RED URINE
PIGMENTURIA HEMATURIA
(exclude UTI)
GLOMERULAR EXTRAGLOMERULAR
RENAL COLLECTING
SYSTEM
TRAUMA TUMORS STONES
HEMATURIA:denotes blood in the urine which may be visible or microscopic.
Visible or gross hematuria is the appearance of red or brown urine, a change that can be produced by as little as 1 ml of blood per liter of urine.
Microscopic hematuria: blood (either red blood cells or hemoglobin) in the urine discovered on urinalysis (> 2 rbc/hpf in centrifuged urine) or dipstick done for other purposes.
Clinical Clues
• Ask about
o Transient or persistent, since transient hematuria, especially in younger patients may be of no consequence. If older (> 50 years), investigation is required.
o Whether red urine is grossly visible or microscopic (found on urinalysis or dipstick done for other purposes)?
o Menstruation, post-partum state, suggestive of contamination.
Investigations
• Urine sediment examination under the microscope is the gold standard for detection of hematuria. E.g. semen found in the urine after ejaculation may cause a positive heme reaction on dipstick.
Comments
• Hematuria approach: first ensure that the problem is true hematuria rather than pigmenturia.
• False positive results may occur when urine pH > 9 or contamination with oxidizing agents used to clean perineum. Therefore a positive dipstick test must always be confirmed by microscopic urinalysis. A negative dipstick generally excludes abnormal hematuria.
• Hematuria itself is not dangerous hemodynamically (the underlying cause may be dangerous: e.g. tumors). If clots are present (indicative of brisk bleeding), ureters may become obstructed.
Diagnoses to consider
• Pigmenturia
• Hematuria
RED URINE
PIGMENTURIA HEMATURIA
PIGMENTURIA OR HEMATURIA Clinical Clues
Investigation
• Urine sample is centrifuged and both the supernatant and the urine sediment are observed for color.
• If the supernatant is clear and the red color is in the sediment, then hematuria is present and pigmenturia is excluded.
• If the red color is in the supernatant and the sediment is not colored, then pigmenturia is present and hematuria is excluded.
• Absence of rbc’s on microscopic examination of the urine sediment confirms that hematuria can be excluded.
Diagnoses to consider
• Pigmenturia
o Endogenous pigments (hemoglobin or myoglobin)
o Exogenous pigments (beets, porphyria, phenazopyridine)
• Hematuria
RED URINE
PIGMENTURIA HEMATURIA
Hemoglobinuria Myogloburia
Beets (15%) Porphyria Phenazopyridine
PIGMENTURIA:ENDOGENOUS PIGMENTS OR EXOGENOUS PIGMENTS
Clinical clues
• Ask about
o Pallor, lack of energy, palpitations, suggestive of anemia o Muscle pain or weakness, suggestive of rhabdomyolysis
o Ingestion of beets, suggestive of excretion of betalaine/betanin, especially if ingested concurrently with foods high in oxalates (spinach, rhubarb, oysters).
Investigation
• The supernatant is tested for heme with a urine dipstick.
• If the supernatant is heme positive, then hemoglobin or myoglobin is present in the supernatant and rbc’s are absent on microscopic examination of the centrifuged urine (for an approach to these problems see “Anemia” and “Rhabdomyolysis”)
• If the supernatant is heme negative, then the possible causes for the presence of color are relatively few: porphyria, phenazopyridine intake, Betalaine contained in beets (only about 15% of people on beets produce red urine), vegetable dyes, urates, Serratia
marcescens infection, and Phenolphthalein.
• Serum CK: if elevated, consistent with rhabdomyolysis
• Peripheral blood smear for schistocytes, reticulocyte count, serum LDH, haptoglobin, abnormal in hemolytic anemia.
Evidence
• Woolhandler, S, Pels, RJ, Bor, DH, et al. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I. Hematuria and proteinuria. JAMA 1989; 262:1214.
Comment
• Increased intestinal absorption of betalaine from the ileum is the abnormality in subjects affected by ‘beeturia’.
