Approach to Proteinuria and Hematuria

Ryan Kunjal

Timothy Yau

Proteinuria

General Principles

Definition

The glomerulus functions as a barrier, preventing cells and large particles, such as proteins, from spilling into the urine.
With an intact glomerulus, individuals excrete <150 mg of total protein and <30 mg of albumin in urine every 24 hours.
- The urine protein found in normal individuals may derive from tubular secretion (Tamm–Horsfall proteins) or from minute amounts of filtered proteins that have escaped reabsorption and degradation by the renal tubular cells.
- Higher rates of protein excretion (proteinuria) suggest glomerular disease.
Nephrotic range proteinuria is an excretion of >3500 mg of protein per 24 hours. This can be associated with idiopathic glomerular conditions (e.g., minimal change disease, focal segmental glomerular sclerosis [FSGS]) or systemic diseases (e.g., diabetic nephropathy, lupus). When it coexists with hypoalbuminemia, hyperlipidemia, and edema, it forms the nephrotic syndrome.
The degree of proteinuria is a component of the Kidney Disease Improving Global Outcomes (KDIGO) classification of chronic kidney disease (CKD).¹
Its importance is underscored by the following:
- Proteinuria can be an early sign of kidney disease, often preceding a detectable change in glomerular filtration rate (GFR).
- Significant excretion of the protein albumin is associated with subsequent risk of acute kidney injury (AKI), CKD progression, and cardiovascular mortality.
- Interventions that reduce the amount of proteinuria may slow the progression of kidney disease and improve the prognosis of cardiovascular disease.

Classification

Proteinuria mainly occurs due to glomerular dysfunction. Tubular dysfunction may also cause slight increase in proteinuria, but rarely to the nephrotic range (>3.5 g/day).
Glomerular proteinuria results from disruption of the glomerular filtration barrier, leading to increased filtration of plasma proteins in amounts that exceed tubular reabsorption capacity. It is comprised mainly of albumin.
Tubular proteinuria is due to inadequate reabsorption of filtered low–molecular-weight proteins (e.g., beta₂-microglobulin or lysozyme). It can coexist with glomerular proteinuria or be an isolated finding in the setting of defective proximal tubule function. Typically, tubular proteinuria is <1 g per 24 hours.
Overflow proteinuria occurs when there is excessive systemic production of abnormal proteins of small molecular weight that exceeds the capacity of the tubule for reabsorption. Examples include urinary excretion of filtered free light chains in multiple myeloma and lysozymuria in acute monocytic leukemia.

Etiology

Transient (functional) proteinuria:
- Transient proteinuria is primarily seen in children and adolescents who are healthy and asymptomatic, and have normal renal function with bland urine sediment.
- It is believed to result from alterations in renal hemodynamics in hyperadrenergic states like fever, exercise, congestive heart failure, seizures, use of vasopressors, pregnancy, and obstructive sleep apnea.
- Transient proteinuria disappears on repeat testing and requires no further evaluation.
Orthostatic (postural) proteinuria:
- This syndrome is characterized by the excretion of abnormal quantities of protein in the upright position, with normal levels of protein excretion while in supine position.
- This is demonstrated by a 24-hour split urine collection divided into a 16-hour daytime (upright) portion and an 8-hour overnight (supine) portion.
- Exclusion may be possible with normal protein excretion in a first pass early morning urine protein to creatinine ratio (PCR) <0.15 mg/mg.
- Most patients have rates of protein excretion <1 g per 24 hours.
- It is present in up to 3% to 5% of adolescents and young men, aged mostly <30 years.
- It has not been associated with long-term adverse outcomes and also requires no further evaluation.²
Persistent proteinuria:
- Persistent proteinuria is present regardless of position, activity level, or functional status. It is established by confirming proteinuria on subsequent testing days to weeks after the first positive test. This category comprises the majority of patients with proteinuria.
- It may result from an isolated kidney disease or may be part of a multisystem process with renal involvement.
- Patients with persistent proteinuria are typically classified as having nephrotic (>3.5 g/day) or nonnephrotic range proteinuria (<3.5 g/day), and by the presence or absence of features of the nephrotic syndrome.

Diagnosis

A 24-hour urine collection for protein is the definitive means of demonstrating the presence of proteinuria but spot testing is usually more convenient. When spot testing is done, a random urine sample for urine protein and urine creatinine can be measured. The urine PCR roughly estimates the 24-hour excretion rate (with some exceptions below). For screening, the routine urine dipstick is usually the first sign that leads to further testing.

