Marios Theodoridis

Metformin-related lactic acidosis in patients with acute kidney injury

BackroundMetformin is nowadays considered as first-line therapy in individuals with non-insulin dependent diabetes mellitus (NIDDM). Metformin-related lactic acidosis (MALA) occurs more frequently after inappropriate use especially in patients with acute kidney injury (AKI) or chronic kidney disease (CKD). Thus, its prescription in these patients is contraindicated, while the role of dialysis is under evaluation.MethodsWe describe two cases of severe metformin-related lactic acidosis with underlying acute kidney injury, which were treated with dialysis.ResultsIn both cases, lactic acidosis occurred on a background of acute decline in renal function, possibly due to drug accumulation. It is interesting that metformin was contraindicated in one case.ConclusionLactic acidosis is a rare but potentially fatal adverse effect of metformin, particularly in patients with AKI, which should always be considered in clinical practice. Dialysis seems to contribute significantly to the management of this life-threatening condition and the improvement in outcome.

C-Terminal Fragment of Agrin (CAF): A Novel Marker for Progression of Kidney Disease in Type 2 Diabetics

Background Diabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics. Methods Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF. Results We found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2–14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule. Conclusion Serum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy.

Upper limb vascular calcification score as a predictor of mortality in diabetic hemodialysis patients

OBJECTIVE This study evaluated the correlation between an upper limb vascular calcification (Vc) score (VcS) and late all-cause mortality in diabetic hemodialysis patients with distal upper limb arteries medial wall sclerosis (Mönckeberg disease). METHODS We retrospectively reviewed Vc in bilateral upper limb plain radiographs and in duplex ultrasound images performed before radial-cephalic fistula (RCF) creation in diabetic hemodialysis patients. Only medial linear calcifications outlining the vessel wall were considered positive on X-ray images, whereas for ultrasound reviews, only continuous highly echogenic plaques producing bright white echos with shadowing were considered to be medial calcification. A VcS was then applied in each patient. Every half of each of the three main arterial conduits (brachial, radial, and ulnar arteries) in each arm was counted as 1 if it contained ≥ 6 cm of linear calcification, whereas absence of calcification or minimum calcification (length <6 cm) was counted as 0. Long-term all-cause mortality was compared between patients with a low or moderate VcS <8 (group I), patients with a high VcS ≥ 8 (group II), and patients with VcS = 0 (control group). Kaplan-Meier statistics were used for comparisons among the groups. RESULTS Nineteen patients had a VcS <8, 21 had VcS ≥ 8, and 43 patients had VcS = 0. The study patients had a mean age of 68 ± 10 years (range, 42-83 years; P = .23). Before early conversion to a RCF, dialysis therapy in 59 (71.1%) had already been initiated through central venous catheters (CVCs). The mean follow-up for groups I, II, and controls was 41.4 ± 41.2 months (range, 4-144 months), 34.15 ± 31.3 months (range, 1-108 months), and 66.7 ± 32.5 months (range, 12-126 months), respectively (P = .0009). Forty-seven patients died during the follow-up period (12 in group II and 24 in the controls; P = .88). Survival rates at 12, 24, 36, and 48 months were 78.3%, 65.7%, 54.8%, and 48.1% for group I; 75.2%, 58.8%, 49.3%, and 42% for group II; and 97.7%, 93.1%, 76.8%, and 71.8% for the control group, respectively (P = .013 for all groups; P = .044 for group II vs controls). Patients with (subgroups) or without CVCs at baseline had similar late mortality rates. Patients with CVCs/Vc had lower survival rates than those with CVCs/no Vc at 1 year (73.3% vs 96.5%) and at 3 years (47.7% vs 75.8%; P = .038). CVCs were related to increased risk of death only in subgroup II patients compared with the subcontrol group patients (75.4% vs 37.9% at 5 years, respectively; P = .034). CONCLUSIONS Diabetic hemodialysis patients exposed to high levels of upper extremity arterial medial VcSs upon receiving RCFs have an increased long-term mortality risk compared with diabetic hemodialysis patients with no Vc and receiving the same access. Patients with CVCs/Vc had the lowest survival rates.

