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Brad H. Rovin, MD Professor of Medicine and Pathology

Director, Nephrology Division

A Practical Approach to the Work-Up of

Hematuria

Hematuria: Definitions• Macroscopic

• Microscopic

• Asymptomatic: Not associated with pain (dysuria,loin pain, renal colic), renal dysfunction,hypertension, proteinuria, or macroscopichematuria.

• Asymptomatic Microscopic Hematuria (AMH) iscommon and presents the most significantdiagnostic and therapeutic challenges.

• Everyone excretes RBCs in their urine. Atraditional approach to quantifying hematuria is bycounting the total number of RBCs in a timed (12hour) urine sample.

• “Normals” excreted a mean of 66,000 RBCs with arange of 0-425,000. In contrast, patients withglomerular disease excreted 40-120 million RBCs.

• Abnormal Hematuria: Generally taken to meanmore than 500,000 RBCs/12 hours.

• But this type of measurement is not clinicallypractical.

• Abnormal hematuria defined as above is roughlyequivalent to 2 RBCs/HPF.

Hematuria: Definitions

Hematuria: Scope of the Problem

• Definitive Diagnosis: Made in only 50-80% of cases • This leads to costly work-ups and often involvesrepeated, invasive urologic and radiologic studies

• Using >3 RBC/hpf on 3 occasions over 2-3 weeks:• Prevalence

Children: 2-6%Adults: 4%• Men: 2-5%• Women 5-11%• 39% may have single episode

Potential kidney donors: 12%

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Approach to Hematuria - Confirm True Hematuria

• False positive dipstick: The dipstick relies onoxidation of an organic peroxide on the test stripby the peroxidase-like activity of hemoglobin. Thiscan be mimicked by myoglobin, povidone-iodine,H2O2, bacterial peroxidases.

• False negative dipstick: Presence of ascorbic acid(supplements), formaldehyde (preservative), low pH.

• Dipstick sensitivity-93-100%, specificity-60-80%:Negative predictive value ~98%. (Schroder, BMJ,1994; Huussen, Neth J Med, 2004)

PigmenturiaEndogenous

Exogenous

Globins, porphyrins

Beets, rhubarb, phenothiazines

Use Urine Microscopy to Verify RBCs

Approach to HematuriaIdentify Origin of the Blood

Glomerular Hematuria Non-Glomerular HematuriaMicro- or Macroscopic Micro- or Macroscopic

Abnormal Morphology Normal Morphology

Proteinuria, active sediment Isolated Finding

May be familial

- Check first degree relatives

- Look for hearing loss

Glomerular Hematuria-CharacteristicsAcanthocytes:98% specific, 52% sensitive if >5% of RBCs in a urine sample; sensitivity >80% if found in 3 consecutive urine samples

Not inducible by changes in pH, osmolality

Note: Alkaline urine dissolves casts!

Glomerular Hematuria-Differential Diagnosis

Normal IgA Nephropathy Thin GBM Alport’s

Post-Infectious Systemic Inflammatory/Vasculitides

<250 nm

PMN

Humps

Basket-weave

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YES NOProteinuria Present (≥ 500 mg/day)

Abnormal Renal Fxn (Cr≥1.3)

Possible Systemic Process

Potential Kidney Donor

No Proteinuria

Normal (stable) Renal Fxn

No Systemic Process

Renal Biopsy for Hematuria?

RATIONALE FOR NOT DOING A BIOPSY: The glomerular diseases that are most likely to cause isolated hematuria have no proven treatments, and in the absence of proteinuriacarry an excellent renal prognosis

Pathologic Diagnosis of HematuriaMicroscopic Hematuria in 165 patients with no other renal or systemic findings:Pathologic Diagnosis % of PatientsNone 53 (but 13%-no EM)IgAN 30Thin GBM 4Mesangial Proliferation 7FSGS 3HTN, Membranous, Int Nephritis 3

Topham et al, Q.J. Med., 7:329:1994

Effect of Proteinuria on the Differential Diagnosis of Hematuria

Microscopic Hematuria in 135 patients:Proteinuria <0.3 g/d Proteinuria up to 2.4 g/d

