Rimda Wanchoo

Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review

Background: Cancer immunotherapy, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1), has revolutionized the treatment of malignancies by engaging the patients own immune system against the tumor rather than targeting the cancer directly. These therapies have demonstrated a significant benefit in the treatment of melanomas and other cancers. Summary: In order to provide an extensive overview of the renal toxicities induced by these agents, a Medline search was conducted of published literature related to ipilimumab-, pembrolizumab-, and nivolumab-induced kidney toxicity. In addition, primary data from the initial clinical trials of these agents and the FDA adverse reporting system database were also reviewed to determine renal adverse events. Acute interstitial nephritis (AIN), podocytopathy, and hyponatremia were toxicities caused by ipilimumab. The main adverse effect associated with both the PD-1 inhibitors was AIN. The onset of kidney injury seen with PD-1 inhibitors is usually late (3-10 months) compared to CTLA-4 antagonists related renal injury, which happens earlier (2-3 months). PD-1 as opposed to CTLA-4 inhibitors has been associated with kidney rejection in transplantation. Steroids appear to be effective in treating the immune-related adverse effects noted with these agents. Key Message: Although initially thought to be rare, the incidence rates of renal toxicities might be higher (9.9-29%) as identified by recent studies. As a result, obtaining knowledge about renal toxicities of immune checkpoint inhibitors is extremely important.

Carfilzomib-related acute kidney injury may be prevented by N-acetyl-l-cysteine:

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. We describe a case of a 78-year-old man with refractory multiple myeloma with acute kidney injury associated with carfilzomib treatment. We show that use of N-acetyl-l-cysteine in our patient partially mitigated the renal injury upon re-challenge. 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.

Harvoni (Ledipasvir With Sofosbuvir)-Induced Renal Injury.

less likely. As sofosbuvir is cleared by the kidney, patients with CKD have impaired excretion ( 4 ), leading to a more prolonged exposure of its metabolites, perhaps delaying recovery of renal function. We report the fi rst case of biopsy-proven AIN with Harvoni. Hepatologists, infectious disease specialists, and nephrologists need to be aware of the potential side eff ect of this novel agent.

Intravenous Iron Exposure and Outcomes in Patients on Hemodialysis

Iron is an essential trace element that is important for normal body function. However, excess iron in animal studies has been shown to be toxic, because it can enhance radical oxygen generation, impair neutrophil and T-cell function, and also promote bacterial growth ([1][1],[2][2]). This dichotomy

Endovascular aneurysm repair (EVAR)– and transcatheter aortic valve replacement (TAVR)–associated acute kidney injury

Acute kidney injury (AKI) after surgery or intervention is an important complication that may impact mortality, morbidity, and health care costs. Endovascular procedures are now performed routinely for a variety of pathologies that were traditionally treated with open surgery because randomized trials comparing endovascular and open surgery have shown at least equally good results and reduced complication and hospitalization rates with endovascular techniques. However, endovascular procedures have been associated with an increased risk for postoperative AKI, predominantly owing to contrast nephrotoxicity. Over the years, endovascular techniques have progressively been applied for the treatment of complex cardiovascular pathologies, and in recent years, nephrologists have increasingly encountered patients who developed AKI after endovascular aneurysm repair or transcatheter aortic valve replacement. These 2 procedures typically involve high-risk patients who have several established AKI risk factors prior to intervention. Several studies have investigated the incidence, risk factors, and natural course of AKI after endovascular aneurysm repair and transcatheter aortic valve replacement. This review summarizes current data on incidence, risk factors, pathophysiology, prognostic implications, and treatment of AKI associated with endovascular aneurysm replacement and transcatheter aortic valve replacement.

Immune Checkpoint Inhibitors in the Cancer Patient with An Organ Transplant

The use of immune checkpoint inhibitors (ICI) in several cancers is expanding; however, their use in patients with cancer and an organ transplant is very limited. In this review, we summarize the literature and the experience of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) inhibitors in the organ transplant patient. The immunology of CTLA-4 and PD-1 inhibitors and their role in tolerance breakdown is also reviewed. While CTLA-4 inhibitors have been successfully used in kidney, liver, and heart transplant patients without rejection, the uses of PD-1 inhibitors and the combination therapy of CTLA-4 and PD-1 inhibitors have been associated with cellular- and antibody-mediated rejection. While immunosuppression minimization is needed for ICI to provide the best response when managing transplant patients who develop malignancy, this can lead to rejection episodes. Prevention strategies, such as the use of ongoing steroids and sirolimus, could prevent rejection while sustaining tumor response. As the experience grows with these agents, we will learn more about tolerance and the use of ICI in the organ transplant patient. Therefore, the use of an immune checkpoint blockade in transplantation is extremely difficult, and future research should focus on finding the right balance between unleashing the immune system to provide an anti-tumor effect but at the same time sustaining tolerance so that rejection is suppressed. Also, the ability to identify biomarkers that may predict rejection early and allow for the fine tuning of doses and frequencies of drug administration would be very helpful.

Renal Toxicities of Novel Agents Used for Treatment of Multiple Myeloma.

Survival for patients with multiple myeloma has significantly improved in the last decade in large part due to the development of proteasome inhibitors and immunomodulatory drugs. These next generation agents with novel mechanisms of action as well as targeted therapies are being used both in the preclinical and clinical settings for patients with myeloma. These agents include monoclonal antibodies, deacetylase inhibitors, kinase inhibitors, agents affecting various signaling pathways, immune check point inhibitors, and other targeted therapies. In some cases, off target effects of these therapies can lead to unanticipated effects on the kidney that can range from electrolyte disorders to AKI. In this review, we discuss the nephrotoxicities of novel agents currently in practice as well as in development for the treatment of myeloma.

Left Ventricular Assist Devices and the Kidney

Left ventricular assist devices (LVADs) are common and implantation carries risk of AKI. LVADs are used as a bridge to heart transplantation or as destination therapy. Patients with refractory heart failure that develop chronic cardiorenal syndrome and CKD often improve after LVAD placement. Nevertheless, reversibility of CKD is hard to predict. After LVAD placement, significant GFR increases may be followed by a late return to near baseline GFR levels, and in some patients, a decline in GFR. In this review, we discuss changes in GFR after LVAD placement, the incidence of AKI and associated mortality after LVAD placement, the management of AKI requiring RRT, and lastly, we review salient features about cardiorenal syndrome learned from the LVAD experience. In light of the growing number of patients using LVADs as a destination therapy, it is important to understand the effect of these devices on the kidney. Additional research and long-term data are required to better understand the relationship between the LVAD and the kidney.

A case of acute kidney injury from crystal nephropathy secondary to pomalidomide and levofloxacin use

Pomalidomide is an analog of thalidomide with immunomodulatory, anti-angiogenic, and anti-neoplastic activity indicated for the treatment of multiple myeloma refractory to at least two prior therapies. The incidence for renal failure was <5% in a single phase II study of pomalidomide and dexamethasone in patients with multiple myeloma that failed both lenalidomide and bortezomib therapy. We report a case suggesting crystal nephropathy as the mechanism for acute kidney injury in pomalidomide and fluoroquinolone use.

Update on the End-Stage Renal Disease Quality Incentive Program

The End‐Stage Renal Disease Quality Incentive Program continues to evolve and expand. In this article, we will review the programs structure and critically assess the clinical metrics in place. In addition, we will discuss upcoming program changes to help prepare dialysis facilities and nephrologists to meet new proposed metrics.