• Betalaine is protected by reducing agents such as oxalate and decolorized by ferric ions, HCl, and colonic bacteria. As a consequence, beeturia is more likely to occur in
o Iron deficiency anemia (if corrected, beeturia is eliminated) o Achlorhydria due to pernicious anemia
o Ingestion of foods high in oxalates along with beets
• Because hemoglobin is larger than myoglobin (mol. wt. = 69,000) and is protein bound to haptoglobin, it is poorly filtered. Only the
unbound dimmer is filtered (mol. wt. = 34,000) and hemoglobinuria occurs only after filtered load exceeds proximal reabsorption (total hemoglobin concentration > 100 – 150 mg/dL). This amount of hemoglobin results in red to brown color in the plasma.
• Myoglobin is smaller (mol. wt. = 17,000) and is not protein bound. It is easily filtered and excreted. Plasma remains a normal straw color.
Diagnoses to consider
• Pigmenturia o Exogenous o Endogenous
• Hematuria
HEMATURIA
Extra-glomerular Glomerular
Red or pink Clots at times Proteinuria < 500 mg/d Rbc’s isomorphic Rbc casts absent
Red or “coca cola”
Clots absent Proteinuria > 500 mg/d Rbc’s dysmorphic Rbc casts present
HEMATURIA:EXTRAGLOMERULAR OR GLOMERULAR
Clinical clues
• Ask about
o History of a recent upper respiratory infection, suggestive of glomerular disease (post-infectious GN or IgA nephropathy) o History of renal disease in the family (e.g. hereditary nephritis
or polycystic kidney disease).
o Flank pain, radiating to the groin (suggestive of calculus, papilla, or blood clot)
o In older (> 40 – 50 yrs.) patients, history of tumors of urinary tract in family, since even transient but isomorphic hematuria requires exclusion of tumors.
Investigation
• Urinalysis: brown/cola-colored urine, red cell casts, protein excretion
> 500 mg/day (in microscopic hematuria), most red cells having a dysmorphic appearance, consistent with glomerular hematuria
• Red or pink urine, clots, no protein or protein excretion < 500 mg/day, isomorphic rbc and no casts, all are consistent with extra-glomerular hematuria; if infected, may also have wbc & bacteria
Comments
• There are two reasons for distinguishing glomeruli as the source of bleeding from extra-glomerular sources. First, it is important
prognostically. Second, it is beneficial to optimize the subsequent evaluation. Patients with clear evidence of glomerular hematuria do not need to be evaluated for potentially serious urologic disease and as a consequence can avoid a multiplicity of invasive, expensive procedures such as cystoscopy.
Evidence
• Fairley, KF, Birch, DF. Hematuria: A simple method for identifying glomerular bleeding. Kidney Int 1982; 21:105.
• Pollock, C, Pei-Ling, L, Gÿory, AZ, et al. Dysmorphism of urinary red blood cells value in diagnosis. Kidney Int 1989; 36:1045.
• Topham, PS, Harper, SJ, Furness, PN, et al. Glomerular disease as a cause of isolated microscopic haematuria. Q J Med 1994; 87:329.
Diagnoses to consider if glomerular hematuria is excluded
• Extra-glomerular hematuria
Infection of the urinary tract
Hematuria originating in renal parenchyma and above bladder
Hematuria originating in bladder and below
• Glomerular hematuria
EXTRA-GLOMERULAR
HEMATURIA
Collecting System
(Bladder & Below)
Renal parenchyma
(Includes collecting system above bladder)
UTI & other transient hematuria
Clinical clues
• Ask about
o Whether hematuria is transient or persistent, transient being suggestive of infection, trauma, exercise, fever, stones, endometriosis, thromboembolism, etc.
o Hesitancy, dribbling (BPH), dysuria, pyuria, ⇑ frequency, urgency, supra-pubic discomfort, suggestive of infection.
o Fever (> 38ºC), flank pain, and nausea or vomiting suggest upper tract infection (pyelonephritis).
o Cyclic hematuria in association with menses may represent urine contamination or endometriosis of urinary tract.
o Bleeding from multiple sites suggests a bleeding disorder or excessive anti-coagulation.
o Vigorous exercise or trauma suggests origin of hematuria o Age: if the patient is >40 years, tumors have to be excluded o Although hematuria caused by stones/calculi is usually
transient, on occasion the hematuria is prolonged/recurrent, to be discussed under hematuria according to site.
