Proteinuria Workup

Updated: Dec 14, 2021
  • Author: Beje Thomas, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Approach Considerations

Evaluation of proteinuria normally is conducted on an outpatient basis, unless the patient develops a complication of severe nephrotic syndrome. All patients with evidence of glomerular disease or any reduction in kidney function should be referred to a nephrologist.

Integral to the process of evaluating for proteinuria is quantification of the total amount of protein spilling into the urine. The various methods to detect proteinuria include urine dipstick and sulfosalicyclic acid test (SSA); quantification methods include the ratio of albumin or protein to creatinine and the 24-hour urine protein collection. 

The urine dipstick detects albumin primarily. Albuminuria is seen in glomerular proteinuria. False-positive results can occur with recent exposure to iodinated radiocontrast agents, alkaline urine, and gross hematuria. SSA detects all proteins, not just albumin. Proteinuria involving non-albumin proteins as well as albumin is seen more in tubular or overflow proteinuria. Iodinated radiocontrast also will interfere with the accuracy of the SSA test.

The gold standard for quantification of proteinuria is the 24-hour urine collection. The normal amount of protein in the urine is < 150 mg/day.

The 24-hour urine collection is performed by voiding upon waking and then collecting all urine on subsequent voids until the first void of the next day. Obviously, the process can be cumbersome and inaccurate. Results are considered reliable based on comparison with the typical amount of creatinine secreted per kilogram of lean body mass. On average, males secrete 20-25 mg/kg per day and females secrete 15-20 mg/kg. However, after the age of 50 years, lean body muscle mass is lost, so these estimates can be inaccurate in older patients. Another option—possibly more accurate, as it accounts for race and sex—is the following calculation (can be calculated with or without phosphorus):

Estimated creatinne excretion (mg/day) = 1115.89 + (11.97 x weight in kg) - (5.83 × age) - (60.18 × phosphorus in mg/dL) + (52.82 if black) - (368.75 if female) 

The spot albumin or protein–to-creatinine ratio was developed to help make the quantification of proteinuria easier and less laborious. However, the ratio can vary depending on the time of day and the amount of creatinine excreted. Consequently, the patient should collect all samples at about the same time of day. The amount of creatinine excretion to adequately reflect a 24-hour urine collection should be about 1 gram. If it significantly less, that could lead to underestimation of the degree of proteinuria, while overestimation may occur if there is much more than 1 g of creatinine.

A spot protein or albumin–to-creatinine ratio of > 3-3.5 mg protein/mg creatnine or a 24-hour urine collection showing > 3-3.5 g of protein is nephrotic-range proteinuria.

Screening for proteinuria can be done using a urine dipstick or early-morning spot protein or albumin–to-creatinine ratio. If significant proteinuria is found or the clinical situation is suspicious for significant proteinuria, a 24-hour urine collection should be done. The spot albumin or protein–to-creatinine ratio can be used for followup. If the ratio shows a significant increase, the 24-hour urine collection should be repeated. [5, 29, 30]  

Laboratory studies

To determine whether patients have transient proteinuria, perform the following:

  • Urinalysis and microscopic examination on at least three separate occasions
  • Albumin-to-creatinine or protein-to-creatinine ratio in a random urine sample [31, 32]
  • Urinalysis on an early-morning sample, before the patient is involved in physical activity

To determine whether patients have orthostatic proteinuria, perform the following:

  • Urine microscopy
  • Split urine collection - Daytime (7 am to 11 pm) and overnight (11 pm to 7 am)

To determine whether proteinuria may be glomerular in origin, perform the following:

  • Urine microscopy – To search for dysmorphic red blood cells and casts
  • Urine collection (24 h) for quantification of albumin (or protein) excretion and creatinine clearance – Especially if the patient is muscular or cachectic; spot protein/creatinine ratio can be used for subsequent assessments
  • Serum creatinine, albumin, cholesterol (see HDL cholesterol and LDL cholesterol), and blood glucose determinations
  • Autoantibody determinations - If indicated, including antistreptolysin O titers, antinuclear antibodies (ANAs), anti-DNA antibodies, complement levels (C3 and C4), anti-phospholipase A1 receptor autoantibody, and cryoglobulins
  • Hepatitis B, hepatitis C, and HIV serologies - If indicated
  • Urine and plasma protein electrophoresis for light chains - If indicated
  • Anti–glomerular basement membrane (anti-GBM) antibodies and antineutrophil cytoplasmic antibodies (ANCA) – If there is a suspicion of pulmonary renal syndrome.
  • Hemoglobin A1C

Techniques for calculating proteinuria, to determine prognosis in patients with glomerular proteinuria, include the following [33] :

  • Time-averaged  (obtained from average values over the duration of follow-up
  • Time-varying (calculated from any instantaneous value at any given time point)
  • Time-varying cumulative (obtained from the time-weighted average of all values prior to that same time point)

Results of a study by Kee et al suggest that in patients with glomerular disease, time-varying proteinuria can delineate the association between proteinuria levels and risk of renal progression better than a time-averaged model, as time-varying proteinuria reflects the dynamic change of proteinuria over time. [34]

Imaging studies

Imaging studies in proteinuria can include the following:

  • Renal ultrasonography – If glomerular disease is being considered, it is important to review the size and echogenicity of the kidneys
  • Chest radiography or computed tomography – If indicated

Kidney Biopsy

Kidney biopsy should be considered in adult patients with persistent proteinuria (usually, above 1 g per day), because the diagnostic and prognostic information yielded is likely to guide the choice of specific therapy.

In children, most cases of nephrotic syndrome are due to steroid-sensitive minimal-change disease. The clinician may reasonably assume this to be the diagnosis and give a trial of therapy, reserving biopsy for unresponsive cases.

In adult patients who have isolated proteinuria of less than 1 g/day and no other indicators of kidney disease, the renal prognosis is good and the need for specific treatment is unlikely. Most nephrologists would treat these patients with nonspecific measures (see Treatment) and would proceed to biopsy only if the degree of proteinuria increases or if the patient undergoes progressive decline in kidney function.