Treatment of Resistant Glomerular Disease
Patrick H. Nachman, MD, FASNApril 12, 2015
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!
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)
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?
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.
Laurin, LP et al. 2014
D’Agati V et al. Clin J Am Nephrol 2013;8:
» Eg: ANCA remissions vs. recovery of renal function
» Consider Patient Reported Outcomes
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.
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
5/6/2015 11
0 1 2 3 4 5 6 7 8 9 10 11
Resistance is Relative To the Outcome of Interest
Resistance is Relative To the Risk of Therapy:
• Perceived risk of treatment leads to “under-treatment”
• Real risk:
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%])
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.
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.
Resistance is Relative To Access to Treatment
Ward MM. J Rheumatol 2010;37:1158-63
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)
(Non-)Adherence
Julian LJ et al. Arthritis Rheum. 2009 Feb 15;61(2):240-6
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
The Borg:
locutus of Borg
Fakeposters.com
https://www.youtube.com/watch?v=ItHcsIHshhs
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?
ANCA Vasculitis: Resistant Disease
Nachman PH, Hogan SL et al. J Am Soc Nephrol 1996; 7:33-9
23
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
24
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
25
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
26
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.
Causes of Resistance (?)
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
Mutation screening in children with SRNSRood et al NDT 2012
Mutation screening in adults with FSGSRood et al. NDT 2012
5/6/2015 32
Proteinuria Reduction as Endpoint:
Gipson DS et al, Kidney Int 2011, 80(8):868-78.
What is the human and financial cost of a chip testcompared to 6-12 mosof CyA?
Pharmacogenetics
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
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
OR=14 p=0.002
The SNP had no effect on CSA-response
Pharmacogenetics
Pharmacogenetics
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
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
5/6/2015 42
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
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.
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
5/6/2015 46
Parting Wisdom
• LL&P
Rituximab for “resistant” (dependent) Minimal Change Disease
Munyentwali H. et al Kidney International (2013) 83, 511–516;