Kidney Disease, Proteinuria: Implications for Cardiovascular Risk

Hillel Sternlicht, MD

George L. Bakris, MD

Introduction

Albumin is a protein produced by the liver with a half-life of 28 days and reflects our nutritional status. It is also responsible for maintaining our plasma oncotic pressure to prevent peripheral edema. In healthy people, the filtering head of the nephron, the glomerulus, is impermeable to albumin (molecular weight: 65,000 Da) and therefore, only present in minute quantities. Hence, high levels of albumin in the urine, ie, albuminuria, signify some underlying pathophysiologic problem associated with an inflammatory process in almost all cases.

Although the terms proteinuria and albuminuria are often employed interchangeably, this is not correct. Albumin is but one of several proteins that may be found in the urine. The most frequently encountered and largest is uromodulin (Tamm-Horsfall proteins), a mucinous, glycosylated urinary protein. Because uromodulin weighs 80,000 Da and the glomerulus only allows proteins less than 40,000 Da in mass to traverse the basement membrane, it does not enter the urine by filtration but rather is secreted by the distal tubule (ie, tubular proteinuria).¹ “Low-molecular-weight” proteins (<25,000 Da) such as immunoglobulins, beta-2 microglobulin, and light chains are freely filtered but subsequently reabsorbed by the proximal tubule.²

Levels of albuminuria between 30 and 300 mg/d are defined as high albuminuria (formerly microalbuminuria) and levels above 300 mg/d designated as very high albuminuria (previously macroalbuminuria).³ Levels at 30 mg/d or higher signify underlying inflammation that can be from a variety of causes (Figure 31.1). Albuminuria levels above 300 mg/d signify the presence of kidney disease and an even higher inflammatory burden. Because albuminuria has been extensively investigated concerning cardiovascular and renal outcomes, albuminuria and its integration into cardiorenal risk stratification is the focus of this chapter.³

Pathophysiology

The glomerulus and the proximal tubule of the nephron are responsible for plasma filtration and albumin retention. A nearly albumin-free ultrafiltrate (ie, urine) is assured through glomerular pores with size- and charge-selective restrictions; the proximal tubule reabsorbs albumin that does pass into the urinary space.² Cytoarchitectural distortions resulting in a loss of glomerular sieving capacity may be the result of mutations in the gene NPHS1, which encodes the protein nephrin; abnormalities in the proximal tubule protein cubilin would result in defects in albumin reabsorption.⁴,⁵

Among those with diabetes, glycosylation of albumin is associated with the generation of reactive oxygen species, a potential agent of vascular damage.⁶ This injury can be further exacerbated by angiotensin II, which generates a vascular “leakiness” that predisposes to extravasation of albumin into the extravascular space.⁷ Impaired vasodilation in response to nitric oxide release by the endothelium among those with albuminuria, particularly those with diabetes, further suggests an element of vascular dysfunction.⁸,⁹ Finally, circulating levels of von Willebrand Factor antigen (vWF), a glycoprotein secreted in greater amounts when the vascular endothelium is damaged, has been identified as being proportionate to the severity of albuminuria among hypertensives such that those with greater degrees of albuminuria have higher serum levels of von Willebrand Factor.¹⁰

Despite the well-established association between albuminuria levels and cardiovascular and kidney disease, alterations within the kidney that result in the loss of albumin in the urine are incompletely understood. Moreover, while injury to the nephrons leads to albuminuria, this final “common pathway” obfuscates the diverse number of disease states that can serve as the upstream precipitant (Figure 31.1). The precise pathways whereby atherosclerotic disease precipitates albuminuria have yet to be identified. As such, the
concepts herein represent only a partial understanding of these processes with underlying inflammation being a unifying hypothesis (Figure 31.1).

Figure 31.1 An overview of inflammatory conditions that contribute to the development of high albuminuria. (From Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014;37:867-875.)

