Longitudinal analysis of a cohort of type 1 diabetes Mellitus individuals for characterization of renal function decline rate

A doença renal diabética (DRD) é uma das principais causas de mortalidade em indivíduos com diabetes mellitus (DM), sendo a principal causa de doença renal terminal (DRT) no mundo. Estima-se que 20 a 30% dos indivíduos com DM desenvolvem DRD e acredita-se que, mesmo com o uso das terapias nefroprotetoras, a incidência de DRT não esteja diminuindo. A microalbuminúria é empregada como um marcador precoce de acometimento renal no DM. No entanto, devido a sua incapacidade de prever a evolução da DRD, novos biomarcadores de lesões glomerulares e/ou tubulares têm sido estudados. A expressão de alguns RNA mensageiros (mRNAs) no sedimento urinário tem sido investigada como potencial biomarcador da taxa de declínio da função renal e nosso grupo de pesquisa já propôs dois mRNAs-alvo, o do gene TXNIP, que codifica a proteína de interação com a tiorredoxina, e o do gene B2M, que codifica a beta-2 microglobulina. Considerando a escassez de dados acerca da progressão da DRD em nossa população e a importância de investigar marcadores preditivos da taxa de declínio da função renal, o presente trabalho realizou uma análise longitudinal da função renal de indivíduos com DM tipo 1 (DM1), acompanhados em um hospital terciário, para determinar (1) a taxa de declínio da função renal, identificando os fatores a ela associados e (2) se a expressão do mRNA dos genes TXNIP, TXN e B2M nas células do sedimento urinário de indivíduos com DM1 influencia a taxa de declínio da função renal. Um total de 465 indivíduos com DM1 foram incluídos (55,3% do sexo feminino; idade média de 31,0 [± 11,3] anos; duração da doença de 18,0 [± 9,7] anos e HbA1c média de 8,8 [± 2,1] % no início do seguimento). Os tempos médio e mediano de seguimento clínico foram de 8,9 e 10 anos, respectivamente. No início do seguimento, 100 indivíduos (21,5%) apresentavam DRD. A incidência acumulada de DRD foi de 28,2% e a densidade de incidência foi de 2,47 por 100 pessoas-ano. O tempo médio até a ocorrência da DRD foi de 13,6 anos. A incidência acumulada de DRT foi de 15,6% e a densidade de incidência do evento foi de 1,82 por 100 pessoas-ano; o tempo médio até a ocorrência de DRT foi de 14 anos. O declínio médio anual observado na taxa de filtração glomerular estimada (TFGe) foi de - 6,15 mL/min/1,73m2 e o declínio mediano foi de -2,43 mL/min/1,73m2. Um declínio anual > -7,0 mL/min/1,73m2 foi caracterizado como declínio renal rápido (DRR) e foi observado em 26,9% dos indivíduos; um declínio entre - 6,9 e - 2,43 mL/min/1,73m2 foi caracterizado como declínio renal moderado (DRM), observado em 23,2% dos indivíduos e um declínio acima da mediana foi caracterizado como declínio renal lento ou ausente (DRLA) e foi observado em 49,9% dos indivíduos. Os fatores associados ao DRR em relação ao DRLA foram: pior controle glicêmico, maior albuminúria, maior frequência de hipertensão arterial, dislipidemia, neuropatia autonômica cardiovascular, hiperfiltração e DRD no início do seguimento e menor duração do DM. As expressões dos mRNA de TXNIP e de B2M foram avaliadas em um modelo de regressão linear misto em um subgrupo de 46 indivíduos e modificaram significantemente a evolução da TFGe ao longo do tempo ( = -2,4 e P=0,010 para TXNIP e = -27,1 e P=0,001 para a B2M). Em conclusão, na população de indivíduos com DM tipo 1 avaliada, 50% apresentaram um padrão de declínio renal rápido ou moderado, que se associou a um pior controle glicêmico e à presença de outras comorbidades. Os mRNAs de TXNIP e de B2M no sedimento urinário são candidatos a biomarcadores para predizer a progressão da DRD e requerem avaliação em coortes independentesDiabetic kidney disease (DKD) is one of the leading causes of mortality in individuals with diabetes mellitus (DM), being the leading cause of end-stage renal disease (ESRD) worldwide. It is estimated that 20 to 30% of individuals with DM develop DKD and even with the use of nephroprotective therapies, the incidence of ESRD is not decreasing. Microalbuminuria is used as an early marker of renal impairment in DM. However, due to its inability to predict the evolution of DKD, new biomarkers of glomerular and/or tubular lesions have been studied. The expression of some messenger RNAs (mRNAs) in the urinary sediment has been investigated as potential biomarkers of the rate of renal function decline and our research group has already proposed two target mRNAs, TXNIP, which encodes thioredoxin interacting protein, and B2M, which encodes beta-2 microglobulin. Considering the scarcity of data on the progression of DKD in our population and the importance of investigating predictive markers of the rate of renal function decline, the present study performed a longitudinal analysis of the renal function of individuals with type 1 DM (T1D) followed at a tertiary hospital to determine (1) the rate of renal function decline, identifying the factors associated with it, and (2) whether the mRNA expression of TXNIP, TXN and B2M genes in cells of the urinary sediment of individuals with T1D influences the rate of renal function decline. A total of 465 individuals with T1D were included (55.3% female; mean age of 31.0 [± 11.3] years; disease duration of 18.0 [± 9.7] years and mean HbA1c of 8.8 [± 2.1] % at beginning of follow-up). The mean and median times of clinical follow-up were 8.9 and 10 years, respectively. At the beginning of the follow-up, 100 individuals (21.5%) had DKD. The cumulative incidence of DKD was 28.2% and the incidence density was 2.47 per 100 personyears. The mean time until the occurrence of DKD was 13.6 years. The cumulative incidence of ESRD was 15.6% and the incidence density of the event was 1.82 per 100 person-years; the mean time to the occurrence of ESRD was 14 years. The mean annual decline observed in estimated glomerular filtration rate (eGFR) was -6.15 mL/min/1.73m2 and the median decline was -2.43 mL/min/1.73m2. An annual decline > -7.0 mL/min/1.73m2 was characterized as rapid renal decline (RRD) and was observed in 26.9% of the individuals; a decline between -6.9 and - 2.43 mL/min/1.73m2 was characterized as moderate renal decline (MRD) and was observed in 23.2% of the individuals, and a decline above the median was characterized as slow or absent renal decline (SARD) and was observed in 49.9% of the individuals. The factors associated with RRD in relation to SARD were: worse glycemic control, higher albuminuria; higher frequency of arterial hypertension, dyslipidemia, cardiovascular autonomic neuropathy, hyperfiltration and DKD at the beginning of the follow-up and shorter DM duration. TXNIP and B2M mRNA expressions were evaluated in a mixed linear regression model in a subgroup of 46 individuals and significantly modified eGFR evolution over time ( = -2.4 and P=0.010 for TXNIP and = - 27.1 and P=0.001 for B2M). In conclusion, in the evaluated population of individuals with T1D, 50% had a pattern of rapid or moderate renal decline, which was associated with worse glycemic control and the presence of other comorbidities. The expression of TXNIP and B2M mRNAs in the urinary sediment are candidates for biomarkers to predict DKD progression and require evaluation in independent cohort

Rs4862705 in the melatonin receptor 1A gene is associated with renal function decline in type 1 diabetes individuals

AimThe pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A).MethodsEight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated.ResultsThe group of individuals with a renal function decline ≥ 5 mL min−1 1.73 m−2 year−1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20–2.82; p = 0.0046). No other significant associations were found.ConclusionsThis is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting