An introduction to biomarkers: applications to chronic kidney disease

Lemley, Kevin V.

doi:10.1007/s00467-007-0455-9

Cited by 18 publications

(7 citation statements)

References 68 publications

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“…CKD is a progressive disease, and there are many possible medical interventions over its course if the disease is recognized and treated in a timely manner. Current biomarkers of CKD progression, i.e., creatinine and albuminuria, have their limitations in terms of achieving this goal (50). An ideal biomarker should reflect tissue pathology, act as a critical component of disease, and be easily detectable by noninvasive approaches.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

Viau

Karoui²,

Laouari³

et al. 2010

J. Clin. Invest.

329

298

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Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction -FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration -coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2 -/-mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1α (Hif-1α) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2 -/-mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis.

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Section: Discussionmentioning

confidence: 99%

Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

Viau

Karoui²,

Laouari³

et al. 2010

J. Clin. Invest.

329

298

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“…Extensive effort has been devoted to search for early biomarker for kidney diseases focusing mostly on acute kidney disease 82 and less on CKD. 83 Proteins such as adiponectin, 84 ␥-glutamyltransferase, 85 cystatin C, 16 N-acetyl-␤-D-glucosaminidase, 86 fatty acid-binding protein 1, 87 and endothelin-1 88 were proposed as biomarkers. We documented that patients with early stage CKD (stage 1 and 2) already have significantly lower urinary Klotho, and urinary Klotho is progressively lowered with declining eGFR.…”

Section: Potential Clinical Utilitymentioning

confidence: 99%

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

Hu¹,

Shi²,

Zhang³

et al. 2011

Journal of the American Society of Nephrology

809

877

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Soft-tissue calcification is a prominent feature in both chronic kidney disease (CKD) and experimental Klotho deficiency, but whether Klotho deficiency is responsible for the calcification in CKD is unknown. Here, wild-type mice with CKD had very low renal, plasma, and urinary levels of Klotho. In humans, we observed a graded reduction in urinary Klotho starting at an early stage of CKD and progressing with loss of renal function. Despite induction of CKD, transgenic mice that overexpressed Klotho had preserved levels of Klotho, enhanced phosphaturia, better renal function, and much less calcification compared with wild-type mice with CKD. Conversely, Klotho-haploinsufficient mice with CKD had undetectable levels of Klotho, worse renal function, and severe calcification. The beneficial effect of Klotho on vascular calcification was a result of more than its effect on renal function and phosphatemia, suggesting a direct effect of Klotho on the vasculature. In vitro, Klotho suppressed Na ϩ -dependent uptake of phosphate and mineralization induced by high phosphate and preserved differentiation in vascular smooth muscle cells. In summary, Klotho is an early biomarker for CKD, and Klotho deficiency contributes to soft-tissue calcification in CKD. Klotho ameliorates vascular calcification by enhancing phosphaturia, preserving glomerular filtration, and directly inhibiting phosphate uptake by vascular smooth muscle. Replacement of Klotho may have therapeutic potential for CKD.

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“…Unfortunately, as with many potential surrogate endpoints [64], it does not automatically follow that interventions which lower proteinuria will be effective in preventing renal disease progression. Another problem with the use of changes in albuminuria as an outcome in the above trials is the possibility that ACEI/ ARB therapy simply 'masks' proteinuria or the injury that causes it.…”

Section: The Use Of Surrogate Endpoints For Renoprotection In Diabetementioning

confidence: 97%

When to initiate ACEI/ARB therapy in patients with type 1 and 2 diabetes

Lemley

2010

Pediatr Nephrol

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Angiotensin converting enzyme inhibitors (ACEI) and angiotensin 2 receptor blockers (ARB) have become a mainstay of adjunctive therapy for the prevention and amelioration of diabetic nephropathy. Although ACEI were shown over 20 years ago to slow the rate of loss of renal function in diabetic subjects with decreased renal function, the question of how early in the course of diabetes to introduce them remains unresolved. Recent studies suggest that very early initiation of ACEI/ARB therapy may not have demonstrable beneficial effects even over a period of years.

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An introduction to biomarkers: applications to chronic kidney disease

Cited by 18 publications

References 68 publications

Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

Klotho Deficiency Causes Vascular Calcification in Chronic Kidney Disease

When to initiate ACEI/ARB therapy in patients with type 1 and 2 diabetes

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