Hematuria differential diagnosis

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Steven C. Campbell, M.D., Ph.D. Associate Editor(s)-in-Chief: Omer Kamal, M.D.[1], Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Overview

Gross hematuria(GH) must be distinguished from pigmenturia, which may be due to endogenous sources (e.g., bilirubin, myoglobin,and porphyrins), foods ingested (e.g., beets and rhubarb), drugs (e.g., phenazopyridine), and simple dehydration. This distinction can be made easily by urinalysis with microscopy. Notably, myoglobinuria and other factors can cause false-positive chemical tests for hemoglobin, so urine microscopy is required to confirm the diagnosis of hematuria. GH also must be distinguished from vaginal bleeding in women, which usually can be achieved by obtaining a careful menstrual history, collecting the specimen when the patient is not having menstrual or gynecologic bleeding, or, if necessary, obtaining a catheterized specimen. GH may also be detected by the presence of blood spotting on the undergarments of incontinent patients. After ruling out vaginal bleeding and mimics of hematuria, a urologic source must be suspected.

Differential Diagnosis

Hematuria should be differentiated from other disease which mimic hematuria especially hemoglobinuria and myoglobinuria which are dipstick positive but negative for microscopy.

Hematuria differential diagnosis

Differentiating the diseases that can cause hematuria:

