Evaluation of the Hematuria,

Evaluation of the Hematuria,
Muhammad Y Ebrahim, MD. Consultant Nephrologists SRMC & MBH Director of inpatient dialysis at SRMC, SRCH & MBH. Co-medical director at out patient dialysis unit at Dialysis & Clinics Inc DCI. Chief Department of Nephrology at SRMC.

HEMATURIA

Hematuria Transient phenomenon of little significance Sign of serious
renal disease

Definition Macroscopic (gross) Hematuria Microscopic Hematuria
4/28/2017 Definition Macroscopic (gross) Hematuria any discolored urine visible to the human eye Microscopic Hematuria >5 RBC/hpf seen under microscope 50 RBC per microliter of unspun urine on a dipstick is also suggestive of hematuria RBC seen on dipstick must be confirmed with an U/A microscopic urine is done on fresh centrifuged urine sample

Classification of hematuria
Macroscopic - Microscopic Symptomatic - Symptomless Transient - Persistent According to the act of void: -Initial. -Terminal. -Total. Initial – see blood in the first part of your pee Terminal – see blood in the last part of your pee Total – see blood all throughout your pee while peeing

Microscopic Hematuria
Definition > 3-5 RBC/HPF > 5 RBC/mm³ > 8000 RBC/ml

According to the amount of RBC in the urine, hematuria can be classified as:
microscopic hematuria: normal color with eyes gross hematuria: tea-colored, cola-colored, pink or even red Skipped

Glomerular or Extra Glomerular bleeding?

Glomerular versus extra glomerular bleeding
Urinary finding Glomerular Extraglomerular Red cell casts May be present Absent Red cell morphology Dysmorphic Uniform Proteinuria Clots Color May be red or brown May be red Clots absent up upper, present in lower Color is not impt bc it varies Some situations of nephritic GN may have more blood and less protein (such as in PIGN) or vice versa (like with FSGS)

Glomerular Vs extra glomerular
Ex. Someone that has antiphospholipid Ab syndrome (someone who is hypercoaguable), or someone with lupus  they make clots, but do NOT have clots with the hematuria With stone or some kind or bladder lesion (____ carcionma), bladder pathology, cancer, etc… cause total bleeding in all three samples

Causes of Hematuria Kidney disease Lesions along the urinary tract
Conditions unrelated to kidney and urinary tract

Hematuria not representing kidney or urinary tract disorder
Following exercise Febrile disorders Gastroenteritis with dehydration Contamination from external genitalia

Exercise induced hematuria:
Jogging at a high altitude they are not accustom to and not drinking water, and worse if have sickle cell disease

Exercise induced hematuria

Renal causes of Hematuria
Glomerular - Acute Post infectious Glomerulonephritis - IgA Nephropathy - Hereditary Nephritis ( Alport syndrome) - Benign Recurrent or Persistent Hematuria ( Thin Membrane Disease ) 1.Sporadic 2.Familial - Membranoproliferative Glomerulonephritis - Crescentic Glomerulonephritis - Lupus Nephritis - Nephritis of Henoch-Shönlein Purpura - Focal Glomerulosclerosis - Hemolityc-Uremic Syndrome Acute Post infectious Glomerulonephritis - see after sore throat (6-10 days later) IgA Nephropathy Painless microscopic hematuria (why he does routine analysis) Usually in young adult Most common cause world wide for GN lesions Hereditary Nephritis ( Alport syndrome) Alport – assoc with deafness -Benign Recurrent or Persistent Hematuria ( Thin Membrane Disease ) = TBM 1.Sporadic 2.Familial Need to know when or when not to do biopsy Usually benign Membranoproliferative Glomerulonephritis Assoc with Hep Esp Hep C but it I can be B too Nephritic  more blood than protein Lupus Nephritis Can be nephretic (concentric?) or nephrotic (membranous) Tx will differ according to the disease FSGS use to be a disease of AA pts, but now rises in other races Usually in white fat peeps Also seen with HIV called _____  a collapsing kind of GN Progress to dialysis quickly No effective tx S s

