Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Editorials
You have accessRestricted Access

Monoclonal Gammopathies and Kidney Disease

Searching for Significance

Christina Hao Wang and Jonathan J. Hogan
CJASN December 2018, 13 (12) 1781-1782; DOI: https://doi.org/10.2215/CJN.12401018
Christina Hao Wang
Division of Nephrology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan J. Hogan
Division of Nephrology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading
  • Monoclonal gammopathy
  • ESRD
  • Paraprotein
  • chronic kidney disease
  • Paraproteinemias
  • Kidney Diseases
  • ESKD
  • end stage kidney disease

Over the past decade, there has been increasing interest in kidney diseases related to monoclonal gammopathies. These may occur in the setting of hematologic malignancy or when the underlying plasma or B cell clone does not meet criteria for cancer (multiple myeloma or systemic lymphoma, respectively). In the latter case, patients are diagnosed with monoclonal gammopathy of renal significance, which has historically been associated with poor prognoses; however, recent studies suggest improved kidney outcomes with treatment of the underlying clone (1). Increased recognition of paraprotein-associated kidney disease has led to important, but as of yet unanswered questions regarding screening patients with CKD for monoclonal gammopathy, and when present, determining whether the monoclonal Ig is causing kidney damage or is of undetermined significance (MGUS). These questions are especially relevant in older patients because the prevalence of both CKD and MGUS increase with age: an estimated 3.2% of patients ≥50 years of age, and up to 9% of patients >70 years of age in the United States have MGUS (2). Monoclonal gammopathy of renal significance, on the other hand, remains a rare entity, accounting for about 6%–10% of cases of MGUS, which suggests a total prevalence of <0.5% in the total United States population (2,3). Consequently, best practices for monoclonal protein testing in patients with CKD are not well established.

In this issue of Clinical Journal of the American Society of Nephrology, Burwick et al. (4) combined data from the Department of Veterans Affairs database, US Renal Data System, and Medicare to assess whether the presence of a monoclonal gammopathy is associated with higher risk of ESKD. They retrospectively analyzed 2,156,317 patients who had at least one outpatient serum creatinine and eGFR in a 1-year period from 2000 to 2001. Of the 21,898 patients who had undergone testing by either serum or urine protein electrophoresis (SPEP or UPEP) with immunofixation within 1 year of cohort entry, 2% (4593 patients) were classified as having a monoclonal gammopathy.

Medicare claims data and the US Renal Data System was then utilized to calculate ESKD risk up until 10 years from the beginning of the cohort, with an average follow-up time of 123.5 months (interquartile range, 77.5–128.5 months). In unadjusted analysis, test-positive patients had a higher risk of ESKD versus test-negative patients across all eGFR categories. However, after adjustment for factors associated with kidney disease progression, a U-shaped relationship was observed. A higher ESKD risk was observed in the groups of test-positive patients with initially preserved (eGFR≥60 ml/min per 1.73 m2) kidney function and severely reduced (eGFR 15–29 ml/min per 1.73 m2) kidney function (hazard ratio [HR], 1.67; 95% confidence interval [95% CI], 1.22 to 2.29; and HR, 1.38; 95% CI, 1.07 to 1.77, respectively), but not in test-positive patients with moderately reduced (eGFR 30–59 ml/min per 1.73 m2) kidney function (HR, 1.09; 95% CI, 0.81 to 1.47). A subgroup analysis for the small number of patients who had available data on proteinuria or with a diagnosis of multiple myeloma yielded similar ESKD HRs. The authors conclude that testing for monoclonal gammopathy does not provide meaningful information on the risk of ESKD in most patients with reduced eGFR, and that the observed U-shaped curve prompts the need for further research to better understand the role of testing for those with preserved and severely reduced eGFR.

The details of ESKD etiology in this study are important to highlight. In test-positive patients with preserved eGFR at cohort entry, 27.6% (21 out of 76 patients) of ESKD was attributed to plasma cell dyscrasias (light chain nephropathy, amyloidosis, or multiple myeloma) versus 9% of test-positive patients with moderately reduced eGFR and 4% with severely reduced eGFR. This is substantially higher than the proportion of ESKD attributed to plasma cell dyscrasias among test-negative patients across all eGFR categories. This striking difference further complicates the interpretation of the results. Indeed, one could hypothesize that more widespread screening for monoclonal gammopathy in patients with preserved kidney function could lead to earlier diagnosis of plasma cell dyscrasias. Earlier diagnosis could have a substantial effect on kidney prognosis, particularly given the improved outcomes for patients with multiple myeloma and AL amyloidosis in the past two decades due to autologous stem cell transplantation and modern antiplasma cell chemotherapies (1,3,5). However, widespread screening for monoclonal gammopathy will clearly yield more diagnoses of MGUS than paraprotein-associated kidney disease. Thus, it remains unclear which patients with preserved kidney function would benefit most from screening.

