Hematuria: classification, causes, management

Clinical classification of hematuria

Macroscopic hematuria

• Visible with a visual inspection
• few drops are enough!

Microscopic hematuria

• Urine seems macroscopically unremarkable
• 3-5 RBCs / μl

Etiological classification of hematuria
A. Glomerular hematuria

B. Non (post) -Glomerular Hematuria

C. Hematuria mimetics

A. Glomerular hematuria

Immune complex nephropathy

• IgA nephritis (M. Berger)
• lupus nephritis
• Postinfectious glomerulonephritis:

1. Poststreptokokkal
2. Associated with endocarditis
3. Shunt nephritis

• Membranoproliferative glomerulonephritis:

1. Immune complex mediates
2. Hypocomplementemic GN

Anti-GBM disease (Goodpasture syndrome)
ANCA-associated vasculitis

• Granulomatosis with polyangiitis (GP)
• microscopic polyangiitis (MPA (
• Churg-Strauss syndrome (EGP)

Family illness

• Alport syndrome
• thin basement membrane nephropathy

IgA nephritis

clinical journal of American Society of Nephrology

Source: Medscape

M. Berger 1968

One of the most common cause of glomerulonephritis
Men affected 2-3 times more often
Association with IgA vasculitis (Schönlein-Henoch), SLE.
Hepatitis, cirrhosis, celiac disease, HIV and others

Clinical picture :

• asymptomatic
• 80% ass. with upper respiratory tract infection (Haemophilus parainfluenza)
• Microhematuria and episodic gross hematuria

1. Simultaneously or 2-3d after the onset of the infection (synpharyngitic Nephritis)
2. flank pain
3. In children and young adults

• proteinuria

1. Rapidly progressive glomerulonephritis
2. Nephrotic syndrome

• Art. Hypertension
• Renal failure and renal insufficiency

Lupus nephritis

Occurs in approximately 70-100% of all SLE patients

pathophysiology

• GN with immune complex deposits of auto-Ak
• tubulointerstitial nephritis
• with vascular changes and microangiopathy
• Immune complex deposits in the vessels
• very rarely pauci-immune-glomerulonephritis

symptoms

• Proteinuria (100%), nephrotic syndrome (50%)
• Microhematuria (80%), erythrocyte cylinder (10% )
• rarely also gross hematuria
• Renal insufficiency (40-80%)
• Hypertension (50%)

Postinfectious glomerulonephritis

Bacteria (endocarditis, abscesses, pneumonia,..)

• Gram-positive: streptococci, staphylococci (MRSA)
• Gram-negative: Salmonella, Shigella, E-Coli, Klebsiella, Yers
• Pseudomonas,.
• Mycobacteria, Chlamydia, mycoplasma

parasites

• Malaria (18% with GN), schistosomiasis (15% with GN), Toxoplasmosis, worms, amoebiasis.

fungi

• Candida, Histoplasma, Coccidioides

virus

• HBV, VZV, EBV, hCMV, Parvo, Adeno, HIV, Hanta, Rota, Mumps, measles, HAV, HCV, Coxsackie, echo, dengue

Post-streptococcal glomerulonephritis

A complication of the convalescent period of scarlet fever in the 18th century
2 times more common in men
More common in tropical areas (more frequent infections)
More common in children (pore size of basement membrane)
nephritogenic strains of hemolytic streptococci
Immune complex disease (type III allergy)

• 2 Streptokekken antigens SPEB and NAPlr
• Incorporation of circulating immune complexes into
• glomerular interstitium
• Activation of macrophages, CS and cytokines
• Recruitment of monocytes and neutrophils

Clinical picture

• Streptococcal infection is conditio-sine-qua-non
• Latency of 1-2 weeks in pharyngitis 3-6 weeks at skin infection
• Abrupt onset of hematuria (30% macro), proteinuria, edema
• (Eyelids) and hypertension with or without oliguria (Nephritic syndrome)
• constitutional symptoms, nausea/vomiting
• Heart failure, LV dysfunction, valvular heart disease
• Ahus
• Alveolar bleeding (lung-kidney syndrome )
• Seizure (posterior reversible encephalopathy syndrome)
• kidney failure
• ANA-positive

Not streptococcal glomerulonephritis

• Staphylococci-associated GN

1. MRSA
2. Common in elderly patients with diabetes mellitus
3. Shunt nephritis
4. Endocarditis-associated GN: more common in subacute form
5. Renal failure, hematuria, severe proteinuria
6. Requires antimicrobial therapy

Formation of the immune complex

• Ak directly with Viral Ag
• Ak with Ag after viral-induced cell damage

Pathophysiology of the immune reaction

• In-situ immune complex reaction: humoral immune response
• Cell-mediated immune response (macrophages and neutrophils)
• Activation of the complement system
• Superantigen (staphylococci): Bypass antigen presentation process ( non-specific activation of T cells)
• Autoimmune reaction against glomerular structure induced in pathogen

clinical

• Chronic viral infections give rise to various forms of GN ( IgA, ANCA, MPGN, FSGN, MN)
• diffuse proliferative GN, collapsing focal segmental (cFSGN) or membranous GN

Goodpasture's syndrome

Rare autoimmune disease, which mainly affects the kidneys and Lungs affected

Rulers IgG deposition in the GBM (Source: Medscape)

Clinical picture: 

• triggers: smoking, exposure to hydrocarbons, Influenza 
• Hematuria, edema, hypertension 
• RPGN 
• Hemoptysis 
• chest pain 
• anemia 

Therapy concept

• Elimination of Ab: Plasmapheresis 
• Prevent the production of more AK: immunosuppression 
• Fixed the trigger

ANCA-associated vasculitis 

Systematic diseases associated with inflammation of the small vessels 

characterized by autoimmunity and ANCA 

Autoantibodies (mainly IgG) against neutrophils and monocytes 

ANCA binds 2 proteins (antigens) in neutrophil cytoplasm: 

• PR3 (usually cytoplasmic c-ANCA) 
• MPO (usually perinuclear p-ANCA)

Immunofluorescence of p-ANCA and c-ANCA. Source: UNC Kidney Center

Granulomatosis with polyangiitis GPA (Wegener's disease) 

• Rare multisystemic disease 
• Prevalence 3: 100,000 
• More common in white people 
• Granulomatous inflammation of the respiratory tract (nose, NNH, larynx) 
• Necrotising vasculitis of small and medium vessels (capillaries, small vein, arterioles, and arteries) 
• Necrotizing GN often 
• 95% are ANCA positive at diagnosis 
• Associated with c-ANCA (PR3) 65% and rarely with p-ANCA (MPO) 
• antibody

symptoms 

• Frequent respiratory infections (especially children), cough, atelectasis, hemoptysis 
• Nodules, infiltration, RF, stenoses, bronchiectasis, pleural effusions, LK 
• Constitutional complaints and weight loss 
• Myalgia, arthralgia, and arthritis 
• Fever, night sweats, and inappetence 
• Ophthalmological manifestation 
• Ear, nose and throat involvement 
• Renal insufficiency (11%), proteinuria, hematuria 
• Neurological symptoms (CNS and PNS) 
• Rash, ulceration, petechiae, and purpura especially in the lower extremities 
• Myocardial infarction, pericarditis, and death 
• 2/3 of patients have RF + (low titer)

Microscopic Polyangiitis (MPA) 

• Prevalence 2: 100,000 
• More common in whites, males with ages ~ 50 
• Very closely related to GPA, but without the formation of granulomas 
• Infestation of the upper respiratory tract is less common than in GPA, however 
• The symptoms of kidney and lungs are more pronounced. 
• Infestation of the kidney at diagnosis often 
• Necrotizing vasculitis with few or no immune vacancies 
• Infestation of small and medium-sized vessels (capillaries, no vein, and arterioles) 
• Frequent necrotizing GN and pulmonary capillaritis 
• 90% are ANCA positive at diagnosis 
• Associated with p-ANCA (MPO) 55% and c-ANCA (PR3) antibodies

symptoms

• fever 
• Constitutional complaints and weight loss 
• myalgia 
• Rash, leukocytoclastic angiitis, purpura, levido retucularis, Ulceration, necrosis, gangrene, and peripheral ischemia 
• GI bleeding and other GI symptoms such as pancreatitis or ischemia 
• Lower respiratory tract infections, rattling, dyspnea 
• Chest pain, myocardial infarction, pericarditis, and heart failure 
• Neurological symptoms 
• Uremic symptoms, uremia, proteinuria, hematuria and leukocyturia 
• Arterial hypertension