Renal causes of Hematuria
Non-glomerular - Infection ( Pyelonephritis ) - Interstitial Nephritis - Metabolic ( Uric Acid, Nephrocalcinosis ) - Renal Malformation ( Cystic Kidney ) - Tumors ( Wilm’s, Acute Leukemia) - Idiopatic Hypercalciuria - Trauma

Causes of urinary tract related Hematuria
Infection Urolithiasis Obstruction ( UPJ Stenosis ) Trauma Drugs ( Cyclophosphamide ) Tumors

Isolated Hematuria (microscopic)
No other urinary abnormalities No renal insufficiency No evidence for systemic disease Incidence ( school-aged children ) 4-6% - single urine examination 0.5-1% - repeated testing over 6-12 months Like with IgA nephropathy Benign, doesn’t progress, but it is not transient and is persistent… It just doesn’t normally lead to renal failure ***

Etiologies of isolated Hematuria
Glomerular - Benign Recurrent or Persistent Hematuria 1.Sporadic 2.Familial - IgA Nephropathy - Alport syndrome - PSAGN (post strep) Non-glomerular - Idiopathic Hypercalciuria - Cystic Kidneys - Urinary Tract obstruction - Tumors - Trauma Yellow – most common Make sure hypercalcinurea is not the cause of their hematuria

Hematuria with familial association
Glomerular - Benign Familial Hematuria - Alport syndrome Non-glomerular - Idiopathic Hypercalciuria - Polycystic Kidney Disease - Urolithiasis - Tumors IgA may have assoc

Gross hematuria: Suspected if a red or brown color change of urine
Intermittent red or brown color urine a/w variety of clinical setting Medications (phenazopyridine, microbid, NSAID) Ingestion of beets or certain dyes Metabolities Myoglobinuria or hemoglobinuria If pass clot, indicate lower urinary source If you see a lot of blood in the urine, but not a lot of RBC, points towards rhabdomyolysis

Work up Centrifuge the specimen,
Supernatant be tested for heme (hemoglobin or myoglobin) with a urine dipstick.

Causes of heme-negative red urine
Medications Food dyes Metabolities Doxorubicin Beets (in selected patients) Bile pigments Chloroquine Blackberries Homogentisic acid Deferoxamine Food coloring Melanin Ibuprofen Methemoglobin Iron sorbitol Porphyrin Nitrofurantoin Tyrosinosis Phenazopyridine Urates Phenolphthalein Rifampin Rifampin Pink color Ibuprofen very common

Approach to the patient with red or brown urine
Spent time explaining this slide Questions on this shit If sediment is red  diag for hematuria and needs further workup Do a dipstick if supernatant is red  not blood +  myoglobuin if clear, hemoglobin if red Ex. Of question  pt took a drug that is known to cause muscle breakdown and then come in with cramping, myalgia, renal failure, and had a large amt of blood in urine with few RBCs = rhabdomyolysis

Definition of Microscopic Hematuria
More than three red blood cells are found in centrifuged urine per high-power field microscopy ( > 3 RBC/HP).

Microscopic hematuria:
Accidental finding from UA or urine dipstick 3 or more RBC/hpf in spun urine sediment. No "safe" lower limit below which significant disease can be excluded Often asymptomatic The degree of hematuria does not correlate with the seriousness of the underlying cause of the bleeding.

Diagnosis: The urine sediment is the gold standard for the detection of microscopic hematuria Dipsticks for heme are as sensitive as urine sediment examination, but result in more false positive tests due to the following Semen is present in the urine after ejaculation An alkaline urine with a pH greater than 9 or contamination with oxidizing agents used to clean the perineum. The presence of myoglobinuria. A positive dipstick test must always be confirmed with microscopic examination of the urine

3. Is the hematuria transient or persistent?
The evaluation should address the following three questions 1. Are there any clues from the history or physical examination that suggest a particular diagnosis? 2. Does the hematuria represent glomerular or extraglomerular bleeding? 3. Is the hematuria transient or persistent? 16 TI Clinical practice. Microscopic hematuria. AU Cohen RA; Brown RS SO N Engl J Med 2003 Jun 5;348(23):

a three-tube test may also help to locate the source of bleeding in selected cases.
Urethral: First mL Bladder: Final mL Upper urinary tract: Throughout

