Approach to a Patient with Proteinuria

Definition

• Comprehensive Clinical Nephrology, 7th Edition, Chapter 16

Classification of Proteinuria

1. By Mechanism

2. By Quantity

• Harrison's Principles of Internal Medicine 22e, Table 326-1
• Comprehensive Clinical Nephrology, 7th Edition

3. By Duration/Pattern

• Transient/Functional: Fever, vigorous exercise, emotional stress, obesity, sleep apnea, congestive heart failure. Generally < 1 g/24 h, non-sustained. Benign.
• Orthostatic (Postural): Protein appears only in urine collected when upright; absent in recumbent (first-morning) specimen. Most common cause of isolated proteinuria in adolescents and young adults. Excellent prognosis.
• Persistent/Fixed: Present in upright and supine samples. More likely to indicate significant underlying renal disease.

Causes of Proteinuria

Glomerular Diseases

• Primary: Minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy, membranoproliferative GN (MPGN), IgA nephropathy
• Secondary: Diabetic nephropathy, lupus nephritis, amyloidosis, hypertensive nephropathy, post-infectious GN

Tubulointerstitial Diseases

• Reflux nephropathy, obstructive uropathy, interstitial nephritis, pyelonephritis, polycystic kidney disease, proximal tubulopathy

Overflow States

• Multiple myeloma (light chains/Bence Jones protein), hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria), lysozymuria (monocytic leukemia)

Other

• Preeclampsia/eclampsia, heart failure, fever, exercise, hypertension

Clinical Presentation

• Frothy/foamy urine (heavy proteinuria)
• Edema (hypoalbuminemia in nephrotic syndrome)
• Incidental finding on urine dipstick

• Harrison's Principles of Internal Medicine 22e

History

• Duration and severity of edema, frothy urine
• History of diabetes mellitus or hypertension (most common systemic causes)
• Recurrent UTIs, kidney stones, flank pain
• Drug history: NSAIDs, gold, penicillamine, heroin, captopril (rarely)
• Family history of kidney disease (Alport syndrome, FSGS)
• Recent URTI (post-streptococcal GN), skin infections, hepatitis B/C exposure (membranous nephropathy, MPGN)
• Symptoms of systemic disease: joint pain, rash, oral ulcers (SLE), weight loss (malignancy/myeloma)
• Recent vigorous exercise, fever (to exclude functional causes)

Physical Examination

• Vital signs: Blood pressure (hypertension suggests glomerular disease)
• Edema: Periorbital (early, especially in children), dependent, anasarca
• Skin: Malar rash (SLE), purpura (vasculitis, HSP), skin thickening (amyloid)
• Eyes: Diabetic retinopathy, Kayser-Fleischer rings
• Abdomen: Ascites, flank masses (polycystic kidneys)
• Signs of chronic liver disease: If secondary to hepatic disease

Investigations

Step 1: Urine Dipstick

• Minimum 1+ if specific gravity ≤ 1.015; 2+ if SG > 1.015 is considered significant
• Detects albumin only - may miss Bence Jones proteins (use sulfosalicylic acid test for total protein)
• Positive result needs confirmation on repeat testing

Step 2: Quantification - Spot Urine Protein/Creatinine Ratio (UPr:UCr)

• Preferred to 24-hour collection in clinical practice
• Excellent correlation with 24-hour excretion
• Adults: > 0.2 is abnormal (equivalent to > 200 mg/g); > 3.0 = nephrotic range
• If at risk (DM, HTN): use albumin-specific dipstick then albumin/creatinine ratio (UACR); > 30 mg/g warrants further evaluation

Figure: Approach to proteinuria in adults (Textbook of Family Medicine 9e, Fig. 40-7)

Step 3: Urine Microscopy

• RBC casts / dysmorphic RBCs: Glomerulonephritis
• WBC casts: Pyelonephritis, interstitial nephritis
• Granular casts: Non-specific, suggests parenchymal disease
• Oval fat bodies / lipid droplets: Nephrotic syndrome
• Free RBCs alone: May suggest urologic source

Step 4: Confirm Persistence

• Repeat dipstick on 2-3 occasions over weeks
• Most proteinuria in children (and some adults) is transient

Step 5: Orthostatic Testing

• Collect first-morning void (recumbent sample) and daytime (upright) sample separately
• Absence of proteinuria in morning sample = orthostatic proteinuria (benign)
• Confirmed by split 24-hour urine collection

Figure: Approach to proteinuria in children/adolescents (Textbook of Family Medicine 9e, Fig. 40-8)

Step 6: Blood Tests

Step 7: Imaging

• Renal ultrasound: Kidney size, echogenicity, cortical thickness, cysts, hydronephrosis, renal vein thrombosis (in nephrotic syndrome)
• Doppler for renal vein thrombosis (complication of nephrotic syndrome)
• CT/MRI: If structural anomaly or malignancy suspected

