[Calcific uremic arteriolopathy - treatment with sodium thiosulfate]. / Kalcifikující uremická arteriolopatie - lécba tiosulfátem sodným.

Calcific uremic arteriolopathy or calciphylaxis is a rare disorder characterized by systemic medial calcification of arterioles that leads to ischemia and subcutaneous necrosis. It most commonly occurs in patients with end-stage renal disease who are on haemodialysis or who have received a renal transplant. Calciphylaxis is dangerous by its fast progression into tissue necrosis, difficult healing process and a great risk of secondary infection which is the most common cause of death in this condition. The reported mortality rates are as high as 60-80 % in a couple of months once it is diagnosed. The key to successful treatment of calciphylaxis is fast diagnosing of the disease and appropriate treatment management. On the examples of three patients from our haemodialysis centre we demonstrate typical clinical manifestation of calciphylaxis and its treatment, which requires close patient-medical staff cooperation. The basic principle of treatment of all our patients was normalization of calcium-phosphate metabolism and secondary hyperparathyroidism. Sodium thiosulfate had been administered to all patients at the end of haemodialysis session. The wound care played another major role with gentle debridement and intensive local care. After five to six months the skin defects resolved in the first patient, partially resolved in the second patient and deteriorated in the third patient. We have observed no side effects of sodium thiosulfate application.

Genetic variability in enzymes of metabolic pathways conferring protection against non-enzymatic glycation versus diabetes-related morbidity and mortality.

BACKGROUND: We hypothesized that genetic variability in genes encoding enzymes metabolizing glycolytic intermediates produced in excess under hyperglycemic conditions [i.e., transketolase (TKT), transaldolase, TKT-like protein 1, fructosamine 3-kinase (FN3K), glyoxalase 1 and glucose-6-phosphate dehydrogenase] could influence progression of diabetic nephropathy (DN) and diabetes-related morbidity and mortality. METHODS: A total of 19 single nucleotide polymorphisms (SNPs) in six candidate genes were studied in 314 type 2 diabetic subjects with variable stage of kidney disease (normo- and microalbuminuria, proteinuria, end-stage renal disease). SNP selection criteria were based on known functional effect and gene coverage. SNPs were detected using polymerase chain reaction based methods. Subjects were followed up for median of 38 months. Time-to-event analysis considered three end-points: 1) DN progression by at least one stage; 2) major cardiovascular event; and 3) all-cause mortality. RESULTS: We found combined effect of TKT SNP rs11130362 and FN3K SNP rs1056534 on DN progression (p<0.01). Additionally, TKT rs3736156 alone and also in combination with the previous two SNPs exhibited significant effect on incidence of major cardiovascular events (p<0.01 and p=0.01, respectively). CONCLUSIONS: Genetic variability in rate-limiting enzymes of pathways proposed to confer hypothetical protection against hyperglycemia might act as an important determinant of hyperglycemia toxicity in long-standing diabetes.

[Metabolic syndrome after kidney transplantation]. / Metabolický syndrom po transplantaci ledviny.

INTRODUCTION: Metabolic syndrome is a risk factor for cardiovascular diseases. Higher risk of the metabolic syndrome and its components in patients after kidney transplantation is caused by immunosuppressive therapy. THE AIM OF OUR STUDY was to evaluate the prevalence of the metabolic syndrome and its components in kidney transplant recipients and to analyse their influence on allograft function and albuminuria. PATIENTS, METHOD AND RESULTS: In the study we monitored 69 patients after cadaveric kidney transplantation. The prevalence of the meta-bolic syndrome was 61.3 % 3 years after kidney transplantation. The prevalence of new onset diabetes mellitus after transplantation was 27 % and that of abdominal obesity 59.7 % of patients. The age of kidney transplant recipients with the metabolic syndrome was higher than of these without it, but not statistically significant. The age of kidney transplant recipients with new onset diabetes mellitus after transplantation was significantly higher, 54.0 (35.0; 69.0) years, than in patients without it, 45.5 (27.0; 60.0) years, OR (95% IS) 1.116 (1.031; 1.207), p = 0.006.The number of components of the metabolic syndrome was negatively correlated with the graft function (rs -0,275, p = 0,031). In patients with impaired renal function with estimated glomerular filtration (using MDRD equation) < 1 ml/s 3 years after kidney transplantation the prevalence of the metabolic syndrome and hypertriglyceridaemia was significantly higher. Chronic allograft dysfunction was predicted by donor age, delayed allograft function, rejection, low level of HDL-cholesterol, hypertriglyceridaemia and hyperuricaemia. Hyperuricaemia was the only significant predictor of allograft dysfunction independently of the presence of delayed allograft function, rejection episodes and donor age. The metabolic syndrome, elevation of apolipoprotein B and nonHDL-cholesterol and increased systolic blood pressure were associated with albuminuria. Higher levels of apolipoprotein B and total cholesterol were independent predictors of increased albumin-creatinine ratio. Obesity had no impact on graft function nor on albuminuria, the influence of the new onset diabetes mellitus after transplantation was not significant independently on other factors. We confirmed the correlation of the presence of the metabolic syndrome with increased levels of AFABP (adipocyte fatty acid-binding protein) and leptin. Increased level of AFABP predicted allograft dysfunction 3 years after kidney transplantation. CONCLUSION: The influence of imunosuppressive treatment on new onset diabetes mellitus after transplantation is well documented. However, we conclude that age is an important additional risk factor for the development of diabetes mellitus in kidney transplant recipients group and it is recommended to follow mainly older patients. Early detection of metabolic abnormalities and dietary and therapeutic intervention in kidney transplant recipients may help to prevent chronic allograft dysfunction.

