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;