04. Proteinuria

Resident Editor: Alfredo Aguirre, M.D.

Faculty Editor: Lowell Lo, M.D.

BOTTOM LINE

✔ Proteinuriadetected on urine dipstick should be quantified and worked up.

✔ Proteinuria may be the earliest sign of chronic kidney disease.  

✔ In the absence of a clear etiology, consult nephrology.

Background

  • Definition: Urinary protein excretion > 150 mg/day (>300 in pregnancy); nephrotic proteinuria is > 3.5 g/day.
  • May be earliest sign of chronic kidney disease, even with normal GFR.
  • Proteinuria can give clues about underlying etiology of CKD.
  • Degree of proteinuria is the strongest single predictor of CKD progression.

Signs and symptoms

  • Foamy urine is neither sensitive nor specific for proteinuria.
  • Nephrotic syndrome: edema, dyslipidemia, hypoalbuminemia, lipiduriaproteinuria.
  • Gross hematuria and tea-colored urine may occur but are more common in nephritic diseases

 

Differential diagnosis

  • Glomerular: Diabetic nephropathy, orthostatic proteinuria, exercise-induced proteinuria, all glomerular diseases (e.g., membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, membranoproliferative, amyloidosis)
  • Tubular: Most common form of proteinuria. Due to failure of tubules to reabsorb normally filtered proteins (e.g., ATN, CKD from hypertensive nephropathy, acute/chronic interstitial nephritis). Usually in sub-nephrotic range. May be associated with other tubular abnormalities including proximal renal tubular acidosis (type 2 RTA), phosphaturia, aminoaciduria, glucosuria with normoglycemia (Fanconi’s syndrome).   
  • Overflow: Due to excess production of proteins (usually immunoglobulins in multiple myeloma and other monoclonal gammopathies) that exceeds the reabsorptive capacity of the tubules.

Screening

• In absence of clinical guidelines addressing proteinuria screening, patients with the following are considered at risk for proteinuria and should be screened:

  • DM
  • HTN
  • Consider in other high risk groups: age >60, vascular disease (cardiovascular, peripheral, or cerebrovascular), vasculitis, SLE, family history of renal disease.

Quantification of Proteinuria

  • 24-hour urine collection is the gold standard, but is inconvenient and difficult to perform.
    • Always include urine creatinine in any 24-hour urine sample to assess the adequacy of the specimen. Calculate the creatinine index in mg creatinine excreted/kg body weight.  Women excrete 15-20 mg/kg/day, and men excrete 20-25 mg/kg/day.
  • Urine dipstick can be used for screening in the clinic.
  • Spot urine albumin:creatinine is the preferred measure of proteinuria (has a greater sensitivity for detecting kidney damage). Now used to define CKD severity in addition to GFR, as endorsed by the KDOQI guidelines:  
    • A1: <30 mg/g creatinine
    • A2: (aka microalbuminuria in DM): 30-300 mg/g
    • A3: (aka macroalbuminuria in DM): >300 mg/g

Spot urine protein;creatine ration roughly predicts proteinuria in g/day/1/73m². For example, a urine protein:creatine ration of 2.2 predicts 2.2 g/day per 1.73m².

Evaluation

A. Isolated non-nephrotic proteinuria

  • Transient and intermittent proteinuria should be excluded. If the proteinuria resolves on multiple subsequent assays, no further workup is necessary. In particular, fever and exercise are two common causes of benign transient proteinuria. If there is intermittent proteinuria (<80% of samples), a yearly urinalysis, urine protein quantification, and serum creatinine should be checked.

B. Persistent proteinuria

  • History and physical
    • History of kidney disease, urologic disorder
    • Signs and symptoms suggestive of DM, CHF, nephrotic syndrome (i.e. edema) and autoimmune disease
  •  Labs/tests
    • UA with microscopy
    • Spot urine protein:creatinine and/or albumin:creatinine ratio, or 24-hour urine collection for quantification of proteinuria
    • Chem panel and CBC (for anemia) 
    • Lipid panel
    • Other specific labs (see below) as clinical suspicion for etiology suggests
    • Renal ultrasound should be performed prior to nephrology referral to confirm kidney sizes, rule out obstruction, and assess for congenital abnormalities that could complicate kidney biopsy. Biopsy may be necessary for definitive diagnosis and prognosis.
  • Orthostatic proteinuria should be ruled out in patients < 30 years old with a split urine collection (i.e., first morning/supine sample and standing sample). Orthostatic proteinuria is a benign condition with an excellent prognosis.
  • Serologies to consider: The selection of serologies should be guided by clinical suspicion. All patients above 50 years old with chronic kidney disease, proteinuria, and anemia should be ruled out for multiple myeloma. 
    • Autoimmune: ANA, anti-streptolysin O, ANCA, complements (C3 and C4)
    • Gammopathy: SPEP/UPEP/IFE (immunofixation)
    • Infection: HBV, HCV, HIV, and RPR
  • Be aware that nephritic diseases can often have nephrotic-range proteinuria (i.e. IgA nephropathy, SLE nephritis), while some nephrotic diseases may have sub-nephrotic proteinuria with/without hematuria and RBC casts (i.e. FSGS).