Diseases		Clinical manifestations									Para-clinical findings						Gold standard	Additional findings
		Symptoms						Physical examination
											Lab Findings	Imaging			Histopathology
		Low back pain	Fever	Nausea/ Vomiting	Urinary symptoms			Hypertension	Pitting edema	Other		Ultrasonography	CT scan	Other
					Dysuria	Frequency	Oliguria								Light microscopy	Immunoflourescence pattern
Glomerular diseases	IgA nephropathy (Berger nephropathy)		+	-	-	-	+	+	+	-	-	-	-	Electron microscopy shows mesangial hypercellularity and increased mesangial matrix	Focal or diffuse mesangial proliferation Extracellular matrix expansion	IgA deposited in a diffuse granular pattern in the mesangium	Biopsy	-
	Hereditary nephritis (Alport syndrome)	-	-	-	-	-	-	+	-	Cataract Hearing loss	Pyuria Red cell casts Cylindrical casts	Shrunken kidneys	-	High-frequency sensorineural hearing loss	-	Monoclonal antibodies directed against alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen	Genetic Analysis	-
	Poststreptococcal glomerulonephritis	+/-	+	-	-	+	+	+	+	Edema Anemia Increased Blood Pressure	Urine samples for protein and blood	Renal Biopsy Irregularly thin and attenuated GBM Splitting of GBM Scarring	-	-	Hypercellularity of the glomeruli Endothelial and mesangial cells and migrant inflammatory cells Hyaline droplets	Immunoglobulin G and C3 in a diffuse granular pattern Starry sky pattern	Biopsy	-
	Focal segmental glomerular sclerosis	-	-	-	-	-	-	+	+	Nephrotic syndrome ESRD Pleural effusion Ascites Abdominal pain	Urinalysis reveals large amounts of protein, along with hyaline and broad waxy casts Hepatitis B or C infection Antineutrophil cytoplasmic antibody titers, serum protein electrophoresis	Shrunken kidneys	-	-	Segmental solidification in the perihilar region and peripheral areas, specially the tubular pole	Coarsely granular deposits of IgM and C3	Biopsy	-
	Rapidly progressive glomerulonephritis	+	+	+	-	-	-	+	-	Abdominal pain Painful cutaneous nodules Migratory polyarthropathy Sinusitis Cough Hemoptysis.	Low iron Eosinophilia Increased serum creatinine level Eleated LDH and CPK Proteinuria	-	-	-	Diffuse, proliferative, necrotizing glomerulonephritis with crescent formation	-	Biospy	80% of patients have ANCA-positive microscopic polyangiitis
	Lupus nephritis	-	+	-	-	-	-	+	+	Foamy dark urine Weight gain	Hematuria Pyuria Proteinuria Cellular casts Low iron	-	-	-	-	-	Biopsy	-
	Fabry disease	-	-	-	-	-	-	+	+	-	Hematuria Proteinuria	-	-	-	Non-specific+/- nephrotic picture	-	-	-
Disease		Low back pain	Fever	Nausea/ Vomiting	Dysuria	Frequency	Oliguria	Hypertension	Pitting edema	Other	Lab Findings	Ultrasonography	CT scan	Other	Light microscopy	Immunoflourescence pattern	Gold standard	Additional findings
Tubulointerstitial diseases		+	+	+	–	–	–	–	–	Rash	Eosinophilia Eosinophiluria Isosthenuria	N	Rules out obstruction, if any	–	Edema and infiltration by mononuclear cells, (principally lymphocytes) Eosinophils are present, often in large numbers.	–	Renal biopsy
Nephrolithiasis		+	±	+	±	±	±	–	–	Radiating pain to groin	Hypercalciuria Hyperoxaluria Hypocitraturia Hyperuricemia Hyperuricosuria	Hydronephrosis +/-	Diagnostic tool	–	–	–	Abdominal Ct scan without contrast	–
Reflux nephropathy (hydronephrosis)		+	+	-	-	-	-	-	+	Abdomen pain Chest pain Shortness of breath	Elevated WBC count Elevated BUN Hyperkalemia	Hydronephrosis +/-	Hydronephrosis +/- Kidney shrinkage in some cases	–	Kidney scar	–
Malignancy	Renal cell carcinoma (RCC)	-	-	-	-	-	-	±	±	Flank mass	Anemia Hematuria	Ultrasound (US) may be helpful when CT scan results are equivocal. It is noteworthy to mention that not all renal cell carcinomas are detectable on ultrasound.	Both CT and MRI may be used to detect neoplastic masses that may define renal cell carcinoma or metastasis of the primary cancer. CT scan and use of intravenous (IV) contrast is generally used for work-up and follow-up of patients with renal cell carcinoma.	The histological pattern of renal cell carcinoma depends whether it is papillary, chromophobe or collecting duct renal cell carcinoma.
	Nephroblastoma (Wilms tumor)	-	-	-	-	-	-	-	-	Abdominal pain	Anemia Hematuria	It is the best initial diagnostic study used in cases suspected with Wilms tumor. Ultrasonography can help identify the mass as a kidney mass. It can distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor.	Findings on CT scan which can be suggestive of Wilms tumor include: Heterogeneous soft-tissue density masses These masses have frequent areas of calcification (~10%) and fat-density regions Lymph node metastasis CT scan of the renal mass can further reveal: Invasion of surrounding organs Thrombus in or occlusion of the renal vein and/or the inferior vena cava Abdominal lymph nodes and contralateral involvement	Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells: Stromal Epithelial Blastemal All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Beckwith and Palmer reported in NWTS the different histopathologic types of Wilms tumor to categorize them based on prognosis. Spindled cell stroma surrounding abortive tubules and glomeruli is characteristic. The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
