Approach to Hematuria

An approach to hematuria (unedited)

1. Approach to Hematuria Sushil Gyawali MS Resident Urology and Kidney Transplant Unit

2. Hematuria Hematuria: Greek words  haima  (blood) and  ouron  (urine) to refer to the presence of blood in the urine. Hematuria is defined as the presence of at least 5 red blood cells/HPF in 3 of 3 consecutive centrifuged specimens obtained at least 1 week apart. A diagnosis of hematuria is confirmed by demonstration of red blood cells in the urinary sediment as shown by qualitative and quantitative microscopy 

3. Types Gross or Microscopic . -Microscopic hematuria refers to the detection of blood on urinalysis or urine microscopy . -   Gross/macroscopic: presence of red or brown urine. The color change does not necessarily reflect the degree of blood loss, since as little as 1 mL of blood per liter of urine can induce a visible color change. I ntermittent or persistent. Painful or Painless -Asymptomatic or symptomatic and may be associated with other urinary tract abnormalities

4. According to Timing (when it occurs during urination):  Early (initial) haematuria : Urethral origin, distal to external Sphincter  Terminal haematuria : Bladder neck or prostate origin  Diffuse (total) haematuria : Source is in the bladder or upper urinary tract

5. Pathophysiology • Glomerular • Non glomerular   False hematuria: Discolouration of urine from pigments such as food colouring and myoglobin.   Silent hematuria is due to tumours of kidney or bladder unless proved otherwise.

6. Etiology Glomerular   TubuloInterstitial    Uroepithelium    Vascular Systemic diseases Infections

7. Glomerular causes Thin basement membrane disease (benign familial hematuria ) Alport Syndrome IgA nephropathy HUS Postinfectious glomerulonephritis Membranoproliferative glomerulonephritis Lupus Nephritis Henoch- Schonlein Purpura

8. Tubulointerstitial disease Papillary necrosis Interstitial nephritis Analgesic nephropathy Nephrolithiasis Reflux nephropathy Hydronephrosis Ureteropelvic junction obstruction

9. Uroepithelium Malignancy    Trauma   Papillary Necrosis   Cystitis/Urethritis/Prostatitis  (UTI)   Parasitic Diseases (Schistosomiasis)   Stones  

10. Vascular Arterial emboli or thrombosis   Arteriovenous fistulae   Renal vein thrombosis Renal Infarction Malignant hypertension Vasculitis (Henoch– Schonlein purpura, periarteritis nodosa , ¨ Wegener granulomatosis)

11. Other causes : Fever Strenuous exercise Mechanical trauma Menstruation Foreign bodies Instrumentation/ Cathetarization Hypercalciuria //Hyperuricosuria Sickle cell disease/trait Coagulopathy Drugs/toxins :NSAIDs, anticoagulants, cyclophosphamide, ritonavir, indinavir , sulfonamide, phenytoin Anatomic abnormalities: ( hydronephrosis , polycystic kidney disease, vascular malformations ) Diseases of adjacent organs to urinary tract: Appendicitis, carcinoma of the rectum, carcinoma of the colon, uterocervical cancer

12. Initial Approach a history and physical examination to assess risk factors for genitourinary malignancy, medical renal disease, gynecologic and non-malignant genitourinary causes of microhematuria . (AUA guidelines)

13. Detailed History Efforts should be made to distinguish glomerular causes from extraglomerular one : Passage of clots in urine suggests an extraglomerular cause Fever , abdominal pain, dysuria, frequency, and recent enuresis in older children may point to a urinary tract infection as the cause Recent trauma to the abdomen may be indicative of hydronephrosis Early-morning periorbital puffiness, weight gain, oliguria, dark-colored urine, and edema or hypertension suggest a glomerular cause, Hematuria due to glomerular causes is painless Recent throat or skin infection may suggest postinfectious glomerulonephritis

