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Lupus Nephritis Screening and Diagnosis:Is Change Needed?

Derek Fine, MDDivision of Nephrology

Johns Hopkins University School of Medicine

Objectives Discuss appropriate screening strategies

or lupus renal disease, particularly for the assessment of proteinuria

Recognize the role of kidney biopsy in those wit low levels of proteinuria

Describe practice patterns amongst American rheumatologists

Case Presentation: Clinical History

20 yo female college student with SLE and proteinuria

February: Joint pain in fingers and knees, then elbows and wrists.

June: ANA 1:1280, + ds-DNA, WBC 2.9K

August: Rx with 8mg medrol – joint symptoms resolved.

October: Fatigue, alopecia, low-grade fever, mild PIP joint pain. BP 100/66 P60. Thin at 131 lbs. Unremarkable exam.

Case Presentation: Laboratory Evaluation

Normal electrolytes, BUN/Cr = 12/0.5

WBC 4500, Hemoglobin 11.0, Platelet count 167

C3 low at 48, C4 low at 7

Urinalysis trace protein, 5-8 RBC/hpf, 3–5 WBC/hpf

24 hour urine protein – 680 mg

Case Presentation: Questions What diagnoses do we find in patients with

low urine protein levels?

How good is the dipstick urinalysis at detecting low levels of proteinuria?

What is the practice amongst American rheumatologists regarding proteinuria screening and thresholds of significance

SLE and Renal Disease

Highly variable clinical presentation Cardinal feature is proteinuria

25 % renal involvement at time of diagnosis 60 % lifetime risk of renal involvement

45-65% present with nephrotic range proteinuria

Clinical presentation does not sufficiently predict histopathological findings

Early diagnosis = improved outcome Improved renal survival in those with lower levels

of proteinuria at time of diagnosis and lower creatinine at time of diagnosis

Treatment recommendations in LN

Bihl,Fine et al, NDT, 2006

Questions?

What diagnoses do we find in patients with low urine protein levels?

How good is the dipstick urinalysis at detecting low levels of proteinuria?

What is the practice amongst American rheumatologists regarding proteinuria screening and thresholds of significance?

Lupus Survey

To assess screening and referral patterns with regard to proteinuria in lupus patients

ACR members surveyed by e-mail using the survey tool SurveyMonkey.com

Siedner MJ, Christopher-Stine L, Astor BC, Gelber AC, Fine DM. Screening for proteinuria in patients with lupus: A survey of practice preferences among American rheumatologists. J Rheumatol. 2007

Lupus Nephritis and Proteinuria Data Collection

499 respondents out of 2667 ACR members Questions:

Demographic data Practice characteristics Proteinuria screening methods

Study Questions What proteinuria thresholds are being used? What methods of screening are

rheumatologists using? Who is more likely to use qualitative vs.

quantitative?

0

10

20

30

40

50

60

70

80

Male SW US NW NE SE Academic Hosp Based Solo Practice GroupPractice

>40 LupusPts/yr

>20 yrsPracticing

% of Responders

% of Non-Responders

Geographic Region Practice Type

Lupus Nephritis and Proteinuria

Survey Questions If a 24 hour urine is obtained on a patient,

at what minimum level of new proteinuria (assuming a stable creatinine and NO hematuria) do you refer the patient for evaluation for a kidney biopsy?

If a 24 hour urine is obtained on a patient, at what minimum level of new proteinuria in a patient with hematuria (assuming a stable creatinine) do you refer the patient for evaluation for kidney biopsy?

Threshold of proteinuria prompting referral to nephrologist in the absence of acute renal failure

0

5

10

15

20

25

30

35

40

< 300 300-499 500-999 1000-1999 > 2000

No Hematuria

With Hematuria

Urine Protein Threshold (mg/24 hours)

Perc

ent

resp

onden

ts

Survey Questions

By which method do you SCREEN patients with known Lupus for proteinuria?