Eosinophilic Granulomatosis with Polyangiitis (EGPA) (Churg-Strauss syndrome)

• Rarely, men are more affected than women (1.4: 1) 
• Granulomatous inflammation with numerous eosinophils in the respiratory tract
• Necrotizing vasculitis of small and medium-sized vessels 
• Often associated with asthma and eosinophilia 
• Asthma is often difficult to control compared to seasonal bronchial asthma 
• Infestation of the skin, nervous system and heart 
• Only 40% are ANCA positive at diagnosis 
• Associates 70% with p-ANCA (MPO) and more rarely with c-ANCA (PR3)

symptoms

• 80-90% asthma, rhinitis, sinusitis, and hemoptysis 
• Loeffler syndrome, infiltration, eosinophilic pleural effusion 
• eosinophilia 
• Dyspnea, chest pain 
• Fever and weight loss 
• Rash, Raynaud's phenomenon 
• Arthritis, myalgia, myositis 
• Heart failure (sys. And dias.), Shock, cardiomegaly, pericardial effusion and ECG abnormalities, valvular and myocarditis 
• renal insufficiency 
• Neurological symptoms (CNS and PNS), cramps, ICB 
• Arterial hypertension 
• GI bleeding, diarrhea, jaundice 
• 70% of the patients are RF +, often LDH +

Alport syndrome (Q87.8) 
Hereditary disease with kidney, eye, and Innenohraffektion
inheritance patterns:

• 80% X-linked 
• 15% autosomal recessive 
• 5% autosomal dominant 

Gene mutation for collagen type IV protein chains
Dysfunction of the basement membrane

Clinic

• Proteinuria, microhematuria with intermittent 
• gross hematuria 
• Advanced kidney failure 
• Sensorineural hearing loss 
• Lenticonus anterior with reduced visual acuity

Nephropathy of the type of the thin basement membrane 

• Of the common causes of hematuria in children and 
• adult 
• Thin glomerular basement membrane 
• Arterial hypertension 
• Mild proteinuria 
• Good prognosis (benign familial hematuria)

Non-post-glomerular hematuria

• pyelonephritis 
• Renal cell carcinoma 
• PCK 
• papillary necrosis 
• renal infarction 
• Nutcracker syndrome 
• Medullary sponge kidney
• Urinary Tract Infection 
• schistosomiasis 
• urothelial carcinoma 
• stones 
• strictures 
• Fistula, malformations 
• Hemorrhagic cystitis 
• traumatic 
• Iatrogenic
• Benign prostatic hyperplasia 
• prostatitis 
• Prostate cancer 
• diverticulum
• Exercise-induced hematuria 
• Loin-Pain-hematuria syndrome 
• idiopathic

Blood detection in urine strips: 

• Principle: Color change of the reagent in contact with the HemeMolecule 
• Visual or automatic interpretation 
• Detection limit 5 Erys / μl urine 
• Also positive for hemoglobinuria (detection limit 60 μmol / l) or myoglobinuria

Hämaturiememetika

• Erythrocyturia: contamination, fictitious
• Hemoglobinuria: Hemolytic anemia, Burning, Sepsis, Streptococcal infections, Physical damage
• Myoglobinuria: Crush syndrome, muscle ischemia, myocardial infarction, myopathy, snake bite
• Other causes: porphyria, ingestion of beets/beet, carrot or blackberry, medication (rifampicin, antipsychotics, ..)

Management with hematuria

Anamnese

• Beginning, course, duration, episodic or consistent 
• Other urological symptoms: dysuria, nocturia, incont., Urgency
• Other symptoms: fever, chills, flank pain, Weight loss, coughing, airborne
• Previous stones? Autoimmune diseases, chr. Infections, ctx, Radiotherapy, smoking, urological examination, art. Hypertension

Investigation

Vital signs, abdomen, rectum, skin, lungs 

Laboratory

Routine laboratory routine, urinalysis, urine microscopy, UK, possibly further 

Examination of Suspected glomerular hematuria

imaging

Sonography, ACT, CT urography, cystoscopy