Thin GBM 43% IgAN 46%

IgAN 20% FSGS 13%

Normal 37% Membranous, MPGN, AINAcute prolif, Alport’s

Hall et al, Clin Nephrol, 2004

Natural History of Hematuria in 49 Patients with Negative Urologic Evaluation

Presentation IgAN Thin GBM Normal* Misc**# of patients 12 13 20 4

Mean Age 30 35 30 44

Macroscopic Hematuria 6 1 10 1

Cr Clearance 109 115 113 93

11 Year Follow-upHematuria 10 13 7*** 3Cr Clearance 100 110 113 75*Mean Duration Hematuria 4 years; ** Int Nephritis (3), FGS (1); ***5 of the 7 patients developed stones over the 11 year follow-up, suggesting they may have had crystaluria to start.

Niewuhof et al., KI, 49:222, 1996

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In IgAN:

Proteinuria (g/d) ESRD over 7-10yrs

0.3-0.99 10%

1-1.99 25-35%

2-2.99 40%

>3 60%

Hall et al, Clin Nephrol 2004

Proteinuria Changes Everything

Natural History of Hematuria: Is Screening for Microscopic Hematuria Recommended?

Iseki et. al. (Kidney Int., 49:800, 1996) screened 107,192 subjects in Japan with a single urine dipstick, and found that the incidence of hematuria increased linearly with age:

18-29 >80

Men 0.9% 8.5%

Women 7.3% 15.3

Ten years after the original dipstick the prevalence of ESRD wasdetermined and the odds ratio for ESRD calculated:

Men vs. Women 1.4

Hematuria vs. no hematuria 2.3

Proteinuria vs. no proteinuria 14.9

This low, but increased risk suggests patients with an incidental finding of microscopic hematuria should be followed for any indication (proteinuria, hypertension) of developing renal disease.

• Nephrolithiasis(also hypercalcuria, hyperuricosuria)

• Malignancy

• Infection

• BPH

• Cysts (non-simple)

Non-Glomerular Hematuria-Differential Diagnosis

Non-Glomerular Hematuria-Differential Diagnosis

• Anatomic LesionsA-V fistula/malformationAngiomyolipomaHemangiomaRenal variceal veins

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Non-Glomerular Hematuria-Differential Diagnosis

• Hematologic IssuesCoagulopathyIntrinsicIatrogenic (58% may have underlyingurinary tract disease)Platelet dysfunctionHemoglobinopathy

Non-Glomerular Hematuria-Differential Diagnosis

• OtherIschemia/infarctEmboliExerciseMalignant hypertension

Hematuria in AdultsDiagnosis Microscopic Macroscopic

(n>2000) (n>1200)

Cancer 2.3-5% 23%

Nephrolithiasis 5% 5-11%

Infection 1.7-4% 33%

BPH 3-13% 13%

Intrinsic Renal 2-11% -

No Diagnosis 43-57% 8-21%Sutton, JAMA, 263:2475, 1990; Boman, Scand J Urol Neph, 2001; Murakami, J Urol, 144:49, 1990, Sultana, Br J Urol, 78:691,1996

Approach to Patients with Asymptomatic Non-Glomerular Hematuria

Image Upper TractHelical CT (MRI?)>US>IVU

Appropriate Referral

Cytology (??) (SENS=55%;SPEC=99%)

Cystoscopy-virtual cystoscopy?

Age >40 or risk factors for bladder CA

Age <40, no risk factors for bladder CA

Cystoscopy R/O crystaluria, prostate exam

Consider angiogram Observation

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+

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Imaging of the Upper Urinary TractTraditionally, upper tract imaging has been done with IVU or US

US vs CT for Small LesionsSize (mm) US CT<5 0% 47%5-10 21% 60%10-15 28% 75%15-20 58% 100%20-25 79% 100%25-30 100% 100%For small lesions CT is superior than US

Jamis-Dow et. al., Radiology, 1996

IVU vs Helical CT for HematuriaLesions missed by IVU but found by CT in 74 patients with negative work-upPapillary Necrosis 25Calculi (including sponge) 28Cancer

-renal cell 6-transitional cell 3

Angiomyolipoma/cyst 4Infarction 3Vascular anomalies 5Lang et. al., Urology, 2003.

