Kinetics of Torque Teno Virus Viral Load Is Associated with Infection and De Novo Donor Specific Antibodies in the First Year after Kidney Transplantation: A Prospective Cohort Study.

Torque teno virus (TTV) was recently identified as a potential biomarker for the degree of immunosuppression, and potentially as a predictor of rejection and infection in solid organ transplant patients. We evaluated TTV viral load in kidney transplant (KT) patients during the first year post-transplant to examine overall kinetics and their relationships with deleterious events, including episodes of infection and the formation of de novo donor-specific antibodies (DSAs). In a single-center, prospective observational cohort study, 81 KT patients were monitored at baseline, week 1, and month 1, 3, 6, 9 and 12, post-KT, and whenever required by clinical events. Kidney function, plasma TTV load, immunoglobulins and lymphocyte subpopulations were assessed at each time point. Twenty-six patients (32.1%) presented a total of 38 infection episodes post-KT. Induction immunosuppression with thymoglobulin, compared to basiliximab, was not associated with more infections (p = 0.8093). Patients with infectious events had lower T-cells (p = 0.0500), CD8+ T-cells (p = 0.0313) and B-cells (p = 0.0009) 1 month post-KT, compared to infection-free patients. Patients with infection also showed higher increases in TTV viral loads between week 1- month 1, post-KT, with TTV viral load variations >2.65 log10 cp/mL predicting the development of infectious events during the 12-month study period (p < 0.0001; sensitivity 99.73%; specificity 83.67%). Patients who developed de novo DSAs had lower TTV DNA viral loads at month 12 after KT, compared to patients who did not develop DSA (3.7 vs. 5.3 log10 cp/mL, p = 0.0023). Briefly, evaluating early TTV viremia is a promising strategy for defining infectious risk in the 1st year post-KT. The availability of standardized commercial real-time PCR assays is crucial to further validate this as an effective tool guiding immunosuppression prescription.

Renal function markers and metformin eligibility.

BACKGROUND: Metformin is the cornerstone of the pharmacological therapy for type 2 diabetes mellitus (T2DM). It belongs to the biguanide class of drugs and it improves hepatic insulin resistance and enhances GLP-1 and peptide YY secretion. Despite being considered safe regarding hypoglycemic risk, renal dysfunction remains the main obstacle to its use due to the underlying risk of lactic acidosis. In the recent past many authors used creatinine values as the decisive marker when it came to choose between pharmacological agents in DM. Serum creatinine values equal or above 1.4 and 1.5 mg/dL were considered contraindications for metformin use in women and men respectively. Nowadays, creatinine is not the only surrogate of renal dysfunction and formulas such as the MDRD and CKD-EPI, that besides serum creatinine also include variables such as gender, age and race, have replaced serum creatinine as the standard for renal function assessment. Furthermore, since the associations between metformin and lactic acidosis in renal disease are not straightforward, its use has been considered safe down to creatinine clearances of 30 mL/min/1.73 m2. The authors describe a population with T2DM being treated with metformin and evaluate the impact of the solo evaluation of serum creatinine or CKD-EPI on biguanide prescription. METHODS: Retrospective, observational, single-center study. All type 2 diabetic patients with regular follow up in a Central University Hospital Endocrinology-Diabetology Outpatient Clinic who were being treated with metformin and had at least 2 creatinine and estimated glomerular filtration rate (eGFR) measurements in the last decade were included. Patients were stratified according to renal function-based metformin contraindication criteria: creatinine group included patients with serum creatinine levels above 1.4 and 1.5 mg/dL in women and men respectively, and eGFR group included patients with eGFR below 30 mL/min/1.73 m2. The entire population and both groups are described and compared regarding comorbidities, demographic and laboratory data. The authors report the impact of each renal function marker (serum creatinine or eGFR) when used solo regarding metformin prescription eligibility. RESULTS: A total of 2218 patients (61.3% females) with a mean age of 70±12 years is studied. Mean diabetes duration was 11.8±8.8 years. No cases with an eGFR below 30 mL/min/1.73 m2 were identified. On the other hand, in patients with GFR greater than 30 mL/min/1.73 m2, creatinine alone would contraindicate therapy in 274 patients (12.4% of the study population). Comparing Stage 3 chronic kidney disease patients without creatinine contraindication criteria with those with creatinine based contraindication, the data reveals that a higher prevalence of males, with longer diabetes duration, higher target organ damage (cerebrovascular disease, peripheral artery disease, heart failure, neuropathy and retinopathy) and with worse glycemic control were prevalent more in the elevated creatinine group. The use of serum creatinine as the single marker for renal function would significantly reduce metformin eligibility (OR=0.88, 95% CI: 0.8-0.95, P=0.002). CONCLUSIONS: Metformin is the first line pharmacological agent in type 2 diabetes mellitus patients, being associated with significant HbA1c reductions and improvements in both micro and macrovascular outcomes. Avoiding its use due to imprecise renal function markers would potentially render the patient deprived of optimal pharmacological therapy for T2DM. Creatinine contraindication criteria alone are associated with unnecessary under prescription of metformin.

[Vitamin B12 Deficiency in Type 2 Diabetes Mellitus]. / Défice de Vitamina B12 na Diabetes Mellitus Tipo 2.