History and Physical

Important questions to ask in patients History
Has there been any signs of a UTI as dysuria & frequency? Any suprapubic pain? Has there been any recent URI symptoms or sore throat? Has there been any type of skin rashes or sores? Any abdominal pain or colicky pain? Are the stools loose or bloody? Has there been any recent trauma? Has there been any joint pains or swellings? Is there any history of sickle cell disease or trait? Is there any family history of renal disease, transplants, or dialysis? Is there a family history of hearing deficits? What medications does the child take? Post strep – occurs weeks after sore throat IgA neph – occurs concurrently SLE – skin rash, joints, pain, swelling HUS (?) – abdominal pain

Family history: Hematuria , Hearing loss, (Alports) HTN, Stones,
Renal disease, Dialysis or transplant, Sickle cell trait *: Coagulopathy,

Medication Hx Substances and Medications Affecting Urine Color
Artificial food coloring Beets Berries Chloroquine (Aralen) Furazolidone (Furoxone) Hydroxychloroquine (Plaquenil) Nitrofurantoin (Furadantin) Phenazopyridine (Pyridium) Phenolphthalein Rifampin (Rifadin) .

Mechanisms by Which Selected Drugs May Cause Hematuria
Medication History: Mechanisms by Which Selected Drugs May Cause Hematuria Interstitial nephritis Captopril (Capoten) Cephalosporins Chlorothiazide (Diuril) Ciprofloxacin (Cipro) Furosemide (Lasix) NSAIDs Olsalazine (Dipentum) Omeprazole (Prilosec) Penicillins Rifampin (Rifadin) Silver sulfadiazine (Silvadene) Trimethoprim-sulfamethoxazole (Bactrim, Septra Papillary necrosis Acetylsalicylic acid (aspirin) NSAIDs Hemorrhagic cystitis Cyclophosphamide (Cytoxan) Ifosfamide (Ifex) Mitotane (Lysodren) Urolithiasis Carbonic anhydrase inhibitors Dichlorphenamide (Daranide) Indinavir (Crixivan) Mirtazapine (Remeron) Ritonavir (Norvir) Triamterene (Dyrenium) Interstitial nephritis See eosinophil casts

Important areas to check on the physical examination
Blood Pressure Check for edema, especially around the eyes (Esp in the morning) Careful inspection of the external genitalia Look for any rashes, evidence of trauma and bruising, petechiae Exam all joints for signs of arthritis-red, warm, or swollen Feel the abdomen carefully for any masses or tenderness. Check for CVA tenderness. Try to feel for enlarged kidneys. Check for evidence of paleness or jaundice Accurately measure length and weight and plot on growth chart. Can try to feel the kidney if they are thin (but usually people are fat)

Physical Examination Findings and Associated Causes of Hematuria
Cause of hematuria General (systemic) examination Severe dehydration Renal vein thrombosis Peripheral edema Nephrotic syndrome, vasculitis Cardiovascular system Myocardial infarction Renal artery embolus or thrombus Atrial fibrillation Hypertension Glomerulosclerosis with or without proteinuria Abdomen Bruit Arteriovenous fistula Genitourinary system Enlarged prostate Urinary tract infection Phimosis Meatal stenosis Valve leak (esp if mechanic value), blood can leak around that and cause hemolysis  hematuria

