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Dr. Sam Silver and Dr. Sarah Moran

Medical Grand Rounds: Onconephrology

Kiera Liblik, MSc Candidate (Translational Medicine)
 

Dr. Sarah Moran and Dr. Samuel Silver presented Grand Rounds for the Departments of Medicine and Oncology. They discussed onconephrology, the field which aims to “help cancer teams identify, treat, and, if possible, prevent kidney problems”(1).

Onconephrology specifically explores how cancer-therapy/specific-factors, patient-specific factors, acute kidney injury (AKI), monoclonal gammopathy of renal significance, hematopoietic stem cell transplantation, electrolyte disorders, and pain management intersect to contribute to the development of chronic kidney disease (CKD)(1). As cancer survival improves, oncology patients are living long enough to develop CKD and require complex nephrology care. Oncology patients with declining renal function also have lower rates of initiation of chemotherapy, radiation, and palliative care(2-4). It follows that inpatient chemotherapy and active cancer are independent predictors of 1-year mortality following AKI(4). Despite the increased need for intervention in the onconephrology population, these patients are often subject to ‘renalism’ or underutilization of interventions and exclusion from clinical research due to concern of adverse events. Consequently, these patients are unable to properly benefit from clinical practice guidelines which have not been tested in their population(5).

Dr. Moran and Dr. Silver presented clinical cases to demonstrate the beneficial role of onconephrology in practice. The first case demonstrated clinical predictors of finding monoclonal gammopathy of renal significance on biopsy, including proteinuria ≥1.5g/day, hematuria, and an abnormal free light chain ratio(6). Next, they discussed intravenous contrast, pemetrexed, and pembrolizumab as possible causative agents of AKI in a patient with adenocarcinoma. The risk of contrast-associated AKI is low and it is important to consider the diagnostic benefit of its use(7). If the immune checkpoint inhibitor (ICI) is the suspected cause, a few factors can help guide clinicians as to whether therapy should be resumed. If the patient fully recovers, acute interstitial nephritis (AIN) is seen on biopsy, other causes of AIN can be discontinued, and/or the patient has an ICI sensitive tumor, rechallenge may be considered. Conversely, continued renal dysfunction, severe multi-organ involvement, previous completion of extended ICI therapy, and/or glomerulonephritis reduce the likelihood of benefitting from rechallenge(8, 9). The final case comprised a discussion on kidney biopsies as well as ICI-associated minimal change disease, which is treated with high-dose steroids. It is important to weigh the complications of biopsy, such as hematomas, bleeding, pain, macroscopic hematuria, and 0.06% risk of death (10).

Overall, oncology patients who are suspected to have AKI or electrolyte disturbances secondary to cancer therapy, have acute decline in renal function, an eGFR <30mL/min/1.732, and/or albumin-to-creatinine ratio >60mg/mmol should be referred to onconephrology. This collaboration not only benefits patients, but their healthcare team and the broader healthcare system.

Following Grand Rounds, Dr. Moran and Dr. Silver generously engaged in a discussion with Translational Medicine students. First, they discussed barriers to developing an onconephrology program. Clinically, it may be challenging to optimize renal function in patients who are at increased risk for CKD and AKI but need to continue on potentially renal-toxic therapeutics to manage their cancer. Additionally, patient beneficence must be balanced with clinical efficiency and resource stewardship in the context of a healthcare system with finite physicians and funding. Regardless, we must prioritize taking the time for knowledge translation in order to help patients make informed decisions. This is particularly important as the public understanding of kidney disease is limited by complex terminology, low health literacy, and that it is a ‘silent disease’ in early stages. Those in the patient’s care team must venture to understand their priorities throughout their disease course. To facilitate effective care, it is also important that we utilize markers of renal function that are reliable across demographic groups, such as cystatin C(11).

Dr. Moran and Dr. Silver’s closed by sharing their career journeys, which began an ocean apart. Dr. Moran went to medical school in Ireland, completing her Internal Medicine and Nephrology training followed by fellowships in Glomerulonephritis and Obstetric Nephrology at the University of Toronto. She reflected that she was drawn to nephrology as it is akin to ‘detective work’ and allows for long-term patient care with a focus on increasing not just lifespan, but quality of life. Dr. Silver also trained at the University of Toronto, where he completed his training in Internal Medicine and Nephrology before he was a research fellow at Stanford. His interest in nephrology similarly stems from an interest in longitudinal care, as well as the multi-system nature of care in this population. Both Dr. Moran and Dr. Silver are interested in quality improvement and system-based change, which is demonstrated by the success of the onconephrology program.

The students of the Translational Medicine program would like to thank Dr. Moran and Dr. Silver for their time as well as their incredible contributions to patient care.

 

References

 

1.         Rosner MH, Jhaveri KD, McMahon BA, Perazella MA. Onconephrology: The intersections between the kidney and cancer. CA Cancer J Clin. 2021;71(1):47-77.

2.         Kitchlu A, McArthur E, Amir E, Booth CM, Sutradhar R, Majeed H, et al. Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study. J Natl Cancer Inst. 2019;111(7):727-36.

3.         Kitchlu A, Chan CT, Leung N, Chen S, Latcha S, Tam P. Perspectives From an Onconephrology Interest Group: Conference Report. Can J Kidney Health Dis. 2020;7:2054358120962589.

4.         Silver SA, Harel Z, McArthur E, Nash DM, Acedillo R, Kitchlu A, et al. Causes of Death after a Hospitalization with AKI. J Am Soc Nephrol. 2018;29(3):1001-10.