• Look for
o Suprapubic or/and costovertebral angle tenderness Investigation
• Repeated urinalyses to determine whether hematuria is transient or persistent as well as microscopic examination of centrifuged urine:
hematuria, pyuria, wbc casts, bacteruria suggests infection
Comments
• Persistent hematuria, may be a symptom of an underlying disease that on occasion is life threatening & requires investigation.
• Patients with bladder tumor may present as a urinary tract infection.
• Patients with BPH may present with urinary infections. It is uncertain whether BPH alone leads to hematuria (the cellular proliferation of BPH is associated with ⇑ vascularity and new vessels are fragile).
• If hematuria is transient rather than persistent, the most common cause is infection of the urinary tract. Consequently, the pragmatic approach is to exclude this possibility before embarking on more extensive investigations (follow-up required if > 40 years).
• In women, if hematuria is related to menses, exclude urine contami-nation from vaginal bleeding or endometriosis of the urinary tract.
• Other benign causes of transient hematuria to be excluded are
exercise-induced (glomerular hematuria), or trauma (direct trauma to kidney and/or collecting system or exercise bladder trauma).
Evidence
• Hooton, TM, Scholes, D, et al. A --- risk factors for symptomatic urinary tract infection in young women. N EJM 1996; 335:468.
• Abarbanel, J, et al, D. Sports hematuria. J Urol 1990; 143:887.
Diagnoses to consider
• Extraglomerular hematuria
o Renal parenchyma including collecting system above bladder
Tumors (renal cell, transitional
Tubulointerstitial {calculi, (AIN/CIN), cysts (PCKD, MSK)}
Vascular: papillary necrosis, infarction, AV malformation
EXTRA-GLOMERULAR
HEMATURIA
COLLECTING SYSTEM (bladder & below)
RENAL PARENCHYMA (includes collecting system above
bladder)
STONES TUMORS TRAUMA TUMORS
TUBULO-INTERSTITIAL VASCULAR UTI
EXTRAGLOMERULAR HEMATURIA:RENAL/UPPER COLLECTING SYSTEM
Clinical clues
• Ask about
Renal disease in family, suggestive of PCKD, sickle cell (in blacks), etc.
Flank pain radiating to groin suggest calculus, papilla, clot.
Diabetes mellitus ± infection, SS/SA disease, analgesic
nephropathy, obstructive nephropathy ± infection, suggestive of papillary necrosis.
Hematuria, abdominal mass, pain, and weight loss suggest renal cell carcinoma; hematuria from cancer suggests
invasion of the collecting system; if bleeding severe, it leads to clots and "colicky" discomfort when cancer is in the kidney.
Acute onset of flank or abdominal pain, fever, nausea and vomiting suggest renal infarction
History of trauma, medication review for AIN from drugs
• Look for
Renal cell cancer may present as an abdominal/flank mass, usually non-tender, moves with respiration, scrotal varicocele, usually left-sided, hypertension, fever
PCKD also presents as an abdominal/flank mass
Flank or abdominal tenderness, acute elevation in blood pressure, signs of extra-renal embolization (such as skin lesions or focal neurologic deficits) suggest renal infarction.
Investigation
• Sterile pyuria, wbc casts ± hematuria, suggestive of TB, analgesic nephropathy or other interstitial diseases
• Cbc for anemia of chronic disease or erythrocytosis
• Serum calcium for hypercalcemia, abnormal liver function tests
• Non-contrast-enhanced helical CT scan is the gold standard for examination of the renal parenchyma, for stones, as well as other causes (or IVP for medullary sponge kidney or ultrasonography)
• Elevated LDH level, renal isotope scan to exclude renal infarction
• If all other possibilities are excluded, the rare entity of AV malformation may require angiography for diagnosis
Comments
• Hypertension in renal infarction is mediated by angiotensin .
