In the NEWS: PD-1 inhibitors and ATN, not AIN

Check point inhibitors have been associated with kidney injury. The incidence of check point inhibitor associated renal injury varies widely in the literature. The most common kidney biopsy observed has been acute interstitial nephritis and in a few rare cases- podocytopathies. 

In a recent study from France, the authors report on the incidence of pembrolizumab associated kidney toxicity in a French single-center nephrology referral center and report that renal adverse events occur in 1.77% of patients. A renal biopsy was performed in all 12 patients and acute tubular injury was the most common lesion noted. The most common glomerular pathology in this case series was minimal change disease. In this study, surprisingly, acute tubular injury was the most commonly observed pattern of injury on histology. This is in contrast with other reports that identified acute tubulo-interstitial nephritis as the dominant form of renal injury associated with immunotherapy treatment. A possible explanation is the low threshold to perform a kidney biopsy in this study. 

About half of their patients had ATN. Those patients had more frequently cardiovascular risk factors and marked histological vascular lesions and are more frequently men than AIN patients. Two of them received platinum but at least 1 year before pembrolizumab was introduced. No known mechanism is postulated for the ATN related to pembrolizumab.

This is an important study as this highlights the varied degree of renal toxicities seen with these agents. AIN will respond to steroids and ATN won’t. A kidney biopsy will be important to distinguish that. Empiric steroid treatment by oncologist should not be the gold standard but should be based on kidney biopsies performed and or a nephrology consultation. 

Besides AIN and podocytopathies, it appears that PD-1 inhibitors also can cause ATN.

Topic Discussion: CAR-T therapy and the Kidney

A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval at the FDA for pediatric and young adult patients (age 3-25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).

Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells.  These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them.  The main action happens mostly about 2 weeks after those CAR-T cells have been re-infused.  Some have termed this form of therapy as the “ living drug”

Autologous CAR-T cell therapy first shot into headlines about 4-5 years ago when it was thought about in CLL patients.   Then several other studies were done essentially confirming that the concept is correct but there are serious toxicities.

https://www.ncbi.nlm.nih.gov/pubmed/25317870 (leukemias)

https://www.ncbi.nlm.nih.gov/pubmed/26760100 (myelomas)

https://www.ncbi.nlm.nih.gov/pubmed/28029927 ( gliobastoma)

The technology is complicated and initially when tried in CLL led to multiple toxicities of various organs including CNS, cardiac, renal and mostly requiring ICU admissions from acute cytokine release syndrome. This happens due to high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation.  Etanercept and tocilizumab have been used to block the IL-6 activity to treat such side effects.

Acute renal injury following CAR T-cell infusion is multifactorial and almost always reversible. Reduced renal perfusion is often the most important cause of renal injury. Reduced renal perfusion can be caused by cytokine-mediated vasodilation, decreased cardiac output, or intravascular dehydration due to insensible losses from high fevers. Tumor lysis syndrome and drug effect from medications such as antibiotics are other possible causes of renal injury. Electrolyte disturbances, such as hyponatremia, hypokalemia, and hypophosphatemia are not uncommon but have been reported. A recent article in Blood summarizes all toxicities.

Now the therapy has returned and we may see this in many centers. We must be aware of the cytokine release storm that it can cause leading to AKI in that setting.  There might be more in the pipeline of similar products such as the one that just got approved for ALL.

Figure source: http://www.lymphomation.org/programing-t-cells.htm

Topic Discussion: New Glomerular diseases cases with targeted therapies

Targeted therapies can lead to a glomerular disease. Previously, two reviews didn’t find any glomerular diseases associated with BRAF inhibitors and PD-1 inhibitors.  In the last 6 months, 3 recent papers have highlighted interesting cases of both BRAF-MEK combination and PD-1 inhibitors leading to glomerular diseases.

Encorafenib, a new BRAF inhibitor, and binimetinib, MEK inhibitor—Proliferative GN
Pembrolizumab ( PD-1 inhibitor)- Minimal Change Disease
Dabrafenib, BRAF inhibitor and tramitinib( MEK inhibitor)- Podocytopathy- like MCD

  

While the PD-1 inhibitor case is the first of it’s kind, we must be mindful of GN in these patients as well. In terms of the BRAF+MEK combo, both authors of the above listed papers. Showed that it was the BRAF inhibition that decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte–vascular endothelial growth factor (VEGF) system leading to perhaps a component of TMA as well.

Targeted therapies and the Kidney

Novel targeted anti-cancer therapies have resulted in improvement in patient survival compared to standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized.

The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. A recent uptodate review by us discusses the adverse renal effects associated with a selection of currently approved targeted cancer therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to VEGF/R and TKIs.

Based on another study and look at the FDA database, electrolyte disorders, renal impairment and hypertension are the most commonly reported events with this agent. Of the novel targeted agents, ipilumumab and cetuximab have the most nephrotoxic events reported. 