When using urine dipstick as a screening tool, at what level of proteinuria do you suggest further testing and/or nephrology referral?

Lupus Nephritis and ProteinuriaMethods of Proteinuria Screening for Lupus Nephritis by 499 Practicing Rheumatologists

4.1%

4.1%

7.8%16.7%

(64.6%)

Urinary Dipstick

Spot Pr:Cr

24 hr Pr

24hr Pr:Cr

Albumin Quantitative Methods

(32.7%)

Qualitative

Methods

At what level of proteinuria do you refer to nephrologist ?

1

15

56

25

3

0

10

20

30

40

50

60

Don't Screen Tr 1+ 2+ >=3+

N = 479

Per

cent

resp

onden

ts

Lupus Nephritis and Proteinuria

40

50

60

70

80

% of each Subgroup Using Dipstick as PrimaryMethod of Screening Proteinuria

*p=0.005 p=0.78 p=0.65

<10 years >10 years

Years in Practice Type of Practice

Academic NonAcademic

<60 pts/yr >60 pts/yr

SLE patients/yr

All Respondents

Perc

ent

resp

onden

ts

Survey Study Summary Protein quantification

If no hematuria, 37% would not refer until 1 g or greater proteinuria

Even in the presence of hematuria, 17 % would not refer until > 1g protein

Dipstick 65% of American rheumatologists use the

dipstick for proteinuria screening 86% use a 1+ or greater cutoff for further

workup (28% 2+ or greater)

Case Presentation: Questions

What is the practice amongst American rheumatologists regarding proteinuria screening and thresholds of significance

What diagnoses do we find in patients with low urine protein levels?

How good is the dipstick urinalysis at detecting low levels of proteinuria?

Renal Biopsy Outcome in Patients with Low Levels of Proteinuria

Retrospective analysis of biopsied patients

21 SLE patients with < 1000 mg/24 hours proteinuria

No acute renal failure (creatinine and eGFR not changed from baseline)

Hematuria defined as >= 5 RBC/hpf

Christopher-Stine L, Siedner M, Lin J, Parekh HJ, Petri M, Fine DM. Renal biopsy in lupus patients with low levels of proteinuria. J Rheumatol. Feb 2007;34(2):332-335.

Renal Biopsy Outcome in Patients with Low Levels of Proteinuria

Renal Biopsy Outcome in Patients with Low Levels of Proteinuria

14 with “significant disease” 10 class III (5 with superimposed V) 2 class IV 1 class V 1 Thrombotic microangiopathy

7 with other lesions 3 Class II 1 Thin basement membrane 2 FSGS 1 Mild chronic changes

Proteinuria < 1000 mg/24 hr and No ARF

Christopher-Stine et al, J. Rheum, 2007Christopher-Stine et al, J. Rheum, 2007

Comparison of those with and without “significant” disease

Summary Patients with < 1 g proteinuria frequently

have lesions requiring intervention

Those with “significant” lupus related disease have lower complement and positive dsDNA titers

Even in the absence of hematuria significant disease may be present (4/7)

Even at lower levels of proteinuria (<0.5g) there may be significant disease

Case Presentation: Questions

What is the practice amongst American rheumatologists regarding proteinuria screening and thresholds of significance?

What diagnoses do we find in patients with low urine protein levels?

How good is the dipstick urinalysis at detecting low levels of proteinuria?

How good is the dipstick in predicting proteinuria?