Step 8: Renal Biopsy

• Nephrotic syndrome in adults without obvious cause
• Persistent nonnephrotic proteinuria (> 1-2 g/day) without explanation
• Suspected systemic disease with renal involvement
• Unexplained progressive renal failure with proteinuria
• Suspected rapidly progressive GN

• Children < 10 years with pure nephrotic syndrome (likely MCD - start steroids empirically)
• Orthostatic proteinuria (benign)
• Diabetic nephropathy with classic clinical picture and no atypical features

Age-Related Prevalence of Nephrotic Causes

• Comprehensive Clinical Nephrology, 7th Edition, Table 16.3

Management Principles

General (before specific diagnosis)

• Treat underlying cause
• BP control: Target < 130/80 mmHg; ACE inhibitors or ARBs are first-line (antiproteinuric effect via reducing intraglomerular pressure + podocyte protection)
• Dietary protein restriction: 0.8 g/kg/day in CKD (avoid excessive restriction)
• Sodium restriction and diuretics: For edema
• Statin therapy: For hyperlipidemia in nephrotic syndrome
• Anticoagulation: Consider in nephrotic syndrome if serum albumin < 2.5 g/dL (high risk of thromboembolism)
• Infection prophylaxis: Pneumococcal vaccine (impaired opsonization in nephrotic syndrome)

Specific

• MCD: Corticosteroids (prednisone 1 mg/kg/day) - excellent response rate
• Lupus nephritis: Hydroxychloroquine ± immunosuppression depending on class
• Diabetic nephropathy: Optimize glycemia, BP control with RAAS blockade, SGLT-2 inhibitors (renoprotective)
• Membranous nephropathy: Observation for spontaneous remission vs. rituximab/cyclophosphamide/cyclosporine

Follow-up of Persistent Isolated Proteinuria

• Yearly assessment: BP, serum creatinine, serum albumin, urine microscopy, UPr:UCr ratio
• Orthostatic proteinuria: Annual first-morning urine check, reassurance
• Non-orthostatic isolated proteinuria persisting > 1 year: Renal biopsy may be indicated

Summary Algorithm

1. Dipstick screening (risk-stratified: standard vs. albumin-specific)
2. Confirm on repeat testing (exclude transient causes)
3. Quantify with spot UPr:UCr ratio (or UACR)
4. Orthostatic test - first-morning urine
5. Urine microscopy - look for casts, dysmorphic RBCs
6. Blood tests - renal function, albumin, glucose, immunology panel
7. Imaging - renal ultrasound
8. Renal biopsy - if indicated

Sources: Textbook of Family Medicine 9e; Comprehensive Clinical Nephrology, 7th Edition; Harrison's Principles of Internal Medicine 22e; Brenner and Rector's The Kidney, 2-Volume Set

Examination of the Pulse - Practical Guide

Introduction

• S Das, A Manual on Clinical Surgery, 13th Edition

Sites of Pulse Examination

The carotid and brachial arteries are preferred for assessing character and contour of the pulse because they are closer to the heart and the waveform is less distorted.

Practical Technique of Pulse Examination

Patient Position

• Patient relaxed, preferably supine or sitting
• Arm resting comfortably at the level of the heart
• Avoid examining immediately after exertion

Examiner's Position

• Stand to the patient's right side
• For radial pulse: hold the patient's wrist with your right hand, using 2nd, 3rd, and 4th finger pads placed on the lateral aspect of the volar wrist (never use the thumb - it has its own pulsation)
• Apply moderate, steady pressure - too light misses it; too heavy obliterates it

Parameters to Assess (RRTVC + W)

1. Rate

• Normal: 60-100 bpm
• Bradycardia: < 60 bpm
  • Causes: Athletes, vagal stimulation, hypothyroidism, complete heart block, beta-blockers, inferior MI
• Tachycardia: > 100 bpm
  • Causes: Fever (each 1°F rise ~ +10 bpm), pain, anxiety, anemia, thyrotoxicosis, heart failure, shock, SVT/VT

2. Rhythm

3. Tension (Compressibility)

• Press on the artery proximal to your palpating fingers until the pulse is obliterated
• Increased tension = high diastolic pressure (hypertension)
• Decreased tension = low diastolic pressure (shock, aortic regurgitation)

4. Volume (Amplitude)

5. Character (Waveform Contour)

Figure: Normal and abnormal arterial pulse waveforms - Fuster and Hurst's The Heart, 15th Edition

Figure: Carotid pulse waveform patterns - A. Normal; B. Aortic Stenosis (anacrotic/parvus et tardus); C. Bisferiens pulse (severe AR); D. Bisferiens pulse in HOCM; E. Dicrotic pulse - Harrison's Principles of Internal Medicine 22e

Normal Pulse Waveform

• Gradual smooth upstroke followed by a rounded peak and downstroke
• Dicrotic notch - small notch on the descending limb caused by aortic valve closure (only visible on waveform tracings, not palpable normally)