INTRODUCTION: Type 2 diabetes mellitus is a common disease, affecting up to 13.1% of the Portuguese population. In addition to the known micro and macrovascular complications, drug side effects constitute a major concern, leading to changes in the treatment guidelines, which favor safety over efficacy. Metformin is the first-line pharmacological treatment for most patients with type 2 diabetes mellitus; however, it has been associated with vitamin B12 deficiency in up to 30% of treated patients. The authors describe the prevalence of vitamin B12 deficiency in a diabetic population and explore the possible underlying factors. MATERIAL AND METHODS: Retrospective, observational study. Clinical and laboratory data of type 2 diabetes mellitus patients whose vitamin B12 status was evaluated in the last decade (2005 - 2016) were analyzed. Patients with known malabsorptive syndromes or having undergone bariatric surgery were excluded from the study. Statistical analysis of the data was done and the results were considered statistically significant at p values < 0.05. RESULTS: The study included a total of 1007 patients (58% women) with a mean age of 66.4 ± 12.2 years and 11 ± 10.4 years of type 2 diabetes mellitus duration. These patients had a high prevalence of complications: diabetic renal disease 47.7%, neuropathy 9.2%, retinopathy 14.9%, coronary artery disease 8.4%, cerebrovascular disease 10.9%, and peripheral arterial disease 5.5%. Vitamin B12 deficiency (< 174 ng / dL) was present in 21.4% of the population and this subgroup was older (68.4 vs 65.8 years, p = 0.006), had a longer type 2 diabetes mellitus duration (13.35 vs 10.36 years; p = 0.001), higher prevalence of retinopathy (20.9% vs 13.3%; p = 0.005) and thyroid dysfunction (34% vs 23.7%; p = 0.002). Vitamin B12 deficiency was also more frequent in patients treated with metformin (24.7% vs 15.8%; p = 0.017), antiplatelet agents (25.4% vs 16.2%, p < 0.001), and calcium channel blockers (26.8% vs 18.2%; p = 0.001). After adjustment for possible confounders, the variables associated with B12 deficiency were: metformin, hypothyroidism, age and type 2 diabetes mellitus duration. DISCUSSION: Despite the retrospective design, the results report a high prevalence of vitamin B12 deficiency in the type 2 diabetic population. This study also demonstrates that the B12 deficiency risk is higher in older people, with longer diabetes mellitus duration, hypothyroidism and treated with metformin. CONCLUSION: Further studies are needed to identify the risk factors for the B12 deficit. The recognition of these variables will contribute to optimize the screening and prevention of the B12 deficiency in type 2 diabetes mellitus.

Introdução: A diabetes mellitus tipo 2 é uma entidade comum, afetando até 13,1% da população portuguesa. Para além das conhecidas complicações micro e macrovasculares, as iatrogenias medicamentosas tornaram-se uma crescente preocupação contribuindo para as observadas alterações das recomendações terapêuticas, que cada vez mais privilegiam a segurança em detrimento da eficácia. A metformina é o agente farmacológico de primeira linha na maioria dos doentes com diabetes mellitus tipo 2, contudo, está descrita a associação com défice de vitamina B12 em até 30% dos doentes. Os autores descrevem a prevalência de défice de vitamina B12 numa população diabética e os possíveis fatores associados à mesma. Material e Métodos: Foi efectuado um estudo retrospectivo, observacional no qual foram registados os dados clínico-laboratoriais de doentes com diabetes mellitus tipo 2 com doseamentos de B12 na última década (2005 - 2016). Foram excluídos doentes submetidos a cirurgia bariátrica e com síndromes malabsorptivos conhecidos. Foi efectuada análise estatística dos dados e os resultados foram considerados estatisticamente significativos para p < 0,05. Resultados: Foram estudados 1007 doentes com uma idade média de 66,4 ± 12,2 anos e 11 ± 10,4 anos de evolução da diabetes mellitus tipo 2, das quais 58% eram mulheres. Apresentavam uma elevada prevalência de complicações: doença renal diabética 47,7%, neuropatia 9,2%, retinopatia 14,9%, doença coronária 8,4%, doença vascular cerebral 10,9% e doença arterial periférica 5,5%. O défice de B12 (< 174 ng/dL) foi documentado em 21,4% da população e neste subgrupo constatou-se uma idade mais avançada (68,4 vs 65,8 anos; p = 0,006), maior duração da diabetes (13,35 vs 10,36 anos; p = 0,001), maior prevalência de retinopatia (20,9% vs 13,3%; p = 0,005) e disfunção tiroideia (34% vs 23,7%; p = 0,002). O défice de B12 foi mais frequente nos doentes expostos à metformina (24,7% vs 15,8%; p = 0,017), antiagregantes (25,4% vs 16,2%; p < 0,001) e bloqueadores dos canais de cálcio (26,8% vs 18,2%; p = 0,001). Após ajuste para factores de confundimento, a metformina, hipotiroidismo, idade e anos de evolução da diabetes mellitus tipo 2 mantiveram uma associação estatisticamente significativa, o que não se verificou com a retinopatia e os bloqueadoresdos canais de cálcio. Discussão: Apesar do desenho retrospectivo, os resultados alertam para a elevada prevalência do défice de vitamina B12 na população com diabetes mellitus tipo 2. O presente estudo demonstra que o risco parece ser maior em populações com idades mais avançadas, com maior tempo de evolução da diabetes mellitus, com hipotiroidismo e sob metformina. Conclusão: São necessários mais estudos para que se possam identificar os factores de risco para o défice de B12. O reconhecimento dessas variáveis contribuirá para optimizar o rastreio e prevenção do défice de B12 na diabetes mellitus tipo 2.