5.         Kitchlu A, Shapiro J, Amir E, Garg AX, Kim SJ, Wald R, et al. Representation of Patients With Chronic Kidney Disease in Trials of Cancer Therapy. JAMA. 2018;319(23):2437-9.

6.         Klomjit N, Leung N, Fervenza F, Sethi S, Zand L. Rate and Predictors of Finding Monoclonal Gammopathy of Renal Significance (MGRS) Lesions on Kidney Biopsy in Patients with Monoclonal Gammopathy. J Am Soc Nephrol. 2020;31(10):2400-11.

7.         Weisbord SD, Palevsky PM, Kaufman JS, Wu H, Androsenko M, Ferguson RE, et al. Contrast-Associated Acute Kidney Injury and Serious Adverse Outcomes Following Angiography. J Am Coll Cardiol. 2020;75(11):1311-20.

8.         Johnson DB, Jakubovic BD, Sibaud V, Sise ME. Balancing Cancer Immunotherapy Efficacy and Toxicity. J Allergy Clin Immunol Pract. 2020;8(9):2898-906.

9.         Seethapathy H, Herrmann SM, Sise ME. Immune Checkpoint Inhibitors and Kidney Toxicity: Advances in Diagnosis and Management. Kidney Medicine. 2021.

10.       Poggio ED, McClelland RL, Blank KN, Hansen S, Bansal S, Bomback AS, et al. Systematic Review and Meta-Analysis of Native Kidney Biopsy Complications. Clin J Am Soc Nephrol. 2020;15(11):1595-602.

11.       Helmersson-Karlqvist J, Lipcsey M, Arnlov J, Bell M, Ravn B, Dardashti A, et al. Cystatin C predicts long term mortality better than creatinine in a nationwide study of intensive care patients. Sci Rep. 2021;11(1):5882.

 

Comments

Name
Sophia

Mon, 10/25/2021 - 13:59

Thank you Kiera for your well-written and thoughtful post.

A major takeaway of this lecture for me was how multidisciplinary onconephrology is. If someone were to design a multidisciplinary clinic for onconephrology, who/what specialties would you include and why?

Name
Sophia

Hello Sophia,
Thank you for your comment. The short answer is, it depends on the budget.. Other than oncology and nephrology, I would say there is definitely a role for palliative care. It's difficult to give a short list because I'm sure many consults would be made to pathology, cardiology, urology, obstetrics, endocrinology, geriatrics - the list goes on! In terms of interdisciplinary care, I think it is important to include occupational therapy (especially for patients on dialysis in renal rehabilitation programs). Nurses and nurse practitioners are also incredibly important to medical management of patients and outpatient care.
I'd be curious to know who others would include?
Warm regards,
Kiera

Name
Kiera Liblik

Hi Sophia,

That’s a great question! I found this paper by Cosmai et al. to be quite insightful at outlining the complexities of launching an onconephrology clinic: https://academic.oup.com/ndt/article/33/9/1503/5049712. The authors discuss the variety of patients and conditions who may be referred to such a clinic, including but not limited to cancer patients with kidney impairments and patients with urothelial cancer. The success of the clinic relies on the multidisciplinary approach, including a Core Team of nephrologists, hematologists, and oncologists. Other possible specialties whose insights may be worthwhile in the onconephrology clinic, include urologists, radiation therapists, pathologists, radiologists, and palliative care providers. Additionally, the availability of certain diagnostic tests, such as histological reports, and ability to run efficient testing supports the success of the clinic.

Looking forward to hearing others’ thoughts!

Lubnaa

Name
Lubnaa Hossenbaccus

Hello Lubnaa,
Thank you for sharing this manuscript! It seems that quite a few resources are necessary, even when adequate staff is hired. Perhaps a good compromise is to continue to run these clinics out of hospital to increase ease of access to healthcare practitioners, diagnostic tests, and existing infrastructure. I look forward to seeing how the onconephrology program in Kingston progresses!
Warm regards,
Kiera

Name
Kiera Liblik

Hi Sophia, Lubnaa and Kiera,

I made another comment thread about the consideration for hepatology for getting involved in an initiative such as this to manage toxicities (which may have also been fitting to post here). As oncotherapies continue to grow at a rapid rate and our understanding of cancer and different phenotypes increase, I think it is valuable to involve different health care professionals with different expertise.

-Alyssa

Name
Alyssa Burrows

Name
Emmanuel Fagbola

Mon, 10/25/2021 - 21:08

Hey Kiera,

I think you did an outstanding job successfully facilitating and summarizing last week's medical grand rounds session.

During our sit-down with Dr. Moran and Dr. Silver, we got into an interesting conversation about serum creatinine being an inequitable measure of kidney function. Prior to this discussion, I've read that certain ethnicities are prone to having higher levels of this biomarker, and their kidney function can be inadequately assessed as a result. Despite a physician's best efforts, some patients may not receive optimal treatment. Furthermore, Dr. Moran brought up that women tend to have lower baseline serum creatinine levels than men. Do you think that the primary variable of these discrepancies is muscle mass? If so, should serum creatinine normal levels be standardized in relation to patient muscle mass? Could another variable also be contributing to these discrepancies?

Name
Emmanuel Fagbola

Hello Emmanuel,
Thank you so much for your thoughtful comment! It is interesting to consider that instead of using an alternative marker, we could perhaps better calibrate our eGFR interpretation. A recent publication (1) actually found that there is not just variability associated with muscle mass, but also appendicular skeletal muscle index. Interestingly, they conclude that although cystatin C is not altered by sex/body habitus/diet, the most accurate indicator of kidney function may be an equation that uses both cystatin C and eGFR.
Warm regards,
Kiera
(1) Nankivell, B. J., Nankivell, L. F., Elder, G. J., & Gruenewald, S. M. (2020). How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy. EClinicalMedicine, 29, 100662.
(2) Levey, A. S., Coresh, J., Tighiouart, H., Greene, T., & Inker, L. A. (2020). Measured and estimated glomerular filtration rate: current status and future directions. Nature Reviews Nephrology, 16(1), 51-64.

