SOAP. – Proteinuria – SỔ TAY LÂM SÀNG

Proteinuria

Cheryl A. Glass

Definition

A.Proteinuria is excess protein (albumin) in urine. Proteinuria may be an incidental finding and have no symptoms. Use of a urine dipstick for screening is acceptable for first detecting proteinuria (see Table 15.5); however, the dipstick should not be used to quantify the amount of urinary protein. Protein concentration is a function of urine volume as well as the quantity of protein present.

B.The measurement of protein excretion is used to establish the diagnosis and to follow the course of glomerular disease. The normal rate of albumin excretion is less than 30 mg/d; the rate is about 4 to 7 mg/d in healthy young adults and increases with age and an increase in body weight. Persistent albumin excretion between 30 and 300 mg/d is called microalbuminuria. Values of 300 mg/d of protein are considered overt proteinuria or macroalbuminuria.

C.When proteinuria coexists with hematuria, the likelihood of clinically significant renal disease is high. In patients with diabetes, microalbuminuria usually indicates incipient diabetic nephropathy. In nondiabetics, the presence of microalbuminuria is associated with left ventricular hypertrophy and cardiovascular (CV) disease. Protein is also the cardinal sign of pregnancy-induced hypertension (PIH).

D.Functional/transient proteinuria is associated with fever, exercise, dehydration, cold exposure, and stress, and is not associated with underlying renal disease. Orthostatic proteinuria, a transient proteinuria condition, is related to postural changes that affect the glomerular hemodynamics. Orthostatic proteinuria rarely exceeds 1 g/d. Significant renal disease is not usually found upon further testing and workup.

E.Persistent proteinuria is defined as greater than 4 mg/m²/hr of protein in a 24-hour urine collection or greater than 0.02 mg/mg of protein creatinine ratio on a spot urine. Persistent proteinuria requires further evaluation to rule out underlying renal pathology. There are four basic types of proteinuria:

1.Glomerular proteinuria (albuminuria) caused by increased filtration of macromolecules across the glomerular capillary wall. The standard urine dipstick is able to detect glomerular proteinuria. Some causes of glomerular proteinuria include diabetes; hypertension (HTN); nephrotic syndrome; infections including hepatitis, HIV, cytomegalovirus (CMV), malaria, syphilis, and streptococcal infections; chemotherapeutic agents; Alport syndrome; and hemolytic uremic syndrome:

TABLE 15.5 Dipstick Analysis—Detecting and Quantifying Proteinuria

Dipstick Grade	Quantity of Protein
Negative	<10 mg/dL
Trace	10–20 mg/dL
1+	15–30 mg/dL
2+	40–100 mg/dL
3+	150–300 mg/dL
4+	>500 mg/dL

a.In non-nephrotic proteinuria, the amount of proteinuria is <3.5 g/24 hours and is persistent. These patients require close follow-up and may need a renal biopsy if they have abnormal urine microscopy results and/or impairment of kidney function.

b.Orthostatic proteinuria is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. The exact mechanism is unclear. Total protein excretion is generally less than 1 g/day; however, in orthostatic proteinuria it may exceed 3.5 g/day in selected patients.

c.Nephrotic range proteinuria is defined as >3.5 g of proteinuria on a spot urine protein-to-creatinine ratio. This finding denotes significant glomerular disease and requires a renal biopsy for diagnosis and management.

2.Tubular proteinuria is nonglomerular (i.e., nonalbumin form of protein), related to interference with proximal tubular reabsorption. The amount of proteinuria is <2 g and urinary dipstick is generally unable to detect tubular proteinuria. Some causes of tubulointerstitial proteinuria include toxins, pyelonephritis, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and inherited causes such as Lowe syndrome and Wilson disease.

3.Secretory (overflow) proteinuria is nonglomerular (i.e., nonalbumin form of protein). Increased excretion from the tubules is secondary to an overproduction of a particular protein, most commonly noted in interstitial nephritis. A urinary dipstick is unable to detect overflow protein.

4.Postrenal proteinuria: Inflammation in the urinary tract and urinary tract infection (UTI) can cause increases in urinary protein excretion. The excreted proteins are often nonalbumin, and only small amounts are excreted. Leukocyturia is frequently present. Patients with nephrolithiasis or tumors of the urinary tract may also have proteinuria.

Incidence

A.Approximately 6.1% of males and 9.7% of females have proteinuria detected by a single routine dipstick test.

B.The prevalence of proteinuria is higher in the elderly and in patients with comorbidities:

1.The prevalence of proteinuria starts increasing at 40 years of age.

2.The incidence of HTN and diabetes increases with age. In consequence, the incidence of persistent proteinuria (and microalbuminuria) also increases with age.

3.The prevalence of microalbuminuria is 28.8% in persons with diabetes, 16% with HTN.

