Case 14.5 – Haematuria [SDL]

History

• Age, gender, occupation, smoking history
• Is it painful (suggests inflammation; infection, calculus) or painless (suggests neoplasm)
• Timing of haematuria during stream: initial haematuria suggests urethral bleeding, terminal haematuria suggests bladder neck/prostate origin, and total haematuria of upper urinary tract origin
• Is there passage of blood clots? (Absence of clots suggests glomerular origin)
• Frequency / urgency / dysuria
• Past history of UTI, renal calculi or renal disease
• Past history of trauma, or recent instrumentation of the urinary tract
• Recent sore throat (post-streptococcal glomerulonephritis)
• Medication history (anticoagulation therapy, cyclophosphamide, rifampicin (red urine))
• Family history of renal disease (adult polycystic disease, hereditary nephritis, sickle cell disease)
• Occupational (aniline dyes, rubber industries associated with bladder tumours)
• Associated symptoms: Abdominal pain, weight loss, fever

Examination

• General: hypertension (renal disease), fever (UTI, renal cell carcinoma), rashes, bruising (haemorrhagic diatheses), arthritis, lymphadenopathy
• Abdomen: renal mass (tumour, polycystic kidneys), bladder mass, enlarged prostate
• Urine dipstick and MSU

Kidney

• Glomerulonephritis
• Pyelonephritis
• Renal calculus
• Renal cell carcinoma
• Adult polycystic kidney disease
• Renal trauma
• Bleeding diathesis
• Renal infarction
• Papillary necrosis

Ureter

• Ureteric calculus
• Transitional cell carcinoma of the ureter

Bladder

• Cystitis
• Transitional cell carcinoma of bladder
• Bladder calculus
• Schistosomiasis (most common cause worldwide)

Prostate

• Benign prostatic hypertrophy
• Prostatic carcinoma
• Prostatitis

Urethra

• Urethritis
• Trauma
• Foreign body

Macroscopic haematuria

• History and examination
• Urine microscopy, culture and sensitivity
• Renal function: serum urea, electrolytes and creatinine
• CT urography or IVP: to image the entire urinary tract – kidneys, ureters and bladder
• Cystoscopy: flexible cystoscopy for outpatient assessment

Microscopic haematuria

• History and examination
• Repeat urine dipstick and MSU
• If persistent microscopic haematuria confirmed on repeat testing (1-2 weeks)
• Check blood pressure
• Renal function: serum urea, electrolytes and creatinine
• Urine microscopy for red cell casts and dysmorphic red cells (suggests glomerulonephritis)
• Urine protein:creatinine ratio
• Further investigations if proteinuria or elevated creatinine or hypertension or if patient is <40 years (more likely to have glomerular cause): renal ultrasound ± renal biopsy
• Further investigations if patient is >40 years without proteinuria, elevated creatinine or hypertension (more likely to have structural lesion): CT urography and cystoscopy

Renal adenocarcinoma (Renal cell carcinoma)

• Epidemiology: Male to female ratio 2:1. Peak incidence sixth and seventh decades. 2% of all adult malignancies.
• Aetiology: Cigarette smoking doubles the risk. Obesity, hypertension, unopposed oestrogen therapy and chronic renal failure are associated with an increased risk. Von Hippel-Lindau disease (mutation in VHL gene on chromosome 3) – autosomal dominant disorder. Adult polycystic kidney disease – increased incidence of renal cell carcinoma.
• Pathology: 85% arise from proximal tubular epithelium (clear cell adenocarcinoma). Remaining 15% derived from distal tubule cells.
• Clinical presentation: Classic triad of loin pain, haematuria and an abdominal mass (occurs in less than 15% of patients). Haematuria is the most common presenting symptom. Systemic symptoms include fever, night sweats, malaise and weight loss. Polycythaemia (increased erythropoietin production), hypercalcaemia (PTH-related peptide secretion), hypertension (increased renin production). Varicocele – tumour invasion/occlusion of testicular vein (more commonly left sided). Stauffer's syndrome – syndrome of hepatic dysfunction in the absence of metastatic disease. Reverses after nephrectomy. Left supraclavicular lymphadenopathy or hepatomegaly due to metastatic spread. 25-30% of patients present with metastatic disease.
• Investigations: FBC (anaemia or polycythaemia), Renal function (urea, creatinine, electrolytes), Serum calcium, LFTs. CT scan – investigation of choice. Chest X-ray to look for cannonball metastases.
• Treatment: Radical nephrectomy for organ-confined disease. Immunotherapy with IL-2 and INF alpha for metastatic disease. Radiotherapy for bone metastases.
• Prognosis: Prognosis is related to tumour stage. 5-year survival for stage I disease approaches 95%, and that for stage IV disease is only 10%. Overall 5-year survival for renal cell carcinoma is approximately 50%.