14. Joint pains, skin rashes, and prolonged fever in adolescents suggest a collagen vascular disorder(Rheumatoid arthritis, Systemic lupus erythematosus) Skin rashes and arthritis can occur in Henoch- Schönlein purpura and systemic lupus erythematosus Information regarding exercise, menstruation, recent bladder catheterization, intake of certain drugs or toxic substances, or passage of a calculus may also assist in the differential diagnosis. A family history that is suggestive of Alport syndrome, collagen vascular diseases, urolithiasis , or polycystic kidney disease is important

15. Examination: BP and volume status is especially important when glomerulonephritis is a consideration . periorbital puffiness or peripheral edema : nephrotic syndrome Detailed skin examination to look for purpura . Abdomen: palpable mass reveals a renal tumor or hydronephrosis may exist, A palpable bladder after voiding indicates obstruction or retention Abdominal bruit: AAA Always check for extrarenal manifestations and co morbid conditions. Check for other sites of bleeding

16. PR/DRE: prostatitis , prostate cancer, BEP Genitalia: epididymitis , meatal stenosis, and other structural causes of hematuria; signs of trauma Atrial fibrillation : renal artery embolic infarction, especially if the patient has flank pain Costovertebral angle tenderness : pyelonephritis , nephrolithiasis, or PUJ obstruction . Detailed ophthalmologic evaluation (in familial hematuria)

17. Diagnosis Urine dip strip analysis it is the most commonly used method of testing the urine for blood is the urine test strip or dipstick, which utilizes the peroxidase-like activity of hemoglobin to generate a color change. Dipstick: pH , glucose, protein, blood, bilirubin -also u seful screening test for diabetes, ketones, nitrates renal and hepatic disease the simplest and most common test ,91 %–100% sensitive and 65%–99% specific for detecting more than three RBCs per hpf ( Woolhandler et al., 1989). False-positive tests(up to 35%) may occur in the setting of myoglobinuria or hemoglobinuria, , semen, highly alkaline urine (pH greater than 9), and concentrated urine. , confirmed by the absence of RBCs on microscopic examination . False Negative: Vit C intake

18. Urinalysis Microscopic examination of the urinary sediment (urinalysis) is the gold standard test . It not only detects the presence of RBCs, but also the morphologic features of RBCs, the presence of white blood cells (WBCs), casts, or crystals, hence it is helpful in distinguishing glomerular and nonglomerular causes of hematuria. presence of dysmorphic RBCs (irregular outer cell membrane of RBCs), RBC casts, or proteinuria supports a diagnosis of hematuria of glomerular origin.

19. Glomerular hematuria : Brown-colored urine, RBC casts, and dysmorphic (small, deformed, misshapen, sometimes fragmented) RBCs and proteinuria Nonglomerular hematuria : Reddish or pink urine, passage of blood clots, and eumorphic /isomorphic (normal-sized, uniform, biconcavely shaped) RBCs.

20. If proteinuria is detected on a dipstick test, a random or 24-h quantitative measurement can be done. Proteinuria >500 mg/24 h or urinary protein concentration to urine creatinine ratio >0.3 on random specimen is typically associated with glomerular disease . If clinically significant proteinuria or elevated serum creatinine is present, the patient should be referred to a nephrologist.

21. Phase-contrast microscopy to help determine the source of the bleeding ( urine for the presence of a significant number of dysmorphic RBCs suggests a renal (glomerular) source of the hematuria) Hematologic and coagulation studies ( eg,CBC , platelet counts, PT/INR) Blood urea nitrogen (BUN) for paraneoplastic syndrome and serum Cr levels for kidney failure . RFT, PSA, Serologic testing ( eg , complement, antistreptolysin [ASO], anti- DNase B, antinuclear antibody [ANA], and double-stranded DNA [dsDNA]) Urine culture for suspected UTI: midstream or clean-catch specimen

22. Imaging Xray KUB: Detect bony metastases, paget’s disease, soft tissue masses, abnormal calcification  USG abd /pelvis: Assessment of renal and scrotal masses and bladder emptying  CT urography (replaces IVU): Delineates entire urinary tract MRI Retrograde pyelography. TRUS: prostate disease Voiding cystourethrography Cystoscopy Renal biopsy: in nephrological cases

23. Ultrasound/USG Macroscopic hematuria in the absence of significant proteinuria or RBC casts is an indication for a renal and bladder ultrasound study to exclude malignancy or cystic renal disease . Urinary tract anomalies, such as hydronephrosis , hydroureter , nephrocalcinosis , tumor, and urolithiasis , are readily revealed with ultrasonography. Advantage: Compared with other imaging studies, sonography is rapid, noninvasive, readily available, and devoid of exposure to radiation. Disadvantage: USG is less sensitive (50% sensitive and 95% specific) in detecting urothelial lesions, small renal masses, and urinary calculi. User dependent; diagnostic uncertainty , and may lead to indeterminate findings that result in additional imaging and costs

24. CT Urography  it combines the benefits of conventional CT (with and without contrast) and IVU . a noncontrast phase to diagnose hydronephrosis and urinary calculi, a nephrogenic phase to evaluate the renal parenchyma for pyelonephritis or neoplastic lesions, and an excretory phase to detect urothelial disease, appearing as filling defects. CT urography is the imaging procedure of choice in the evaluation of microscopic hematuria because of its high sensitivity (91% to 100%) and specificity (94% to 97%), and its ability to provide excellent diagnostic information in a single imaging session .   |Spiral CT scan is particularly useful in the detection of urolithiasis , Wilms tumor, and polycystic kidney disease.  Major concern: radiocontrast exposure

25. The appropriate upper tract imaging method should be determined by clinical circumstances, patient preferences, and available resources. 

26. Evaluation for lower tract Cystoscopy is recommended in all patients with asymptomatic microscopic hematuria who present with risk factors for malignancy, regardless of age.  Cystoscopy can identify urethral stricture disease, benign prostatic hyperplasia, and bladder masses . In patients younger than 35 years, the probability of urinary tract malignancy is low; therefore, in the absence of risk factors, cystoscopy should be performed at the discretion of the urologist.

27. Urine cytology Cytologic examination of exfoliated cells within the urine is currently a noninvasive and cost-effective test for detecting urothelial malignancy . Early morning urine specimen Sensitivity of 40%–76%, depending on the stage of malignancy and the expertise of the cytopathologist . Sensitivity is higher if the specimen tested is obtained from the first void in the morning on three consecutive days or bladder wash during cystoscopy. high specificity; hence, positive urinary cytologies are almost diagnostic of urothelial malignancy (Yun et al., 2004 ) The American Urological Association recommends that for those who refuse cytoscopy or are considered at low risk for malignancy, voiding urine cytologic testing alone can be done ( Grossfeld et al., 2001b )

28. Patients at high risk for uroepithelial tumors should undergo complete evaluation with cystoscopic examination of the bladder. There are new, rapid urinary assays available for bladder cancer detection (e.g., nuclear matrix protein 22 test, bladder tumor antigen stat test, urinary bladder cancer antigen, fluorescence in situ hybridization ), but these have not been shown to be superior to cystoscopy or cytology in the initial detection of urothelial malignancies and should not be obtained by primary care physicians

29. Functional studies  Function Radioisotope renography : Assess function of each kidney separately -DTPA-99mTc-dimercaptosuccinic acid, -DMSA- diethylenetriamine pentaacetic acid . Urodynamics : Voiding cystourethrograms are valuable in detecting urethral and bladder abnormalities that may result in hematuria ( eg , cystitis). - Urine flow rates: Useful is assessing degree of obstruction to micturition  Cystometry (static and ambulant): differentiate stress and urge incontinence

30. Biopsy Kidney biopsy is rarely indicated: Significant proteinuria Abnormal renal function Recurrent persistent hematuria Serologic abnormalities (abnormal complement, ANA, or dsDNA levels) Recurrent gross hematuria A family history of end-stage renal disease Hematuria workup: Dr Sanjeev Gulati et al; Medscape May10, 2020

31. Management: Hematuria is a sign and not itself a disease; thus, therapy should be directed at the process causing it Asymptomatic (isolated) hematuria generally does not require treatment. In conditions associated with abnormal clinical, laboratory, or imaging studies, treatment may be necessary, as appropriate, with the primary diagnosis

32. Surgical intervention may be necessary with certain anatomic abnormalities ( eg ,  ureteropelvic junction obstruction, tumor, or significant urolithiasis ) Dietary modification is usually not indicated, except for children who may tend to develop hypertension or edema as a result of the primary disease process ( eg , nephritis ) Patients with persistent microscopic hematuria should be monitored every 6-12 months for the appearance of signs or symptoms indicative of progressive renal disease

33. Risk stratification ( AUA guidelines on hematuria 2020)

34. In low-risk patients : repeating urinalysis within six months or proceeding with cystoscopy and renal ultrasound.  Low-risk patients who initially elected not to undergo cystoscopy or upper tract imaging and who are found to have microhematuria on repeat urine testing should be reclassified as intermediate- or high-risk. In such patients, clinicians should perform cystoscopy and upper tract imaging in accordance with recommendations for these risk strata.

35. Intermediate risk : cystoscopy and renal ultrasound in patients with microhematuria categorized as intermediate-risk for malignancy.  High risk: cystoscopy and axial upper tract imaging (CT Urography or MRI) in patients with microhematuria categorized as high-risk for malignancy.

36. In patients with a negative hematuria evaluation , clinicians may obtain a repeat urinalysis within 12 months . For patients with a prior negative hematuria evaluation who develop gross hematuria , significant increase in degree of microhematuria , or new urologic symptoms, clinicians should initiate further evaluation. 

37. Asymptomatic Hermaturia (AMH) Microscopic hematuria in the absence of an obvious benign cause assessment include a careful history, physical examination, and laboratory examination to rule out benign causes of AMH such as infection, menstruation, vigorous exercise, medical renal disease, viral illness, trauma, or recent urological procedures .   then the presence of asymptomatic microhematuria should prompt a urologic evaluation: cystoscopic evaluation for age 35 and older & who present with risk factors for urinary tract malignancies (e.g., irritative voiding symptoms, current or past tobacco use, chemical exposures) regardless of age. AUA Guidelines, 2016

38. Initial evaluation with imaging: CT Urography, MRI  In patients with persistent microhematuria following a negative work up or those with other risk factors for carcinoma in situ (e.g., irritative voiding symptoms, current or past tobacco use, chemical exposures), cytology may be useful.  For persistent asymptomatic microhematuria after negative urologic work up, yearly urinalyses should be conducted.

39. Dutch Guideline 2018

40. Follow-up If appropriate workup does not reveal nephrologic or urologic disease, then annual urinalysis should be performed for at least two years after initial referral . If these two urinalyses do not show persistent hematuria, the risk of future malignancy is less than 1 %, and the patient may be released from care. However , if asymptomatic microscopic hematuria persists on follow-up urinalysis, a full repeat evaluation should be considered within three to five years of the initial evaluation .  Patients' risk factors for urologic malignancy should guide clinical decision making about reevaluation

41. Take home message Every case of hematuria requires investigation. Macrohematuria requires more extensive investigation. Because of the lack of high-quality scientific evidence, there are no consistent guideline recommendations for the investigation of hematuria, especially asymptomatic microhematuria . Findings of red cell casts, large numbers of dysmorphic red blood cells, or more than 5% acanthocytes indicate the presence of glomerular hematuria, which requires a nephrology referral. For a basic investigation, for all patients a history should be taken and clinical and laboratory tests carried out, and possibly also red cell morphology studies and renal and bladder ultrasonography. Patients who have been exposed to exogenous toxins (including tobacco smoke), are older, are of male sex, or have macrohematuria , should be further investigated by urethrocystoscopy and perhaps CT urography.

42. References Sharp VJ, Barnes KT, Erickson BA. Assessment of asymptomatic microscopic hematuria in adults.  Am Fam Physician . 2013;88(11): 747-754 Shen X. Diagnostic algorithm for the evaluation of hematuria.  J Am Acad Nurse Pract . 2010;22(4):186-191. Bolenz C, Schröppel B et al. The Investigation of Hematuria. Dtsch Arztebl Int. 2018 Nov 30;115(48):801-807. American Urological Association Guidelines : Microhematuria : AUA/SUFU Guideline 2020