Name
Kiera Liblik

Hi Kiera and Emmanuel,

Great discussion, something I am also cognisant of is when studies I read use race and/or ethnicity to categorize clinical markers from what I’ve heard about eGFR and kidney transplants. Many trainees are taught to use a racial multiplier to eGFR for Black patients, the implication of an artificially higher eGFR value also raises concerns that CKD diagnosis could be delayed. As stated by the National Kidney Foundation, the reason for this, is the “higher average muscle mass and creatinine generation rate in African Americans.” Some schools have worked to phase out this in medical education through an anti-racist lens for medical practice [1]. Off note, pulmonary function tests (PFTs) are another measurement that also contains a race-based correction factor [2]. It is important to be critical of when ethnicity is being used in medical tests however, there are some exceptions, most notably the cytochrome P450 enzymes which are involved in drug metabolism, some groups may experience different toxicities than others [3].

Along the same line, I wanted to ask Drs. Silver and Moran the impact of eGFR measurements on transgender individuals given hormonal and muscle changes that they may experience. In a case study of a 33 year old transgender man received inappropriate care and delayed kidney transplant because the clinical guidelines were based on an incorrect interpretation of estimated glomerular filtration rate (GFR) calculated from serum creatinine and the patient’s gender rather than their sex [4]. A narrative review on this topic suggested that individuals with CKD have decreased levels of endogenous sex hormones therefore, transgender persons with CKD may require reduced exogenous sex hormone dosing, estradiol therapy increases the risk of thromboembolism and cardiovascular disease which is an increased risk in CKD, whereas testosterone increases the risk of polycythemia. The overall impact of gender-affirming hormone therapy on GFR is unclear, however body composition and lean body mass changes affect eGFR and should be monitored closely [5]. A retrospective analysis by Fadich et al., found Female-based equations may underestimate kidney function in transgender adults undergoing testosterone or estrogen treatment and more prospective cohort studies are needed [6]. Another study suggested that measuring Cystatin C may be more appropriate for transgender people as it is not affected by muscle mass and is less affected by age, sex, and race compared to serum creatinine. Unfortunately, serum cystatin C is influenced by systemic infection, obesity, smoking, corticosteroids, and hyperthyroidism. 24-hour urine creatinine collection to determine GFR may be more accurate for these patients as well [7]. I’m glad that some groups are looking at this question, are there any other medically vulnerable populations that you’re aware of that would be affected by kidney tests or other tests?

-Alyssa

1. Afolabi T, Borowsky HM, Cordero DM, Paul DWJ, Said JT, Sandoval RS, Davis D, Ölveczky D, Chatterjee A (2021) Student-Led Efforts to Advance Anti-Racist Medical Education. Academic Medicine 96:802–807
2. SGIM Forum - Leisman S, Karani R. Systemic, or institutionalized, racism occurs when resources are distributed and practices are enacted that benefit white people at the expense of people of color. Accessed 26 Oct 2021
3. Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM (2004) The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicology and Applied Pharmacology 199:193–209
4. Whitley CT, Greene DN (2017) Transgender Man Being Evaluated for a Kidney Transplant. Clinical Chemistry 63:1680–1683
5. Collister D, Saad N, Christie E, Ahmed S (2021) Providing Care for Transgender Persons With Kidney Disease: A Narrative Review. Can J Kidney Health Dis 8:2054358120985379
6. Fadich SK, Kalayjian A, Greene DN, Cirrincione LR (2021) A Retrospective Analysis of Creatinine-Based Kidney Function With and Without Sex Assigned at Birth Among Transgender Adults. Ann Pharmacother 10600280211050120
7. Assessment of renal function in transgender patients | American Journal of Health-System Pharmacy | Oxford Academic. https://academic.oup.com/ajhp/article/77/18/1460/5890807?casa_token=N06…. Accessed 26 Oct 2021

Name
Alyssa Burrows

Dear Alyssa,
Thank you for your reply and thoughtful discussion! It is important that we consider the different facets of inequity and exclusion in medical guidelines for care. As you've identified, transgender individuals deserve to have safe and effective care that considers factors such as gender-affirming hormones.
You asked if there are any other populations I could think of and socioeconomic status came to mind - especially in terms of dialysis. To have the time and space in your home to complete home dialysis or, alternatively, the ability to travel to a hospital/clinic and perhaps miss work to do so for in-hospital/clinic dialysis is a privilege. In fact, a report by the Kidney Foundation of Canada found that:
"The reported annual average out-of-pocket costs related to dialysis treatment ranged from $1,400 to $2,500 (depending on treatment modality). This is significant when you consider that 55% of respondents reported an annual household income of less than $35,000 and 23% of respondents reported an annual household income of less than $20,000."(1)
It is important that we continue to have these discussions, but also that we lobby for healthcare infrastructure to change in order to serve all Canadians.
Cheers,
Kiera
(1) https://kidney.ca/KFOC/media/images/PDFs/3-2-1-NAT-Burden_of_Out-of-Poc…

Name
Kiera Liblik

Name
Georgia Kersche

Mon, 10/25/2021 - 22:59

Hi Kiera, thank you for your excellent summary of the discussion last week!

