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Letters to the Editor

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Chronic pain and premature mortality in men and women, using data from UK Biobank
Gary J. Macfarlane, … , Marcus Beasley, Gareth T. Jones
Gary J. Macfarlane, … , Marcus Beasley, Gareth T. Jones
Published March 1, 2023
Citation Information: J Clin Invest. 2023;133(5):e166949. https://doi.org/10.1172/JCI166949.
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Chronic pain and premature mortality in men and women, using data from UK Biobank

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Authors

Gary J. Macfarlane, Marcus Beasley, Gareth T. Jones

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Chronic pain and premature mortality in men and women, using data from UK Biobank. Reply.
Marc Parisien, … , Luda Diatchenko, Jeffrey S. Mogil
Marc Parisien, … , Luda Diatchenko, Jeffrey S. Mogil
Published March 1, 2023
Citation Information: J Clin Invest. 2023;133(5):e168070. https://doi.org/10.1172/JCI168070.
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Chronic pain and premature mortality in men and women, using data from UK Biobank. Reply.

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Authors

Marc Parisien, Audrey V. Grant, Arjun Muralidharan, Luda Diatchenko, Jeffrey S. Mogil

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Does treating with anti–PD-1 to improve glomerular health come without a cost?
Kenar D. Jhaveri, … , Abhijat Kitchlu, Ala Abudayyeh
Kenar D. Jhaveri, … , Abhijat Kitchlu, Ala Abudayyeh
Published November 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e164747. https://doi.org/10.1172/JCI164747.
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Does treating with anti–PD-1 to improve glomerular health come without a cost?

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Kenar D. Jhaveri, Abhijat Kitchlu, Ala Abudayyeh

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Is treating with anti PD-1 to improve glomerular health come without a cost? Reply
Stuart J. Shankland, … , Jeffrey W. Pippin, Oliver Wessely
Stuart J. Shankland, … , Jeffrey W. Pippin, Oliver Wessely
Published September 22, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI165287.
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Is treating with anti PD-1 to improve glomerular health come without a cost? Reply

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As representatives for our entire team, we thank Jhaveri et al. (1) for their insightful comments on our recent study investigating the increased expression of programmed cell death protein-1 (PD1) in kidneys during aging and FSGS.(2) In our manuscript we showed that PD1 was predominantly increased in podocytes and kidney tubular epithelial cells in both mice and humans. Moreover, in humans, age-elevated glomerular PCDC1 (gene encoding human PD1) levels were associated with a lower eGFR, increased segmental glomerulosclerosis, and reduced arterial intima-to-lumen ratio. We also demonstrated a mechanistic link between increased PD1 levels in podocytes and their shortened lifespan. Finally, specifically antagonizing the PD1 pathway with a specific anti-PD1 antibody (similar to humanized Pembrolizumab or Nivolumab) in aged mice and mice with experimental FSGS had major benefits on kidney histology, podocyte life- and health-span, and tubular epithelial injury.(2) In their response, Jhaveri and colleagues, experts in onco-nephrology, eloquently discuss the clinical kidney-specific adverse events (AEs) when using immune checkpoint inhibitors (ICI) in cancer patients.(1) They provide important clinical insights and an up-to-date summary of the incidence and types of glomerular lesions, acute kidney injury and acute interstitial nephritis observed in patients receiving ICI for cancer treatment.(3,4) Importantly, complete or partial remission of kidney-specific AEs upon discontinuation of ICI treatment in a subset of patients suggests a causal link.(3, 4) We unreservedly agree with Jhaveri et al. that caution is warranted when using ICI clinically. In fact, we have not advocated the clinical use of anti-PD1 treatment to limit or reverse kidney aging, nor to be used as a therapy for FSGS. The clinical data highlighted by Jhaveri et al. underscore the importance of gaining a better understanding of the mechanism(s) underlying kidney complications in patients. While T cell activation, proliferation and subsequent kidney infiltration is the leading hypothesis,(3, 4) how this cumulates into kidney dysfunction is unknown. ICIs block the CTLA-4 and/or PD1 pathways. CTLA-4 acts early in tolerance induction, stopping potentially autoreactive T cells at the initial stage of naive T-cell activation, while PD1 acts late to maintain long-term tolerance, primarily in peripheral tissues.(5) Typically a lower incidence of AEs is associated with PD1 blockade compared with CTLA-4 blockade.(3, 4) Interestingly, in our study mice Ctla4 mRNA levels in contrast to PD1 were not elevated in podocytes with age. There are also several differences between humans and mice that may influence the response to anti-PD1 treatments. To reconcile these, one needs to experimentally align the animal studies with the therapeutic scenario in human cancer patients. Possible considerations include: (i) the duration of therapy - in our study mice received 8 weeks of treatment, while human patients typically receive a 13-week median drug exposure before glomerular disease is first detected; (ii) the presence of comorbid conditions is oftentimes present in humans (e.g., patients receiving additional medications or already exhibiting altered kidney function before receiving ICI agents), but was absent in our mice; (iii) sex and age – the median age of patients developing glomerular disease after ICI treatment is 63 years and 75% thereof are male,(4) while our mouse study was based on males only; (iv) drug dosing – the therapeutic doses of ICIs used in humans might be much higher than the doses of the mouse-specific anti-PD1 antibody yielding beneficial effects in mouse podocytes; (v) finally, genetic variation in humans may influence the response to anti-PD1 treatments, while mice strains are genetically very homogenous. We believe that our study has provided some exciting new considerations that has moved us ahead scientifically. First, the PD1 signaling is a new pathway contributing to the aging of podocytes and other kidney epithelial cells, as well as the response of podocytes in disease. Second, podocyte aging and diseased-induced podocyte injury share a new common pathway – PD1. This raises the possibility that PD1 signaling is one of the pathways responsible for the more severe kidney injury when FSGS is superimposed on an aged kidney. Third, the effects of the anti-PD1 antibody treatment are not restricted to the kidney, but also reduced some aspects of liver aging. This suggests that it might be a common aging pathway, that needs to be studied further. Fourth, the unexpected discovery of PD1 signaling in aging leads us to predict that there will be additional surprises in new pathways contributing to kidney aging and disease that will translate into new druggable targets.