An emerging theory is that the presence of albuminuria may also promote hypertension. Causality is possible because albuminuria can precede elevations in blood pressure and cardiovascular disease. A putative mechanism for the relationship of albuminuria antedating hypertension has yet to be described. Some have proposed that proteinuria, more broadly, can activate the epithelial sodium channel in the distal tubule of the kidney. By promoting sodium retention, blood pressure is thus increased.¹¹

Measurement of Albuminuria

The urinary dipstick can detect albumin, but determination of the severity of urinary albumin loss is imprecise because of grading (eg, 1+, 2+, etc), and currently this is not a recommended screening test by the American Diabetes Association¹². Quantitative assays of daily urinary albumin excretion using a 24-hour collection or single void (“spot urine”) are preferable. A 24-hour urine sample is ideal but often difficult for patients to execute correctly. Therefore, a total urine creatinine is mandated to ensure accuracy with this type of collection. A spot urine sample collected upon awakening is an endorsed alternative but should be repeated at least once because there is as much as a 20% daily variance in albumin excretion.¹³ Single void proteinuria quantification is reported in the unit “mg/g” and approximates an individual’s daily urine albumin loss.

There is no unified national guideline concerning screening for albuminuria such as those made by the United States Preventive Services Task Force (USPSTF).¹⁴ Subspecialty and disease-specific guidelines such as those issued by the American Diabetes Association recommend screening at the time of diagnosis of type 2 diabetes (DM2) or 5 years after the onset of diabetes in those with type 1 diabetes (DM1). The American Heart Association categorizes urinary albumin testing as optional among those with newly diagnosed hypertension but states it should be considered if (renal) end-organ damage is suspected.¹⁵ The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend annual screening for albuminuria among those with chronic kidney disease (CKD), ie, estimated glomerular filtration rate (eGFR) < 60 mL/min per 1.73 m².³ Despite these specialty society recommendations, the USPSTF has concluded there is insufficient evidence to recommend screening for all people without risk factors such as hypertension or diabetes.¹⁶ Cost-effectiveness analysis only supports screening among those with these or other risk factors for kidney or cardiovascular (CV) disease.¹⁷ Thus, all people with hypertension and Stage 2 or higher kidney disease should be evaluated annually for albuminuria. If levels are >300 mg/d, then reassessment should occur every 6 months with reductions of 30% sought.¹⁸ This will be discussed later in the chapter. Quantitative screening through a 24-hour urine collection or spot urine albumin:creatinine ratio (ACR) is acceptable but should be repeated within 2 to 3 months in order to exclude transient causes of albuminuria.¹⁹ Confirmation of elevated
levels of albuminuria are necessary because daily fluctuations of 20% can occur as a result of infection, sodium intake, or rheumatologic disease.²⁰,²¹,²²

Link Between Albuminuria, Kidney Disease, and Cardiovascular Disease

The formal staging of chronic kidney disease was introduced in 2002 and subsequently updated in 2011 to incorporate albuminuria, reflecting not only a poor kidney prognosis but also the presence of higher CV risk (Figure 31.2).²³ The incorporation of albuminuria into the staging of CKD was based on studies demonstrating that increased levels were a potent and reproducible predictor of a wide range of CV events from heart failure to stroke and from cardiovascular to all-cause mortality.³ A meta-analysis of 21 community-based studies of more than 100,000 individuals analyzing the effects of GFR or albuminuria on mortality supports this assertion. The authors found that the hazard ratio for CV and all-cause mortality over 8 years rose once the eGFR fell below 60 mL/min per 1.73 m² in the absence of albuminuria. Among those with preserved GFR (ie, 90-105 mL/min per 1.73 m²), similar endpoints were encountered more frequently once daily albuminuria exceeded 10 mg (Figure 31.3).²⁴ These results have been configured in the form of “heat-maps” in order to demonstrate the relative risk of various outcomes of interest as a function of a variety of levels of kidney disease and albuminuria (Figure 31.2).²³

Figure 31.2 Composite Ranking for Relative Risks by glomerular filtration rate (GFR) and Albuminuria. Green = no risk for CV/CKD events, yellow = very low risk for CKD/CV, orange = moderate risk for CKD/CV events, red = high risk for both CKD/CV events, and striped red = very high risk for CKD/CV events. (From Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80:17-28.)

Only gold members can continue reading. Log In or Register to continue