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Approach to Pyuria and Hematuria on Urine Complete Examination: A Clinical Guide for the Ward Resident

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Part 1 - Definitions and Significance

• 3 RBCs/HPF on three separate urinalyses

• A single urinalysis with >100 RBCs/HPF
• Any gross hematuria

Important: In catheterized patients, pyuria and bacteriuria are almost universal and do not by themselves diagnose UTI. Symptoms are required.

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Part 2 - The First Step: Characterize the Urine Sediment

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Part 3 - Localizing the Disease: A Step-by-Step History

A. Onset and Time Course

• Acute onset (days): acute GN (post-streptococcal), acute pyelonephritis, drug-induced AIN, urolithiasis, trauma
• Episodic gross hematuria concurrent with URTI: IgA nephropathy ("synpharyngitic hematuria" - same-day onset is key; 10-14 day delay suggests post-streptococcal GN)
• Chronic / smoldering: CKD, chronic interstitial nephritis, thin basement membrane disease, Alport syndrome, urothelial malignancy

B. Symptoms to Ask Directly

C. Drug and Toxin History

• PPIs, sulfa drugs, cephalosporins, fluoroquinolones, NSAIDs, checkpoint inhibitors: drug-induced ATIN
• Analgesics (phenacetin, acetaminophen combinations), lithium: chronic interstitial nephritis
• Rifampicin: granulomatous interstitial nephritis
• Aniline dyes (occupational), cyclophosphamide: urothelial malignancy
• Herbal remedies (aristolochic acid): Balkan nephropathy / chronic TIN

D. Past History and Systemic Disease

• Diabetes mellitus: diabetic nephropathy, susceptibility to infections
• Hypertension: hypertensive nephrosclerosis
• Prior sore throat / skin infections: post-infectious GN
• Systemic diseases: SLE, ANCA vasculitis, amyloidosis, myeloma
• Recurrent UTI, urological abnormalities: complicated UTI

E. Family History

• Renal failure in family: Alport syndrome (COL4A5 mutation, X-linked), PCKD
• Microscopic hematuria in family members: thin basement membrane disease
• Multiple bilateral renal cysts: PCKD (also look for cerebral aneurysm history)

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Part 4 - Physical Examination: What to Look For

General

• Blood pressure: hypertension is a cardinal feature of both GN and pyelonephritis
• Edema: periorbital (suggests nephrotic), peripheral, anasarca
• Pallor: anaemia of CKD, haemolytic anaemia in TMA (HUS/TTP)
• Weight (fluid overload in acute GN)

Skin and Mucous Membranes

• Malar/"butterfly" rash: SLE
• Palpable purpura (lower limbs): IgA vasculitis (Henoch-Schonlein Purpura), ANCA vasculitis
• Livedo reticularis: atheroembolic disease, antiphospholipid syndrome
• Rash: drug reaction in ATIN

Eyes

• Uveitis/iritis: TINU syndrome
• Fundoscopy: diabetic retinopathy (coexisting with microalbuminuria suggests diabetic nephropathy), hypertensive changes

Ears

• Sensorineural hearing loss: Alport syndrome

Abdomen

• Flank/costovertebral angle tenderness (gentle percussion): acute pyelonephritis, acute GN (tender inflamed kidneys)
• Ballotable kidneys: PCKD, hydronephrosis
• Palpable bladder (percussion): outflow obstruction
• Suprapubic tenderness: cystitis

Respiratory

• Signs of pulmonary haemorrhage (haemoptysis, crackles): Goodpasture's syndrome, ANCA vasculitis (pulmonary-renal syndrome)

Joints

• Arthritis: SLE, ANCA vasculitis, reactive arthritis

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Part 5 - Key Clinical Syndromes to Keep in Mind