The pattern of exclusion of kidney disease patients from clinical trials brought up during their lecture intrigued me. It seems difficult to balance the risks associated with giving new treatments to people with comorbidities such as CKD, while acknowledging the risk of excluding this population of patients from new treatments altogether. I agree with Dr. Moran and Dr. Silver that arbitrarily excluding patients with kidney disease from clinical cancer trials likely causes more harm than good, since it inhibits investigators from weighing the actual pros and cons, therefore withholding a potentially safe and helpful treatment from some of those who may benefit. As it turns out oncology studies are not the only culprit of this, but COVID-19 trials also had varying rates of renal patient inclusion. A review from one year ago found that despite CKD patients being one of the most high-risk groups for adverse outcomes due to COVID-19 and there being very few valid pharmacologic reasons for it, CKD patients are still excluded from nearly half of all registered clinical trials (1). Further, they found that kidney disease-related terms often did not have specific definitions (1). Perhaps contributions from nephrologists in the design of clinical trials of various fields would benefit the populations that the trials aim to evaluate, just as the presenters' work in onconephrology have helped cancer patients. How do you think we can balance the inclusion of kidney disease in trials without putting these participants at significantly increased risk of harm compared to their renally unimpaired counterparts?

Reference
1. Major, R., Selvaskandan, H., Makkeyah, Y., Hull, K., Kuverji, A., & Graham-Brown, M. (2020). The Exclusion of Patients with CKD in Prospectively Registered Interventional Trials for COVID-19—a Rapid Review of International Registry Data. Journal Of The American Society Of Nephrology, 31(10), 2250-2252. doi: 10.1681/asn.2020060877

Name
Georgia Kersche

Hello Georgia,
I appreciate your comment! I agree that an unfortunate reality of clinical trial development generally is that an ideal population to test an intervention on is one with no comorbidities (other than the condition of interest). As you identified, this can be very harmful when those with comorbidities are disproportionately affected (as is the case with COVID-19). That being said, I do understand that if someone has an event during a trial (even if it has nothing to do with the intervention), it can delay getting that intervention to market at all. I think that adding a specific subgroup of trial patients with these comorbidities (but who are medically stable) may be a solution. Of course, then we run into the question .. with so many types of comorbidities and illness, who do we include? And who pays for it?
Warm regards,
Kiera

Name
Kiera Liblik

Hi Keira and Georgia,

Some great commentary on a complex topic! The inclusion and exclusion criteria for clinical trials are quite extensive, while also still trying to capture a large enough sample size to have significant statistical power. This leads to the "healthiest of the sick" patient dilemma. On one hand including only the idealist patients, the ones without too many comorbidities, may give you the best chance to reach the trial's endpoints which will provide strong evidence to the FDA and Health Canada for regulatory approval, allowing your drug to enter the market and help MORE patients. The worry might be that if you include patients with lots of comorbidities, lots of adverse events may arise because of there other diseases, and that you will not reach the study's endpoint and it may not get approved which would help less/no patients. It's a really complex issue that clinical trials test therapies ideal conditions that may not be truly reflective of the real world. I think some potential solves are to allocating more sponsor money to conduct phase 4 trials with patients with common comorbidities or to integrate real world data in an informative way or lastly, to create a regulatory path that allows for the inclusion of patients with comorbidities but accounts for this in their approval process.

-Alyssa

Name
Alyssa Burrows

Hi Georgia, Kiera (great job with facilitating the discussion and this summary by the way), and Alyssa,
I wanted to chime in on this conversation as I found it really stood out to me during the in-class discussion. I decided to research more on the extent to which CKD patients are excluded from clinical trials and found some interesting work that I wanted to share. Of particular interest to me was a narrative review on the prevalence of CKD patient exclusion from clinical trials on coronary artery disease. Of 411,653 patients (86 clinical trials) accounted for in the review, 80% and 75% of patients with end-stage kidney disease and CKD, respectively, were excluded (1). Shockingly, the same review found that only 3 of the aforementioned trials excluded patients with diabetes. I think it is of vital importance that exclusion criteria regarding CKD patients from clinical trials be rethought, especially considering the high prevalence of CKD, which was estimated to affect 19.2 million individuals in the US adult population in a 2003 comparative study (2). I'm curious if besides COVID-19 and coronary artery disease clinical trials, has anyone found any other instances of high exclusion rates for CKD patients from clinical trials?
Best,
James
1. Charytan D, Kuntz RE. The exclusion of patients with chronic kidney disease from clinical trials in coronary artery disease. Kidney Int. 2006 Dec;70(11):2021-30. doi: 10.1038/sj.ki.5001934. PMID: 17051142.
2. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003 Jan;41(1):1-12. doi: 10.1053/ajkd.2003.50007. PMID: 12500213.

Name
James King

CKD patient exclusion in clinical trials was also one of my main takeaways Georgia! Thanks for the insightful comments and for highlighting the relevance during the COVID-19 pandemic. As Kiera and Alyssa mention too, this patient exclusion is an interesting phenomenon that can lead to challenges in treating patients who do not meet the strict inclusion criteria of clinical trials. There are some interesting initiatives and ideas being developed and implemented that use artificial intelligence (AI) to help manage these challenges and improve care for patients who are excluded from clinical trials based on comorbid conditions. An interesting review by David Fogel highlights several challenges introduced by the tight clinical trial inclusion criteria that can be addressed using AI tools, beginning at study design through in-depth analysis of existing literature to optimize inclusion criteria, and enriching the project all the way through execution (1). I'm interested to know what the team thinks of other opportunities to use the technology at our fingertips to ensure that our research can be targeted to a representative patient population.
(1) Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164. Published 2018 Aug 7. doi:10.1016/j.conctc.2018.08.001

Name
Katie Lindale

Name
Lubnaa Hossenbaccus

Mon, 10/25/2021 - 23:09

Hi Kiera,

I really enjoyed reading your summary! You did a great job succinctly highlighting the key points discussed.