4.The incidence of microalbuminuria is only 5.1% in patients without diabetes, HTN, cardiovascular disease, or elevated serum creatinine levels.

Pathogenesis

A.Pathogenesis depends on the underlying etiology. An alteration in glomerular filtration that increases excretion (filtration) of plasma proteins occurs. Increased glomerular permeability, increased production of abnormal proteins (Bence Jones protein), decreased tubular reabsorption, surgical traumas, and infections may increase urinary protein. Urinary protein may also be affected by dietary protein intake.

Predisposing Factors

A.Fever.

B.Age 65 years or older.

C.Ethnic groups including African Americans, Hispanics, Asians, and American Indians.

D.Increased exercise.

E.UTI/pyelonephritis.

F.Medications:

1.Penicillamine.

2.NSAIDs.

3.Angiotensin-converting-enzyme (ACE) inhibitors.

4.Aminoglycosides.

5.Cisplatin.

6.Amphotericin B.

7.Quinolones.

8.Sulfonamides.

9.Cimetidine (Tagamet).

10.Allopurinol (Zyloprim).

11.Antiretroviral drugs can be nephrotoxic.

G.Heavy metal exposure:

1.Gold.

2.Cadmium.

3.Mercury.

4.Lead.

5.Copper.

H.Collagen vascular disease or vasculitis.

I.Family history of proteinuria or pyelonephritis.

J.HTN.

K.Renal disease.

L.Congestive heart failure (CHF) or endocarditis.

M.Diabetes.

N.Lupus.

O.Infections:

1.HIV.

2.Syphilis.

3.Hepatitis B and C.

4.Group A beta-hemolytic streptococcus.

5.Viral infection (e.g., mononucleosis).

6.Malaria.

P.Malignancy:

1.Lymphoma.

2.Hodgkin’s disease.

3.Breast tumor.

4.Lung tumor.

5.Colon tumor.

Q.Heroin use.

R.PIH.

S.Radiocontrast media.

Common Complaints

A.Asymptomatic.

B.Increased weight.

C.Decreased urine output.

Other Signs and Symptoms

A.Edema: Periorbital, presacral, genital, or ankle.

B.Nephrotic syndrome: Hypercholesterolemia and hypertriglyceridemia.

C.Protein malnutrition: Anorexia and vomiting.

D.Frothy urine.

Subjective Data

A.Review the onset, course, and duration of presenting complaints.

B.Question the patient concerning urinary output, thirst or fluid intake, edema, or increase in weight. Establish usual weight history.

C.If a woman, establish the first day of the patient’s last period. Is she pregnant? If so, what is the fetus’s gestational age? Is there edema, HTN, headache, visual changes (scotoma), hyperreflexia, and/or right upper quadrant pain?

D.Review the patient’s past medical history for renal disease, diabetes, CHF, systemic disorders such as lupus, and substance abuse.

E.Does the patient have signs or symptoms of a UTI or pyelonephritis?

F.Review the patient’s recent history for exertion, emotional stress, surgical trauma, fever, and any acute illness.

G.When was the patient’s last evaluation for cholesterol? Is he or she on any special diet?

H.Review medication list, including prescribed and over-the-counter (OTC) medications and herbal products.

I.Review the patient’s occupational exposure, smoking history, and risk factors for infectious diseases.

Physical Examination

The patient’s physical examination may have few abnormalities unless there are features of multisystem disease:

A.Check temperature (if indicated), erect and supine blood pressure, pulse, respirations, and weight (massive weight gain because of fluid is very common).

B.Inspect:

1.Inspect overall general appearance for edema (pedal, hand, facial, or periorbital edema), butterfly rash [lupus], or ascites.

2.Evaluate for protein wasting.

3.Evaluate for jugular vein distension.

4.Funduscopic exam: Evaluate for retinopathy.

5.Inspect for pharyngitis.

C.Auscultate:

1.Assess heart.

2.Assess lungs (may have decreased breath sounds because of pleural effusions).

D.Palpate:

1.Examine the abdomen; evaluate bladder distension, suprapubic tenderness, masses, or ascites; check abdominal tenderness.

2.Palpate for costovertebral angle (CVA) tenderness.

3.Check deep tendon reflexes, especially in pregnant women.

Diagnostic Tests

A.Urine dipstick is a screening tool in the outpatient setting.

B.Single void spot urine testing:

1.The first urine specimen of the morning is optimal and is guideline recommended. Evaluation of the first morning specimen excludes any postural effect on the protein component.

2.The gold standard for measurement of protein excretion is a 24-hour urine collection but is now being replaced by the easier to obtain and less complicated spot test. The 24-hour urine is considered impractical for generalized testing.

C.Polymerase chain reaction (PCR) test or albumin-to-creatinine ratio (ACR) test on a first morning or a random spot specimen. The PCR or ACR is useful in following trends in the patient’s proteinuria.