Abnormal Character - Named Pulses

• Low amplitude + delayed, prolonged upstroke
• Cause: Severe aortic stenosis (fixed LV outflow obstruction slows ejection)
• May have an anacrotic notch (vibration felt on ascending limb = "anacrotic pulse")

• Rapid forceful upstroke followed by an abrupt, sudden collapse
• High volume + wide pulse pressure
• Cause: Severe aortic regurgitation, also thyrotoxicosis, patent ductus arteriosus, severe anemia, arteriovenous fistula
• Clinical test: Elevate the patient's arm above the head - the collapsing quality becomes more dramatic; felt as a slapping sensation against the examiner's palm

• Two distinct systolic peaks per heartbeat
• Causes:
  • Mixed aortic valve disease (AR predominant) - two peaks in systole
  • HOCM - first peak = percussion wave (early systole, before obstruction); second peak = tidal wave; "spike-and-dome" pattern
• Harrison's: "A bifid pulse is also described in patients with hypertrophic obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves."

• Two peaks - one systolic, one diastolic (exaggeration of dicrotic notch becomes palpable)
• Cause: Severe hypotension/shock, sepsis, severe peripheral vasoconstriction; also seen during intra-aortic balloon counterpulsation

• Beat-to-beat alternation in amplitude of pulse (alternating strong and weak beats)
• Regular rhythm (not respirophasic - distinguishes from pulsus paradoxus)
• Cause: Severe LV systolic dysfunction (e.g., advanced heart failure)
• Ominous sign of profound ventricular dysfunction
• Fuster and Hurst: "The presence of pulsus alternans is an ominous sign, suggesting very profound severe ventricular systolic dysfunction."

• Exaggerated fall in systolic BP > 10 mmHg during normal inspiration
• Measured with sphygmomanometer: note pressure at which Korotkoff sounds are first heard (expiration only) vs. heard every beat; difference > 10 mmHg = paradoxus
• Causes: Cardiac tamponade (most classic), massive pulmonary embolism, severe asthma/COPD, tension pneumothorax, hemorrhagic shock
• Mechanism: Inspiration expands right heart at the expense of LV (interventricular dependence) - tamponade exaggerates this
• Harrison's: "A pulsus paradoxus may be palpable at the brachial or femoral artery when the pressure difference exceeds 15 mmHg."

• Alternating strong and weak beats, but the weak beat follows prematurely (not evenly spaced)
• Cause: Bigeminy (every normal beat followed by a PVC)
• Distinguished from pulsus alternans by the irregular rhythm

6. Wall Condition (Vessel Wall)

• Normal: Soft, pliable, non-palpable wall
• Thickened/tortuous: Atherosclerosis ("pipe-stem" artery in severe disease)
• Hard, non-compressible: Calcified wall (Monckeberg's sclerosis)

Radio-Femoral Delay

• Normally both are felt simultaneously
• Delay of femoral behind radial: Suggests coarctation of the aorta (narrowing distal to subclavian artery)
• Also check radio-radial inequality (unequal carotid-subclavian anatomy, aortic dissection, subclavian artery aneurysm/stenosis)

Radio-Radial Inequality

• Causes of absent/reduced pulse on one side:
  • Thoracic outlet syndrome
  • Aortic dissection
  • Subclavian artery stenosis / Takayasu's arteritis
  • Previous arterial line / trauma

Special Maneuvers

Carotid Pulse Assessment

• Best for character - palpate medial to sternocleidomastoid at the mid-neck level
• Use one side at a time - never bilateral simultaneous (risk of carotid sinus stimulation causing syncope or arrhythmia, especially in elderly)
• Mobilize SCM laterally to palpate the artery properly

Hepatojugular Reflux

• Apply firm pressure over the right upper quadrant for 30 seconds while watching JVP
• Rise > 3 cm = raised venous pressure / right heart failure

Summary Table: Pulse Abnormalities at a Glance

Clinical Correlates to Always Remember

1. AF = Irregularly irregular + pulse deficit (use apex-radial pulse difference)
2. Complete heart block = Slow rate (~30-40 bpm), cannon 'a' waves in JVP
3. Cardiac tamponade = Low volume + pulsus paradoxus + raised JVP (Beck's triad: raised JVP + muffled heart sounds + hypotension)
4. Severe AR = Collapsing pulse + wide pulse pressure + low diastolic BP
5. Severe AS = Pulsus parvus et tardus + narrow pulse pressure
6. HOCM = Spike-and-dome bisferiens pulse + increases with Valsalva
7. Coarctation = Radio-femoral delay + hypertension in arms + hypotension in legs

Sources: Fuster and Hurst's The Heart, 15th Edition; Harrison's Principles of Internal Medicine 22e; S Das, A Manual on Clinical Surgery, 13th Edition