 

Treatment

  • Management depends both on the quantity of protein (i.e., nephrotic-range or not), symptoms, medical co-morbidities, systemic diseases, and urinary sediment. Management of renal disease diagnosed on biopsy should be done in consultation with a nephrologist.
  • Proteinuria suppression
    • Aim of therapy should be to reduce proteinuria, ideally to <500 mg/day (threshold above which proteinuria itself can cause kidney damage).
    • ACE inhibitors/ARBs – The most effective intervention to delay progression of CKD in diabetic patients (type 1 and 2) with albuminuria, and in patients with non-DM CKD. Caution with AKI (from ischemic injury) and hyperkalemia. Can check electrolytes in 10-14 days after initiation/dose changes, though rise in SCr should not prompt discontinuation as long as not progressive and increase <30% over first 2 months. Can still be used in advanced CKD to delay progression to ESRD with nephrology consultation.
    • SGLT2 inhibitors – New data showing empagliflozin and canagliflozin reduces rate of GFR decline and proteinuria among type 2 diabetic patients.
    • Aldosterone antagonists –Significantly decreased proteinuria and blood pressure with the addition of an aldosterone antagonist (e.g., spironolactone) to a regimen already containing an ACEi or ARB if patients have not achieved proteinuria/BP targets. Has not been shown to reduce rates of ESRD. Patients need to be monitored for hyperkalemia (up to 2x risk) and not recommended for GFR <30 ml/mim/1.73m2.
  • HTN management: Goal BP for CKD and proteinuria is <130/80 mmHg. SPRINT study showed mortality benefit and CV disease reduction in CKD patients with lower SBP goal <120 vs. <140 mmHg (as well as reduction in albuminuria) although at expense of certain adverse effects (hypokalemia/hyperkalemia, AKI).
  • Lipid management: Albuminuria is an independent predictor for CV events. Per 2013 KDIGO guidelines, all patients over the age of 50 with CKD should be on a statin (or statin/ezetimibe combination for GFR <60 ml/min/1.73m2); treatment-to-target strategy (i.e., an LDL goal) is not recommended.
  • Dietary protein restriction: Controversial as the MDRD study did not show a benefit to dietary protein restriction, however may have been a benefit in patients with greater proteinuria.  Given challenges of adherence and risk for malnutrition, dietary restriction is seldom widely implemented.
  • Hypercoagulability: Heavy proteinuria increases the risk for thromboembolism, especially renal vein thrombosis in membranous nephropathy. Secondary prevention with anticoagulation after initial VTE recommended. Anticoagulation not routinely given for primary prophylaxis but can be considered in higher risk patients (e.g., serum albumin <2-2.5 g/dL).

Diabetic Nephropathy

  • All diabetics should be screened annually for microalbuminuria
  • Both type 1 and type 2 diabetics with microalbuminuria should be started on an ACEi or ARB, regardless of the presence of HTN.
  • In diabetics who are hypertensive but do not have microalbuminuria, ACEi or ARBs are the preferred first-line agent.
  • Type 1 and type 2 diabetics with microalbuminuria should be managed with diet, lipid management, glycemic control, and ACEi. Regression of microalbuminuria has been shown in patients in response to blood pressure, lipid, and glycemic management. 
  • No indication for ACEi or ARB to prevent diabetic nephropathy in normotensive diabetics without albuminuria.

When to refer

  • Refer to nephrology for nephrotic-range proteinuria, symptomatic proteinuria (i.e., refractory edema or hypertension), proteinuria with chronic kidney disease (stage 3b or worse), progressive renal dysfunction, active urine sediment (RBC casts or dysmorphic RBCs) or lack of a clear etiology.
  • Progressive proteinuria in a stable diabetic should raise the possibility of non-diabetic kidney disease; refer to nephrology for consideration of renal biopsy.

References

Bolignano D, et al. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014 Apr 29; (4):CD007004.

Browne OT, et al. Interpreting and investigating proteinuria. BMJ 2012; 344:e2339 (5 Apr 2012)

Cheung AK, et al. Effects of Intensive BP Control in CKD. J Am Soc Nephrol 28: 2812–2823, 2017.

Hemmelgarn, et al. Relation between kidney function, proteinuria, and adverse outcomes. JAMA 2010; 303(5):423-429.

Inker LA, et al. KDOQI US Commentary on the 2012 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD. Am J Kidney Dis. 2014 May;63(5):713-35.

KDIGO Clinical Practice Guidelines for Lipid Management in Chronic Kidney Disease. Kidney Int Supp Nov 2013; 3:263-265

Modification of Diet in Renal Disease Study Group. Effects of dietary protein restriction on the progression of moderate renal disease in the modification of diet in renal disease study. J Am Soc Nephr 1996; 7(12):2616-2626.

Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.

Petersen JC, et al. Blood Pressure Control, Proteinuria, and the Progression of Renal Disease: The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995 Nov 15;123(10):754-62.

The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med 2015; 373:2103-2116.

Wanner C, et al. Empaglifozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323-334.

Yamagata K; Yamagata Y; Kobayashi M; Koyama A. A long-term follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol 1996 May;45(5):281-8.