treatment of resistant glomerular disease...measure of non-adherence hydroxychloroquine has a very...
TRANSCRIPT
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Treatment of Resistant Glomerular Disease
Patrick H. Nachman, MD, FASNApril 12, 2015
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Dr William Finn (or was it someone else?)
• Give enough,• but not too much
Patricelli’s Corollary• If it wasn’t enough, give some more
• But don’t overdo it!
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Einstein's miracle year - Larry LagerstromTED Ed talk, Youtube
While the speed of light remains constant,Time, Space and
Resistance are Relative to the Observer!
(May 1905)
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Resistance is Relative To the Likelihood of Success
• Perceived likelihood: • therapeutic nihilism: failure to treating vs.
treatment failure• “Real” likelihood:
• E.g. treatment of Collapsing FSGS?
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Collapsing
Tip
NOS
Perihilar
Deegens JK, Dijkman HB, Borm GF, Steenbergen EJ, van den Berg JG, Weening JJ, Wetzels JFNephrol Dial Transplant , 2008, 23:186-92
Collapsing
Tip
NOSPerihilar
% R
enal
Sur
viva
l
Time (years)Time (years)
Thomas DB, Franceschini N, Hogan SL, ten Holder S, Jennette CE, Falk RJ, Jennette JC: Kidney Int 2006;69:920-926
Structural patterns of injury correlate with clinical presentations and outcomes.
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Laurin, LP et al. 2014
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D’Agati V et al. Clin J Am Nephrol 2013;8:
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» Eg: ANCA remissions vs. recovery of renal function
» Consider Patient Reported Outcomes
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A Patient with Membranous Nephropathy37-yo w man referred with MN.Severe swelling, 27lbs gain Fatigue, DOE, cramps, recurrent “colds”. Poor appetite + nausea + diarrhea. Flank pain with renal vein thrombosis.P. Ex: 204lbs; 124/80,• severe swelling to the
groin. 5/6/2015 9
He underwent therapy x 6 m. -> follow up at 11 m:Energy is good & is exercising daily (swimming, running, elliptical). Normal appetite. No diarrheaNo pain
P. Ex: 191lbs; 100/54• Trace swelling of the
ankles.
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Questions:• Is my patient better?
» Yes» No
• Did the treatment “work”?» Yes» No
» He is better, but maybe not from the treatment
5/6/2015 10
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5/6/2015 11
0 1 2 3 4 5 6 7 8 9 10 11
Resistance is Relative To the Outcome of Interest
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Resistance is Relative To the Risk of Therapy:
• Perceived risk of treatment leads to “under-treatment”
• Real risk:
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GDCN Cohort (n=639)
Therapy
(n=331 [95%])
No Therapy
(n=16 [5%])
Remission
(n=255 [77%])
Therapy Resistant
(n=76 [23%])
Patients available for analysis
(n=347)
Continued remission with
no evidence of relapse
(n=149 [58%])
Relapse
(n=106 [42%])
French Cohort (n=533)
Therapy
(n=417 [96%])
No Therapy
(n=17[4%])
Remission
(n=359 [86%])
Therapy Resistant
(n=58 [14%])
Patients available for analysis
(n=434)
Continued remission with
no evidence of relapse
(n=166 [46%])
Relapse
(n=193 [54%])
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Criteria GDCN Predictors of Resistance(n = 331)*
French Predictors of Resistance(n = 417) *
Odds Ratio (95% CI)‡ P Value‡
Odds Ratio (95% CI)‡ P Value‡
Age per 10 years 1.21 (1.00–1.47) 0.046 1.32 (1.05–1.66) 0.018
Age among cyclophos-treated only
1.15 (0.92-1.45) 0.227
ANCA: Multivariable Predictors of Treatment Resistance
Adapted from Pagnoux C et al. Arthritis Rheum.2008; 58(9):2908-18.
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Criteria GDCN Predictors of Resistance(n = 331)*
French Predictors of Resistance(n = 417) *
Odds Ratio (95% CI)‡ P Value‡
Odds Ratio (95% CI)‡ P Value‡
Female versus male 1.84 (1.02–3.33) 0.044 1.06 (0.58–1.94) 0.862
Female among cyclophos-treated only
1.62 (0.82-3.21) 0.168
White versus non-white 0.47 (0.20–1.14) 0.097 2.06 (0.26–16.66) 0.498
Serum creatinine per 100 μmol/L||
1.22 (1.12–1.34) < 0.001 1.10 (0.98–1.24) 0.113
ANCA: Multivariable Predictors of Treatment Resistance
Adapted from Pagnoux C et al. Arthritis Rheum.2008; 58(9):2908-18.