1. Nephritic Syndrome

• Haematuria (dysmorphic RBCs / RBC casts) + proteinuria (1-2 g/24h) + hypertension + oedema + oliguria + rising creatinine
• Causes: post-infectious GN, IgA nephropathy, lupus nephritis, ANCA vasculitis, Goodpasture's

2. Nephrotic Syndrome

• Heavy proteinuria (>3 g/24h) + hypoalbuminaemia + oedema + hypercholesterolaemia + microscopic haematuria
• Causes: minimal change disease, FSGS, membranous nephropathy, diabetic nephropathy

3. Rapidly Progressive GN (RPGN) - EMERGENCY

• Rapid rise in creatinine over days-weeks + active nephritic sediment (RBC casts, dysmorphic RBCs)
• Pathological equivalent: crescentic GN
• Three immunological categories: ANCA-positive (anti-MPO, anti-PR3), anti-GBM (Goodpasture's), immune complex (low C3 - SLE, post-infectious, cryoglobulinaemia)
• If pulmonary haemorrhage present: pulmonary-renal syndrome

4. Acute Tubulointerstitial Nephritis (ATIN)

• Drug exposure + fever + rash + eosinophilia + rising creatinine
• Urine: WBC casts, activated T lymphocytes, eosinophils (Hansel stain), no/minimal proteinuria
• May have polyuria (nephrogenic DI), electrolyte disorders (RTA pattern)

5. Lower UTI (Cystitis)

• Dysuria + frequency + urgency + suprapubic pain
• Urine: pyuria + bacteriuria; no casts; no significant proteinuria
• No systemic signs

6. Upper UTI (Pyelonephritis)

• Fever + rigors + CVA tenderness ± lower UTI symptoms
• Urine: WBC casts + bacteriuria; pyuria
• Requires urine culture + sensitivity

7. Sterile Pyuria - must be explained

• WBCs present, culture negative. Think of:
  • Genitourinary tuberculosis (early morning urine x 3 for AFB, TB PCR)
  • Atypical organisms: Chlamydia, Ureaplasma, Mycoplasma, gonorrhoea (STI screen)
  • Allergic/drug-induced interstitial nephritis
  • Interstitial cystitis
  • Sarcoidosis / IgG4-related TIN
  • Prior antibiotic treatment masking positive culture

8. Isolated Microscopic Hematuria

• Commonest glomerular causes: IgA nephropathy, thin basement membrane disease, hereditary nephritis (Alport)
• If dysmorphic RBCs + RBC casts + protein >500 mg/d: virtually diagnostic of GN - needs biopsy
• If no casts, non-dysmorphic RBCs, no proteinuria: urological workup (stones, tumour, BPH)
  • Age >35 years or risk factors for urothelial cancer: cystoscopy mandatory
  • CT urography for upper tract evaluation

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Part 6 - Investigations to Order in the Ward

Tier 1 - For every patient (Basic workup)

• Urine complete examination (UCE): dipstick + microscopy - always examine fresh urine personally
• Urine culture and sensitivity (midstream clean catch)
• Spot urine protein-to-creatinine ratio (UPCR) or 24-hour urine protein
• Spot urine albumin-to-creatinine ratio (UACR) (especially for diabetics and early disease)
• Serum creatinine + eGFR
• Blood urea nitrogen (BUN)
• Serum electrolytes (Na, K, Cl, HCO3)
• Complete blood count - anaemia (CKD, haemolysis, myeloma), eosinophilia (ATIN, atheroembolic), thrombocytopenia (TMA)
• Blood pressure (essential at every visit)
• Renal ultrasound: kidney size (small = CKD; large = acute GN, PCKD, DM), cortical thickness, echogenicity, hydronephrosis, stones

