hematological characteristics of PGNMID Disclosure of Conflict of - - PowerPoint PPT Presentation

Clinical and hematological characteristics of PGNMID

Jonathan Hogan, MD Clinical Director, Glomerular Disease Center Perelman School of Medicine University of Pennsylvania Philadelphia, PA

Disclosure of Conflict of Interest

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Objectives

• Review the renal and hematology

characteristics of patients with PGNMID

• How do we “move the needle” for the

diagnosis and treatment of PGNMID?

PGNMID is unique among the MGRS disorders

• Renal-limited
• Low rate of paraprotein detection
• Low rate of clone detection
• Does not seem to be a ”pre-malignant” condition
• Therefore, there seems to be more variable buy-

in from hematologists to help manage this condition

PGNMID: Patient Demographics

Nasr et al. JASN 2009 Bhutani et al. Mayo Clin Proc 2015 Gumber et al. KI 2018 Kousios et al. KI 2019 Institution Columbia Ohio State Mayo Clinic University of Pennsylvania University College London N 37 60 19 14 Female 62% 47% 37% NR Age 54.5 (range 20-81) 56 (IQR 44-69) 58 (range 25-83) 62 (47-76) Race 81.1% white 11% Hispanic 8% black 97% white 63% white 5% Hispanic 32% black NR

PGNMID: Renal Presentation

Nasr et al. JASN 2009 Bhutani et al. Mayo Clin Proc 2015 Gumber et al. KI 2018 Kousios et al. KI 2019 Kidney function SCr 2.7 (range 0.7- 17.0) eGFR 36 (IQR 22-52) ml/min/1.73m2 eGFR 38 (IQR 25-58) ml/min/1.73m2 eGFR 53 (range 7-82) ml/min/1.73m2 Proteinuria 5.7 g (range 0.4-17) 3.6 g (IQR 1.9-8.1) 3.6 g (IQR 2.3-8.0) 4440 mg/g (range 360-9970 mg/g) Hematuria 77% NR NR NR Full Nephrotic syndrome 49% NR NR NR SAlb (g/dL) 3.1 (1.1-4.9) <3.0 in 33% NR NR

The Natural History of PGNMID

(Limited description and may be influenced by treatment) During an average of 30.3 months of follow-up for 32 patients… → 38% had complete or partial recovery → 38% had persistent renal dysfunction → 22% progressed to ESRD Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike.

Nasr et al. JASN 2009

2 instructive examples…

Clone Detection in PGNMID

Paraprotein Detection Rate Clone detection rate Nasr et al. JASN 2009 (n=37)* 30% 9% Bhutani et al. Mayo Clinic Proceedings 2015 (n=40) 43% 25% Gumber et al. Kidney International 2018 (n=19) 37% 32% Kousios et al. Kidney International 2019 (n=14) 36% 42% *sFLC assay checked in 4 patients, BM bx in 22 patients

Bhutani et al. Mayo Clinic Proceedings 2015

Nasr et al. (n=2) Bhutani et al (n=10) Gumber et al (n=6) Kousios et al. (n=5) B cell clone 1 (50%) 4 (40%) 2 (33%) 2 (40%) Plasma cell clone 1 (50%) 5 (50%) 3 (50%) 3 (60%) Lymphoplasmacytic clone 0 (0%) 1 (10%) 1 (17%) 0 (0%)

Clone Type in PGNMID

Clone Characteristics in PGNMID

N 19 Mean age at dx 58 M:F 63%/37% % African ancestry 32% Mean (IQR) baseline eGFR 38 (23-58) mL/min/1.73m2 Median baseline proteinuria 3.6 (2.3-8.0) grams Paraprotein detected 7/19 (37%) Clone detected 6/19 (32%) (n=2 B cell, n=4 plasma cell) # patients treated 16

Gumber R…Hogan JJ, Kidney Int. 2018 Jul;94(1):199-205.

The PGNMID Experience

• 14 patients with PGNMID (IgA heavy chain)
• Similar clinical demographics and renal

presentation to other PGNMID series

• 2 patients with extra-renal manifestations

Kidney Internation2017al () 91, 720–728;

50% MG detection rate 21% clone detection rate

PGNMID in Children and Adolescents

Xing et al, Pediatr Nephrol (2018) 33:1531–1538

Kidney International(2018)94,159–169 20% paraprotein detection rate by SPEP-SIFE; 12.5% (2/16) clone detection rate

Relapses (not surprising)

• In our series, there was a 40% relapse rate in those

who responded to therapy initially

– median time to relapse 15 months after initial treatment (range 3-60 months) – Other patients have subsequently relapsed (unpublished)

• 44% relapse rate for those who responded to

treatment in Mayo Clinic series of PGNMID recurrence after transplant

Important Steps in the Last Decade

• Recognition of PGNMID as an important and

unique disease entity

• Multiple, independent case series with high-

quality hematologic characterizations

– Found similar hematologic and renal presentations

• With longer follow-up, observations of clinical

relapses after ”successful” treatment

Why such low detection rates for monoclonal gammopathy and clones in PGNMID? Why such low detection rates for monoclonal gammopathy and clones in PGNMID?

Kidney biopsy diagnosis Clone detection rate Paraprotein detection rate Light chain cast nephropathy ~100% ~100% Monoclonal Ig amyloidosis

• Light chain (AL) amyloidosis
• Heavy chain (AH) amyloidosis
• Light and heavy chain (AHL) amyloidosis

~100% ~100% Monoclonal Ig deposition disease (MIDD)

• Light chain deposition disease (LCDD)
• Heavy chain deposition disease (HCDD)
• Light and heavy chain deposition disease (LHCDD)

LCDD: 90-100% HCDD: 100% LHCDD: 90-100% LCDD: 90-100% HCDD: 80-100% LHCDD: 100% Type I (monoclonal) cryoglobulinemic GN 90-100% 90-100% Immunotactoid glomerulopathy (ITG) 67% 63% Proliferative GN with monoclonal Ig deposits (PGNMID) 30-40% 30-40% Monoclonal gammopathy-associated C3 glomerulopathy Unknown *100% Light chain proximal tubulopathy 90-100% 90-100% Monoclonal IgM mediated kidney disease ~100% ~100% Monotypic fibrillary GN **NA **NA

Hogan JJ, Alexander MP, Leung N, AJKD, in press

Sink Effect? More sensitive detection methods?

• Look for clones elsewhere?
• Are we seeing “truth” on

kidney biopsy?

Sethi S. et al, Current Opinions in Nephrology and HTN, 2013

BACK TO THE BIOPSY (THERE IS NO EGG...)

Kidney International, 2014

Larsen C et al., Kidney International, 2014 IgG (Pronase on paraffin) IgG (frozen)

Kappa (pronase on paraffin)

Lambda (pronase on paraffin)

How Can We Move the Needle in PGNMID?

• Organization is essential!
• Collaborative, multinational and prospective PGNMID

registry and biobank with uniform kidney and hematologic workup

• Innovative, multi-disciplinary, multicenter and

multinational approaches to diagnosis and treatment

Acknowledgements: Penn Amyloidosis Center Brendan Weiss, MD Adam Cohen, MD Al Garfall, MD Dan Vogl, MD Adam Waxman, MD Laura Dember, MD Abdallah Geara, MD Matthew Palmer, MD, PhD PGNMID project Ramnika Gumber, MD Jordana Cohen, MD