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Resistance is Relative To Access to Treatment
Ward MM. J Rheumatol 2010;37:1158-63
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Resistance is Relative to Adherence to Treatment• Causes of Non-Adherence
» Adverse effect» Fear of adverse effect, especially with prolonged use» Perceived lack of efficacy (lack of perceptible change in
symptoms [or lack thereof])» Depression» Cognitive impairment (loss of memory, concentration,
functioning etc)
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(Non-)Adherence
Julian LJ et al. Arthritis Rheum. 2009 Feb 15;61(2):240-6
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Measure of Non-Adherence
Hydroxychloroquine has a very long terminal half-life (>40 days).Useful as a measure of non-adherenceNon-adherence was associated with relapse of SLE and higher measure of disease activity on day of measure, and higher likelihood of subsequent relapse.
Costedoat-Chalumeau N et al Ann Rheum Dis 2007;66:821-24
Non-Adherent patients
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The Borg:
locutus of Borg
Fakeposters.com
https://www.youtube.com/watch?v=ItHcsIHshhs
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1-year outcome in treated anti-GBM disease
Patient survival
Renal survival
n (%) (%)
Cr < 500µmol/L 19 100 95
Cr > 500µmol/L 13 83 82
Dialysis 39 65 8
Total 71 77 53
Levy JB et al. Ann Intern Med. 2001;134:1033-1042.
Merkel F et al . Nephrol Dial Transplant. 1994;9:372-6.
Resistance is Futile: The Point of No Return?
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ANCA Vasculitis: Resistant Disease
Nachman PH, Hogan SL et al. J Am Soc Nephrol 1996; 7:33-9
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ANCA GN with Severe Renal Failure:Patient Cohort and Outcomes
ANCA‐GN biopsied from Oct. 1985 to Jun. 2011, N= 599
eGFR <15ml/min at presentation, N= 278 (46%)
Total cohort, N = 155 (55%)At
baseline:
Dialysis‐free remission: N=79 (51%)
At 4 months:
Remission: N=77 (50%)
At 12 months:
ESKD: N=50 (32%)
Death: N=28 (18%)
Dialysis‐dependent:N=55 (35%)
Death:
N=21 (14%)
4 died during dialysis
2 died after remission 3 recovered late
3 relapsed to ESRD
Screening:
Exclusion: ‐ No immuno‐suppression , N=3‐ Overlap with other disease, N=16‐ F/U <12 mo, or insufficient information N=104
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Risk factors of ESKD or deathCox models Parameters HR 95% CI P‐value
Univariate Age ≥ 75 years 1.37 0.86‐2.18 0.184
eGFR ≥ 10 ml/min/1.73m2 0.54 0.28‐0.99 0.047
MPO/P‐ANCA 1.21 0.80‐1.83 0.374
Cyclophophamide 0.35 0.21‐0.58 0.001
Plasmapheresis 0.92 0.58‐1.46 0.726
Activity index score of biopsy 1.01 0.95‐1.08 0.682
Chronicity index score of biopsy 1.07 1.00‐1.13 0.038
Arteriosclerosis ≥ mild 1.72 0.83‐3.55 0.145
Normal glomeruli ≥ 10% 0.65 0.43‐0.98 0.043
Treatment response at 4mo* 0.10 0.06‐0.17 <0.001
Multivariate Cyclophosphamide 0.36 0.21‐0.60 <0.001
Treatment response at 4mo 0.24 0.11‐0.53 <0.001
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Paris, 4/16/2013
Risk factors of treatment response at 4 months
Logistic regression
Parameters OR 95% CI P‐value
Univariate Age ≥ 75 years 0.67 0.31‐1.44 0.30
eGFR ≥ 10 ml/min/1.73m2 2.75 1.17‐6.45 0.02
MPO/P‐ANCA 0.43 0.22‐0.83 0.01
Cyclophophamide 7.69 2.15‐27.51 0.002
Plasmapheresis 1.09 0.54‐2.21 0.82
Activity index score of biopsy 0.93 0.84‐1.03 0.16
Chronicity index score of biopsy 0.85 0.77‐0.95 0.003
Arteriosclerosis ≥ mild 0.27 0.09‐0.89 0.03
Normal glomeruli ≥ 10% 0.40 0.20‐0.80 0.01
Multivariate eGFR ≥ 10 ml/min/1.73m2 2.71 1.07‐6.87 0.04
Cyclophosphamide 4.51 1.2‐16.93 0.03Chronicity index score of biopsy 0.87 0.78‐0.98 0.02
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ANCA: Estimated probability of response to treatment
•The likelihood of response to treatment is associated with:
•Cyclophosphamide use•eGFR > 10 ml/min/1.73m2 at presentation•Lower chronicity index score on kidney biopsy
Among cyclophosphamide-treated patients, no “futility-threshold” could be identified.
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Causes of Resistance (?)
