Mediating function of heart failure in the causal relationship between diastolic blood pressure and hypertensive renal disease with renal failure: a mediated Mendelian randomization study^†

Hypertensive renal disease is one of the common chronic kidney diseases (CKDs) and an important cause of end-stage renal disease (ESRD) all over the world.¹ At present, the pathogenesis of renal failure caused by hypertensive renal disease has not been fully elucidated in the academic community, which may be related to blood pressure, metabolic excretion disorder, acid–base balance disorder, electrolyte disorder, and so on.² Later studies have shown that there is a correlation between diastolic blood pressure (DBP) and hypertensive renal disease with renal failure (HRDRF).³ Previous studies have found that hypertensive patients with elevated DBP are more likely to develop HRDRF and have a higher severity of the disease.⁴ However, most of these results are from observational studies and may be affected by confounding factors, so the causal relationship between DBP and HRDRF is not clear. In addition, cardiac function (e.g., heart failure [HF], heart arrhythmia [HA], and atherosclerotic heart disease [AHD]) is decreased in patients with DBP. HF is a complex syndrome with impaired ventricular filling or ejection capacity, which is the end-stage state of cardiovascular disease in most patients.⁵ HF is often used as a risk factor to predict the morbidity and mortality of renal disease with renal failure.⁶

It was found that HF was associated with the increased risk of HRDRF.⁷ This suggests that HF may be a mediating factor affecting the causality relationship between DBP and HRDRF. Therefore, this study uses the network Mendelian randomization (MR) method, and the causality relationship between DBP and HRDRF was analyzed. It was also tested whether HF as a mediating factor mediates the relationship between DBP and HRDRF.

MR analysis is often used to study the causal effect between exposure factors and outcome factors.⁸ This method was proposed by Katan9 in 1986. The core idea is to use genetic variation as instrument variables (IVs) to study the causal relationship between exposure factors and outcome factors. This method avoids the interference of reverse causality and potential confounders encountered in traditional randomized controlled trials.⁹ We investigated the role of mediating factors using mediated MR, a causal inference method developed from traditional MR methods.¹⁰ Assuming that part of the causal relationship between exposure factors and outcome factors is mediated by mediating factors, the causal effect between mediating factors and outcome variables is attributed to the indirect effect of exposure factors on outcome factors.

Hypertension is one of the common complications of CKD, and the two cause and effect each other, forming a vicious cycle. Clinical studies have shown that if blood pressure is not well controlled, glomerular arteriolar sclerosis, renal parenchymal ischemia, glomerular fibrosis, and other pathological changes can often be caused, and then accelerate renal artery atherosclerosis, resulting in the decline of renal function.³¹ In severe cases, CKD can accelerate the progression to ESRD, and hypertension is also a risk factor for cardiovascular events.³²

This study used the statistical results of large-scale GWAS to analyze the causal relationship between DBP and hypertensive nephropathy complicated with renal failure and used network MR to analyze the mediating effect of HF.³³ The results showed that DBP increased the risk of hypertensive nephropathy complicated with renal failure and increased the risk of HF.³⁴ HF is considered as a risk factor for hypertensive nephropathy complicated with renal failure. Therefore, DBP is a risk factor for hypertensive nephropathy complicated with renal failure and can increase the condition by mediating the increase of HF.³⁵ The results of the MR–Egger and leave-one analyses showed that the results of MR analysis were not disturbed by pleiotropy.³⁶ Earlier studies exploring the causality relationship between DBP and HRDRF sought DBP from the genetic level Therefore, it is closely related to the interpretation of genetic factors that are common to renal disease with renal failure.³⁷ Some patients have better vascular elasticity, when heart diastolic comes, the aortic elastic retraction is strong, coupled with the surrounding blood vessels in a state of contraction, then the pressure (that is, DBP) will be higher.³⁸ Long-term DBP at a high level will cause damage to the heart, brain, kidney, and other important organs. Studies have shown that when DBP was stratified by every 10 mmHg, the eGFR was significantly increased when DBP was 81–90 mmHg and 91–100 mmHg compared with DBP of 60–70 mmHg.³⁹ DBP is regulated by nerve–blood vessels, then nerve - endocrine dysfunction occurs, and target organ perfusion imbalance, cardiac diastolic dysfunction and other factors, make the CKD patients with hypertension with renal function changes, especially in patients with stage 3 or 4 CKD, can be kidney damage due to long-term high blood pressure and blood pressure fluctuation is bigger, and its happening mechanism are made more complicated, Aggravating vascular sclerosis and causing renal function decline.⁴⁰ When the concentration of urine trace albumin in the urine increased, renal tubular resorption ability to drop, GFR will also rise, ACR levels, accelerate the destruction of the nephron, hardening and fibrosis, increase water sodium retention, increased vasoconstriction, increase peripheral resistance, and activate the renin - angiotensin, reduce prostaglandin, slow in renal antihypertensive material such as activated peptides. In turn, the blood pressure level increases, aggravating vascular sclerosis and promoting renal failure.⁴¹ This study makes it clear that there is a causal relationship between DBP and HRDRF. However, this study also has some limitations. Although the sample size of the data used was large, the conclusions were based on a population sample of European ancestry. Large-scale GWAS studies in global populations are lacking. Hypertension renal disease with renal failure data analysis results are not according to clinical classification will be divided into different classes, which makes us unable to study DBP through the mediation effect of hf concrete will affect hypertension nephropathy merger renal failure which the class of the disease, and evaluation of hypertension nephropathy merger related indicator of renal failure. In addition, based on the experimental results, we have found a causal relationship between DBP and renal failure in patients with hypertensive nephropathy, and found that HF plays an important mediating role in this causal relationship. Therefore, in clinical nursing work, we need to closely monitor the DBP of patients with hypertensive nephropathy and reduce the possibility of HF in such patients.

In conclusion, this study confirmed the causal relationship between DBP and hypertensive nephropathy complicated with renal failure by mediating MR analysis and found that HF plays an important mediating role in this causal relationship.