D.Complete blood count (CBC) and serum electrolytes.

E.Serum creatinine.

F.estimated glomerular filtration rate (eGFR): Uses a blood creatinine level along with age and values assigned to gender and race to calculate the estimate rate of urine filtration. The eGFR rate decreases with progressive kidney damage.

G.Lipid profile (high-density lipoprotein [HDL] and low-density lipoprotein [LDL]).

H.Blood urea nitrogen (BUN): Serves as an index of renal excretory capacity. Urea is the nitrogenous end product of protein metabolism.

I.Total protein.

J.Urinalysis, urine culture, and sensitivity (if indicated).

K.Ultrasound of the full urinary tract.

L.Screen for diabetes and other testing related to physical findings.

N.Hepatitis B, hepatitis C, and HIV serologies, if indicated.

Differential Diagnoses

A.See section Predisposing Factors.

Plan

A.General interventions:

1.Current guidelines for evaluation screening of albuminuria/proteinuria vary by country, but recommendations include screening at-risk individuals with diabetes, HTN, and/or obesity; those who are smokers, are members of indigenous populations, have a family history of chronic kidney disease (CKD), and/or older than 50 years; and/or have structural renal tract disease, renal calculi, benign prostatic hyperplasia, vascular disease, and autoimmune disease.

2.Management for nephrotic syndrome includes diet with sodium and protein restriction, loop and distal-acting diuretics, control of cholesterol (low-saturated fat, low-cholesterol diet), lipid-lowering agents, pneumococcal and influenza vaccines to prevent infections, and use of steroids and immunosuppressive agents as necessary.

3.Patients with hematuria and proteinuria need a 24-hour urine collection for protein and creatinine clearance (CLCR).

B.Patient teaching:

1.Encourage low-fat/low-cholesterol diet if hyperlipidemia is present.

2.Encourage sodium- and protein-restricted diet for nephrotic syndrome.

C.Pharmaceutical therapy:

1.There is no specific drug therapy for excess protein.

2.Use drug therapy appropriate to the underlying renal or nonrenal cause and, in particular, whether or not the injury is immune mediated.

3.In patients with CKD, the administration of ACE inhibitors and/or angiotensin II receptor blockers (ARBs) is aimed at reducing the degree of proteinuria.

4.The Advisory Committee on Immunization Practices (ACIP) recommends immunization with 13-valent pneumococcal conjugate vaccine (PCV13), followed by a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23) at least 8 weeks later, in patients with nephrotic syndrome.

Follow-Up

A.If proteinuria is found on a dipstick and the first morning test results are trace or negative for protein, repeat a first morning test in 1 year. It is recommended that a diagnosis of albuminuria be made only after at least three of the patient’s urine samples over a 6-month period fall above normal range.

B.There is no consensus on how often to screen for proteinuria. Guidelines include annual screening, every 5 years for patients older than 50 years or smokers, and every 3 years for patients who have HTN, obesity, or a family history of kidney disease. Monitoring should always include BP, quantitative testing by PCR or ACR, and a serum creatinine.

C.Patients should be assessed at routine examination appointments for vasculitic skin changes, rashes, retinopathy, lymphadenopathy, signs of heart failure, abdominal masses, organomegaly, guaiac stools, prostatic enlargement, and joint inflammation.

Consultation/Referral

A.Consider patient referral if kidney damage is progressing from medical disease (systemic lupus erythematosus, HTN, diabetes).

B.Refer the patient as necessary; HTN is a poor prognostic sign for significant renal impairment.

C.Consultation for diagnostic tests to be considered: Kidney, ureter, and bladder (KUB); intravenous pyelography (IVP); renal ultrasonography; renal biopsy.

D.Referral to a nephrologist should be considered if a definitive diagnosis is required or a renal biopsy is considered.

Individual Considerations

A.Pregnancy:

1.Protein excretion is considered abnormal in pregnancy when it exceeds 300 mg/24 hr or greater than 0.2 g of protein per gram of creatinine in a random urine specimen. A urine specimen with 1+ protein is considered the cutoff for proteinuria.

2.The gestational age at which proteinuria is first documented is important in establishing the likelihood of PIH versus other renal disease. Proteinuria prior to or early in pregnancy suggests preexisting renal disease.

3.Monitor urine protein and BP at each prenatal visit and refer the patient if urinary protein remains elevated.

4.Monitor for intrauterine growth restriction (IUGR).

5.Proteinuria (or HTN) that persists longer than 3 months after delivery should be followed closely.

B.Geriatrics:

1.Renal function deteriorates in the elderly who may also have coexisting medical conditions (HTN, diabetes) that may cause nephropathy.

2.Refer to Appendix C, Table C.4 on non-anti-infective medications that should be avoided or reduced in older adults.