In the third part of the proteinuria series, Dr. NK Hase discusses classification of proteinuria and treatment approach for a patient with proteinuria.

To read other articles by Dr. NK Hase, click here.

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Classification of proteinuria

Transient proteinuria

This is transiently increased protein excretion due to altered glomerular haemodynamic (decreased blood flow, long capillary transit time and increased intraglomerular pressure). Proteinuria is usually mild up to 1g/day with no abnormal urinary sediments. There is no history of diabetes, hypertension, and it is common in children and adolescents who are relatively healthy.

Transient Proteinuria can occur reversibly during fever, after vigorous exercise, heart failure, seizures, use of vasopressors, acute hyperglycaemia and obstructive sleep apnoea. It subsides within one or two weeks and requires no further evaluation. Some individuals may have recurrent episodes that often goes into permanent remission in a few years. Such patients may require long-term follow up.

Orthostatic proteinuria

The proteinuria is related to posture. Exact cause is not known; probably related to haemodynamic alteration in glomerular circulation during standing. There is increased protein excretion in upright or standing ambulatory position and normal level of protein excretion in supine or recumbent position.

Orthostatic proteinuria is relatively common in children and adolescents, occurring in 2 to 5% of patients. It is an uncommon disorder in adults over the age of 30years. Total protein excretion is generally less than 1g/day in upright position but may go upto 3g /day in some patients.

Diagnosis can be made with 24 hours split collection in the supine and upright position: First morning sample is discarded. For the rest of the day, all urine samples should be collected while doing day-to-day activity, in upright position. The patient should finish collection by voiding urine in a jug labelled as day time jug prior to going to sleep. Then patient should sleep in recumbent supine position at least for 8 hours. After getting up early morning sample should be collected in a jug container labelled as night time jug. Both jugs should be sent to the laboratory without delay. If delayed, it should be refrigerated to prevent bacterial growth.

If day time jug shows abnormally high proteins >150 mg and night jug shows normal protein excretion, one can confirm the diagnosis of orthostatic proteinuria. It is a benign condition and does not require kidney biopsy. Urine does not show active urinary sediments like RBCs, WBCs, and casts. Kidney functions are normal. All patients with orthostatic Proteinuria should be followed yearly with monitoring proteinuria and renal functions. Spontaneous resolution of Proteinuria is reported in 50% of patients 10 years after diagnosis.

Persistent proteinuria

If more than one test, one or two weeks apart shows high level of protein in urine, it is called as persistent proteinuria. Proteinuria is present regardless of position, activity or functional status. Persistent proteinuria is an indicator of kidney damage. Persistent proteinuria lasting for more than 3 months is a marker of chronic kidney disease. It needs further evaluation to find out origin and aetiology.

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Approach to a patient with proteinuria

If dipstick is negative and if patient is diabetic, hypertensive, or has IHD-

• Test for Urine albumin
• UACR in early morning and overnight urine sample
• Calculate if eAER is 30-300 mg/day
• This is likely to be moderately-increased albuminuria. Treat with ACEI/ARB alongwith tight control of diabetes and blood pressure.

If dipstick is negative and sulfosalicylic acid test is positive for protein-

• It is likely to be overflow proteinuria or tubular proteinuria; serum protein electrophoresis shows M band
• Do serum-free light chain assay to detect kappa or lambda ratio, immunofixation to rule out multiple myeloma, and bone marrow examination to confirm monoclonal abnormal proliferation of plasma cells

If dipstick is positive and SSA test is positive for proteins and patient is asymptomatic-

• Repeat the test after 7days
• If the patient is symptomatic and dipstick and SSA shows high grade proteinuria, quantify urine proteins in timed 24 hours sample with simultaneous urinary creatinine estimation

If proteinuria is <2 g/day and patient is asymptomatic with no diabetes, hypertension, or systemic diseases-

• Do split urine protein test to rule out orthostatic proteinuria.
• UPCR more than UACR, predominantly low molecular proteins, ACR/PCR <0.4 suggests tubular proteinuria due to tubule interstitial nephritis.
• UACR>UPCR, no haematuria, no diabetes, no hypertension, normal GFR is isolated asymptomatic; proteinuria will require follow-up. Note: Increasing proteinuria, decreasing GFR requires nephrology referral and evaluation.

If proteiuria is more than 2 g/24 hours- It is more likely to be glomerular. It is predominantly albumin.

If proteinuria is 2-3.5 g/day with glomerular haematuria- Dysmorphic RBCs, acanthocytes, and RBC casts are also glomerular origin, and should be referred to a Nephrologist for evaluation. It will require renal biopsy.

If proteinuria >3.5g/day with oedema, hpoalbuminaemia, hyperlipidaemia- It is nephrotic syndrome; always glomerular: may be primary glomerular disease or secondary glomerular diseases like diabetes, amyloid, SLE, malignancy or drug-related. All these patients will require serology work up and renal biopsy and should be referred to a Nephrologist.

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What is role of biopsy in patients with proteinuria?

1. Kidney biopsy will help to determine the aetiology and prognosis, and decide specific therapy. A kidney biopsy is indicated in all adults with proteinuria of more than 3.5 g/day with or without nephrotic syndrome.
2. Patients with non-nephrotic range proteinuria 1-3 g/day with active urinary sediments (dysmorphic RBCs, RBC cast, WBC, WBC cast, acanthocytes) or decreased GFR kidney biopsy will be indicated to find out exact aetiology.
3. In patients with non-nephrotic range proteinuria with glomerular haematuria and rapidly increasing serum creatinine with or without systemic symptoms, kidney biopsy will be indicated to rule out crescentic glomerulonephritis.
4. In patients with isolated proteinuria, less than 1 g and in non-nephrotic range proteinuria in diabetes, kidney biopsy is not indicated.
5. Patients with isolated proteinuria 1-3 g (non-nephrotic range) without serologic biomarkers should be followed by nephrologists. Biopsy should be considered for worsening of proteinuria or kidney function.

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What is treatment of proteinuria/albuminuria?

Diagnose the underlying cause and treat the underlying cause; for example, nephrotic syndrome may need steroid and immunosuppressive drugs. Blood pressure control will reduce proteinuria. Drugs which can reduce proteinuria include:

• ACE inhibitors
• ARB (Angiotensin Receptor Blockers) decrease proteinuria by 30 to 40% by decreasing intraglomerular pressure
• SGLT2 inhibitors
• Nondihyrodropyridine calcium channel blockers verapamil and diltiazem

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In the upcoming parts, Dr. NK Hase will discuss other aspects of proteinuria and albumiuria, and case discussions on the topic.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author Dr. NK Hase is a Director clinical Nephrology & Transplant working at Jupiter Hospital, Thane and former Professor & Head of Department of Nephrology Seth GS Medical College and KEM Hospital, Mumbai.