Workup for Proteinuria

Samuel Snyder, DOa and Jones Sam John, DOb* jjohn@wpahs.org,     a3200 South University Drive, Fort Lauderdale, FL 33328, USA; bNephrology Department, Allegheny General Hospital, 4th Floor, 320 East North Avenue, Pittsburgh, PA 15212, USA

*Corresponding author.

The kidney has anatomic and physiologic features that prevent protein from reaching the urine. In disease processes, this natural mechanism is disrupted, causing protein to leak into the urine. Proteinuria can be used as a marker for disease and disease progression. The general anatomy of the glomerulus along with preliminary workup to evaluate disease based on history, physical and urinalysis results are reviewed in this article. Examples of commonly encountered diseases in the outpatient setting and relevance of proteinuria in chronic kidney disease along with general complications and treatments are also reviewed.

Keywords

Proteinuria

Glomerulus in the prevention of proteinuria

Proteinuria workup

Complications with proteinuria

General treatments in patient with proteinuria

Key points

 The history, physical, and initial laboratory workup, including urinalysis with microscopy, is key to determining the etiology chronic kidney disease.

 Proteinuria is an early sign of renal disease.

 Proteinuria is associated with microvascular complications and mortality, which must be anticipated and prevented.

Introduction

The kidney is fundamentally a filter that has numerous elegant properties and filtration characteristics. Like all filters, it is supposed to let some things through (waste products) and keep other things from going through (large proteins and essential elements). Disturbances in this filter manifest as proteinuria. Although some benign conditions present with proteinuria, proteinuria is generally a marker for renal disease, a manifestation of systemic disease in the kidney, a risk factor for kidney disease progression, or a marker for cardiovascular disease.1-3 Chronic kidney disease (CKD) evaluation guidelines from the Kidney Disease Initiative Global Outcomes (KDIGO) changed in 2012 to include the degree of proteinuria to classify CKD, in addition to the estimated glomerular filtration rate (eGFR).4 Although the leading causes of CKD leading to end-stage renal disease (ESRD) requiring dialysis in the United States are diabetes and hypertension,5 it is important to know how to initiate a workup for other causes of renal dysfunction as well, because early referral to a nephrologist has shown to prevent further renal damage and mortality.6-8 In this article, we discuss glomerular structure, definition of proteinuria, general workup for proteinuria from a primary care standpoint, classification of diseases, the significance and complications of proteinuria, and general aspects of treatment.

How proteinuria occurs: glomerular structure and function

The kidney normally prevents most protein from reaching the final urine. Plasma reaches the glomerulus of Bowman's capsule at the rate of 180 L/d and is filtered across the glomerular basement membrane (GBM). This unique filtration mechanism is accomplished by a complex mix of glycoproteins, sialoproteins, and type 4A collagen with multiple subunits, which extrudes from the mesangial cells supporting the tuft of glomerular capillaries, and layered over the capillary loops in 3 layers: The lamina rara interna, lamina dura, and lamina rara externa (Fig. 1). The molecular size, steric features, and electric charge of the compounds in plasma, along with GBM's sieving characteristics, determine filtration. The space between endothelial cells on the capillary lumen form fenestrae (Latin for windows), which are the initial portals for filtration through which plasma transits, based on the transcapillary pressure gradient. Plasma then meets the lamina rara interna, which has collagen IV a3a4a5 (missing in Alport's syndrome), which provides strength against the filtration forces.9 This layer has negatively charged glycosaminoglycans, which provide an electrostatic barrier against negatively charged proteins (especially albumin), preventing passage. Plasma then passes through the lamina dura, which contains both type 4A collagen as well as laminin, and acts as a selective filter for macromolecules. Before entering Bowmans' space, plasma passes through the lamina rara externa adjacent to podocytes, the foot processes of epithelial cells in Bowman's space. Podocytes normally bear a negative charge along their external surface, thus repelling negatively charged particles in plasma filtrate. This negative charge also repels the walls of adjacent podocytes, which accounts for the typical appearance of separate foot processes.10,11 Podocytes are attached to the GBM with stabilizing proteins such as actin, and produce proteins that regulate motility and interaction between cells and matrix.12 The sieving coefficient of the GBM does not normally allow molecules as large or as negatively charged as albumin (~67 kD) to pass through into the Bowman's space. Thus, there should be little or no albumin present in the final urine (<30 mg/dL/d). Thus, if albumin is present, it is a clear indicator of glomerular damage.

Once plasma filtrate is in Bowman's capsule, it proceeds down the proximal convoluted tubule. Although most albumin, immunoglobulins, and other large molecular weight proteins have been rejected by the GBM, the filtrate would contain small molecular weight proteins and peptides that are positively charged. As these molecules reach the brush border of the proximal tubular epithelial cells, they are reabsorbed from the filtrate by epithelial transport mechanisms or endocytosis, catabolized, and their components returned to the systemic circulation.11

Further down the nephron, epithelial cells of the ascending loop of Henle secrete the glycoprotein uromodulin, previously called Tamm Horsfall protein. As a monomer, this protein is 68 kDa, but can accumulate in the urine in aggregates of more than 1 million Dalton. This protein is usually in liquid state in the urine. However, in conditions of low flow or alkaline pH, it may precipitate in a gel form. It forms the matrix of casts and may also be a part of the matrix of stones. It can appear in urine in significant quantities in benign conditions or in the company of immunoglobulins. Even though the function of uromodulin is not fully understood, there is some suggestion that it protects against urinary tract infections and kidney stone formation, and it may also be seen in larger quantities in the urine of individuals with CKD and hypertension.13

Identification and quantification of proteinuria

Urine dipsticks are often the first indication of proteinuria in the office. The dipstick is both qualitative and semiquantitative. The degree of proteinuria encountered on a urine dipstick must be interpreted in the light of the concentration of the urine determined by the specific gravity of the urine. Thus, a ++ reading in a well-hydrated patient producing large quantities of urine may signify a much greater quantity of protein than a ++ reading in a dehydrated patient producing only small amounts protein, because the concentration of the urine in the dehydrated patient would be higher. Dipsticks that show ++++ reading often signify greater than 1 g of protein per 24 hours, but there is no way to be certain by dipstick how much greater than 1 g of protein there may be.14 The pad on most urine dipsticks that detects protein contains tetrabromophenol blue and citrate buffer; however, other dyes that are more specific and sensitive to albumin are also available.15,16 The electronegativity of proteins causes the dye on the pad to change colors from yellow to blue. Proteins like immunoglobulins that have a positive charge do not change the color of the indicator and thus lead to false-negative dipstick results. An increase in the alkalinity of the urine also causes the indicator to change color (Table 1).16

Table 1

False readings in urine dipstick and benign causes of proteinuria

The dipstick is more or less selective for albuminuria, as discussed. Usually, sulfosalicylic acid (SSA) is used to...