Semiquantitative Methods

Routine urine dipstick:
- The simplest and least expensive method, urine dipsticks may be limited by relatively poor diagnostic accuracy for proteinuria detection.
- This dye-impregnated paper uses tetrabromophenol blue as a pH indicator. Urine albumin binds to the reagent and changes its pH, which then results in a spectrum of color changes depending on the degree of pH change. A typical scale for a positive test is shown in Table 2-1.
- False-positive and false-negative results may occur because these semiquantitative estimates are concentration dependent. Therefore:
  - Highly concentrated urine may show an abnormal result even when the absolute daily protein excretion is normal.
  - Highly dilute urine may show normal or only modestly elevated results for protein concentration even when elevated amounts of protein are excreted. Even with 30 mg/dL of protein, the dipstick can be negative up to 50% of the time.
  TABLE 2-1 SCALE FOR DETECTING PROTEINURIA ON ROUTINE URINE DIPSTICK
  
  Negative
  
  Trace: 15–30 mg/dL
  
  1+: 30–100 mg/dL
  
  2+: 100–300 mg/dL
  
  3+: 300–1000 mg/dL
  
  4+: >1000 mg/dL
- The dipstick will not detect nonalbumin proteins, such as immunoglobulins, and thus false-negative results may be seen in diseases such as multiple myeloma.
- False-positive results can occur in patients who receive contrast up to 24 hours before the test and when highly alkaline urine overwhelms the dye’s buffer.
Albumin-sensitive tests:
- Test strips that are more sensitive to albumin are also available (Albustix).
- Dye-impregnated strips and special immunoassays can detect albumin concentrations as low as 30 mg/day, which is far below the 300 mg/day threshold of the standard dipstick.
Implications of a positive dipstick: Detection of proteinuria should prompt an examination of urinary sediment and further quantification of the proteinuria. Any evidence of hematuria, dysmorphic red blood cells (RBCs), RBC casts, or lipiduria should be noted and may be a sign of underlying pathology.

Quantitative Methods

Spot urine PCR:
- Urinary dilution will directly affect protein concentration. However, creatinine is excreted fairly constantly during the day and its concentration serves as an internal control for urine dilution. The PCR is therefore independent of urine concentration.
- A PCR ratio <150 mg/g is considered normal.
- Correlation with a 24-hour urine collection is based on the assumption that daily creatinine excretion is roughly 1 gram per 24 hours.
- The accuracy of the ratio is diminished when creatinine excretion is either markedly increased (e.g., extremely muscular individuals where the ratio will underestimate proteinuria), or markedly reduced (e.g., acute kidney injury also leads to reduced Cr excretion, and may lead to false values).

Spot urine albumin to creatinine ratio (ACR):

Like the PCR, it uses creatinine concentration as an internal control for urinary dilution.
A value <30 mg/g is considered normal.
Values from 30 to 300 mg/g were formerly termed microalbuminuria but are now referred to as moderately increased albuminuria (A2 in the KDIGO classification).
ACR >300 mg/g are detected by the routine dipstick and fall into the category of severely increased albuminuria (A3, formerly called macroalbuminuria).
ACR at least once annually, is the recommended screening tool for diabetic nephropathy in type 1 diabetics with duration of at least 5 years, in all type 2 diabetics, and in all patients with comorbid hypertension.
Falsely elevated values may be obtained with hyperglycemia, vigorous exercise, infection, and ketoacidosis.

TABLE 2-2 THE APPROXIMATE RELATIONSHIPS OF CATEGORIES OF ALBUMINURIA TO OTHER MEASURES OF ALBUMINURIA/PROTEINURIA

	Category of Albuminuria
Measure	Normal to Mildly Increased (A1)	Moderately Increased (A2)	Severely Increased (A3)
Dipstick	(−) to trace	Trace to (+)	(+) or greater
ACR	<30	30–100	>300
PCR	<150	150–500	>500
AER	<30	30–100	>300
PER	<150	150–500	>500
ACR, albumin to creatinine ratio (mg/g); PCR, protein to creatinine ratio (mg/g); AER, albumin excretion rate (mg/24 hrs); PER, protein excretion rate (mg/24 hrs).