T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects.

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.

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.

Intra-dialytic electrostimulation of leg extensors may improve exercise tolerance and quality of life in hemodialyzed patients.

Hemodialyzed (HD) patients with end-stage renal disease (ESRD) exhibit lower fitness as a consequence of chronic uremic changes that trigger various structural, metabolic, and functional abnormalities in skeletal muscles. The aim of this randomized study was to compare the effect of rehabilitation (RHB) training on a bicycle ergometer and electromyostimulation (EMS) of leg extensors in HD patients with ESRD. Thirty-two HD patients (18 men/14 women; mean age 61.1 ± 8.8 years) were randomized into three groups: (i) exercise training (ET; n = 11) on bicycle ergometer 2 × 20 min; (ii) EMS (n = 11) where stimulation (10 Hz) of leg extensors was applied for 60 min; and (iii) controls (CON; n = 10) without exercise. Exercising was performed between the 2nd and the 3rd hour of HD, three times a week, 20 weeks in total. Ergometric test was performed in order to evaluate peak workload (W(peak)), 6-min corridor walking test (CWT) to evaluate the distance walked, and dynamometry of leg extensors to assess muscle power (F(max)). Urea clearance was monitored and expressed as standard parameters: spKt/V, spKt/V equilibrated (spKt/V-e), and the urea removal ratio (URR). Quality of life (QoL) was assessed by the questionnaire SF-36. A significant increase of F(max) (P = 0.040 in group ET; P = 0.032 in group EMS), of 6-min CWT (P < 0.001 in ET group; P = 0.042 in EMS group), and of W(peak) (P = 0.041 in ET group) was observed. In both exercising groups, significant increase of spKt/V, spKt/V-e, and URR was found as compared with initial values (P < 0.05). In both exercising groups, highly significant changes in summarized mental functions were found (P = 0.001); in summarized physical components, significant improvement was observed in the ET group (P = 0.006). Intradialytic RHB showed comparable positive effects on functional parameters, urea clearance, and QoL. Intradialytic EMS might represent wide therapeutic possibility in the near future.

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.

Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus.

AIMS: The aims of the study were (i) to ascertain prognostic value of serum uric acid (SUA) for diabetic kidney disease (DKD) progression and major adverse cardiovascular event (MACE) in a cohort of T2DM patients, (ii) to ascertain eventual protective effect of allopurinol treatment, (iii) to determine the effect of genetic variability in UA transporters on DKD progression, and (iv) to define optimal cut-off values for SUA in patients with DKD. METHODS: Study comprised 422 subjects with diabetes duration at least 15years followed-up for a median of 43 [IQR 22-77] months. Participants were categorized into stable or progressors according to their change in albuminuria or chronic kidney disease (CKD) stage. At baseline, 68% patients had hyperuricemia (SUA≥420µmol/l for men and ≥360µmol/l for women and/or allopurinol treatment). Five SNPs in the SLC2A9 and ABCG2 genes were determined by PCR. RESULTS: Time-to-event analysis with subgroups defined by the presence/absence of initial hyperuricemia revealed significant differences in all three end-points (P<0.0001 for DKD progression, P=0.0022 for MACE and P=0.0002 for death, log-rank test). Subjects with normal SUA not requiring allopurinol had median time to DKD progression 49months compared with remaining subjects (32months, P=0.0002, log-rank test). Multivariate Cox regression model revealed hyperuricemia (i.e. high SUA and/or allopurinol treatment) significant predictor of DKD progression independent of baseline CKD stage. Optimal cut-off values identified by ROC analysis for T2DM subjects were ≤377.5µmol/l for men and ≤309.0µmol/l for women. We found no differences in allele or genotype frequencies in selected SNPs between patients with and without hyperuricemia (all P>0.05). CONCLUSIONS: Our study demonstrated that initial hyperuricemia or need for allopurinol is an independent risk factor for DKD progression and that SUA levels in diabetic subjects conferring protection against DKD progression might be lower than current cut-offs for general population.

Resting Heart Rate Does Not Predict Cardiovascular and Renal Outcomes in Type 2 Diabetic Patients.

Elevated resting heart rate (RHR) has been associated with increased risk of mortality and cardiovascular events. Limited data are available so far in type 2 diabetic (T2DM) subjects with no study focusing on progressive renal decline specifically. Aims of our study were to verify RHR as a simple and reliable predictor of adverse disease outcomes in T2DM patients. A total of 421 T2DM patients with variable baseline stage of diabetic kidney disease (DKD) were prospectively followed. A history of the cardiovascular disease was present in 81 (19.2%) patients at baseline, and DKD (glomerular filtration rate < 60 mL/min or proteinuria) was present in 328 (77.9%) at baseline. Progressive renal decline was defined as a continuous rate of glomerular filtration rate loss ≥ 3.3% per year. Resting heart rate was not significantly higher in subjects with cardiovascular disease or DKD at baseline compared to those without. Using time-to-event analyses, significant differences in the cumulative incidence of the studied outcomes, that is, progression of DKD (and specifically progressive renal decline), major advanced cardiovascular event, and all-cause mortality, between RHR

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.