Orthostatic Proteinuria

Etiology

There are several proposed mechanisms for the cause of orthostatic proteinuria:

• Normal variant
• Subtle glomerular abnormality
• Exaggerated hemodynamic response
• Left renal vein entrapment

Mahurkar et al. supported the normal variant mechanism. A study with 120 healthy male volunteers showed the difference in proteinuria with laying down versus standing up. The participants were from 11 to 36 years of age. Urine was collected after lying supine for one hour and then again after standing for one hour with only gentle walking allowed. Proteinuria was measured in both urine samples and was higher in 20% of the patients after standing for an hour, compared to the other 80%, who had a decrease in protein excretion with a corresponding reduction in creatinine clearance. The authors concluded that there might be a broader distribution curve for standing protein excretion.[4]

Subtle glomerular abnormalities in the setting of abnormal glomerular hemodynamics may contribute to protein loss in patients with orthostatic proteinuria. A study by Sinniah et al. compared 55 young, healthy men in Singapore via renal biopsy. The subjects had either persistent proteinuria or orthostatic proteinuria. Men with orthostatic proteinuria showed subtle glomerular abnormalities that the researchers thought to be contributing to the proteinuria.[5] Additionally, another study by Robinson et al. looked at 56 healthy men between the ages of 17 and 24 years with asymptomatic orthostatic proteinuria. They obtained renal biopsies, and 43% showed thickening of the glomerular capillary wall that was minimal to moderate. The authors concluded that subtle glomerular abnormalities might contribute to orthostatic proteinuria.[9]

An exaggerated hemodynamic response could cause orthostatic proteinuria by increased efferent arteriolar resistance, likely from the action of angiotensin 2. An article by Vehaskari critiqued this mechanism, suggesting that orthostatic proteinuria is multifactorial and that the exaggerated hemodynamic response mechanism is probably only a contributing factor.[6] The renin-angiotensin-aldosterone system (RAAS) is a component of renal pathogenesis.[10]

Left renal vein entrapment showed to be common in patients with orthostatic proteinuria.[7] There is a hypothesis that partial obstruction of the left renal vein in the upright position causes orthostatic proteinuria by altering glomerular microcirculation and increasing protein filtration.[11]

Epidemiology

Orthostatic proteinuria is the most frequent cause of isolated proteinuria in adolescents and children. It affects approximately 2 to 5% of adolescents and is uncommon after 30 years of age.[2] Orthostatic proteinuria is more common in boys.[12] There have been conflicting results about whether children with obesity or children that are underweight have a higher tendency for orthostatic proteinuria.[12][13]

Histopathology

Robinson et al. evaluated renal biopsies in patients with orthostatic proteinuria and noted these findings:[9]

• Eosinophilic granules within capsular space in 67% of specimens
• Minimal to moderate thickening of the glomerular capillary wall in 43% of specimens
• Glomerular hypercellularity in 41% of specimens
• Focal capillary dilatation in 22% of specimens

History and Physical

A thorough history and physical exam should be obtained from the patient with the assistance of their guardian if needed. Positive family history or past medical disease positive for the renal disease may suggest a pathology other than orthostatic proteinuria.

Evaluation

In patients with suspected orthostatic proteinuria, the clinician should obtain a urinalysis from the first-morning void sample. If the first-morning urine has normal urinary protein, then these patients do not require further investigations for renal disease.[12] Normal urinary protein excretion is usually less than 150 mg/day. There is no indication for renal biopsy in asymptomatic isolated orthostatic proteinuria but should be a consideration if the patient presents with signs of vasculitis, active urinary sediments, hypertension, persistent or gross hematuria, renal insufficiency, or hypocomplementemia.[3] A clinically significant renal disease is more likely when proteinuria presents with hematuria.[14]

A urine protein-to-creatinine ratio can also help with the diagnosis. A normal urine protein/creatinine ratio in a recumbent position (less than 0.2mg/mg creatinine) with a high ratio in samples collected in a standing position establishes the diagnosis.

Treatment / Management

There are no formal guidelines for monitoring patients with orthostatic proteinuria. However, the recommendation has been for annual follow-ups. Diet and physical activity should not be restricted.[3]

Surgical intervention, including stenting for left renal vein entrapment, is not recommended to treat asymptomatic orthostatic proteinuria.[15] Additionally, clinicians should not use angiotensin-converting enzyme (ACE) inhibitors and other medications to treat asymptomatic isolated orthostatic proteinuria.[16](B3)

Differential Diagnosis

Persistent proteinuria is a differential diagnosis that must be kept in mind. Other causes of proteinuria in children include transient proteinuria and persistent proteinuria such as Alport syndrome, diabetes mellitus, glomerulopathy, infections, malignancies, toxins, acute tubular necrosis, polycystic kidney disease, and proximal renal tubular acidosis.[3]

Prognosis

Orthostatic proteinuria is a benign condition. A 20-year follow-up by Springberg et al. in patients with orthostatic proteinuria did not find evidence for progressive renal disease.[17]

In the follow-up evaluation by Springberg et al., they evaluated 64 patients that Robinson et al. had studied 20 years prior.[9][17] They obtained detailed information from 36 of the original 64 patients, and only six patients demonstrated qualitative proteinuria. None of the 64 patients had to undergo kidney transplantation or dialysis in the Veterans Administration hospital system.[17]

Complications

There is no evidence of complications from orthostatic proteinuria as it is generally regarded as a benign condition.[17]