Exploring Genomic Structure Differences and Similarities between the Greek and European HapMap Populations: Implications for Association Studies

Studies of the genomic structure of the Greek population and Southeastern Europe are limited, despite the central position of the area as a gateway for human migrations into Europe. HapMap has provided a unique tool for the analysis of human genetic variation. Europe is represented by the CEU (Northwestern Europe) and the TSI populations (Tuscan Italians from Southern Europe), which serve as reference for the design of genetic association studies. Furthermore, genetic association findings are often transferred to unstudied populations. Although initial studies support the fact that the CEU can, in general, be used as reference for the selection of tagging SNPs in European populations, this has not been extensively studied across Europe. We set out to explore the genomic structure of the Greek population (56 individuals) and compare it to the HapMap TSI and CEU populations. We studied 1112 SNPs (27 regions, 13 chromosomes). Although the HapMap European populations are, in general, a good reference for the Greek population, regions of population differentiation do exist and results should not be light‐heartedly generalized. We conclude that, perhaps due to the individual evolutionary history of each genomic region, geographic proximity is not always a perfect guide for selecting a reference population for an unstudied population.

Rigorous Vibrio vulnificus Soft Tissue Infection of the Lower Leg in a Renal Transplant Patient Managed by Vacuum Therapy and Autologous Growth Factors

Background: Vibrio vulnificus is a gram-negative marine bacterium that grows well in coastal waters. It is an opportunistic pathogen that can cause serious life-threatening infections in patients with certain health conditions. Vibrio-induced wound infections in immunosuppressed patients are difficult to treat because the healing process may be significantly delayed. Reconstructive surgery may not be successful in early treatment as skin grafts are likely to fail, and there may be increased morbidity of donor sites of grafts or flaps. Objective: Herein a case of septicemia and wound necrosis owing to V. vulnificus wound infection in a renal transplant patient is reported. Method: To conservatively yet adequately débride the wound bed, stimulate angiogenesis, and accelerate granulation, vacuum-assisted closure was employed. Granulation was further enhanced by autologous platelet concentrate spray, which has also been reported to increase the epithelialization rate. Result: Complete epithelialization of the wound was achieved 4 weeks after completion of treatment. Conclusion: Noninvasive advanced modalities may be employed to successfully treat infectious soft tissue deficits in immunocompromised patients.

The effect of bicarbonate peritoneal dialysis solutions on cardiac structural and functional alterations

BACKGROUND The systemic effects of absorbed glucose degradation products (GDPs) contained within the conventional peritoneal dialysis solutions (cPDS) are largely unknown, while they appear to affect also cardiovascular function. The aim of the present study was to evaluate if the new bicarbonate-based less bioincompatible new peritoneal dialysis solutions ameliorate cardiac structural and functional status as well as the peritoneal net ultrafiltration (UF) and residual renal function. Patients and methods. This is a single centre, prospective cohort study of 12 stable continues ambulatory peritoneal dialysis patients (four women, eight men) mean aged 71.3 ± of 6.01 years and mean peritoneal dialysis (PD) duration 31.9 ± 21.33 months, treated with the usual cPDS (Medital Bieffe®, with increased GDPs, low pH and lactate as a buffer system). The patients changed for a 6-month period to the newer biocompatible PD solutions (BicaVera, Fresenius® low GDPs, normal pH, bicarbonate as a buffer) and at the end of this time, they returned to their previous schema of conventional solutions, for another 6 months. During the study period, the left ventricle ejection fraction (EF), left ventricle end systolic and diastolic diameter (LVESD, LVEDD), left ventricle mass index (LVMI), glyoxal serum and peritoneal concentrations, net UF and 24 h urine volume were repeatedly estimated: at the beginning of the study (T0), after 6 months with the biocompatible solutions (T6) and at the end of study (T12), after the 6-month period using again the cPDS. The UF volume and glyoxal concentrations were estimated at end of a 4 h dwell of an exchange with a PD solution of 2.27 % glucose. RESULTS There was a statistically significant difference between the mean levels of EF, LVESD, LVEDD, LVMI, UF and glyoxal serum and peritoneal concentrations at the beginning (T0) and in the middle of the study (T6) (for serum glyoxal P = 0.005, for peritoneal glyoxal P = 0.0004, for EF P = 0.0004, for LVESD P = 0.023, for LVEDD P = 0.002, for LVMI P = 0.0005 and for UF P = 0.005) as well as between the mean values in the middle (T6) and at the end of the evaluation period (T12) (for serum glyoxal P = 0.043, for peritoneal glyoxal P = 0.006, for EF P = 0.00009, for LVESD P = 0.012, for LVEDD P = 0.00014, for LVMI P = 0.00013 and for UF P = 0.048). On the other hand, no statistically significant difference was revealed between the T0 and T12 mean values of glyoxal (serum and peritoneal), EF, LVESD, LVEDD, LVMI and UF. During the study period, there was no statistically significant difference in daily urine volume and glomerular filtration rate. CONCLUSIONS The use of bicarbonate-based PDS induced a statistically significant improvement of left ventricle structure (LVESD, LVEDD and LVMI) and functional (EF) indicators. These beneficial effects on left ventricle in combination with the improvement of net UF may designate a protective role of the newer bicarbonate peritoneal solutions on cardiovascular function morbidity and mortality risk of PD patients.