I was surprised by the concept of rechallenging patients to the same dose of immune checkpoint inhibitors (ICPIs) after acute kidney injury (AKI). I would have thought that the resulting side effect would lead to a modified treatment plan, though patients do have to meet certain conditions for the potential of being rechallenged. A multicenter study that followed cancer patients who had experienced episodes of ICPI-AKI found that only 3% of rechallenged patients developed unrecoverable AKI (1), suggesting that ICPI rechallenge should be considered, especially if the patient lacks other treatment options.

In efforts to better diagnose ICPI-AKI and evaluate the potential for rechallenge, I wonder if you’ve seen any biomarkers that may be useful?

I’d love to hear your thoughts,

Lubnaa

(1) https://kidney360.asnjournals.org/content/1/2/130

Name
Lubnaa Hossenbaccus

Name
Kiera Liblik

Tue, 10/26/2021 - 09:26

In reply to by Anonymous (not verified)

Hello Lubnaa,
Thank you for your comment! I agree - it is counterintuitive to readminister a therapeutic agent that caused an adverse event. As you have identified, finding predictors of these poor outcomes will hopefully tell us which patients to monitor for repeat events (or even consider not rechallenging at all). It seems that acute interstitial nephritis secondary to ICPIs may increase risk of rechallenge, and that ICPIs should not be continued until renal toxicity is resolved in these cases (1). Hopefully reliable biomarkers continue to emerge to aid in this clinical decision making!
Warm regards,
Kiera
(1)Herrmann SM, Perazella MA. Immune Checkpoint Inhibitors and Immune-Related Adverse Renal Events. Kidney Int Rep. 2020;5(8):1139-1148. Published 2020 Apr 29. doi:10.1016/j.ekir.2020.04.018

Name
Kiera Liblik

Name
Kyla Tozer

Tue, 10/26/2021 - 11:58

Hello Kiera,

Thank you so much for your insightful summary and thought provoking discussion. I really enjoyed hearing about the team dynamics and how working between disciplines can create a robust patient experience.

I had the same thoughts as Sophia, where I wonder what this approach could look like for other disciplines and how patient care could evolve. Also for research, the potential for discovery that one could find when connecting two disciplines, that have not been connected before. For example, the gut brain axis is something that is currently being investigated. For years this was not something people even thought about. In your opinion, would it be beneficial to make these connections, not only for patient care, but also the potential for advancements in medical research.
Thank you so much Kiera.
And, thank you Dr. Morgan and Dr. Silver for a wonderful lecture.
Kyla

Name
Kyla Tozer

Name
Kiera Liblik

Tue, 10/26/2021 - 15:52

In reply to by Kyla (not verified)

Dear Kyla,
I appreciate your comment and question! I think there is vast potential for expanding medical research by investigating the intersection of different medical subspecialties. In terms of onconephrology, it seems that along with the work being done by Dr. Silver and Dr. Moran, there is emerging literature in this area. For example, a recent review discussed advancements in treating tumor lysis syndrome by collaborating with nephrology.(1) I am excited to see this field grow to benefit patients and the broader research/healthcare community!
Warm regards,
Kiera
(1) Matuszkiewicz-Rowinska, J., & Malyszko, J. (2020). Prevention and treatment of tumor lysis syndrome in the era of onco-nephrology progress. Kidney and Blood Pressure Research, 45(5), 645-660.

Name
Kiera Liblik

Name
Samantha Ables

Wed, 10/27/2021 - 20:02

In reply to by Anonymous (not verified)

Dear Kyla and Kiera,

Thank you for your summary of last week’s discussion.

I completely agree that there’s a lot of room for expanding research and clinics by integrating medical specialties! I hope that as new treatments and drugs are developed, more of these specialized mixed-specialty clinics will come about, in response to very targeted therapies for diseases. For example, an emerging form of treatment for cancer is immunotherapy. I think this will create the potential for cancer immunology clinics, where cancer physicians can consult with immunologists to hopefully avoid harmful immune overreactions or even new forms of autoimmune diseases coming about due to treatments for cancer (1). However, as beneficial as specialized clinics, like the onconephrology clinic, are, this highlights inequity in access to health care, as patients who are not located near large academic hospitals may not have similar clinics nearby. Are there any other medical specialties you could see being useful to integrate to better care for patients?

Thank you,

Samantha

1. “Five emerging medical specialties you’ve never heard of – until now”. Association of American Medical Colleges. https://www.aamc.org/news-insights/five-emerging-medical-specialties-yo…

Name
Samantha Ables

Hello Samantha,
Thank you for your comment and question! I suppose that in an ideal world there are sub-specialists for every type of pathology but unfortunately that is not realistic. As you've identified, the more specialties that exist, the more training and physicians we need (and usually the areas that need them most are least likely to receive that specialized care without travel). I do think that we will see an increased integration of public health into existing specialties, especially in the wake of COVID. It is important that clinical decision making is informed not just by the patient in front of you, but the broader societal/cultural context we live in.
Warm regards,
Kiera

Name
Kiera Liblik

Name
Alyssa Burrows

Tue, 10/26/2021 - 14:39

Thank you for the great summary. We know that most drugs are also processed by the liver, and many are excreted through the kidneys. Given that many cancer drugs are highly toxic this led me to ask if, it would be worthwhile to add a hepatologist specialised in oncology to offer a clinical service similar to Drs. Silver and Moran to preserve liver function and help with therapeutic doses to reduce toxicities? Maybe these specialist could help manage oncology patients with comorbid liver diseases? Are there other clinicians or health care professionals that you think would be valuable to integrate into cancer care?

