Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD: A Longitudinal Subgroup Analysis in SPRINT

Malhotra, Rakesh; Craven, Timothy E.; Ambrosius, Walter T.; Killeen, Anthony A.; Haley, William E.; Cheung, Alfred K.; Chonchol, Michel; Sarnak, Mark J.; Parikh, Chirag R.; Shlipak, Michael G.; Ix, Joachim H.

doi:10.1053/j.ajkd.2018.07.015

Cited by 96 publications

(74 citation statements)

References 36 publications

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“…CKD has a high prevalence in worldwide population . Even though with multiple pathological changes, various types of CKD are characterized with the common pathological feature of renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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Section: Introductionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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“…In addition, it should be taken into account that an intensive BP lowering strategy might induce excessive GFR decline leading to hospitalization and cardiovascular events, especially in elderly or frail patients 15 . It should be noted, however, that the GFR decline in the SPRINT intensive arm predominantly reflected hemodynamic changes rather than renal damage 16 . On the other hand, a J curve phenomenon in CKD patients at systolic BP <110‐120 mmHg has been reported 15 …”

Section: Study Design N Population Follow‐up (Y) Achieved Bp Standamentioning

confidence: 99%

Blood pressure target for hypertension in chronic kidney disease: One size does not fit all

Kyriakoulis

Stergiou

2020

J of Clinical Hypertension

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There is disagreement between the American and the European guidelines for hypertension management in regard to the optimal blood pressure target in patients with chronic kidney disease (CKD). Randomized clinical trials and meta‐analyses of individual patient data pooled from these trials do not clearly support an intensive blood pressure target for the entire population of CKD patients with hypertension. However, some evidence suggests that in CKD patients with proteinuria strict blood pressure control might confer benefit in terms of renal outcome. Tailored treatment strategy based on the individual’s proteinuric profile and tolerability along with standardization of blood pressure measurement methodology including out‐of‐office evaluation are of paramount importance in patients with CKD.

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“…Data from SPRINT also provides some reassurance, as the majority of AKI events appear to have been mild and reversible (51). In a random sample of SPRINT participants with baseline eGFR ,60 ml/min per 1.73 m 2 , tubule injury biomarkers were measured at baseline, year 1, and year 4 (52). None of the eight biomarkers of tubule injury were higher in the intensive BP arm despite decreased eGFR, and two markers (b2-microglobulin, a1-microglobulin) were actually lower in the intensive BP arm.…”

Section: Concerns Of Intensive Bp Loweringmentioning

confidence: 99%

Blood Pressure Goals in Patients with CKD

Chang

Lóser

Malhotra

et al. 2018

CJASN

Self Cite

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Hypertension affects the vast majority of patients with CKD and increases the risk of cardiovascular disease, ESKD, and death. Over the past decade, a number of hypertension guidelines have been published with varying recommendations for BP goals in patients with CKD. Most recently, the American College of Cardiology/American Heart Association 2017 hypertension guidelines set a BP goal of <130/80 mm Hg for patients with CKD and others at elevated cardiovascular risk. These guidelines were heavily influenced by the landmark Systolic Blood Pressure Intervention Trial (SPRINT), which documented that an intensive BP goal to a systolic BP <120 mm Hg decreased the risk of cardiovascular disease and mortality in nondiabetic adults at high cardiovascular risk, many of whom had CKD; the intensive BP goal did not retard CKD progression. It is noteworthy that SPRINT measured BP with automated devices (5-minute wait period, average of three readings) often without observers, a technique that potentially results in BP values that are lower than what is typically measured in the office. Still, results from SPRINT along with long-term follow-up data from the Modification of Diet in Renal Disease and the African American Study of Kidney Disease and Hypertension suggest that a BP goal <130/80 mm Hg will reduce mortality in patients with CKD. Unfortunately, data are more limited in patients with diabetes or stage 4-5 CKD. Increased adverse events, including electrolyte abnormalities and decreased eGFR, necessitate careful laboratory monitoring. In conclusion, a BP goal of <130/80 is a reasonable, evidence-based BP goal in patients with CKD. Implementation of this intensive BP target will require increased attention to measuring BP accurately, assessing patient preferences and concurrent medical conditions, and monitoring for adverse effects of therapy.

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Effects of Intensive Blood Pressure Lowering on Kidney Tubule Injury in CKD: A Longitudinal Subgroup Analysis in SPRINT

Abstract: Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Cited by 96 publications

References 36 publications

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Blood pressure target for hypertension in chronic kidney disease: One size does not fit all

Blood Pressure Goals in Patients with CKD

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