Novel agents have also been tried in myeloma treatment. Renal effects of these agents are being reported as case reports and parts of clinical trials. A recent review in CJASN summaries the novel toxicities associated with new anti myeloma agents. 

The early diagnosis and prompt recognition of these renal adverse events are essential for the general nephrologist taking care of these patients.

Topic Discussion: Anti-PD-1 Therapy and the Kidney

Anti PD-1 Inhibitors and the Kidney

This includes two proteins called programmed death-1 (PD-1), which is expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), which is expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical "shield" protecting tumor cells from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death ligand -2 (PD-L2).

Anti-PD-1 agents are humanized monoclonal antibodies that bind the PD-1 receptor, which are present on tumor infiltrating lymphocytes and Tregs. They prevent the engagement of PD-1 to its ligand on the tumor cells (PD-L1 and PD-L2) thereby asserting its antitumor activity.

Nivolumab

Nivolumab is the first anti-PD-1 antibody tested initially in melanoma.  In December 2014, the U.S. Food and Drug Administration (FDA) granted an accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma. Since then, there have been use of this agent’s approval in lymphoma and renal cell cancer as well.  There also has been some interest of this agent to be used in myeloma.

In one trial, there was an increased incidence of elevated creatinine in the nivolumab-treated group as compared to the chemotherapy-treated group (13% vs. 9%).  Steroids help resolve the renal dysfunction in 50% of the cases. It is presumed to be AIN from an immune mediated process. The FDA label has guidelines to start steroids as the creatinine rises rapidly.  A pubmed search revealed no published cases of AIN or acute renal failure in the peer reviewed literature.

Pembrolizumab

Pembrolizumab (MK-3475) is another monoclonal antibody (MAb) therapy designed to directly block the interaction between PD-1 and its ligands, without antibody dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). This drug also has been used in melanoma and other hematological malignancies since 2014. 

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4.

The time to onset of autoimmune nephritis was 11.6 months after the first dose of pembrolizumab(5 months after the last dose) and lasted 3.2 months; this patient did not have a biopsy.

Acute interstitial nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal failure. All three patients fully recovered renal function with treatment with high-dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) followed by a corticosteroid taper.

Mae et al. from Yale presented a poster in ASN Kidney Week 2015 that highlighted 2 cases of biopsy proven AIN from this agent (Abstract: [TH-PO1051).

It’s not just the kidney- apparently this immune mediated reaction that is initiated might be leading to hepatitis, uveitis, pancreatitis, myocarditis and other concerns. 

Literature search thus far has not revealed any published cases of AIN from this agent. Given this immune mediated reaction- the kidney can be a potential target. I won’t be surprised if both vasculitis and allergic nephritis can be noted on kidney biopsies with these agents. 

B cell malignancies and the Kidney

B cell malignancies and the Kidney from kdj200

Consult Rounds: Ifosfamide Toxicity

Ifosfamide induced renal damage comes in 6 flavors. The toxic agent is metabolite chloroacetaldehyde rather than the parent drug to the tubular cells of the kidney.

1.     Pure hypophosphatemia – this is due to direct proximal damage

2.     Fanconi syndrome

3.     Pure renal potassium wasting syndrome leading to hypokalemia

4.     ATN

5.     Distal RTA

6.     Nephrogenic Diabetes insipidus

Ipilimumab and renal disease

Ipilimumab is a human monoclonal antibody that targets T lymphocytes antigen-4 or CTLA-4 and it’s used in clinical practice to treat melanoma.  Does this agent lead to nephrotoxicity?

Where do we encounter CTLA-4 in the renal literature?

Agonists to reduce immune activity using CTLA-4 Ig are available such as Orencia( abatacept) for SLE and RA.  Belatacept is a similar agent used in transplantation literature for treatment and prevention of rejection.  How are they different from ipilimumab that is used to treat cancer?  This antibody binds to human CD152 and enhances T cell response especially against tumor cells. It basically boosts the immune response against the tumor cells.  So invitation of the T cells into the kidney could be possible- and renal injury a potential side effect.

Literature search revealed three published cases.

One is a case of granulomatous AIN

Other is a vasculitis

And a NEJM case report on the drug causing lupus like nephritis.

It seems that the treatment of this leads to activation of T cells that can stimulate a classic vasculitis or interstitial nephritis. 

As the cancer literature grows,  we have to be mindful of the nephrotoxicites of such agents.

Cisplatin-induced acute kidney injury (AKI): Why is magnesium balance important?