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CSA in Childhood Nephrotic Syndrome
Buscher et al, CJASN, 2010
50 patients with SRNS and a mutation in a podocyte gene; 12 received CSA mean duration of 34 months 41 patients with SRNS and no mutations in the podocyte genes; 31 received CSA with a mean duration of 39 months
Genes StudiedNPHS1-nephrinNPHS2-podocinLAMB2-lamininTRPC6-cation channelPLEC1-phospholipase CWT1-podocyte differentiation
P=0.0001
P=0.005
n=2
CR: n=17PR: n=4
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Mutation screening in children with SRNSRood et al NDT 2012
Mutation screening in adults with FSGSRood et al. NDT 2012
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Proteinuria Reduction as Endpoint:
Gipson DS et al, Kidney Int 2011, 80(8):868-78.
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What is the human and financial cost of a chip testcompared to 6-12 mosof CyA?
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Pharmacogenetics
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MIF and the Therapy of Glomerular Disease
Kidney Sources of MIF: Mesangial, Endothelial, Epithelial Cells
Observations on the Relationship of MIF to Renal Disease:
• MIF over-expression in podocytes→glomerulosclerosis, proteinuria, renal failure
• Anti-MIF improves crescentic GN in rats• MIF deficiency attenuates glomerular injury in lupus-prone mice• Urine MIF increases in patients with FSGS; correlates with level of
proteinuria and expansion of mesangial matrix
MIF antagonists will soon come to clinical trial
Vivarelli et al, Ped Neph, 2008
Pharmacogenetics
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MIF Genotypes in Childhood Nephrotic Syndrome
Vivarelli et al, Ped Neph, 2008
• MIF gene was studied in idiopathic nephrotic syndrome in pediatric patients
• MIF promoter has a G→C SNP at -173; MIF-173*C is associated with increased MIF levels in humans
• 22% of controls were GC+CC (n=355); 31.7% of nephrotic patients were GC+CC (n=257) OR 1.67, p=0.006
• The C allele was present in 22.8% of steroid-responsive patients and 43.5% of steroid-resistant patients OR 2.6, p=0.0005
Pharmacogenetics
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OR=14 p=0.002
The SNP had no effect on CSA-response
Pharmacogenetics
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Pharmacogenetics
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Case #2:
• 74 y.o AA referred with severe edema, and proteinuria.
• On Exam;» Cervical mass» Enlarged prostate» Hemoccult positive stool» CXR with small area of atelectasis L lower
lung field.• 24 Prot excretion: 23 g/d; Cr 1.4 mg/dl• Work Up:
» Benign thyroid nodule» BPH» Colonoscopy with polypectomy: benign +
hermorrhoids» Renal Biopsy: Membranous Nephropathy
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Case #2• Patient treated with ACEi + Cyclosporin
» HeadAches, numbness, tingling, Abd Pain and diarrhea Cr 1.8
» Upr/Cr 5» CyA stopped after 3 months. Reluctant to
other treatments• 5 months later:
» Severe edema. UPr/Cr 9.5; Cr 2.5/dl» Start Cyclophosphamide po daily » Cr peaked at 2.8 mg/dl
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Case #3• 5 months later:
» Upr/Cr improves to 3, Cr Improves to 2.0 mg/dl
» Has syncope -> ED evaluation with Abnormal CXR.
» CT Scan :upper segment of the left lower lobe nodule
» ->T1 N0 invasive poorly differentiated squamous cell carcinoma :
• 3 months later:» U Pr/Cr 1.6; Cr 2.1 mg/dl
• 10 years later:» UA negative for Protein; Cr 1.9 mg/dl5/6/2015 43
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Cancer-associated MN• Lefaucheur C et al. Kidney Int 70:1510-1517, 2006
» Cohort study of 240 patients» Standardized incidence ratio 9.8 [5.5-16.2] for men, 12.3 [4.5-
26.9] for women. » In 48% of the patients, the tumor was asymptomatic. » Most common malignancies: lung and prostate.» Risk factors: older age & smoking» Strong relationship between reduction of proteinuria and clinical
remission of cancer (P < 0.001). • Bjorneklett R. et al. Am J Kidney Dis 50:396-403, 2007
» standardized incidence ratio 2.25 (95% CI, 1.44-3.35).» Median time from MN diagnosis to cancer diagnosis: 60 mo.
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Summary:• Resistant Disease may be real• Should prompt reassessment:
» Access and Adherence» Underlying “primary” cause» Extensive scaring and Risk/Benefit of
Treatment
» Future:• Genetics• pharmacogenetics
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Parting Wisdom
• LL&P
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Rituximab for “resistant” (dependent) Minimal Change Disease
Munyentwali H. et al Kidney International (2013) 83, 511–516;