• Although stones are shown in the diagram under the lower collecting system, clearly stones may reside anywhere along the collecting system tract from the collecting tubules as medullary nephro-calcinosis, to the pelvis, ureters, and eventually bladder.
Evidence
• Corwin HL, Silverstein MD. The diagnosis of neoplasia --- : A decision analysis. J Urol 1988; 139:1002.
Diagnoses to consider
• Collecting system hematuria.
Stones (pelvix, calyx, ureter, bladder)
Tumors
Trauma
EXTRA-GLOMERULAR
HEMATURIA
COLLECTING SYSTEM HEMATURIA (bladder & below)
RENAL HEMATURIA (includes collecting system
above bladder)
STONES Pelvis/Calyx
Ureter Bladder
TUMORS (> 50 yrs.) Bladder (>90%
of tumors)
TRAUMA
EXTRAGLOMERULAR HEMATURIA, LOWER COLLECTING SYSTEM CAUSES
Clinical clues
• Ask about
Supra-pubic pain, intermittent, gross, painless hematuria, present throughout micturition in men over the age of 50 or patients with specific risk factors such as prolonged heavy phenacetin use, smoking, exposure to dyes, or long-term cyclophosphamide, suggestive of bladder cancer.
Dysuria, frequency, and urgency
Initial hematuria, occurring primarily at the beginning of the stream, is usually predictive of a urethral source.
Terminal hematuria, blood appearing towards the end of voiding, generally originates from the bladder neck or prostatic urethral area
Hematuria throughout voiding can originate from anywhere in the urinary tract including the bladder and ureters.
• Look for
Investigation
• Cystoscopy (± retrograde pyelography to examine ureters) recommended in patients at risk for bladder cancer
• Urinary cytology (especially if bladder cancer suspected)
Comments
• Although stones are shown in the diagram under the lower collecting system, clearly stones may reside anywhere along the collecting system tract from the collecting tubules as medullary nephro-calcinosis, to the pelvis, ureters, and eventually bladder.
• Causes of hematuria originating in the bladder or below are better uncovered by cystoscopy. Cystoscopy may reveal urethral
diverticula/strictures, bladder tumors, bladder stones, and bladder inflammation.
Evidence
• Khadra, MH, Pickard, RS, Charlton, M, Neal, DE, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current
diagnostic practice. J Urol 2000; 163:524.
• Sarnacki, CT, McCormack, LJ, Kiser, WS, et al. Urinary cytology and the clinical diagnosis of urinary tract malignancy: a clinicopathologic study of 1400 patients. J Urol 1971; 106:761.
Diagnoses to consider
• Glomerular hematuria
o Isolated glomerular hematuria
IgA nephropathy
Thin membrane disease
Alport’s
o Glomerular hematuria associated with proteinuria
Glomerular Hematuria
(< 5%)
Isolated Associated Proteinuria
IgA nephropathy Thin membrane Alport’s
GLOMERULAR HEMATURIA:ISOLATED OR ASSOCIATED WITH PROTEINURIA + Clinical clues
• Ask about
o Recent upper respiratory infection (< 5 days) with previous similar episodes, episodes of gross hematuria on a
background of microscopic hematuria, suggestive of IgA o Absence of edema or other systemic symptoms
o Family history of hematuria, hearing difficulties, renal failure (mostly in males), suggestive of Alport’s
• Look for
o Absence of edema, hypertension, suggestive of thin membrane disease or early IgA
Investigation
• Persistent hematuria on repeated urinalyses
• Absence of protein excretion > 1.5 g/day, no renal insufficiency
• Urinalysis: brown or cola-colored urine, red cell casts on occasion, majority of red cells having a dysmorphic appearance
• Dysmorphic appearance: rbc morphology differs from distinctive uniform and round red cells (similar to peripheral blood smear) seen with extra-renal bleeding. Dysmorphic appearance refers to red cells
with blebs, budding, and loss of membrane, resulting in variable red cell shape and smaller red cell size. This appearance is seen with renal lesions particularly, not only glomerular diseases. Diagnosis is more certain when all cells (or almost all) are either normal or clearly dysmorphic. If both cell types are present, the origin of the hematuria is less certain unless red cell casts are also present.