Clues from the history that point toward a specific diagnosis:
Concurrent pyuria and dysuria, indicate UTI, may also occur with bladder malignancy. 2. A recent URI, raise the possibility of either post infectious glomerulonephritis or IgA nephropathy 3. A positive family history of renal disease give suspicion of hereditary nephritis, polycystic kidney disease, or sickle cell disease. 4. Unilateral flank pain radiating to the groin, suggesting ureteral obstruction due to a calculus or blood clot, but can occasionally be seen with malignancy. Flank pain that is persistent or recurrent can also occur in the rare loin pain hematuria syndrome. 5. Symptoms of prostatic obstruction in older men such as hesitancy and dribbling. The cellular proliferation in BPH is associated with increased vascularity, and the new vessels can be fragile. Concurrent pyuria and dysuria, which are usually indicative of a urinary tract infection, but may also occur with bladder malignancy. A recent upper respiratory infection, suggesting either postinfectious glomerulonephritis or IgA nephropathy (see "Hematuria following an upper respiratory infection"). A positive family history of renal disease, as in hereditary nephritis, polycystic kidney disease, or sickle cell disease. Unilateral flank pain, which may radiate to the groin, suggesting ureteral obstruction due to a calculus or blood clot, but can occasionally be seen with malignancy. Flank pain that is persistent or recurrent can also occur in the rare loin pain hematuria syndrome. (See "Loin pain hematuria syndrome"). Symptoms of prostatic obstruction in older men such as hesitancy and dribbling. The cellular proliferation in benign prostatic hyperplasia (BPH) is associated with increased vascularity, and the new vessels can be fragile. There is some controversy about whether hematuria is more common in these patients than in age-matched controls [11,17] . However, there is general agreement that the presence of BPH should not dissuade the clinician from pursuing further evaluation of hematuria, particularly since older men are more likely to have more serious disorders such as cancer of the prostate or bladder. Among those with gross hematuria in whom no other cause can be identified, finasteride usually suppresses the hematuria [18,19] . (See "Medical treatment of benign prostatic hyperplasia"). Recent vigorous exercise or trauma (see "Exercise-induced hematuria"). History of a bleeding disorder or bleeding from multiple sites due to uncontrolled anticoagulant therapy. In contrast, it should not be assumed that hematuria alone can be explained by chronic warfarin therapy. In one report of 243 patients prospectively followed for two years, the incidence of hematuria was similar to that in a control group not receiving warfarin [20] . Furthermore, evaluation of patients who developed hematuria revealed a genitourinary cause in 81 percent of cases. Infection was most common, but papillary necrosis, renal cysts, and several malignancies of the bladder were also found. A smaller study found significant urinary tract disease in nine of 30 patients, two of whom had bladder cancer [21] . These observations indicate that hematuria in an anticoagulated patient should generally be evaluated in the same fashion as in other patients unless there is evidence of bleeding from multiple sites with markedly abnormal coagulation studies. Cyclic hematuria in women that is most prominent during and shortly after menstruation, suggesting endometriosis of the urinary tract [22] . Contamination with menstrual blood is always a possibility, and should be ruled out by repeating the urinalysis when menstruation has ceased. Medications that might cause nephritis (usually with other findings, typically with renal insufficiency). Black patients should be screened for sickle cell trait or disease, which can lead to papillary necrosis and hematuria. (See "Renal manifestations of sickle cell disease"). Travel or residence in areas endemic for Schistosoma hematobium, or tuberculosis. Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases. 22 Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case A 34-year-old woman with endometriosis and bilateral hydronephrosis. N Engl J Med 1992; 327:481.

Clues from the history that point toward a specific diagnosis:
6. Recent vigorous exercise or trauma 7. History of a bleeding disorder or bleeding from multiple sites due to uncontrolled anticoagulant therapy. 8. Cyclic hematuria in women that is most prominent during and shortly after menstruation, suggesting endometriosis of the urinary tract . 9. Medications that might cause nephritis (usually with other findings, typically with renal insufficiency). 10. AA should be screened for sickle cell trait or disease, which can lead to papillary necrosis and hematuria. 11. Travel or residence in areas endemic for Schistosoma hematobium . 12.Sterile pyuria with hematuria, which may occur with renal tuberculosis, analgesic nephropathy and other interstitial diseases. Watch out w pts on coumadin

Glomerular or Extra Glomerular bleeding?

Glomerular versus extra glomerular bleeding
Urinary finding Glomerular Extraglomerular Red cell casts May be present Absent Red cell morphology Dysmorphic Uniform Proteinuria Clots Color May be red or brown May be red Same slide as earlier

Dysmorphic erythrocytes are characterized by an irregular outer cell membrane and suggest hematuria of glomerular origin. Red blood cell casts are also associated with a glomerular cause of hematuria. Erythrocytes of uniform character are classified as isomorphic and suggest hematuria of lower urinary tract origin. Microscopic clots of clumped erythrocytes in urine are also suggestive of lower urinary tract bleeding.