Authors

Stuart J. Shankland, Jeffrey W. Pippin, Oliver Wessely

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Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk. Reply.
Won-Mook Choi, Young-Suk Lim
Won-Mook Choi, Young-Suk Lim
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e161425. https://doi.org/10.1172/JCI161425.
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Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk. Reply.

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Authors

Won-Mook Choi, Young-Suk Lim

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Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk
Shi Liu, … , Yongyin Li, Jian Sun
Shi Liu, … , Yongyin Li, Jian Sun
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e161134. https://doi.org/10.1172/JCI161134.
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Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk

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Authors

Shi Liu, Yongyin Li, Jian Sun

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Genetic mechanism for the loss of PRAME in B cell lymphomas
Marek Mraz
Marek Mraz
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e160983. https://doi.org/10.1172/JCI160983.
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Genetic mechanism for the loss of PRAME in B cell lymphomas

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Marek Mraz

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Genetic mechanism for the loss of PRAME in B cell lymphomas. Reply.
Katsuyoshi Takata, Christian Steidl
Katsuyoshi Takata, Christian Steidl
Published July 15, 2022
Citation Information: J Clin Invest. 2022;132(14):e161979. https://doi.org/10.1172/JCI161979.
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Genetic mechanism for the loss of PRAME in B cell lymphomas. Reply.

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Authors

Katsuyoshi Takata, Christian Steidl

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Concerns over functional experiments, interpretation, and required controls
Eddie C.Y. Wang, … , Ceri A. Fielding, Richard J. Stanton
Eddie C.Y. Wang, … , Ceri A. Fielding, Richard J. Stanton
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e157369. https://doi.org/10.1172/JCI157369.
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Concerns over functional experiments, interpretation, and required controls

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Eddie C.Y. Wang, Ceri A. Fielding, Richard J. Stanton

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Concerns over functional experiments, interpretation, and required controls. Reply.
Wan-Chen Hsieh, Shih-Yu Chen
Wan-Chen Hsieh, Shih-Yu Chen
Published March 1, 2022
Citation Information: J Clin Invest. 2022;132(5):e158155. https://doi.org/10.1172/JCI158155.
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Concerns over functional experiments, interpretation, and required controls. Reply.

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Authors

Wan-Chen Hsieh, Shih-Yu Chen

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