Assessment of association between lipoxygenase genes variants in elderly Greek population and type 2 diabetes mellitus

Background: Inflammation plays a pivotal role in the pathogenesis of diabetes and its complications. Arachidonic acid lipoxygenases have been intensively studied in their role in inflammation in metabolic pathways. Thus, we aimed to explore variants of lipoxygenase genes (arachidonate lipoxygenase genes) in a diabetes adult population using a case-control study design. Methods: Study population consisted of 1285 elderly participants, 716 of whom had type 2 diabetes mellitus. The control group consisted of non-diabetes individuals with no history of diabetes history and with a glycated haemoglobin <6.5% (<48 mmol/mol)] and fasting plasma glucose levels <126 mg/dL. Blood samples were genotyped on Illumina Infinium PsychArray. Variants of ALOX5, ALOX5AP, ALOX12, ALOX15 were selected. All statistical analyses were undertaken within PLINK and SPSS packages utilising permutation analysis tests. Results: Our findings showed an association of rs9669952 (odds ratio = 0.738, p = 0.013) and rs1132340 (odds ratio = 0.652, p = 0.008) in ALOX5AP and rs11239524 in ALOX5 gene with disease (odds ratio = 0.808, p = 0.038). Rs9315029 which is located near arachidonate ALOX5AP also associated with type 2 diabetes mellitus (p = 0.025). No variant of ALOX12 and ALOX15 genes associated with disease. Conclusion: These results indicate a potential protective role of ALOX5AP and 5-arachidonate lipoxygenase gene in diabetes pathogenesis, indicating further the importance of the relationship between diabetes and inflammation. Larger population studies are required to replicate our findings.

Alterations of dialysate markers in chronic peritoneal dialysis patients treated with the new less bioincompatible bicarbonate solutions.

nephrology peritoneal dialysis access program. Semin Dial 2003; 16:266–71. 8. Goh Bl, Ganeshadeva YM, Chew Se, Dalimi MS. Does peritoneal dialysis catheter insertion by interventional nephrologists enhance peritoneal dialysis penetration? Semin Dial 2008; 21:561–6. 9. Mendelssohn DC. Increasing PD utilization: should suitable patients be forced? Perit Dial Int 2009; 29:144–6. 10. lim Yn, lim To, eds. Sixteenth report of the Malaysian Dialysis and Transplant registry 2008. Kuala lumpur: Malaysian Society of nephrology; 2009. 11. li PK, Chow KM. Importance of peritoneal dialysis catheter insertion by nephrologists: practice makes perfect. Nephrol Dial Transplant 2009; 24:3274–6. 12. Zaman F. Peritoneal dialysis catheter placement by nephrologist. Perit Dial Int 2008; 28:138–41. doi:10.3747/pdi.2009.00237