Microscopic hematuria DDx
Glomerular ARF primary nephritis (post streptococcal glomerulonephritis, Ig A nephropathy, Anti-GBM disease) 2nd nephritis(SLE, goodpasture’s syndrome, ANCA related vasculitis) Alport’s syndrome (hereditary nephritis) thin basement membrane nephropathy (benign familial hematuria)

Microscopic hematuria DDx
non glomerular Renal malignancy vascular disease (malignant hypertension, AVM, nutcracker syndrome, renal vein thrombosis, sickle cell trait/disease, papillary necrosis) infection (pyelonephritis, TB, CMV, EBV) hypercalciuria hereditary disease (polycystic kidney disease, medullary sponge kidney) Nonrenal malignancy (prostate, ureter, bladder) BPH Nephrolithiasis Coagulopathy Trauma

Rare cause of Microscopic Hematuria
Arteriovenous malformations and fistulas Nutcracker syndrome Loin pain-hematuria syndrome Nutcracker syndrome Renal vein trapped between superior mesenteric artery - hematuria Loin pain  disease of exclusion

Arteriovenous malformations and fistulas — An AV malformation (AVM) or fistula of the urologic tract may be either congenital or acquired. The primary presenting sign is gross hematuria, but high-output heart failure and hypertension also may be seen . The latter is presumably due to activation of the renin-angiotensin system resulting from ischemia distal to the AVM Nutcracker syndrome — The nutcracker syndrome refers to compression of the left renal vein between the aorta and proximal superior mesenteric artery. Nutcracker syndrome can cause both microscopic and gross hematuria, primarily in children (but also adults) in Asia . The hematuria is usually asymptomatic but may be associated with left flank pain. Nutcracker syndrome has also been associated with orthostatic proteinuria. Lets say a middle age female comes into the office with low grade proteinuria Loin pain-hematuria syndrome — The loin pain-hematuria syndrome is a poorly defined disorder characterized by loin or flank pain that is often severe and unrelenting, and hematuria with dysmorphic red cell features suggesting a glomerular origin. Affected patients usually have normal kidney function.

Transient or persistent hematuria

Transient hematuria Exception:
Transient microscopic hematuria is a common problem in adults Fever, infection, trauma, and exercise are potential causes It is reasonable to repeat an abnormal urinalysis in a few days Exception: Malignancy risk in older patients with transient hematuria In older patients, even transient hematuria carries an appreciable risk of malignancy (assuming no evidence of glomerular bleeding) The risks includes : age >50, smoker and Hx of analgesic abuse. Impt slide Esp if transient hematuria is isomorphic

When persistent hematuria is essentially the only manifestation of glomerular disease, one of three disorders is most likely IgA nephropathy, in which there is often gross hematuria, and sometimes a positive family history but without any clear pattern of autosomal inheritance Alport syndrome (hereditary nephritis), in which gross hematuria can occur in association with a positive family history of renal failure, and sometimes deafness or corneal abnormalities. Thin basement membrane nephropathy (also called thin basement membrane disease or benign familial hematuria), in which gross hematuria is unusual and the family history may be positive (with an autonomic dominant pattern of inheritance) for microscopic hematuria but not for renal failure . TBM – blood seeps through thin membrane

Laboratory Tests (initial work up)
Repeat UA in a few days UA and microscopy to determine the number and morphology of RBC, crystal and casts, Consider urine Cx CBC, PT, INR, electrolytes, kidney function Further urologic evaluation is warranted if more than three RBC/phf are found on at least 2 of 3 properly collected urine specimens or if high-grade microscopic hematuria (>than 100 red blood cells per high-power field) is found on a single urinalysis.17 Serum chemistries and serologic studies for glomerular causes of hematuria as directed by the medical history ANA, C3 , C4, Hepatitis B and C, HIV, ESR, Anti DNA and other lupus studies, ASO, ANCA, AntiGBM antibodies, SPEP, UPEP, M spike. Imaging stuidies like US kidney and Bladder . CT Scan, MRI , MRA, Renal angiogram , IVP, Cystoscopy, Retrograde Pyelogram, kidney biopsy Consultation to Nephrologist or Urologist SPEP, UPEP – meiloma May recheck UA, but consider cytology and check for lupus, HIV, etc…

