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

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

Disclosure of Conflict of Interest ❑ I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose x ❑ I have a relationship with a for-profit and/or a not-for-profit organization to disclose Name of for-profit or not-for-profit Description of relationship(s) Nature of relationship(s) organization(s) Retrophin Consultant Any direct financial payments including Goldfinch Bio receipt of honoraria Dimerix Membership on advisory boards or ZyVersa (Variant) speakers’ bureaus Complexa Site-PI for industry-sponsored clinical trials Retrophin Funded grants or clinical trials Omeros Achillion Patents on a drug, product or device All other investments or relationships UpToDate.com Royalties (Author) that could be seen by a reasonable, Dynamed well-informed participant as having the potential to influence the content of the educational activity

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

PGNMID: Renal Presentation Nasr et al. Bhutani et al. Mayo Gumber et al. Kousios et al. JASN 2009 Clin Proc 2015 KI 2018 KI 2019 Kidney SCr 2.7 eGFR 36 (IQR 22-52) eGFR 38 (IQR 25-58) eGFR 53 (range 7-82) ml/min/1.73m 2 ml/min/1.73m 2 ml/min/1.73m 2 function (range 0.7- 17.0) Proteinuria 5.7 g (range 3.6 g (IQR 1.9-8.1) 3.6 g (IQR 2.3-8.0) 4440 mg/g (range 0.4-17) 360-9970 mg/g) Hematuria 77% NR NR NR Full 49% NR NR NR Nephrotic syndrome 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) Nasr et al. JASN 2009 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. 2 instructive examples…

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

Bhutani et al. Mayo Clinic Proceedings 2015

Clone Type in PGNMID Nasr et al. Bhutani et al Gumber et al Kousios et al. (n=2) (n=10) (n=6) (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 0 (0%) 1 (10%) 1 (17%) 0 (0%) clone

Clone Characteristics in PGNMID

The PGNMID Experience N 19 Mean age at dx 58 M:F 63%/37% % African ancestry 32% 38 (23-58) mL/min/1.73m 2 Mean (IQR) baseline eGFR 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.

Kidney Internation 2017 al () 91, 720 – 728; • 14 patients with PGNMID (IgA heavy chain) • Similar clinical demographics and renal presentation to other PGNMID series • 2 patients with extra-renal manifestations

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

Kidney biopsy diagnosis Clone detection Paraprotein rate detection rate Light chain cast nephropathy ~100% ~100% Monoclonal Ig amyloidosis ~100% ~100% ● Light chain (AL) amyloidosis ● Heavy chain (AH) amyloidosis ● Light and heavy chain (AHL) amyloidosis Monoclonal Ig deposition disease (MIDD) LCDD: 90-100% LCDD: 90-100% ● Light chain deposition disease (LCDD) HCDD: 100% HCDD: 80-100% ● Heavy chain deposition disease (HCDD) LHCDD: 90-100% LHCDD: 100% ● Light and heavy chain deposition disease (LHCDD) 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

More sensitive detection methods? Sink Effect? - 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

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

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