Significant differences in pTh, pThDP, eryThDP and eryTKT between DN-stage groups were ascertained (P < 0.05) with advancing stage of DN being accompanied with increasing values of pTh, pThDP and eryTKT but not eryThDP. A highly significant negative correlation (r = - 0.41, P < 0.001) was found between pThDP and eryThDP, and the tertiles of the ratio of eryThDP/pThDP were significantly associated with all-cause mortality rates (P = 0.0072). We also identified significant differences in the rate of DN progression between different pTDP tertile groups (P = 0.0017). No significant genetic effects were found. CONCLUSIONS: The results support the role of 'functional' thiamine deficiency in the development of hyperglycaemia-related pathology. Limited intracellular availability of active TKT co-factor seems to be a dominant abnormality.

Soluble RAGE, diabetic nephropathy and genetic variability in the AGER gene.

Diabetes mellitus, especially when complicated with decline of renal function due to diabetic nephropathy (DN), is associated with accumulation of advanced glycation end products (AGEs) exerting their adverse effects via receptor of AGE (RAGE). Soluble RAGE (sRAGE) is a truncated form of RAGE functioning as an inhibitor of AGE-mediated signalling. We studied relationships between sRAGE, renal function and genetic variability in the AGER gene in diabetic subjects. Study comprised a total of 265 diabetics (type 1 or 2 or LADA) with normoalbuminuria (n = 94) or DN (n = 171). sRAGE (assessed by ELISA) was significantly higher in DN than normoalbuminuria subjects (P = 0.007) and positively correlated with age, S-urea, S-creatinine and albuminuria and AGEs (determined spectrofluorimetrically), negatively with GFR (all P < 0.05); however, multivariate regression revealed that GFR was the only independent variable associated with sRAGE (P = 0.047). sRAGE did not correspond with carrier state of risk-haplotype copies (RAGE2) (P > 0.05). In conclusion, GFR is a principal determinant of sRAGE concentration and gradual sRAGE increase in subjects with advancing impairment of renal function is paralleled by AGEs.

Systemic AL amyloidosis with unusual cutaneous presentation unmasked by carotenoderma.

We present a case study of an elderly woman with systemic lambda-type AL amyloidosis that featured unusually extensive cutaneous involvement. The case initially presented with a sudden hyper ß-carotenemia with carotenoderma that instigated the clinical examination including skin biopsy. A diagnosis of systemic amyloidosis was made. Immunohistochemistry and Western-blot analysis indicated the presence of lambda light chain proteins in skin amyloid deposits. However, notable co-deposition of wild-type apoA-I and transthyretin was observed which caused initial diagnostic confusion. Proteomic analysis of microdissected skin amyloid deposits by mass spectrometry confirmed lambda light chain proteins in amyloid deposits and co-deposition of apolipoprotein A-IV and serum amyloid P-component. The patient died from renal failure caused by amyloid nephropathy combined with analgesic nephropathy. The autopsy disclosed vascular, cardiac, renal and pulmonary amyloid deposition. While all amyloid deposits were positive for lambda light chain proteins, the immunodetection of apoA-I and transthyretin varied significantly among the visceral amyloid deposits. Although the patient exhibited a 1000-fold increase in serum ß-carotene levels, only a mild increase in retinol and lutein concentrations was observed. Increased ß-carotene values were also found in the liver and the skin. The mechanisms underlying this hyper ß-carotenemia remain undetermined.