Radiologic and other tests for the evaluation of hematuria
Advantages Disadvantages Intravenous pyelogram (IVP) Excellent visualization of the kidney, collecting system, and ureter May miss bladder lesions; can cause nephrotoxicity, idiosyncratic reactions (1/10,000) Cystoscopy Best way to examine the bladder, which is not as well visualized by IVP or ultrasound Invasive, uncomfortable and expensive Ultrasound If of good quality, as sensitive as IVP for renal lesions, with less morbidity and cost Less sensitive than IVP for ureter and bladder Retrograde pyelography The best test for examing the ureters, can be combined with cystoscopy Invasive, not useful for examining other parts of the urinary collecting system Urinary cytology Sensitivity 67 percent, specificity 96 percent for uroepithelial cancer Useful only for cancer, mainly of the bladder CT scan Excellent for examining the renal parenchyma Expensive Angiography Useful for gross hematuria when other tests have not revealed the cause; the only good test for vascular malformations Invasive, expensive If CrCl <30 don’t use MRA with dec kidney function (gallium) or can cause nephritic systemic fibrosis

Renal Biopsy: A biopsy is not usually performed for isolated glomerular hematuria (i.e., no proteinuria or renal insufficiency,) since there is no specific therapy for these conditions, unless the patient is considering becoming a kidney donor However, biopsy should be considered if there is evidence of progressive disease as manifested by an elevation in the plasma creatinine concentration, increasing protein excretion, or an otherwise unexplained rise in blood pressure, even when the values remain within the normal range. Do biopsy with intent to treat Do if they have elevated creatinine Can do with normal creatinine if there is hematuria + proteinuria or hematuria + renal shit getting worse Can do in DM pt with diabetic neuropathy if they have sig changes in proteinuria There are risk of a biopsy, but they are low don’t just do if isolated hematurea and no proteinema (no specific tx anyways) If they had both you would do biopsy bc there is tx for that

Initial Evaluation of Asymptomatic Microscopic Hematuria*
Adapted with permission from Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter DC, Carroll P. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy recommendations. Part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001;57(4) (In press). 1st make sure this is benign Check to see if signs of primary renal disease are present (proteinuria, RBC casts, high creatinine, etc…) Shit gets worse Go to nephrology and get workup Of no renal disease present, no other reason they should have this menaturia, can do cystoscopy and make sure nothing else is going on

HEMATURIA --Approaching to the patient– proteinuria (>500mg/24h)
(Harrison’s Principle of Internal Medicine,14th Ed) HEMATURIA proteinuria (>500mg/24h) Dysmorphic RBC or RBC casts (-) (+) (+) Pyuria,WBC casts urine culture eosinophils serologic and hematologic evaluation: blood culture, anti-GBM Ab, ANCA, complement, cryoglobulin HBV,HCV,VDRL,HIV, ASLO (-) Hb electrophoresis, urine cytology, UA of family member, 24h urinary calcium/uric acid (-) As indicated: retrograde pyelography or arteriogram of cyst aspiration (+) IVP+/-renal ultrasound renal biopsy (-) (+) cystoscopy biopsy (-) CT scan ANCA:antineutrophil cytoplasmic antibody, VDRL:venereal dis. research laboratory, ASLO: antisteptolysin O, IVP: intravenous pyelography (+) open renal biopsy (-) follow

Hematuria and Proteinuria combined:
4/28/2017 Hematuria and Proteinuria combined: Dipstick detects mostly ALBUMIN negative (0 mg/dL) trace (10-20 mg/dL) 1+ (30 mg/dL) 2+ (100 mg/dL) 3+ (300 mg/dL) 4+ ( mg/dL) Hematuria, proteinurea, and GN = BAD combo **** Know Foamy urine = high nephrotic synd Bag the pt w a cath and get 24 hr urine sample

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Thank you for your attention!
4/28/2017 Thank you for your attention! HOLY GOD. NEVER AGAIN. I HATE YOU KIDNEYS. HATE YOU.

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