Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

Abstract

Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. Am J Kidney Dis. xx(x):xxx. © 2013 by the National Kidney Foundation, Inc. INDEX WORDS:Chronic kidney disease; vitamin D deficiency; blood pressure; proteinuria; phosphate.C hronic kidney disease (CKD) is a silent killer.Four of 5 people with advanced CKD are not aware of the disease until death is imminent and kidney replacement therapy (dialysis or kidney transplantation) is unavoidable. Unfortunately, Ͻ10% of people requiring replacement therapy have access to it, and more than 1 million people worldwide die of untreated kidney failure each year because dialysis or kidney transplantation is unaffordable in most countries. This represents a huge economic burden, with global costs from 2000-2010 surpassing $1 trillion. 1,2 Worsening kidney function is associated with a marked increase in cardiovascular morbidity and mortality 1,3 independent of other risk factors. Coexistent hypertension is present in ϳ80% of patients with CKD and worsens cardiovascular outcomes because only 64% of patients with CKD achieve adequate blood pressure control. 4 As a consequence, only a minority of the hundreds of thousands of patients with stages 3 and 4 CKD reach kidney failure. 5 Proteinuria also is an important prognostic factor in patients with CKD. Although patients with nonproteinuric CKD are at greater risk of cardiovascular mortality than progression to kidney failure, the opposite may be true for the presence of proteinuria. Patients from the REIN (Ramipril Efficacy in Nephropathy) Study who were in the highest tertile of baseline proteinuria (protein excretion Ն3.8 g/d) also experienced the highest rate of glomerular filtration rate (GFR) loss during followup. 6 In addition, although post hoc analysis of RENAAL (Reduction of Endpoints in NIDDM [Non-InsulinDependent Diabetes Mellitus] With the Angiotensin II Antagonist Losartan) showed that 85% of patients with proteinuria with protein excretion Ն3 g/d reached the composite end point of doubling of serum creatinine level or end-stage renal disease (ESRD), only 44% of these patients reached the composite cardiovascular outcome. 7 Besides the we...

Sodium thiosulfate attenuates angiotensin II-induced hypertension, proteinuria and renal damage11These authors contributed equally to this manuscript.

“…Inflammation is one of the major consequences of renal exposure to hypertension and proteinuria [4]. STS completely prevented Ang II-induced influx of interstitial macrophages, whereas NaHS only showed a trend.…”

“…Hypertension and proteinuria are major contributors to the progression of CKD. Both are important actors in enhancing structural and functional renal deterioration through changes in intrarenal hemodynamics and inflammation, thereby promoting the release of chemokines and reactive oxygen species (ROS) [1][2][3][4]. This results in stimulation of extracellular matrix synthesis and enhancement of cellular apoptosis.…”

Folic Acid and Homocysteine in Chronic Kidney Disease and Cardiovascular Disease Progression: Which Comes First

“…However, a constant incidence rate at over 100,000 per year cannot be a source of satisfaction (USRDS Annual Data Report 2014). The complex interactions among the different pathways of CKD progression also involving FGF-23 and Klotho, blunt the specific renoprotective effects of traditional RAAS-blocking agents [6]. However, new drugs and therapeutic approaches would be highly desirable to effectively slow the progressive renal function loss and hopefully reducing the cardiovascular burden of CKD patients.…”

Serum Phosphorus and Progression of CKD and Mortality: A Meta-analysis of Cohort Studies

“…Besides well-established risk factors, including high blood pressure and proteinuria, accumulating evidence indicates an important role for serum phosphorus. 5 Abnormal phosphorus homeostasis is a hallmark of CKD. Serum phosphorus level is used as a biomarker for phosphorus homeostasis and has been reported to be an important risk factor for both all-cause and cardiovascular mortality in individuals with CKD.…”