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Selection Committee Member: Matthew Abramson @M_Abramson

Matthew Abramson is an academic nephrologist at Icahn School of Medicine at Mount Sinai in Manhattan, NY. He completed nephrology fellowship training at Weill Cornell Medicine, followed by additional subspecialty training in onco-nephrology at Memorial Sloan Cancer Center. He was a runner-up in NephMadness 2022. His passions include improving quality of care for oncology patients who suffer from kidney-related issues.

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Writer: Scott Stockholm

Scott Stockholm is a nephrology fellow at Washington University in St. Louis. He completed residency at Cape Fear Valley in Fayetteville, NC. His areas of interest include acid-base physiology and electrolyte disturbances.

 

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Writer: Morgan Schoer

Morgan Schoer is a second-year nephrology fellow at Washington University in St. Louis, where she currently serves as chief fellow. She will remain on faculty next year as an assistant professor. Her clinical and research interests include home modalities and urine microscopy.

Competitors for the Onconephrology Region

Team 1: Chemotherapy Associated Hypomagnesemia versus Team 2: Immune Checkpoint Inhibitor-Associated Acute Kidney Injury

Copyright: Antoine2K/Shutterstock

Team 1: Chemotherapy Associated Hypomagnesemia

Introduction

Who doesn’t love electrolytes? Sodium, potassium, chloride, bicarb, and calcium all make it onto the basic metabolic panel, but why does magnesium end up on the bench?  After all, it is the second most abundant intracellular cation after potassium and is not only an invaluable cofactor for innumerable reactions in the body, but also forms protein and nucleic acid structures.  When patients don’t have enough magnesium, they can experience a range of symptoms including nausea, fatigue, muscle tetany, seizures, and even cardiac arrhythmias.

One population that is particularly prone to the development of hypomagnesemia is that of patients with cancer. With the advent of new agents such as anti-epidermal growth factor receptor (EGFR) inhibitors, which have a high prevalence of magnesium wasting, understanding the balance of this electrolyte in our body becomes even more crucial.  This year’s team makes an argument for magnesium to be included with the starting five of the chemistry panel.

Copyright: Wooden Owl/Shutterstock

 Magnesium Homeostasis

Like potassium, magnesium is primarily an intracellular cation stored in bone, muscle, and soft tissue, with only 1% of magnesium present in the extracellular fluid. Of this 1%, about ⅓ is plasma protein bound, and the remaining ⅔ is freely filtered through the kidney. In the gastrointestinal tract, foods high in magnesium such as meats, cereals, and dairy products are responsible for replenishing magnesium stores (30%-80% can be absorbed). Bulk absorption occurs in the small intestine and is modulated by paracellular tight junction proteins claudin 2, claudin 7, and claudin 12. The absorption in the colon is transcellular via TRPM6 and TRPM7. We’ll see similar junctions and channels in the kidney as well!

Magnesium that is not protein bound is readily filtered across the glomerulus. Approximately 2.4 g of magnesium is freely filtered through the kidneys with the majority of this filtrate being reabsorbed. In the setting of hypomagnesemia, the kidneys are able to reduce this amount of excretion to less than 12 mg per day. For most other components of glomerular filtrate, the proximal tubule is the workhorse and reabsorbs about ⅔ of what it sees. However, the proximal convoluted tubule is only responsible for 15% of magnesium resorption through a paracellular mechanism.  The majority of magnesium reabsorption occurs in the thick ascending loop of Henle.  Here, around 70% of magnesium is reabsorbed paracellularly with claudin 16 and claudin 19. A final 15% of magnesium is absorbed in the distal convoluted tubule transcellularly through the TRPM6 channel. With this in mind, let’s consider the mechanisms of hypomagnesemia related to several older agents before diving into the anti-EGFR inhibitors.

Hypomagnesemia in Cancer Patients

Patients with cancer are at particular risk for developing hypomagnesemia.  In addition to potential decreased intake due to appetite loss or poor GI absorption due to bowel resection, medications can have an impact on magnesium homeostasis.  Several adjunctive medications other than chemotherapy can impact magnesium. These include but are not limited to bisphosphonates, aminoglycosides, amphotericin, calcineurin inhibitors, and proton pump inhibitors (PPIs).  The mechanistic impact of these drugs on magnesium varies from cellular shift and disruption of cation-sensing receptors to reducing the expression of magnesium channels like TRPM6.  In many of these cases, hypomagnesemia is associated with hypokalemia. If you don’t understand the mechanism, this Tony Breu Tweetorial will show you the light.

An older class of chemotherapy that is highly associated with hypomagnesemia is the heavy metals cisplatin and, less frequently, carboplatin.  In the earliest phase 1 trials from the 1980s, 10% of patients treated with carboplatin developed hypomagnesemia.  Patients treated with cisplatin were at even higher risk, with more than half of the patients developing hypomagnesemia.  What is striking here is that hypomagnesemia can also persist for more than 5 years after therapy is completed, suggesting irreversible tubular damage from direct injury to cells in the loop of Henle and distal collecting tubule.

The newest chemotherapy agents making a splash in magnesium are the aforementioned anti-EGFR inhibitors. Anti-EGFR inhibitors have been shown to impede cellular apoptosis and promote cell proliferation, angiogenesis, and metastases of malignancy.  These receptors are commonly overexpressed in breast, lung, colorectal, pancreatic, and head and neck cancers, and were the first growth factor receptors proposed as a target for cancer therapy.  Of these agents, the monoclonal antibody agents cetuximab (Erbitux, chimeric IgG1 Ab) and panitumumab (Vectibix, human IgG2 Ab) are most highly linked to hypomagnesemia.  A meta-analysis of over 23,000 patients showed that 34% of patients treated with these two agents developed hypomagnesemia, although the severity was quite variable between studies.  A fascinating study of 98 patients with colorectal cancer showed that nearly all (97%) of patients treated with anti-EGFR inhibitors had a negative slope of serum magnesium over time versus a stable slope in controls treated with other chemotherapy.  They even performed 24-hr urinary magnesium and fractional excretion of magnesium (FeMg) in select patients who received anti-EGFR inhibitors and found mean FeMg levels of 5%, which is inappropriately high in the setting of hypomagnesemia.  IV magnesium load testing in 5 patients was comparable to patients with TRPM6 mutations, implicating renal magnesium wasting as the culprit for the clinical picture.

What explains the profound rate of hypomagnesemia when using anti-EGFR inhibitors?  Remember from earlier that the final location of magnesium absorption is the distal convoluted tubule via TRPM6.  Under normal circumstances, pro-EGF undergoes cleavage with extracellular proteases to form EGF in the distal tubule. This then binds EGFR at a basolateral membrane which activates tyrosine kinase and increases TRMP6 expression.  Anti-EGFR inhibitors suppress TRMP6 expression and subsequently impede the final 15% of magnesium absorption.

Diagnosis and Treatment

Measuring a serum magnesium is easy enough, but it’s important to remember that hypomagnesemia is frequently overlooked due to the vague course of symptom onset and range in severity of symptoms.  When obtaining general labs, other electrolyte abnormalities such as hypocalcemia or hypokalemia often prompt the clinician to check for hypomagnesemia.  Clinicians should have a high index of suspicion and should check for magnesium regularly in patients on any of the above therapies.  In scenarios where there are both renal and GI losses, calculating a fractional excretion of magnesium can be helpful.  FeMg values greater than 2% with preserved GFR strongly suggest a component of magnesium wasting in the kidney.

Magnesium repletion by any route of administration has unique pharmacodynamics to be aware of.  Patients with mild hypomagnesemia (1.2-1.7 mg/dL) and minimal symptoms can be given oral magnesium.  Several formulations are available, each with different dosing schedules and amounts of elemental magnesium.  The most important side effects of any oral magnesium supplement are gastrointestinal effects such as nausea and diarrhea.  Severe (< 1 mg/dL) or symptomatic hypomagnesemia usually requires intravenous administration.  A typical dose is 1-2 grams of magnesium sulfate over 15 minutes, but repeated doses may be required.  Patients with preserved renal function will excrete more than 80% of IV magnesium, so higher doses of IV repletion over a short period of time do not raise the serum Mg significantly.  Instead, the administration of small IV doses over several days is often the best therapy for severe hypomagnesemia.  Interestingly, rapid increases in plasma magnesium have been shown to stimulate the calcium-sensing receptor in the loop of Henle, which subsequently inhibits paracellular magnesium transport and promotes magnesium wasting. On the other side of the court, patients with chronic kidney disease are at risk for developing hypermagnesemia with large IV doses of replacement.

Let’s not forget about dietary ways to supplement magnesium.  An 8 oz glass of 1% milk has 39 mg of magnesium, and 2 tbsp of peanut butter has 50 mg.  A quick after-school snack of both of these will net nearly 100 mg of magnesium and won’t give you any diarrhea; diet modifications like this can be very helpful for patients with mild hypomagnesemia!

Lastly, there are adjunctive therapies to assist with improving magnesium levels in addition to replacement alone. Amiloride is a potassium-sparing diuretic that acts to block sodium reabsorption in the distal convoluted tubule and collecting duct, which can conserve magnesium. This strategy is particularly effective for patients with nephrotoxicity after amphotericin and cisplatin therapy. The rising star of drug classes, Sodium Glucose Transporter-2 Inhibitors can slow down magnesium wasting. A meta-analysis showed that there were small but significant increases in magnesium (0.15-0.24 mg/dL) across all SGLT2-inhibitors without causing changes to potassium or calcium.  The precise mechanism of this remains unknown.

With the increased usage of anti-EGFR inhibitors and incidence of hypomagnesemia being recognized in this population, it’s increasingly important to understand, recognize, and treat this disorder.  Magnesium is emerging as a dark horse candidate to win this year’s onconephrology matchup!

COMMENTARY BY BEN HUMPHREYS:
Ready to Rumble

Team 2: Immune Checkpoint Inhibitor-Associated Acute Kidney Injury

Introduction

Immune checkpoint inhibitors (ICI’s) have been reforming cancer treatment since their introduction in the early 2000s (with the Food and Drug Administration’s approval of ipilimumab in 2011). They are now first- and second-line therapies for more than 50 types of cancer. The ability to achieve long-standing or complete remission in previously nearly incurable cancers (eg, melanoma) has been revolutionized by these drugs. 

Copyright: Grigvovan/Shutterstock

Normally, T-cells have immunologic brakes that prohibit them from attacking “self” tissue of the host organism. ICI’s remove these brakes to permit T-cells to target and destroy cancer cells. There are three major categories of ICI’s: CTLA-4 inhibitors, PD1 inhibitors, and PD-L1 inhibitors (see Table 1 for examples and uses, Figure 1 for mechanism of action). 

Schematic representation of T-cell activation regulated by checkpoint inhibition with 3 hypothetical mechanisms of acute tubulointerstitial nephritis. Antigen carried by the antigen-presenting cell (APC) activates a T-cell receptor (TCR) with intracellular signal transduction by CD3 resulting in T-cell proliferation, survival, and differentiation. This signal also stimulates the expression of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), which competes for binding CD80/86 with CD28, the costimulatory protein required for T-cell activation, thereby leading to T-cell anergy. Programmed cell death 1 ligand (PD-L1) is variably expressed by many native and tumor cells. By binding to PD-1 on a T cell, it suppresses its activation and promotes immunotolerance leading to T-cell exhaustion. A T cell can be activated peripherally by an immunogenic checkpoint inhibitor, an immunogenic metabolite presented by the tubuloepithelial cells, or exhibit lesser immunotolerance for native kidney antigen. Figure 2 from Shingarev et al, AJKD © National Kidney Foundation.

However, in the process of unleashing these immunological checkpoints, autoimmune phenomena can occur (termed immune-related adverse events, or irAE’s). These commonly take the form of dermatitis, hepatitis, colitis, or thyroiditis. Unsurprisingly, in the kidney, ICI-associated acute kidney injury (ICI-AKI) most commonly takes the form of acute tubulointerstitial nephritis (ATIN).  Although ICI-AKI is less common (incidence ~3%) than irAE’s of other organs, it can dramatically affect cancer treatment options and thus, potentially, survival. Therefore, especially in this population with numerous other reasons for AKI (vomiting, diarrhea, hypotension, urinary retention, tumor lysis, other nephrotoxins, etc), it is very important to be able to differentiate ICI-AKI from non-ICI AKI in order to both administer and withhold medications appropriately. 

While there are no definite clinical features to differentiate ICI-AKI from non-ICI AKI, certain characteristics are suggestive, including sterile pyuria (~50%), subnephrotic-range proteinuria (~70%), latency period ~3.5 months (interquartile range 1.5-11 months), preceding or concomitant extrarenal irAEs (40%-90%, commonly dermatitis, hepatitis, thyroiditis, or colitis), simultaneous acute interstitial nephritis (AIN) drug culprit (~70%, mostly PPI use, less commonly non-steroidal anti-inflammatories or antibiotics), and combination therapy with multiple ICI’s. Fever and eosinophilia are only observed in 20% of patients.  Concomitant ATIN-causing drugs portend a favorable renal prognosis, while extrarenal irAE’s are associated with worse kidney outcomes. 

There are numerous lingering questions and debates surrounding the ideal diagnosis and management of ICI-AKI. Guidelines from oncologic societies frequently conflict with expert nephrology opinion. This year, we will address several controversies including the spectrum of disease, determining whether to biopsy, if and when it’s safe to rechallenge the ICI, and whether ICI’s can be used safely in a transplant population. 

 Spectrum of Acute Kidney Injury 

The vast majority (up to ~90%) of biopsied lesions of ICI-AKI are from ATIN, either alone or in combination with another disease process. It is hypothesized that some people have immunologically inactive T-cell populations with specificity for tubular antigens that are released by ICI’s, leading to tubulitis and interstitial inflammation.  

Kidney biopsy specimens from the patient with acute kidney injury while undergoing treatment with programmed cell death 1 checkpoint inhibitor. Light microscopy: (A) low power, (B) higher power. Hematoxylin and eosin stain shows severe acute interstitial nephritis with tubulitis accompanied by acute tubular injury (images courtesy of Dr. Surya V. Seshan). Figure 1 from Shingarev et al, AJKD © National Kidney Foundation.

However, there are numerous other ICI-AKI-associated pathological lesions (T-cell mediated, B-cell mediated, and non-immunologic) that can either co-occur with ATIN or occur independently.  In a 2018 retrospective review, 12 patients on pembrolizumab who developed AKI or proteinuria were biopsied. Five (42%) of them had acute tubular necrosis (ATN) alone; five were noted to have ATIN; two had minimal change disease (MCD). This stands in stark comparison to the two largest series to date: (1) a 2020 multicenter retrospective review of 60 biopsied patients, in which 56 (93%) had ATIN as the predominant lesion (of the other 4, one each had MCD with acute tubular injury, ANCA-negative pauci-immune crescentic GN, anti-GBM disease, and C3 glomerulonephritis), and (2) a 2021 retrospective review of 30 sites in 10 countries, which identified ATIN in 125 of 151 (82%) patients biopsied. Additionally, a 2019 retrospective single-center study highlighted potential frequency of concomitant lesions. Of their 16 biopsied patients, although 14 (88%) had ATIN, 9 had a coexisting glomerular injury, which included IgA nephropathy (IgAN), membranous nephropathy (MN), pauci-immune vasculitis (3 cases, two ANCA-negative), C3 glomerulopathy, focal segmental glomerulosclerosis (FSGS), and AA amyloidosis. Interestingly, the case of MN was noted to resolve completely with removal of the ICI and a course of corticosteroids, differentiating it from malignancy-associated MN.  Lastly, there are case reports of lupus nephritis, thrombotic microangiopathy (TMA), and even renal tubular acidosis associated with ICI exposure, although they collectively comprise a small minority of ICI-AKI.

To Biopsy or Not to Biopsy

There are conflicting opinions without clear guidelines regarding who to biopsy and when in expected ICI-AKI. While variable biopsying practices have likely contributed to the heterogeneous data presented above, heterogeneous interpretation of this data appears to perpetuate variable biopsying practices.

Due to the high incidence (>90% in the largest case series) of ATIN, an argument can be made to empirically hold the ICI and administer corticosteroids, with eventual biopsy if the AKI does not improve.  Most cases of glomerular lesions had nephrotic-range proteinuria, hematuria, and/or were oliguric, all of which should be screened for and would remain indications for biopsy.  On the other hand, there may be substantial diagnostic uncertainty in this complex patient group and the only reliable way to determine an ICI-AKI from ATN is a kidney biopsy.  Empiric steroid treatment could lead to unnecessary ICI discontinuation (with later questionable ICI reintroduction), and thus suboptimal oncologic outcomes. Furthermore, inappropriate addition of corticosteroids could lead to avoidable adverse events (eg, sepsis, VTE, fractures). A recent three-case series highlighted examples of ATN that presented like ATIN (and would not have been biopsied based on the current guidelines). The pro-biopsy argument also recognizes the concomitant glomerular processes that may accompany the ATIN, and argues for prompt diagnosis to assist with earlier appropriate therapy. In the end, the aforementioned 2020 multicenter retrospective study showed no differences in renal recovery outcomes between biopsied and non-biopsied patients.

Re-introduction of Immune Checkpoint Inhibitor After Resolution of AKI

This is yet another area of ICI-AKI with clinical uncertainty; can you try using ICIs again after resolution of AKI?  Currently, there are no reliable clinical features or biomarkers to help determine which patients will respond poorly to re-challenge. Furthermore, not all guidelines agree, with the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommending permanent discontinuation of ICI therapy w/ grade 3 or higher toxicity. In the 2020 multicenter retrospective review mentioned above, 31 patients were rechallenged with an ICI after resolution of their initial ICI-AKI, with 7 recurrences (23%). Six of those patients responded when re-treated with steroids. In an international 2021 retrospective review previously introduced, 121 patients were rechallenged, 16% of which had recurrent AKI.  

 Previously we mentioned that if the AKI occurred in the presence of another ATIN-causing medication, this portended a more favorable prognosis. However, it remains unclear whether a rechallenge is any safer in this population after concomitant drug discontinuation.  What little data we have suggests that repeat AKI can occur in about 20% of patients who are rechallenged with the drug and that alternatives should be used if at all possible.

Immune Checkpoint Inhibitor Use in Transplant

Transplant patients have a cancer incidence rate up to four times higher than the general population, and cancer represents the second leading cause of death (~30%) for this population behind cardiovascular disease. This phenomenon is largely due to their immunosuppressive regimens which, while decreasing T-cell-mediated rejection of their organ, simultaneously decreases T-cell immune surveillance of early cancers, as well as allow proliferation of oncogenic viruses. In this era of increasing ICI use, can these drugs be used safely in transplant patients without substantially increasing their risk of rejection? 

 It should be noted up front that all data comes from systematic reviews of case reports and case series, as transplant patients have been excluded from prospective studies on ICI use. Analysis of rejection rates is further complicated by heterogeneously decreased immunosuppressive regimens implemented at the time of cancer diagnosis or ICI initiation.

 Similar trends of rejection, allograft loss, and ICI response were noted across two recent studies. One is a 2020 systematic review of 27 articles with 44 kidney transplant patients treated with ICI’s, while the other is a 2021 multicenter retrospective cohort study with 69 patients treated with ICI’s between 2010 and 2020 (matched to a non-ICI group). Both studies noted an acute rejection rate of 40%-45%, occurring on average 24 days after initiation of the ICI (with IQR 20-56 days in the retrospective study). Rejection was noted to be half T-cell mediated, and half mixed rejection (antibody and T-cell mediated) or unknown. Of the patients with rejection, 65%-85% had resultant allograft failure. However, these studies also noted a significant benefit of ICI therapy for the underlying malignancy, with 35%-50% of patients responding with stable or improved disease.

Insufficient data exist for recommendations on immunosuppression regimens (calcineurin inhibitors [CNIs], mechanistic target of rapamycin [mTOR] inhibitors, etc) prior to ICI initiation. CNI’s, which are a mainstay of transplant immunosuppression, both increase allograft survival and increase cancer risk. Thus, unsurprisingly, in both of these studies patients on CNI’s had less rejection, but more disease progression. mTOR inhibitors have lower cancer risk than CNI’s, and were also noted to have a lower risk of rejection in ICI use. It is thought that mTOR inhibitors have “dynamic immunosuppression” by “helping to maintain graft tolerance and achieve tumor immunity.” Further studies are required to determine the optimal immunosuppressive strategy in patients who may need ICI administration.

ICIs have now been around since 2011 and are proving to be the veteran leaders on the onconephrology court.  Nothing else comes close to matching their impact over the last ten years, and the team is a strong contender for making it deep into this year’s bracket!

– Executive Team Members for this region: Timothy Yau @Maximal_Change and Anna Vinnikova @KidneyWars

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on June 1, 2023.

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