Using the Johns Hopkins Lupus Cohort (280 pts), Ohio SLE Study (84 pts)

All 24 hour urine collections and dipstick proteins obtained within a week of 24hr collection

3 dipstick assays assessed OSS – Manual Multistix (Bayer) Hopkins - < 2002 – Clinitek (Bayer) Hopkins - > 2002 – Atlas (also Bayer)

For all urines 24 hour pr:cr ratio used Ratio > 0.5 (0.5 g or 500 mg/ 24 hour

equivalent) considered positive

Siedner MJ, Gelber AC, Rovin BH, McKinley AM, Christopher-Stine L, Astor BC, Petri M, Fine D. Unpublished Data

Patient demographics

N/A84135170Patients

N/A100.063.0%65.2%Dipstick and Collection

within 24 hours (%)

<0.01†38.2 (11.7)40.8 (10.7)35.9 (10.9)Age Mean Years (SD)

<0.01*59.434.136.5Race % White

0.85*90.592.691.8Sex % Female

N/A8066821,051Matched Urine Samples

p-valueBayer manual

AtlasClinitek

Quantitative Ranges of 3 Dipstick Assays

Detection of Proteinuria by DipstickProteinuria Range 0.5 and 0.99 mg/day

0

10

20

30

40

50

60

Manual Clinitek Atlas

NEG

TR

1+

2+

3+

Per

cent

by

Ass

ay

Assay

Quantification Ranges of 1+ Proteinuria by Assay

0

10

20

30

40

50

60

70

80

< 0.5 0.5-0.99 1.0-1.99 2.0-2.99 >=3

Manual

Clinitek

Atlas

Proteinuria Range (g pr/g cr)

Perc

en

t o

f D

ipst

icks

by A

ssay

False Positives

Distribution of 1+ and 2+ ProteinAtlas Automated Assay

0

10

20

30

40

50

60

70

80

< 0.5 0.5-0.99 1.0-1.99 2.0-2.99 >=3

Atlas (1+)

Atlas (2+)

Per

cent

of D

ipst

icks

Proteinuria Range (g pr/g cr)

False Positives

ACR Criterion for Renal Involvement in Systemic Lupus Erythematosus

>= 3+ proteinOr

> 500 mg/24 hours

How good is the dipstick as identifying kidney disease if the dipstick criterion is used?

4A. Clinitek Assay

4B. Atlas Assay

4C. Manual Assay

Proport

ion

Proport

ion

Proport

ion

1.5

20.5

62.2

74.1

83.1

0

10

20

30

40

50

60

70

80

90

100

0 - 0.49 0.50 - 0.99 1.00 - 1.99 2.00 - 2.99 >=3.0

Total>=3+

59.363.4

46.6

24.4

4.80

10

20

30

40

50

60

70

80

90

100

0 - 0.49 0.50 - 0.99 1.00 - 1.99 2.00 - 2.99 >=3.0

Quantitative Proteinuria

Total>=3+

83.7

72.3

49.7

13.5

1.10

10

20

30

40

50

60

70

80

90

100

0 - 0.49 0.50 - 0.99 1.00 - 1.99 2.00 - 2.99 >=3.0

Total>=3+

Summary – Dipstick Data

Dipstick assays lack adequate accuracy as screening tools

It may be important to know which assay is being used

Manual assay is not adequately sensitive and Atlas assay too sensitive – specificity poor for both

The ACR criterion for dipstick is of little utility in determining renal involvement

PrCrRandom = .161459+1.06502 * PrCr24hr

R2 = 0.93

Ran

dom

Urin

e Pr

otei

n/Cr

eatin

ine

ratio

0 5 10 15

0

5

10

15

24 hour Protein/Creatinine ratio

Random vs 24 hour urine protein/creatinine ratio(N=51)

Conclusion Biopsy should be performed even at low levels of

proteinuria Dipstick protein is insufficiently accurate to detect

proteinuria in this high risk population Better methods for proteinuria assessment are

necessary to detect early and mild disease ACR criteria for renal involvement should be

reassessed Proteinuria assessment in the American

rheumatology community may be suboptimal

AcknowledgementsJOHNS HOPKINS Mark Siedner Allan Gelber Lisa Christopher Michelle Petri Brad Astor Janice Lin Hemal Parekh

OHIO STATE Brad Rovin Allison McKinley Lee Hebert