ACCURACY of CT estimated at 98.3%; IVU 80.9% (Sears et. al., J. Urol., 2002)

The combination of US+IVU vs CT has not been assessed

• Age (>40)• Sex (males >> females)• Smoking• Episodes of macroscopic hematuria• Irritative voiding symptoms; previous GU history• Exposure to aromatic amines/benzenes• Pelvic radiation• Exposure to cyclophosphamide• Phenacetin use (heavy)• Exposure to aristolochic acid (herbal weight-loss)• Parasitic infection (Schistosoma haematobium)

Risk Factors for Urothelial Cancers

Hematuria in Adults-Cancer as a Function of Age, Symptoms, and Degree

05

101520253035

AM

H<5

0

AM

H>5

0

SMH

<50

SMH

>50

GH

<50

GH

>50

Cancer (%)

Sultana et al, Br. J. Urol., 78:691, 1996

When No Diagnosis is Made

• If no diagnosis is made after initial evaluation,patients should be followed every six months

• It is not clear how often to repeat urologic studies.In one large study of 225 patients (Murakami et al,1990) 91% of the serious (eg cancer, stones)lesions were found at the initial visit.

• An additional 9% (22 cases, 4 malignancies) werediscovered over the next 1.5 years with extensiveurologic testing every 6 months.

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Approach to Proteinuria

Rosemarie Shim, MD, MSAssistant Professor

Division of Nephrology

Objectives• Define abnormal proteinuria• Review detection of proteinuria• Classify degree of proteinuria• When to refer to a nephrologist -

recognition of an urgent referral • Review differential diagnosis• Review diagnostic workup

• Second most important parameter after GFR to evaluate kidney function

Present in early kidney disease• Even before decline in GFR or ↑ serum

creatinineKey risk factor for loss of kidney function• Marker for severity of CKD,

hyperfiltration, ongoing injuryRisk factor for CVD and CV mortality• Generalized endothelial dysfunction

‘Clinical evaluation of kidney function.’ Hsu, C-Y. Primer on Kidney Diseases, 2005

Why do we care about proteinuria?

Detection of Proteinuria• Dipstick urinalysis

Rough estimation of urinary protein excretion

• Spot urine protein/creatinine ratioGood correlate to 24 hour urinary protein excretion

• 24 hour urine collection Precise quantification

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• Practical, office based• Chromatographic method based on pH and

protein concentration• Highly sensitive to albumin

• Detection limit 20 mg/L

Dipstick Urinalysis

• False Negative Results:• Not sensitive to other proteins (i.e.

immunoglobulins)• Can miss important conditions such as light

chain myeloma

• False Positive Results:• Contamination from ammounium skin

cleansers, vaginal secretion, semen etc• Drugs: cephalosporins, tolbutamine,

radiocontrast• Concentrated urine may lead to ‘trace’ result

Dipstick Urinalysis

Dipstick Interpretation

>20>31-20.30-0.2~g/L

>2000300100300-20~mg/dL

4+3+2+1+trace

Proteinuria Results

Nephrotic RangeAbnormal Proteinuria

Microalbumin Dipstick• Early stage DM nephropathy screening• More sensitive than usual dipstick

Detection threshold 20 µg/L albumin• Most accurate with first morning voided

specimen• Dependent on concentration of urine• If positive, should be confirmed

Spot albumin/creatinine ratio to quantify

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24-hour Urine Collection• Excellent quantification of daily excretion• Averages circadian changes in proteinuria

Highest in morning, positional changes• Disadvantages

Inconvenient, inaccuracies due to under collection, over collection, must be stored in refrigerator