Cisplatin is one of the most commonly used chemotherapeutic agents.  In the US, there are more than 2000 ongoing clinical trials investigating cisplatin in patients with ovarian, testicular, bladder, cervical, and head/neck cancers, among others.  Unfortunately, approximately 25-30% of patients receiving cisplatin suffer nephrotoxicity despite its potency as an anti-tumor agent. This is a challenge in the oncology clinical setting where either dose reductions or discontinuation of cisplatin are often required to salvage the kidneys leaving the patient and clinician with limited options given the efficacy and affordability of this drug.  An important contributor to cisplatin-mediated nephrotoxicity is the accompanying electrolyte imbalances, including hypomagnesemia. Magnesium (Mg) is an essential dietary mineral required for normal body functioning and cellular processes.  Surprisingly, Mg consumption (via foods and supplements) among most Americans, particularly the elderly, is below the recommended daily allowance. In addition, many medications and disease conditions reduce the availability of dietary Mg. Therefore, we sought to examine the effects of Mg deficiency and Mg supplementation following Mg deficiency on cisplatin-mediated acute kidney injury (AKI) using a mouse model.  We observed that Mg deficiency exacerbates cisplatin-induced AKI, whereas correction of Mg status protects against cisplatin-mediated AKI.  Additional studies detail the cellular and molecular mechanisms by which Mg provides renoprotection, namely by attenuating cisplatin-induced inflammation, oxidative stress and apoptosis. In addition, we show for the first time that Mg supplementation reduces the platinum accumulation in the kidneys possibly by affecting the efflux of cisplatin by the renal epithelial cells.  While protecting the kidneys, Mg supplementation did not compromise cisplatin-induced cytotoxicity using several human cancer cell lines, suggesting the Mg does not interfere with the chemotherapeutic efficacy of cisplatin in vitro. The results of this study warrant future large scale clinical studies to better monitor patients’ Mg status prior to and during cisplatin treatment and to develop improved Mg supplementation protocols that provide nephroprotection without compromising cisplatin’s potent chemotherapeutic efficacy.

For full link of paper click below

http://www.ncbi.nlm.nih.gov/pubmed/24944268

Post By:

Malvika Solanki, MD

Carfilzomib induced renal injury: mechanism of action?

Multiple myeloma is the second most common type of hematologic malignancy. 

Carfilzomib is a second-generation epoxyketone proteasome inhibitor that is approved for treatment of relapsed and refractory multiple myeloma. Phase 2 trials have reported that 25% of treated patients have renal adverse effects. Pre-renal/vasoconstriction-related insult from this chemotherapy agent has been documented.

Recently, even a case of tumor lysis syndrome has been reported with this agent. According to the product labeling, the frequency of tumor lysis syndrome (TLS) is less than 1% in patients treated with carfilzomib. Is it possible then to prevent AKI via pre treatment with allopurinol and or rasburicase?

Also being presented at NKF 2014 e poster and a recent publication is the use of N-acetyl-l-cysteine to partially mitigated the renal injury upon re-challenge in case of carfilzomib related AKI. This case report hypothesizes that acute renal injury from carfilzomib is caused by vasoconstriction of the renal vessels, which may be prevented by N-acetyl-l-cysteine.

More can be learned about the mechanism of renal injury if biopsy proven cases are published. Thus far no biopsy proven AKI cases have been reported in the literature. 

image source: www.cancer.gov

Crizotinib and the Kidney

Does crizotinib cause AKI? and is it reversible?

Crizotinib is a ROS-1 inhibitor and acts on anaplastic lymphoma kinase (ALK) to treat non small cell lung cancer.It also inhibits the hepatocyte growth factor tyrosine kinase. Hence, another angiogenesis inhibitor.
In 2011, it was approved for use in NSCLC with abnormal ALK gene mutation. There was some initial concern regarding this agent and renal function. A biopsy proven case of ATN was published not too long ago from France.

A recent analysis from Univ of Colorado looked at 38 patients with NSCLC who got this agent. The mean GFR decreased by 23.9% compared to baseline and most happened in the first 2 weeks of therapy. Pre renal causes were excluded. 84% of the patients recovered renal function back to baseline after cessation of therapy. The investigators thought that the rapid reversibility raised the possibility that this was a tubular creatinine secretion effect rather than nephrotoxic effect. They didn't have biopsy data.

Here is a commentary on this study.

Quick Chemotherapy toxicity quiz flashcards using quizlet.com

Newer Chemotherapy agents and Kidney Disease

Check out this presentation that I gave on some newer chemo agents and renal disease:

1. Ifosfamide: proximal tubular damage, fanconi syndrome
2. Clofarabine: ATN vs glomerular damage
3. Carfilzomib: pre renal AKI
4. mTOR inhibitors : new association with ATN
5. Anthracyclines: FSGS and MCD

Newer Chemotherapy agents and renal toxicity from kdj200

Nephrology Crosswords: Onco-Nephrology: Chemotherapy related toxicity

Check out the next KI Nephrology Crosswords on Chemotherapy related renal toxicities.

Concept Map: Chemotherapy Nephrotoxicity Review