Transitional cell carcinoma (Urothelial carcinoma)

• Epidemiology: Most common malignancy of the urinary tract. Male:female ratio 3:1. Peak incidence sixth and seventh decades. 90% of bladder tumours are transitional cell carcinomas. Transitional cell carcinoma of the upper urinary tract (renal pelvis, ureter) is much less common.
• Aetiology: Cigarette smoking is the most important risk factor and accounts for 50% of cases. Occupational exposure to aniline dyes, rubber, and chemicals used in cable and paint industries. Chronic inflammation: long-term catheterization, bladder calculi, schistosomiasis (associated with squamous cell carcinoma). Drugs: phenacetin, cyclophosphamide. Pelvic irradiation.
• Pathology: Transitional cell carcinoma can be papillary (75%), solid (20%) or mixed (5%). Papillary tumours are usually low-grade and have a good prognosis. Solid tumours are usually high-grade and have a poorer prognosis.
• Clinical presentation: Painless macroscopic haematuria is the most common presenting symptom (85%). Frequency, urgency and dysuria may occur if there is carcinoma in situ. Ureteric obstruction may cause loin pain and hydronephrosis.
• Investigations: Urine cytology (low sensitivity for low-grade tumours). CT urography. Cystoscopy and biopsy – definitive diagnosis and to determine extent of disease.
• Treatment: Superficial bladder cancer (stages Ta, Tis, T1): transurethral resection (TURBT). Intravesical chemotherapy or immunotherapy (BCG) to reduce risk of recurrence. Muscle-invasive bladder cancer (stages T2-T4): radical cystectomy with urinary diversion OR radiotherapy with chemotherapy (bladder preservation). Metastatic disease: systemic chemotherapy.
• Prognosis: 5-year survival for superficial disease is 80-90%. 5-year survival for muscle-invasive disease is 50%. Transitional cell carcinoma of the upper urinary tract has a poorer prognosis than bladder cancer.

• Inheritance: Autosomal dominant inheritance. Mutations in PKD1 gene (chromosome 16) account for 85% of cases. PKD2 gene (chromosome 4) mutations account for 15% of cases. PKD1 disease tends to be more severe with earlier onset of renal failure.
• Prevalence: 1 in 1000. Accounts for 10% of patients with end-stage renal failure.
• Pathology: Progressive development of multiple fluid-filled cysts in both kidneys. Cysts arise from all parts of the nephron and progressively enlarge. Normal renal tissue is compressed and eventually destroyed. Kidneys may become massively enlarged.
• Clinical presentation: Usually asymptomatic until middle age (30-50 years). Chronic loin pain or an abdominal mass. Haematuria (rupture of cyst into collecting system). Acute loin pain (haemorrhage into cyst, cyst infection, renal calculi – occur in 20%). Hypertension occurs in 60% before the onset of renal failure. Progressive decline in renal function leading to end-stage renal failure (usually by 60 years of age). UTIs and pyelonephritis are common.
• Extra-renal manifestations:
  • Hepatic cysts (most common extra-renal manifestation – present in 30%)
  • Intracranial berry aneurysms (5-10%). Risk of subarachnoid haemorrhage. Screen with MR angiography if family history of aneurysms or subarachnoid haemorrhage
  • Mitral valve prolapse (25%)
  • Aortic regurgitation
  • Colonic diverticulae
• Diagnosis: Ultrasound is the investigation of choice (renal cysts visible). CT or MRI if ultrasound is equivocal. Genetic testing for PKD1 and PKD2 mutations.
• Management: No specific treatment to prevent cyst formation or slow progression of disease. Blood pressure control is essential (ACE inhibitors or ARBs first-line). Treat UTIs aggressively. Pain management (simple analgesics, cyst aspiration, rarely nephrectomy). Renal replacement therapy (dialysis or transplantation) for end-stage renal failure.
• Screening: Screen family members with ultrasound. Genetic counselling.