Spot Protein-to-Creatinine Ratio

• Unitless ratio of protein excretion and creatinine excretion which estimates 24h protein excretion

• Most people produce and excrete 1 g creatinine daily

• Thus, the ratio is an expression of urine protein in grams relative to excretion rate of 1 g creatinine

Spot Protein-to-Creatinine Ratio

• Advantages:Random sample, convenient, easy to follow over timeDetects all filtered proteins, including paraproteins

• Disadvantages:May be less accurate at extremes of body mass, non-steady state situations (SLE flairs), varies slightly with time of day

• In general, U P/C ratio > 3 is nephrotic range proteinuria

Urine P/C Ratio• Urine P/C ratio estimates grams/day• Example: 50 y/o M found to have 2+

proteinuria on dipstick UA without hematuria on routine physical exam. Normal GFR on serum chemistries. Repeat testing found:

Spot urine protein 1200 mg/dLSpot urine creatinine 100 mg/dLUrine protein/creatinine = 1200/100 = 1.2

• Proteinuria confirmed at ~1.2 g/day by urine P/C ratio

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Correlation Between Spot P/C Ratio and 24 H Urine Collection

Leung, YY, et al Rheumatology 2007;46:649–652

Types of Proteinuria• Physiologic• Benign/Transient• Tubular• Glomerular• Overflow• Tissue

• < 150 mg/day• < 1 g/day• 200 – 2 gm/day• > 3 gm• Varies• < 500 mg/day

Physiologic Proteinuria• Less than 150 mg/24h• Threshold somewhat

higher in pregnantwomen & adolescentsat 200 mg/24h

• Normal

Benign/TransientProteinuria

• Usually < 1 g/day• Fever• Strenuous exercise• Orthostatic

proteinuria• More common in

adolescent boys• Benign course

Tubular Proteinuria• 200 mg – 2 g/day• Inadequate

reabsorption of filtered protein

• ie Fanconi’ssyndrome, interstitial nephritis or fibrosis

• Often coexists with glomerularproteinuria

Glomerular Proteinuria• > 3.5 g/day• Permeability and

selectivity of the GBM altered

• Plasma proteins are filtered

• Nephrotic syndrome• > 3.5 g/day• Edema• Hypoalbuminemia• Hyperlipidemia

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Arthur H. Cohen & Richard J. Glassock

Causes of Nephrotic Syndrome by Age Found by Renal Biopsy

*Other ProliferativeIgANWegenersGoodpasturesFibrillaryImmunotactoidEtc.

Overflow Proteinuria• Large amount of

abnormal protein filtered

• Overwhelms tubular reabsorptioncapacity

• Ie. Light Chain Myeloma or Amyloid

• Dx: UA + U P/C ratio or UPIEP

Tissue Proteinuria• < 500 mg/day

• Due to inflammation of GU tract

Refer UrgentlyRefer

From: Comprehensive Clinical Nephrology; R. J. Johnson, J. Feehally

From: Comprehensive Clinical Nephrology; R. J. Johnson, J. Feehally

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Nephrotic vs Nephritic Syndrome

RBC castsBlandUrine Sediment++ / -Hematuria1-2+3-4+ProteinuriaLow/normalLowSerum albuminElevatedNormalBP1-2+4+EdemaAbruptInsidiousOnsetNephriticNephroticFeatures

From: Comprehensive Clinical Nephrology; R. J. Johnson, J. Feehally

Isolated Proteinuria

Proteinuria↓ GFR

Proteinuriawith

Hematuria

IsolatedNon-glom.Hematuria

Monitor &Refer

ToNephrology

ReferExpeditiously

To Nephrology

EvaluateGU tract &Refer to Urology

Key Points• Proteinuria is second most important parameter

after GFR to evaluate kidney function• Proteinuria is indicative of intrinsic kidney

disease• Urine dipstick sensitive for albumin, may miss

paraproteinuria• Spot protein to creatinine ratio is a useful

estimate of 24 h protein excretion• Refer patients expeditiously who have proteinuria

and/or hematuria with abnormal GFR for renal biopsy