• The type of dysmorphic cell is of diagnostic importance. In particular, dysmorphic red cells alone may be predictive of only renal bleeding while acanthocytes (ring forms with vesicle shaped protrusions) may be most predictive of glomerular disease.
• Elevated IgA levels in serum suggest IgA more likely
• Renal biopsy is only definitive way to make correct diagnosis, but is not usually indicated; skin biopsy may be helpful
Comments
• Red cell injury leading to dysmorphic appearance may be due both to mechanical trauma as the cells pass through rents in the
glomerular basement membrane and osmotic trauma as the cells flow through the different nephron segments.
• Regular follow-up is essential, since disease progression can occur.
This is particularly true with IgA nephropathy since patients first seen with isolated hematuria can progress with the development of proteinuria, hypertension, &/or renal insufficiency) over many years.
Evidence
• Pollock, C, Pei-Ling, L, Gÿory, AZ, et al. Dysmorphism of urinary red blood cells value in diagnosis. Kidney Int 1989; 36:1045.
• Auwardt, R, Savige, J, Wilson, D. A comparison of the clinical and laboratory features of thin basement membrane disease (TBMD) and IgA glomerulonephritis (IgA GN) Clin Nephrol 1999; 52:1.
• Hudson, BG, Tryggvason, K, Sundaramoorthy, M, Neilson, EG.
Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med 2003; 348:2543.
Diagnoses to considerComment
• Hematuria, glomerular, associated proteinuria o Post-infectious
Viral
Bacterial o Polyangiitis o Collagen disease
Glomerular Hematuria
(< 5%)
Isolated Associated
Proteinuria
Post-infectious Polyangiitis Collagen/
Vascular
Capillary Small
Vessel
Medium Vessel
ANCA Immune complex Anti GBM
GLOMERULAR HEMATURIA/PROTEINURIA+:POST-INFECTION OR POST-INFLAMMATORY
Clinical clues
• Ask about
o History of hepatitis B, C, HIV, infectious endocarditis, ventriculo-atrial shunt, chronic visceral abscess, or other chronic infection.
o History of streptococcal infection (with pharyngitis ≈ 10 days previously or with skin infection ≈ 21 days previously)
o Confusion, headaches, anuria/oliguria, bloody diarrhea, rash, fever, seizures, coma, weight loss, suggestive of angiitis.
o Patients with all types of inflammatory rheumatic diseases may develop vasculitis. Symptoms may include myalgias, arthralgias, red eyes, diplopia, skin rash (vesicular, palpable purpuric, ulcerative, and hemorrhagic lesions), numbness, chest discomfort, etc
o Patients with SLE have innumerable symptoms, including fatigue, fever, weight loss, arthritis/arthralgia, skin rash, and renal involvement
• Look for
o Hypertension, edema
o Findings of associated condition (e.g. hepatitis, infectious endocarditis, visceral abscess, skin infection, pharyngitis) o Red eyes, rash, numbness, suggestive of collagen disease;
also chest pain, pleural effusion, interstitial lung disease.
Investigation
• Urine brown or cola-colored, red cell casts, wbc casts, granular casts, proteinuria, most red cells having a dysmorphic appearance
• Serum creatinine and urea level may be elevated
• Urinary protein excretion often > 1.5 g/day (or equivalent protein/creatinine ratio in random urine)
• Abnormal serology for viral antigens, positive blood culture, or other positive bacterial cultures, low complement levels, cryoglobulins
• ANA, antiphospholipid antibodies, antibodies to double stranded DNA
Comments
• The etiology of GN is unknown except for infectious agents: e.g. beta streptococci in post-strept GN, hepatitis C virus in
membrano-proliferative glomerulonephritis (MPGN) or mixed cryoglobulinemia.
• Evidence exists that most GN are a form of autoimmune disease;
etiologic agents may cause GN by inducing loss of tolerance to self-antigens rather than via a direct immune response to etiologic agents as observed with serum sickness or infectious agents.
• Antistreptolysin O titer is elevated in only 50 percent of patients with poststrep GN following impetigo, due to inactivation by skin lipids.
• Virtually all inflammatory rheumatic conditions, including RA, SLE, Sjögren's, inflammatory myopathies, reactive arthritis, etc. may develop ANCA positive vasculitis and associated renal lesions.
Evidence
• Fries, JW, Mendrick, DL, Rennke, HG. Determinants of immune complex-mediated glomerulonephritis. Kidney Int 1988; 34:333.
• Rennke, HG. Secondary membranoproliferative glomerulonephritis.
Kidney Int 1995; 47:643.
• Daghestani, L, Pomeroy, C. Renal manifestations of hepatitis C infection. Am J Med 1999; 106:347.
• Couser, WG. Pathogenesis of glomerular damage in
glomerulonephritis. Nephrol Dial Transplant 1998; 13(Suppl 1):10.
Diagnoses to consider
• Polyangiitis o Capillary o Small vessel
ANCA
Immune complex
Anti GBM o Medium vessel
Glomerular Hematuria
Polyangiitis
Capillary HUS/TTP
Small Vessel
Medium Vessel
ANCA Immune complex Anti GBM
GLOMERULAR HEMATURIA/PROTEINURIA+: CAPILLARY AND MEDIUM VESSEL
Clinical clues
• Ask about
o Patients with confusion or severe headache, anuria/oliguria, suggestive of HUS/TTP
o Bloody diarrhea in young children (caused by Shiga toxin-producing bacteria such as E coli 0157:H7), suggestive of HUS o Development of symptoms during pregnancy or early in the
postpartum period, suggestive of HUS/TTP
o Certain drugs (e.g., mitomycin C, ticlopidine, quinine)
• Look for
o fever on occasion, seizures and coma
Investigation
• Thrombocytopenia and microangiopathic hemolytic anemia, unexplained
• Urinalysis: dysmorphic red cells and rarely red cell casts may be seen in approximately 50%
• Serum creatinine rising daily > 30 – 50 µmol/L (0.3 – 0.6 mg/dl)
• Hypocomplementemia on occasion
• vWF cleaving protease (ADAMTS13) deficiency in some
Comments
• Urinalysis in TTP-HUS is often near normal with only mild proteinuria (usually between 1 – 2 g/day) and few cells or casts, but on occasion red cells and rarely red cell casts are seen. In view of these have common characteristics, the presence of thrombocytopenia may be the primary clue pointing toward TTP-HUS.
• Renal involvement is common in any of the forms of systemic vasculitis. These include classic polyarteritis nodosa (medium vessel disease), Wegener's granulomatosis, Churg-Strauss
syndrome, and the hypersensitivity vasculitides (including Henoch-Schönlein purpura, mixed cryo-globulinemia, and serum sickness)
• The urinalysis may be relatively normal in polyarteritis nodosa (medium vessel disease, not shown on scheme).
Evidence
• Ruggenenti, P, Noris, M, Remuzzi, G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001; 60:831.
Diagnoses to consider
• Small vessel arteritis o Wegener’s o Goodpasture’s
o Immune complex vasculitis
Glomerular Hematuria &
Proteinuria
Pauci-immune
& other RPGN
Capillary HUS/TTP
Small Vessel
ANCA Wegener’s
Immune-complex H-S, IgA
Anti-GBM Goodpasture’s
Medium Vessel
GLOMERULAR HEMATURIA/PROTEINURIA+: TYPE OF VESSEL INVOLVEMENT
Clinical clues
• Ask about
o Rhinorrhea, purulent/bloody nasal discharge, oral/nasal ulcers, arthralgias, myalgias, or sinus pain, stridor, earache, hearing loss, cough, dyspnea, suggestive of Wegener’s
o Hemoptysis (due to an alveolar capillaritis, necrotic lesions, or endobronchial disease), and/or pleuritic pain + hematuria, suggestive of Goodpasture’s or angiitis.
o Abdominal discomfort, arthralgias, and purpuric rash suggest
o Abdominal discomfort, arthralgias, and purpuric rash suggest