These results should be considered in the context of other studies that have explored the role of testing for monoclonal gammopathy in patients with CKD, some of which examined higher-risk populations (such as patients with proteinuria, anemia, and hypercalcemia), but none of which have found an association between the presence of monoclonal gammopathy and kidney outcomes (6). However, no study to date has incorporated modern, standard-of-care testing for monoclonal proteins. Compared with prior studies that used either SPEP alone or SPEP and UPEP, Burwick et al. added sensitivity to detection of monoclonal proteins by evaluating serum and urine immunofixation in addition to SPEP and UPEP; however, it is not clear if patients were screened with either or both tests. Moreover, the serum free light chain assay, which maximizes the sensitivity of detection for monoclonal proteins in combination with serum and urine immunofixation, was not included because of the chosen time period of 2000–2001 (7,8). The effect on monoclonal protein detection is unknown given the variable performance of serum and urine tests across different forms of monoclonal gammopathies and the fluctuations in light chain concentrations as a result of GFR (9,10). Furthermore, in that study, if we consider the noted sensitivity and specificity of the algorithm in conjunction with the proportion of “unclassified tests” (1165 tests categorized as “unclassified” compared with 4593 tests categorized as “positive”), the effect on detection of an underlying monoclonal gammopathy and the subsequent association with risk of ESKD may be significant. The literature to date has also lacked data on monoclonal gammopathy characterization and levels of monoclonal protein over time, which are important for the diagnosis, prognosis, and treatment of clonal B and plasma cell disorders (7).

Burwick et al. also acknowledge that the indications for testing and resultant management as a result of paraprotein testing could not be ascertained. This is an important limitation because the associations between monoclonal gammopathy detection and ESKD risk in different groups may, in part, reflect provider practices rather than the contribution of the monoclonal gammopathy to the risk of ESKD. Interestingly, patients who did not have monoclonal protein testing had a significantly lower risk of ESKD compared with patients who were test-negative across all eGFR categories (HR, 0.37; 95% CI, 0.31 to 0.44; HR, 0.43; 95% CI, 0.36 to 0.52; HR, 0.64; 95% CI, 0.57 to 0.71; and HR, 0.78; 95% CI, 0.67 to 0.90). This may reflect selectivity in provider practices for testing in patients who may have unmeasured confounders that place them at higher risk for kidney disease progression.

Notwithstanding these limitations, the study by Burwick et al. provides further support that most patients with monoclonal gammopathy do not have a higher risk of CKD or ESKD that is attributable to the paraprotein. The challenge of incorporating these findings into clinical practice is their inability to shed light on the monoclonal gammopathy–associated risk for an individual patient. All monoclonal gammopathies are not created equal: host factors and specific physiochemical properties of monoclonal proteins confer the potential for end-organ damage (1,10,11), and no serologic assays exist to distinguish pathogenic from nonpathogenic paraproteins. Given the morbidity and mortality associated with CKD, ESKD, and plasma cell dyscrasias, it seems prudent to continue screening for monoclonal gammopathy in patients with unexplained kidney disease and/or proteinuria, particularly in older patients. Until more sophisticated testing is developed, the kidney biopsy will remain the only test that can truly determine the significance of an individual patient’s monoclonal gammopathy.

Disclosures

J.J.H. receives royalties as an author on UpToDate.com, chapter “Diagnosis and treatment of monoclonal gammopathy of renal significance.”

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related article, “Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans,” on pages 1810–1815.

