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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