Some considerations, traditional chemotherapy is highly toxic, recognizing hepatic conditions, such as sinusoidal obstructive syndrome, steatosis, and pseudocirrhosis that are more commonly associated with chemotherapy that can result and keen clinical as well as radiographic recognition are paramount however most can be managed with supportive therapies and the liver toxicity may resolve after discontinuation of chemotherapy [1]. Newer cancer treatments such as immune check point inhibitors (ICIs) and cellular targets may reduce hepatoxicity. For example in clinical trials fewer than 10% of patients on single-agent ICIs reported elevated liver enzymes [2, 3].

Looking forward to hearing your thoughts,

Alyssa

1. Sharma A, Houshyar R, Bhosale P, Choi J-I, Gulati R, Lall C (2014) Chemotherapy induced liver abnormalities: an imaging perspective. Clin Mol Hepatol 20:317–326
2. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma | NEJM. https://www.nejm.org/doi/full/10.1056/nejmoa1504030. Accessed 26 Oct 2021
3. Motzer RJ, Rini BI, McDermott DF, et al (2015) Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 33:1430–1437

Name
Alyssa Burrows

Dear Alyssa,
Thank you for your comment and engagement in this discussion! I did some searching at it seems that the majority of overlap between oncology and hepatology is in regards to hepatic malignancies. Although, as you identified, hepatic toxicity is a concern for certain chemotherapy agents. In that case, I think having a hepatologist to consult for an onconephrologist team could improve patient care and reduce complications of therapy. I would love to hear what others think!
Warm regards,
Kiera

Name
Kiera Liblik

Hi Kiera and Alyssa,
I wanted to add to the conversation here. I know both in TMED800 and 801 we have discussed immune-checkpoint inhibitors as one of the biologics used for cancer-immunotherapy. I found that checkpoint-inhibitors have been associated with documented liver-induced injuries (1). Given this, and the likely expansion of the use of immune-checkpoint inhibitors due to their excellent success in cancer treatment, I agree with both of you that involving hepatologists to a greater extent could be a great benefit to patients!
Best,
James
1. Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019 Nov;36(6):434-440. doi: 10.1053/j.semdp.2019.07.009. Epub 2019 Jul 24. PMID: 31358424.

Name
James King

Name
Trinity Vey

Tue, 10/26/2021 - 14:49

Hi Kiera,

Thank you for an excellent summary of last week’s grand rounds. I also want to commend you on a job well done facilitating a discussion with multiple speakers.

Something that stood out to me from last week’s presentation was the question that Dr.’s Silver and Moran kept asking during case studies – is a kidney biopsy appropriate and necessary? Given my clinical inexperience, my first thoughts were “If this diagnostic tool is available, why wouldn’t we use it?”. However, as you highlighted, kidney biopsies are associated with many complications, such as hematoma and bleeding, that must be considered. Given these complications, it makes sense that biopsies should generally be avoided for patients with co-morbidities that increase risk of significant post-procedure bleeding, such as uncontrolled hypertension or impaired coagulation (1). Skin infections at the insertion site are also considered absolute contraindications (1). This was a reminder that just because a given treatment or procedure is “available”, depending on factors such as safety, feasibility, or even cost, clinical tools are not always equally available to all patients.

I also wanted to briefly comment on the disproportionate prevalence of kidney disease within certain Canadian populations. As mentioned in our discussion, Indigenous Canadians have a higher prevalence of end-stage renal disease than the general population (2). Furthermore, it’s been noted that Indigenous patients receiving dialysis have a lower-5-year survival rate than the general population, which is thought to be related to inaccessibility to dialysis treatment (e.g., living far from treatment centres) and barriers to kidney transplantation (2). I wonder if you or anyone else have any thoughts on how we might improve renal care for Indigenous Canadians, or Canadians living remotely without easy access to dialysis (or onconephrology!) centres?

Looking forward to hearing your thoughts, and thank you again for a great summary.

Best,

Trinity

References:

1. Luciano, R. L., & Moeckel, G. W. (2019). Update on the Native Kidney Biopsy: Core Curriculum 2019. American journal of kidney diseases: the official journal of the National Kidney Foundation, 73(3), 404–415. https://doi.org/10.1053/j.ajkd.2018.10.011

2. Collier R. (2013). Renal disease more prevalent and problematic for Aboriginal peoples. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 185(5), E214. https://doi.org/10.1503/cmaj.109-4412

Name
Trinity Vey

Dear Trinity,
Thank you for a very thoughtful discussion post! It seems that a lot of medicine (both diagnostic and interventional) requires a thoughtful balance of risk and benefit. Given the incredible amount of confounding variables that influence this risk-to-benefit ratio, even something as helpful as a kidney biopsy really does have to be carefully considered.
In terms of your point on access to care, I do hope that something we can take from the COVID-zoom era is the power of remote consultations. Of course, then we run into barriers such as lack access to technology and important physical examinations. Another possibility is a 'mobile' onconephrology clinic. In fact, there is PGY4 OB/GYN resident (Dr. Nault) in Quebec who is trying to implement this for primary care (1). No matter what, these discrepancies in care are unacceptable and must be prioritized as our healthcare system evolves.
Warm regards,
Kiera
(1) https://newsroom.royalcollege.ca/mobile-clinic-will-bring-care-to-rural…

Name
Kiera Liblik

Hi Keira and Trinity,

I agree making health care more accessible to remote communities should be a major focus in improving today’s healthcare. While virtual consults might not seem like the perfect solution (due to reasons Kiera touched upon), newer technologies are allowing for facilitated monitoring of patients remotely. For instance, some peritoneal dialysis can provide real-time monitoring of blood pressure, and photographs and videos make it easier for remote assessments (1). Additionally, studies have shown patients quality of life to benefit from telenephrology due to increased attendance rates and reduced travel times (2, 3). It is hopeful to hear that small improvements in access are being made through telenephrology, however, we can still do better. One suggestion would be to create more programs to train health care professionals to practice in these rural communities. Additionally, traveling screening clinics could be used to help catch kidney disease earlier in these populations. Bioelectrical impedance analysis (BIA) is a non-invasive tool that estimates water composition of body compartments which can further be used for estimations of creatinine excretion and GFR (4). BIA is also portable and inexpensive, making it ideal for initial screening in remote locations.

I would love to hear if anyone else has any further suggestions on improving renal care in remote communities!

(1) Ovtcharenko, N., & Thomson, B. K. A. (2019). Interventions to Improve Clinical Outcomes in Indigenous or Remote Patients With Chronic Kidney Disease: A Scoping Review. Canadian journal of kidney health and disease, 6, 2054358119887154.
(2) Tan, J., Mehrotra, A., Nadkarni, G. N., He, J. C., Langhoff, E., Post, J., ... & Rohatgi, R. (2018). Telenephrology: providing healthcare to remotely located patients with chronic kidney disease. American journal of nephrology, 47(3), 200-207.
(3) AlAzab, R., & Khader, Y. (2016). Telenephrology application in rural and remote areas of Jordan: benefits and impact on quality of life.
(4) Saxena, A., Gupta, A., Abraham, G., Sakhuja, V., & Jha, V. (2015). Non-invasive screening tool for chronic kidney disease. Saudi Journal of Kidney Diseases and Transplantation, 26(6), 1311.

Name
Cassie Brand

Hello Cassie,
Thank you for your comment! I agree - we need an increased presence of healthcare professionals in these communities. I also think it is important to consider that although increasing accessibility is important, we need to address the underlying causes of inequity in underserved populations.(1,2) This means involvement of not just healthcare workers and policy makers, but consultants in the communities experiencing these inequities who must be adequately recognized and compensated for their time.
(1) Nguyen, N. H., Subhan, F. B., Williams, K., & Chan, C. B. (2020, June). Barriers and Mitigating Strategies to Healthcare Access in Indigenous Communities of Canada: A Narrative Review. In Healthcare (Vol. 8, No. 2, p. 112). Multidisciplinary Digital Publishing Institute.
(2) Davy, C., Harfield, S., McArthur, A., Munn, Z., & Brown, A. (2016). Access to primary health care services for Indigenous peoples: A framework synthesis. International Journal for Equity in Health, 15(1), 1-9.

Name
Kiera Liblik

Name
Bethany Wilken

Wed, 10/27/2021 - 16:43

Hi Kiera,

Thank you for your excellent summary of a fascinating presentation and discussion of onconephrology. Dr. Moran and Dr. Silver are pioneers in multidisciplinary approaches to clinical efficacy. I believe re-structuring the health system away from the organ-based approach, and more towards a symptom-based and multidisciplinary approach can improve patient-centred immensely.

One topic we haven’t elaborated on is the mechanism of how new biologics are causing acute kidney complications. Dr. Moran and Dr. Silver mentioned that some patients they see have acquired acute kidney injury (AKI) from cancer immunotherapy. Immune-related adverse effects (irAEs) are common due to off-target inflammatory effects of checkpoint inhibitors. One common lesion from the nephrotoxicity of immune checkpoint inhibitors is acute tubulointerstitial nephritis (AIN). After doing some research, it appears the mechanisms of pathogenesis are still relatively unknown. The original proposed mechanism of AIN, activation of circulating T cells leading to local immunogenicity by tubular cell processing, has been disproven. No studies have shown checkpoint inhibitor specific T cells in peripheral blood and there is a delayed onset of AKI after therapy, suggesting an alternative mechanism (1). Other possible mechanisms include T cells losing tolerance to native antigens (“multi-hit” theory) or the induction of the hypersensitivity reaction pathway when an immunogenic compound is involved (“2-hit” theory) (2). The unclear mechanism of immune checkpoint inhibitors in AKI highlights the need for continued collaboration in the departments of nephrology and oncology. It also showcases a broader need for collaboration in other disciplines to develop novel translational applications. For example, glomerular filtration rate ensures the proper clearance of many drugs and thus, nephrologists have the ability of improving the delivery of cancer treatment by optimizing kidney function.

I am interested in hearing if my classmates have any experiences in multidisciplinary research. I think we must remember the importance of viewing the body as an intricate interplay of multiple systems.

Best,
Bethany

1. Shingarev, R., & Glezerman, I. G. (2019). Kidney complications of immune checkpoint inhibitors: a review. American Journal of Kidney Diseases, 74(4), 529-537.
2. Murakami, N., Borges, T. J., Yamashita, M., & Riella, L. V. (2016). Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma. Clinical kidney journal, 9(3), 411-417.

