Renal Insufficiency in the Absence of Albuminuria and Retinopathy Among Adults With Type 2 Diabetes Mellitus

Kramer, Holly; Nguyen, Quan Dong; Curhan, Gary C.; Hsu, Chi-yuan

doi:10.1001/jama.289.24.3273

Cited by 550 publications

(454 citation statements)

References 19 publications

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“…30 Recently, it has been noted that a substantial proportion of type 2 diabetes mellitus patients have renal insufficiency without albuminuria. 33,34 MacIsaac et al 34 showed that in type 2 diabetes mellitus patients with renal insufficiency, intra-renal resistive index obtained by Doppler ultrasound, which reflects intra-renal vascular injury, 35 was high regardless of the amount of albuminuria. Considering the results obtained in our studies, abnormal glucose metabolism/insulin resistance may induce tubulointerstitial injury and renal arterio-arteriolosclerosis even before the development of diabetes.…”

Section: Discussionmentioning

confidence: 99%

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

et al. 2010

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Hypertension has an important function in the formation of renal arterio-arteriolosclerosis. However, renal arterioarteriolosclerosis is sometimes found in biopsy specimens of normotensive patients, which indicates unknown factors may contribute to renal arterio-arteriolosclerosis. In this study, we aimed to evaluate the effects of glucose metabolism/insulin resistance on renal arterio-arteriolosclerosis. Forty-eight patients with biopsy-proven non-diabetic chronic glomerular disease were included. Renal arterio-arteriolosclerosis was evaluated as the percentage of vessels showing hyaline changes or wall thickening. We correlated renal arterio-arteriolosclerosis with clinical parameters including indices obtained by 75 g oral glucose tolerance test. Of the 48 patients, 30 had hypertension. The results of univariate analysis showed significant association of renal arterio-arteriolosclerosis with hypertension, increased serum creatinine (S-Cr), hypertriglyceridemia, increased 2-h plasma glucose (PG) and increased 2-h plasma insulin (PI). In stepwise multiple regression analysis, hypertension (b¼0.344, P¼0.009), S-Cr (b¼0.287, P¼0.03) and 2-h PG (b¼0.274, P¼0.03) were independently associated with renal arterioarteriolosclerosis. Eleven of the 30 hypertensive patients did not have renal arterio-arteriolosclerosis. The hypertensive patients with renal arterio-arteriolosclerosis showed significantly higher 2-h PG (134 ± 25 vs. 106 ± 26 mg per 100 ml, P¼0.008) and higher 2-h PI (67.7 ± 34.9 vs. 48.3 ± 30.0 lU ml À1 , P¼0.04) compared with those without renal arterio-arteriolosclerosis, but the difference in S-Cr was not significant. Postprandial hyperglycemia and hyperinsulinemia may contribute to the formation of renal arterio-arteriolosclerosis independently of hypertension.

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Section: Discussionmentioning

confidence: 99%

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

et al. 2010

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“…These phenotypes include microalbuminuria without frank proteinuria, proteinuria and/or microalbuminuria with normal renal filtration, frank proteinuria and nephrosis with or without renal insufficiency, and renal failure. Although proteinuria is generally regarded as a key feature of diabetic nephropathy, some large epidemiological studies also report an increase in diabetic non-proteinuric kidney disease (15). Thus, it is possible that the criteria by which the nonspecific diagnosis ''diabetic nephropathy'' is defined may have increased phenotypic as well as genetic heterogeneity.…”

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confidence: 99%

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Tong

Yang

Patel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

191

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Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P ‫؍‬ 1.91 ؋ 10 ؊3 ; Genetics of Kidneys in Diabetes (GoKinD) Study: P ‫؍‬ 2.66 ؋ 10 ؊8 ; and Boston: P ‫؍‬ 2.1 ؋ 10 ؊2 ]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. diabetic microvascular complication ͉ end stage renal disease ͉ proliferative diabetic retinopathy ͉ SNP ͉ association

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“…Only a small minority of affected subjects receive kidney transplantation (1), and the annual mortality on dialysis is extremely high, 23% per year (1). Although a number of risk factors for ESRD have been identified, including hypertension, diabetes mellitus, and infection with HIV-1, only a minority of individuals with these susceptibilities develop renal complications; the factors that determine whether renal failure will develop and͞or progress are poorly understood (2)(3)(4). As for other areas of pathophysiology, genetic approaches have the capacity to provide insight into the fundamental causes of this important medical problem.…”

mentioning

confidence: 99%

Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3

Gharavi

Ahmad

Wong

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1-associated nephropathy (HIVAN) is a major complication of HIV-1 infection with distinct pathologic features. Introduction of the HIV-1 genome into mice results in a renal disease with all of the histologic and clinical hallmarks of HIVAN on the FVB͞N genetic background (TgFVB). We assessed the influence of genetic background on the development or progression of HIVAN by making F1 hybrids of TgFVB with five other inbred strains (CBA, DBA͞2, CAST͞Ei, C3H͞He, BALB͞c) and determining phenotypes relevant to renal failure among transgenic offspring (histology, blood urea nitrogen, proteinuria, serum albumin, and serum cholesterol). We found striking variation in phenotypes among F1s, ranging from severe renal disease to no renal disease whatsoever (P < 0.001 for ANOVA across all groups). To map genes responsible for this variation, we produced a backcross of TgFVB͞CAST F1 ؋ TgFVB. By genome-wide analysis of linkage in 185 heterozygous transgenic backcross mice, we identified a locus on chromosome 3A1-3, HIVAN1, that showed highly significant linkage to renal disease [logarithm of odds (lod) score 4.9 at D3Mit203, accounting for 15% of the variance in renal disease]. Other loci on chromosomes 11, 14, and 16 were suggestive of linkage to renal disease, and a locus on chromosome 9 influenced serum cholesterol but not nephropathy. Interestingly, HIVAN1 is syntenic to human chromosome 3q25-27, an interval showing suggestive evidence of linkage to various nephropathies. These findings demonstrate a strong genetic influence on HIVAN and demonstrate a major renal disease susceptibility locus on mouse chromosome 3A1-3.

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Renal Insufficiency in the Absence of Albuminuria and Retinopathy Among Adults With Type 2 Diabetes Mellitus

Abstract: Context Kidney disease in type 2 diabetes mellitus (DM) is more heterogeneous than in type 1 DM. Reduced glomerular filtration rate (GFR) among individuals with type 2 DM may not always be due to classic diabetic glomerulosclerosis, which is associated with albuminuria and retinopathy.

Cited by 550 publications

References 19 publications

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

Postprandial hyperglycemia and hyperinsulinemia associated with renal arterio-arteriolosclerosis in chronic kidney disease

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Mapping a locus for susceptibility to HIV-1-associated nephropathy to mouse chromosome 3

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