  • Copyright © 2018 by the American Society of Nephrology

References

  1. ↵
    1. Rosner MH,
    2. Edeani A,
    3. Yanagita M,
    4. Glezerman IG,
    5. Leung N; American Society of Nephrology Onco-Nephrology Forum
    : Paraprotein-related kidney disease: Diagnosing and treating monoclonal gammopathy of renal significance. Clin J Am Soc Nephrol 11: 2280–2287, 2016pmid:27526705
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Ciocchini M,
    2. Arbelbide J,
    3. Musso CG
    : Monoclonal gammopathy of renal significance (MGRS): The characteristics and significance of a new meta-entity. Int Urol Nephrol 49: 2171–2175, 2017pmid:28425076
    OpenUrlPubMed
  3. ↵
    1. Leung N,
    2. Bridoux F,
    3. Hutchison CA,
    4. Nasr SH,
    5. Cockwell P,
    6. Fermand JP,
    7. Dispenzieri A,
    8. Song KW,
    9. Kyle RA; International Kidney and Monoclonal Gammopathy Research Group
    : Monoclonal gammopathy of renal significance: When MGUS is no longer undetermined or insignificant. Blood 120: 4292–4295, 2012pmid:23047823
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Burwick N,
    2. Adams SV,
    3. Todd-Stenberg JA,
    4. Burrows NR,
    5. Pavkov ME,
    6. O’Hare AM
    : Association of monoclonal gammopathy with progression to ESKD among US veterans. Clin J Am Soc Nephrol 13: 1810–1815, 2018
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Hogan JJ,
    2. Weiss BM
    : Bridging the divide: An onco-nephrologic approach to the monoclonal gammopathies of renal significance. Clin J Am Soc Nephrol 11: 1681–1691, 2016pmid:27416775
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Mendu ML,
    2. Lundquist A,
    3. Aizer AA,
    4. Leaf DE,
    5. Robinson E,
    6. Steele DJ,
    7. Waikar SS
    : The usefulness of diagnostic testing in the initial evaluation of chronic kidney disease. JAMA Intern Med 175: 853–856, 2015pmid:25730699
    OpenUrlPubMed
  7. ↵
    1. Dispenzieri A,
    2. Kyle R,
    3. Merlini G,
    4. Miguel JS,
    5. Ludwig H,
    6. Hajek R,
    7. Palumbo A,
    8. Jagannath S,
    9. Blade J,
    10. Lonial S,
    11. Dimopoulos M,
    12. Comenzo R,
    13. Einsele H,
    14. Barlogie B,
    15. Anderson K,
    16. Gertz M,
    17. Harousseau JL,
    18. Attal M,
    19. Tosi P,
    20. Sonneveld P,
    21. Boccadoro M,
    22. Morgan G,
    23. Richardson P,
    24. Sezer O,
    25. Mateos MV,
    26. Cavo M,
    27. Joshua D,
    28. Turesson I,
    29. Chen W,
    30. Shimizu K,
    31. Powles R,
    32. Rajkumar SV,
    33. Durie BG; International Myeloma Working Group
    : International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 23: 215–224, 2009pmid:19020545
    OpenUrlCrossRefPubMed
  8. ↵
    1. Leung N,
    2. Barnidge DR,
    3. Hutchison CA
    : Laboratory testing in monoclonal gammopathy of renal significance (MGRS). Clin Chem Lab Med 54: 929–937, 2016pmid:27107835
    OpenUrlPubMed
  9. ↵
    1. Katzmann JA,
    2. Kyle RA,
    3. Benson J,
    4. Larson DR,
    5. Snyder MR,
    6. Lust JA,
    7. Rajkumar SV,
    8. Dispenzieri A
    : Screening panels for detection of monoclonal gammopathies. Clin Chem 55: 1517–1522, 2009pmid:19520758
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Bridoux F,
    2. Javaugue V,
    3. Bender S,
    4. Leroy F,
    5. Aucouturier P,
    6. Debiais-Delpech C,
    7. Goujon JM,
    8. Quellard N,
    9. Bonaud A,
    10. Clavel M,
    11. Trouillas P,
    12. Di Meo F,
    13. Gombert JM,
    14. Fermand JP,
    15. Jaccard A,
    16. Cogné M,
    17. Touchard G,
    18. Sirac C
    : Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management. Kidney Int 91: 423–434, 2017pmid:27773425
    OpenUrlCrossRefPubMed
  11. ↵
    1. Ying WZ,
    2. Allen CE,
    3. Curtis LM,
    4. Aaron KJ,
    5. Sanders PW
    : Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. J Clin Invest 122: 1777–1785, 2012pmid:22484815
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology: 13 (12)
Clinical Journal of the American Society of Nephrology
Vol. 13, Issue 12
December 07, 2018
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Monoclonal Gammopathies and Kidney Disease
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Monoclonal Gammopathies and Kidney Disease
Christina Hao Wang, Jonathan J. Hogan
CJASN Dec 2018, 13 (12) 1781-1782; DOI: 10.2215/CJN.12401018

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Monoclonal Gammopathies and Kidney Disease
Christina Hao Wang, Jonathan J. Hogan
CJASN Dec 2018, 13 (12) 1781-1782; DOI: 10.2215/CJN.12401018
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Disclosures
    • Footnotes
    • References
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Optimizing Utilization of Kidneys from Hepatitis C–Positive Kidney Donors
  • Mobile Health in Dialysis: The Best Engagement Medium Is the One that’s with Patients
  • Forever Starts Now
Show more Editorials

Cited By...

  • No citing articles found.
  • Google Scholar

Similar Articles

Related Articles

  • Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans
  • PubMed
  • Google Scholar

Keywords

  • monoclonal gammopathy
  • ESRD
  • Paraprotein
  • chronic kidney disease
  • Paraproteinemias
  • kidney diseases
  • ESKD
  • end stage kidney disease

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire