Hematuria: Definitions A Practical Approach to Everyone excretes - - PDF document

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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 macroscopic hematuria.

• Asymptomatic Microscopic Hematuria (AMH) is

common and presents the most significant diagnostic and therapeutic challenges.

• Everyone excretes RBCs in their urine. A

traditional approach to quantifying hematuria is by counting the total number of RBCs in a timed (12 hour) urine sample.

• “Normals” excreted a mean of 66,000 RBCs with a

range of 0-425,000. In contrast, patients with glomerular disease excreted 40-120 million RBCs.

• Abnormal Hematuria: Generally taken to mean

more than 500,000 RBCs/12 hours.

• But this type of measurement is not clinically

practical.

• Abnormal hematuria defined as above is roughly

equivalent 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 involves

repeated, 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 on
• xidation of an organic peroxide on the test strip

by the peroxidase-like activity of hemoglobin. This can 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)

Pigmenturia Endogenous Exogenous Globins, porphyrins Beets, rhubarb, phenothiazines

Use Urine Microscopy to Verify RBCs

Approach to Hematuria Identify Origin of the Blood

Glomerular Hematuria Non-Glomerular Hematuria

Micro- 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-Characteristics

Acanthocytes:

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 NO

Proteinuria 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 proteinuria carry an excellent renal prognosis

Pathologic Diagnosis of Hematuria

Microscopic Hematuria in 165 patients with no other renal or systemic findings:

Pathologic Diagnosis % of Patients None 53 (but 13%-no EM) IgAN 30 Thin GBM 4 Mesangial Proliferation 7 FSGS 3 HTN, 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, AIN

Acute 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-up

Hematuria 10 13 7*** 3 Cr 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 was determined 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

• f 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 Lesions

A-V fistula/malformation Angiomyolipoma Hemangioma Renal variceal veins

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Non-Glomerular Hematuria- Differential Diagnosis

• Hematologic Issues

Coagulopathy Intrinsic Iatrogenic (58% may have underlying urinary tract disease) Platelet dysfunction Hemoglobinopathy

Non-Glomerular Hematuria- Differential Diagnosis

• Other

Ischemia/infarct Emboli Exercise Malignant hypertension

Hematuria in Adults

Diagnosis 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 Tract

Helical 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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Imaging of the Upper Urinary Tract

Traditionally, upper tract imaging has been done with IVU or US US vs CT for Small Lesions

Size (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 Hematuria

Lesions missed by IVU but found by CT in 74 patients with negative work-up Papillary Necrosis 25 Calculi (including sponge) 28 Cancer

• renal cell

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• transitional cell

3 Angiomyolipoma/cyst 4 Infarction 3 Vascular anomalies 5

Lang 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

5 10 15 20 25 30 35 AMH<50 AMH>50 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) were

discovered over the next 1.5 years with extensive urologic testing every 6 months.

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Approach to Proteinuria

Rosemarie Shim, MD, MS

Assistant 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

creatinine Key risk factor for loss of kidney function

• Marker for severity of CKD,

hyperfiltration, ongoing injury Risk 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 ratio

Good 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 >3 1-2 0.3 0-0.2 ~g/L >2000 300 100 30 0-20 ~mg/dL 4+ 3+ 2+ 1+ trace

Proteinuria Results

Nephrotic Range Abnormal 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

• f 1 g creatinine

Spot Protein-to- Creatinine Ratio

• Advantages:

Random sample, convenient, easy to follow

• ver time

Detects 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/dL Spot urine creatinine 100 mg/dL Urine protein/creatinine = 1200/100 = 1.2

• Proteinuria confirmed at ~1.2 g/day by

urine P/C ratio

10 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 pregnant women & adolescents at 200 mg/24h

• Normal

Benign/Transient Proteinuria

• 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’s

syndrome, interstitial nephritis or fibrosis

• Often coexists

with glomerular proteinuria

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 Proliferative IgAN Wegeners Goodpastures Fibrillary Immunotactoid Etc.

Overflow Proteinuria

• Large amount of

abnormal protein filtered

• Overwhelms

tubular reabsorption capacity

• 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 Urgently Refer

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 casts Bland Urine Sediment + + / - Hematuria 1-2+ 3-4+ Proteinuria Low/normal Low Serum albumin Elevated Normal BP 1-2+ 4+ Edema Abrupt Insidious Onset Nephritic Nephrotic Features

From: Comprehensive Clinical Nephrology;

• R. J. Johnson, J. Feehally

Isolated Proteinuria Proteinuria ↓ GFR Proteinuria with Hematuria Isolated Non-glom. Hematuria Monitor & Refer To Nephrology Refer Expeditiously To Nephrology Evaluate GU 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