Renal involvement in malignant diseases

• Direct invasion: Renal cell carcinoma, transitional cell carcinoma, direct invasion from adjacent tumours (e.g. colon cancer)
• Metastatic disease: Common primary sites include lung, breast, melanoma, lymphoma
• Paraneoplastic syndromes:
  • Hypercalcaemia (due to bone metastases or PTH-related peptide secretion) – causes polyuria, dehydration, AKI
  • Tumour lysis syndrome (especially after chemotherapy for haematological malignancies) – hyperuricaemia, hyperphosphataemia, hyperkalaemia – can cause AKI
  • Membranous nephropathy (most commonly associated with solid tumours)
  • Minimal change disease (associated with Hodgkin's lymphoma)
  • Amyloidosis (associated with multiple myeloma, lymphoma)
• Treatment-related: Chemotherapy-induced nephrotoxicity (cisplatin, ifosfamide, methotrexate). Radiotherapy to abdomen/pelvis can cause radiation nephritis. Tumour infiltration of ureters causing obstruction.

Renal involvement in systemic vasculitis

• Small vessel vasculitis (ANCA-associated vasculitis):
  • Granulomatosis with polyangiitis (Wegener's granulomatosis) – c-ANCA positive (anti-PR3)
  • Microscopic polyangiitis – p-ANCA positive (anti-MPO)
  • Clinical features: rapidly progressive glomerulonephritis (haematuria, proteinuria, AKI), systemic symptoms (fever, weight loss, malaise), upper respiratory tract involvement (sinusitis, epistaxis), lower respiratory tract involvement (pulmonary haemorrhage, cavitating lesions)
  • Renal biopsy: necrotizing crescentic glomerulonephritis (pauci-immune – minimal Ig deposition)
  • Treatment: high-dose corticosteroids + cyclophosphamide or rituximab for induction. Maintenance with azathioprine or rituximab. Plasma exchange in severe disease
• Medium vessel vasculitis: Polyarteritis nodosa – can cause renal infarction, AKI, hypertension
• Anti-GBM disease (Goodpasture's syndrome): Antibodies against glomerular basement membrane. Pulmonary haemorrhage + rapidly progressive glomerulonephritis. Linear IgG deposition on immunofluorescence. Treatment: plasma exchange + immunosuppression

Renal involvement in systemic lupus erythematosus (SLE)

• Epidemiology: Renal involvement occurs in 50% of patients with SLE. Lupus nephritis is a major cause of morbidity and mortality in SLE
• Pathogenesis: Immune complex deposition in glomeruli (antibodies against nuclear antigens, especially anti-dsDNA)
• Clinical features: Asymptomatic haematuria and/or proteinuria. Nephrotic syndrome. Acute kidney injury. Hypertension
• Classification (ISN/RPS 2003):
  • Class I – Minimal mesangial lupus nephritis
  • Class II – Mesangial proliferative lupus nephritis
  • Class III – Focal lupus nephritis (\<50% of glomeruli)
  • Class IV – Diffuse lupus nephritis (≥50% of glomeruli) – most severe form
  • Class V – Membranous lupus nephritis
  • Class VI – Advanced sclerosing lupus nephritis
• Investigations: Urinalysis (haematuria, proteinuria, cellular casts). Urine protein:creatinine ratio or 24-hour urine protein. Renal function (urea, creatinine, eGFR). Serology: ANA, anti-dsDNA (titre correlates with disease activity), complement levels (C3, C4 – typically low in active disease). Renal biopsy – essential for classification and guiding treatment
• Treatment:
  • Class I and II: usually do not require specific treatment unless there is significant proteinuria
  • Class III and IV: aggressive immunosuppression – high-dose corticosteroids + mycophenolate mofetil or cyclophosphamide for induction. Maintenance with mycophenolate mofetil or azathioprine
  • Class V: depends on severity of proteinuria – may require immunosuppression similar to class III/IV
  • ACE inhibitors or ARBs for proteinuria and blood pressure control
  • Hydroxychloroquine for all patients with SLE
• Prognosis: Improved significantly with modern immunosuppressive therapy. 10-year renal survival >80% for class III/IV with treatment. Poor prognostic factors: elevated creatinine at presentation, severe histological changes on biopsy, delayed treatment