	Transitional cell carcinoma (TCC)	-	-	-	-	±	±	-	-		Anemia Hematuria
	Prostate cancer	-	-	-	-	±	±	-	-		Anemia Hematuria
Disease		Low back pain	Fever	Nausea/ Vomiting	Dysuria	Frequency	Oliguria	Hypertension	Pitting edema	Other	Lab Findings	Ultrasonography	CT scan	Other	Light microscopy	Immunoflourescence pattern	Gold standard	Additional findings
Familial diseases	Polycystic kidney disease	+	-	-	-	-	-	+	+	Palpable mass in the flank Palpable abdominal mass in the lumbar quadrant Palpable nodular hepatomegaly	Hypocitraturia in 65% on patients Hyperuricemia in 20% of patients Hyperoxaluria in 20% of patients Low urine pH Hematuria (microscopic or macroscopic) Proteinuria usually less than 1 g/day	Unilateral or bilateral cysts	Hyperdense appearance, Septations Calcifications	Genetic testing demonstrates: Frame insertions/deletions Non-canonical splice site alterations Combined missense changes	Interstitial fibrosis Tubular atrophy Thickening and lamellation of tubular basement membranes Microcysts	Negative immunofluorescence for complement and immunoglobulin	Ultrasound
Vascular diseases	Renal vein thrombosis	+	+	+	-	-	-	-	-	Asymptomatic Abdominal pain Acute in onset	Elevation in serum lactate dehydrogenase Cholesterol levels for hypercholesterolemia Albumin levels for hypoalbuminemia Serum complement levels	Used as diagnostic screening		Renal venography: Gold standard
	Polyarteritis nodosa	-	-/+	-	-	-	+	+	-	Fatigue Abdominal pain Unintentional weight loss Muscle aches	CBC may show: Leukocytosis Normochromic anemia thrombocytosis Hypergammaglobulinemia ESR and C-reactive protein Hepatitis B surface antigen and hepatitic C serologies
	Wegner's granulomatosis polyangiitis	-	-	-	-	-	-	+	+	URTI CNS involvement Ophthalmic involvement	Proteniuria Microscopic hematuria RBC casts	-	CT chest Multiple lung nodules Consolidation Ground-glass opacities.	+C ANCA antibodies	Subendothelial edema Microthrombosis, and Degranulation of neutrophils.	-	Biopsy
	Henoch-Schönlein purpura
Disease		Low back pain	Fever	Nausea/ Vomiting	Dysuria	Frequency	Oliguria	Hypertension	Pitting edema	Other	Lab Findings	Ultrasonography	CT scan	Other	Light microscopy	Immunoflourescence pattern	Gold standard	Additional findings
Lower urinary tract diseases	Benign prostatic hyperplasia	+/-	-	-	+	+	-	-	-	Nocturia Other voiding symptoms Slow urinary stream Splitting or spraying of the urinary stream Intermittent urinary stream Hesitancy Straining to void Terminal dribbling	Urinalysis to rule out UTI Elevated BUN/Cr High PSA values	Rule out obstruction		Urine cytology to screen for bladder cancer	Biopsy to rule out cancer
	Urolithiasis	+	+/-	+	+
	Interstitial cystitis
	Radiogenic cystitis
Systemic diseases	Coagulopathy (hemophilia)
	Sickle cell anemia
	Abdominal aortic aneurysm
	Lymphomas
	Multiple myeloma
Disease		Low back pain	Fever	Nausea/ Vomiting	Dysuria	Frequency	Oliguria	Hypertension	Pitting edema	Other	Lab Findings	Ultrasonography	CT scan	Other	Light microscopy	Immunoflourescence pattern	Gold standard	Additional findings
Infectious diseases	Pyelonephritis	+	+	+	+	+	+	-	-	Delirium Headache	Positive leukocyte esterase test and nitrite test. Blood/urine cultures	Enlarged kidneys	Round swollen kidneys Hypodense appearance Abscesses may not be present	Contrast nephrograms Focal areas of striated or wedge-shaped hypoperfusion	Neutrophils Interstitial fibrosis Renal casts	-
	Cystitis	-	-	-	+	+	+	-	-	Dyspareunia Supra pubic tenderness	Pyuria: > 5-10 WBC/hpf or 27 WBC/microliter Positive leukocyte esterase test and nitrite test. Positive urine/blood cultures	Presence of a gas in the bladder wall. Also help to detect the presence of a tumor or a stone.		MRI Fibrosed bladder with a thick wall Hydronephrosis Calcification
	Prostatitis	-	+	-	+	+	+	-	-	Body aches	Increased leukocytes (>10 per high power field) on CBC Bacteria seen on urine culture Elevated C-reactive protein Transiently elevated PSA (prostate specific antigen) levels	Focal hypoechoic region located in the peripheral part of the prostate	Edema of the prostate gland with diffuse enlargement,.	Hyperintense lesions on MRI	Neutrophils Between the epithelial cells or inside the stroma.
	Urethritis	-/-	+	-	+	+	+	-	-	Urethral discharge	Mucoid, mucopurulent, or purulent discharge Gram stain of urethral secretions demonstrating ≥2 WBC per field Positive leukocyte esterase test.	-	Diffuse, circumferential urothelial wall thickening and contrast-enhancement Periureteric or perinephric fat stranding.	-
	Epididymitis	-/+	+	+	-	-	-	-	-
Urogenital trauma	Inserted bladder or ureteral catheters