Tier 2 - Targeted by clinical pattern

• Serum C3, C4 (low in post-infectious GN, SLE, MPGN, cryoglobulinaemia)
• ANA, anti-dsDNA, anti-Sm (SLE)
• ANCA (p-ANCA/anti-MPO; c-ANCA/anti-PR3) - for vasculitis
• Anti-GBM antibody (Goodpasture's)
• Hepatitis B surface antigen, Hepatitis C antibody (membranous, MPGN, cryoglobulinaemia)
• Cryoglobulins
• Serum protein electrophoresis + free light chains (myeloma)
• ASO titre, anti-DNase B, streptozyme (post-streptococcal GN)
• ADAMTS13 level + Shiga toxin if TMA suspected
• Renal biopsy - for definitive diagnosis when GN is suspected and kidneys are normal in size

• Urine eosinophils (Hansel stain is more sensitive than Giemsa)
• FENa (if oliguric - <1% in prerenal, >3% in established ATN)
• Giemsa-stained cytocentrifuged urine for activated T cells, eosinophils, plasma cells
• Beta-2 microglobulin (tubular proteinuria)

• Three early morning urine specimens for AFB (GENITOURINARY TB workup)
• STI screen (endocervical swabs for Chlamydia, gonorrhoea) in sexually active patients
• Fungal culture if immunocompromised

• Non-contrast CT KUB (best for stones)
• 24-hour urine calcium, oxalate, urate, citrate (if recurrent stones)
• Serum PTH if hypercalcaemia (nephrocalcinosis)
• 24-hour urine oxalate if IBD / gastric bypass patient

• CT urography
• Cystoscopy
• Urine cytology

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Part 7 - Quick Decision Framework for the Ward

PYURIA found on UCE
        |
   +-----------+
   |           |
Bacteriuria   No bacteriuria
present       (Sterile pyuria)
   |               |
Lower UTI sx?   Think:
(dysuria, freq)  TB / STI / ATIN /
   |            Interstitial cystitis
   YES → Cystitis (culture + treat)
   NO  ↓
Fever + CVA tenderness?
   YES → Pyelonephritis (admit if severe, IV antibiotics)

HEMATURIA found on UCE
        |
   +------------------+
   |                  |
Gross hematuria    Microscopic hematuria
   |                  |
Clots present?    RBC casts or
                  dysmorphic RBCs?
YES → Postrenal   YES → Glomerulonephritis
(collecting sys)  (serologies + biopsy)
NO  → IgA neph,      |
trauma, lower     NO → Urological cause
tract bleed          (CT + cystoscopy if >35y)

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Part 8 - Pitfalls to Avoid

1. Do not diagnose UTI on pyuria alone in catheterised patients or those recently on antibiotics - symptoms are required.
2. Do not assume hematuria is benign in patients over 35 - exclude malignancy first.
3. Gross hematuria with blood clots is not glomerular - it indicates lower tract/collecting system pathology.
4. Sterile pyuria must be investigated - the three most commonly missed diagnoses are genitourinary TB, interstitial nephritis, and STIs.
5. A negative dipstick does not rule out bacteriuria in pregnancy - send urine culture regardless.
6. Foamy urine + haematuria is not simply "infection" - measure a spot UPCR, as this may be nephrotic syndrome.
7. Do not confuse myoglobinuria with hematuria - dipstick positive but no RBCs on microscopy = rhabdomyolysis until proven otherwise.
8. In IgA nephropathy, haematuria appears at the SAME TIME as URTI (synpharyngitic), NOT 10-14 days later as in post-streptococcal GN.

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• Harrison's Principles of Internal Medicine 22E (2025), Chapter 319 (Approach to Renal/Urinary Tract Disease), Chapter 326 (Glomerular Diseases), Chapter 140 (UTI)
• Goldman-Cecil Medicine, Chapter 100 (Approach to the Patient with Renal Disease), p. 2494 (Pyuria section)
• NKF Primer on Kidney Diseases 8E, p. 3046 (Nephritic Syndrome, IgA Nephropathy)
• Comprehensive Clinical Nephrology 7E, p. 988 (Urinalysis and Urine Microscopy)
• The Washington Manual, p. 551 (UTI Diagnosis)