Name
Bethany Wilken

Hello Bethany,
Thank you for a thorough and well-explained comment on biologics and AKI! To your question - I think one area of medicine that is important to integrate into any subspecialty is psychiatry. For example, we know that mental health impacts long-term outcomes in patients with renal disease and malignancies.(1,2) Given the possibility to improve quality of life, morbidity, and mortality, I hope that we will see an increase psychiatric considerations of patient care in the future.
Cheers,
Kiera
(1) López Revuelta, K., García López, F. J., de Alvaro Moreno, F., & Alonso, J. (2004). Perceived mental health at the start of dialysis as a predictor of morbidity and mortality in patients with end-stage renal disease (CALVIDIA Study). Nephrology Dialysis Transplantation, 19(9), 2347-2353.
(2) Carreira, H., Williams, R., Müller, M., Harewood, R., Stanway, S., & Bhaskaran, K. (2018). Associations between breast cancer survivorship and adverse mental health outcomes: a systematic review. JNCI: Journal of the National Cancer Institute, 110(12), 1311-1327.

Name
Kiera Liblik

Name
Dilakshan Srikanthan

Thu, 10/28/2021 - 13:04

Hi Kiera,
Thank you for your wonderful facilitation of our discussion and succinct review of Dr. Moran’s and Dr. Silver’s talk. One of the things that stood out to me during our discussion is the incidence of cancer in patients with chronic kidney disease and the incidence of kidney disease in cancer patients. The bi-directional association between the two is an interesting one and may provide some insights to how we can further help patients that are in this unique category.
The kidneys are main site of drug elimination from the body and as such as exposed to tremendous concentrations of chemotherapeutic agents, along with drug active and inactive metabolites, which can often lead to nephrotoxicity. However, it is important to note that as mentioned in the talk, kidney diseases in patients with cancer are associated with higher morbidity and mortality. This could be because kidney dysfunction creates an inflammatory microenvironment and oxidative stress, which can establish the ideal environment for cancer development.
A great therapeutic option to treat the cancer while preventing kidney dysfunction is by providing combination therapies which target the cancer while protecting kidney functions. A recent study found that Cisplatin (which causes nephrotoxicity) can be paired to sodium thiosulfate or DPP-4 inhibitor to prevent cisplatin-induced nephrotoxicity (Veggiano et al., 2019; Iwakura et al., 2019).
I believe these combination therapies may be an effective option to treat patients who are in a unique situation of having kidney dysfunction and cancer. Would love to hear your thoughts!

Name
Dilakshan Srikanthan

Name
Nolan Breault

Thu, 10/28/2021 - 14:48

Hi Kiera & Co,

This has been quite the nuanced and considerate discussion thus far! I'd like to add a few words regarding the underpinnings of the Rounds topic.

The relationship between kidney disease and cancer has been described as "circular" (1). This is evidenced through acute kidney injury having the potential to reduce the bioavailability of certain anti-cancer medications, and such medications, like cisplatin (which is widely used in treating lung, ovarian, bladder, and other cancers), bear documented off-target effects that disproportionately affect renal cells (2). While it's far from controversial that cancer therapies have negative impacts throughout the body, efficacy in tumour regression (depending on how aggressive the cancer is) arguably shouldn't be at the cost of inducing another condition that in itself bears a >10% mortality rate (3). Research has shown that sufficient hydration and magnesium supplementation can reduce nephrotoxicity in low-mid dose cisplatin patients, while mannitol is more effective in high-dose recipients (4, 5). As we learned in previous Rounds with Dr. Boyd, even surviving acute kidney injury doesn't mean you're out of the woods. This is to say that I think greater emphasis should be placed on the prevention of secondary complications to treatment where possible, both reducing mental and physical burden on patients as well as healthcare costs.

Best,

Nolan

References
1. Porta, C. Cosmai, L., Gallieni, M., et al. (2015) Renal effects of targeted anti-cancer therapies. Nat. Rev Nephrol. 11: 354-370.
2. Volarevic, V., Djokovic, B., Jankovic, M. G., et al. (2019) Molecular mechanisms of cisplatin=induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J. Biomed. Sci. 26:25.
3. Wang, H. E., Muntner, P., Chertow, G. M., et al. (2012) Acute Kidney Injury and Mortality in Hospitalized Patients. Am. J. Nephrol. 35: 349-355.
4. Yamamoto Y , Watanabe K , Tsukiyama I et al. (2016) Hydration with 15 mEq magnesium is effective at reducing the risk for cisplatin-induced nephrotoxicity in patients receiving cisplatin (≥50 mg/m2) combination chemotherapy. Anticancer Res. 36: 1873–1877.
5. Saito Y , Kobayashi M , Yamada T et al. (2017) Premedication with intravenous magnesium has a protective effect against cisplatin-induced nephrotoxicity. Support Care Cancer 25: 481–487.

Name
Nolan Breault

Name
Pierce Colpman

Thu, 10/28/2021 - 22:52

Hi Kiera firstly I wanted to say thank you for doing such a great job of facilitating this week. I was one of the students being graded on their question asking and I thought you did a great job of keeping the flow of conversation going and started each section with a relevant and intriguing question to start our thinking.

My question to you comes from the last part of our discussion with Dr. Silver and Dr. Moran and mentors. What qualities do you think are important for a mentor to have and do you have an experience you can share where theses qualities made a difference if how comfortable you felt at your position or in your learning? The speakers both emphasized the quality of liking who you are working with and having a personal connection and I wondered what your thoughts were on this. Do you think this is the most important aspect of a mentor? Lastly as an additional question to you I wondered if you think that the practical advantages of having a dedicated onconephrology division at hospitals is worth the resources and space, is the problem big enough? Again thank you for doing a great job!

Name
Pierce Colpman

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