ABSTRACT
Background
The aim of this meta-analysis was to assess the risks and incidence of nephrotoxicity and electrolyte abnormalities in patients receiving programmed cell death protein 1 (PD-1) ...inhibitors.
Methods
We conducted a meta-analysis of clinical trials that monitored electrolyte levels and kidney functions during treatment with nivolumab or pembrolizumab by searching MEDLINE, EMBASE and the Cochrane Database from inception through April 2017. Our protocol is registered with International Prospective Register of Systematic Reviews; no.CRD42017060579.
Results
A total of 48 clinical trials with a total of 11 482 patients were included. The overall pooled risk ratios (RR) of all acute kidney injury (AKI) and all electrolyte abnormalities in patients treated with PD-1 inhibitors were 1.86 95% confidence interval (CI) 0.95–3.64 and 1.67 (95% CI 0.89–3.12), respectively. Compared with non-nephrotoxic controls, the pooled RR of AKI in patients treated with PD-1 inhibitors was 4.19 (95% CI 1.57–11.18). Prespecified subgroup analyses demonstrated a significant association between PD-1 inhibitors and hypocalcemia with a pooled RR of 10.87 (95% CI 1.40–84.16). The pooled estimated incidence rates of AKI and hypocalcemia in patients treated with PD-1 inhibitors were 2.2% (95% CI 1.5–3.0%) and 1.0% (95% CI 0.6–1.8%), respectively. Among patients who developed AKI with PD-1 inhibitors, the pooled estimated rate of interstitial nephritis was 16.6% (95% CI 10.2–26.0%).
Conclusions
Treatment with PD-1 inhibitors is associated with a higher risk of AKI compared with non-nephrotoxic agents. It will be important to characterize the AKI patients to better understand the etiology behind the event. In addition, treatment with PD-1 inhibitors is associated with an increased risk of hypocalcemia. This study highlights a rare but serious adverse event of anti-PD-1 antibodies and we recommend, in addition to electrolytes panel, routine calcium monitoring.
The vascular endothelial growth factor (VEGF) signaling pathway (VSP) fulfills a cardinal role in endothelial cells and its inhibition has profound cardiovascular impact. This is true not only for ...the normal vasculature but also for the tumor vasculature when VSP inhibitors are used as anti-angiogenic therapies. Generalized endothelial dysfunction predisposes to vasoconstriction, atherosclerosis, platelet activation, and thrombosis (arterial more than venous). All of these have been reported with VSP inhibitors and collectively give rise to vascular toxicities, the most concerning of which are arterial thromboembolic events (ATE). VSP inhibitors include antibodies, acting extracelluarly on VEGF, such as bevacizumab and tyrosine kinases inhibitors, acting intracellularly on the kinase domain of VEGF receptors, such as sunintib and sorafenib. The addition of bevacizumab and VSP tyrosine kinase inhibitor therapy to the cancer treatment regimen is associated with a 1.5–2.5-fold and 2.3–4.6-fold increase risk of ATEs, respectively. Risk factors for ATEs while on VSP inhibitor therapy include age older than 65 years, previous thromboembolic events, history of atherosclerotic disease, and duration of VSP inhibitor therapy. In clinical practice, hypertension remains the most commonly noted vascular manifestation of VSP inhibition. Optimal blood pressure goals and preferred therapeutic strategies toward reaching these goals are not defined at present. This review summarizes current data on this topic and proposes a more intensive management approach to patients undergoing VSP inhibitor therapy including Systolic Blood PRessure Intervention Trial (SPRINT) blood pressure goals, pleiotropic vasoprotective agents such as angiotensin converting enzyme inhibitors, amlodipine, and carvedilol, high-dose statin therapy, and aspirin.
Central to the vascular effects of vascular endothelial growth factor (VEGF) inhibitors are the actions on endothelial cell level. Anti-VEGF therapy targets not only endothelial cell proliferation and permeability, which is the goal to antagonize the formation of new tumor vessels, but also endothelial cellsurvival, vasorelaxation, and platelet activation. The end results are systemic hypertension, accelerated atherosclerosis, and arterial thrombotic events. Various interventions are geared to promote endothelial and vascular health and to reduce the detrimental effects of VEGF inhibitor therapy while maintaining its anti-angiogenic efficacy. Display omitted
•Increase in blood pressure is nearly universal with VEGF inhibitor therapy.•Optimal blood pressure goals and preferred therapeutic strategies are not defined.•Systolic Blood Pressure Intervention Trial target goals are justifiable in VEGF inhibitor-induced hypertension, given the high arterial vascular event risk.•Patients on VEGF inhibitor therapy may benefit from cardio-/nephro-oncology care.
We present a case of pseudo–acute kidney injury (AKI) following capmatinib therapy in an 84-year-old man with combined non–small cell (adenocarcinoma) and small cell lung cancer with MET exon ...14–skipping mutation. His past medical history was significant for chronic kidney disease stage 3 with a baseline serum creatinine (Scr) of 1.6mg/dL rising to 2.44mg/dL (estimated glomerular filtration rate GFR 24mL/min/1.73m2) while on capmatinib. Scr improved to 1.84mg/dL with the cessation of capmatinib but rose again to 2.22mg/dL upon resumption of therapy. Further investigation with cystatin C and renal iothalamate clearance showed that despite fluctuation in Scr levels, there was not much variation in GFR calculated using these methods. Urinalysis and urinary protein-creatinine ratio were unremarkable. Treatment with capmatinib was continued at reduced dose and a third instance of rise in Scr was observed, followed by a spontaneous return to baseline. Thus, MET inhibitor therapy can result in an asymptomatic rise in Scr, and it must be distinguished from AKI with more accurate non–creatinine-based methods to evaluate GFR. This could spare such patients from invasive diagnostic tests, such as a kidney biopsy, and premature cessation of prognostically important cancer therapies.
Atherosclerotic renovascular disease (RVD) reduces renal blood flow (RBF) and GFR and accelerates poststenotic kidney (STK) tissue injury. Preclinical studies indicate that mesenchymal stem cells ...(MSCs) can stimulate angiogenesis and modify immune function in experimental RVD. We assessed the safety and efficacy of adding intra-arterial autologous adipose-derived MSCs into STK to standardized medical treatment in human subjects without revascularization. The intervention group (
=14) received a single infusion of MSC (1.0 × 10
or 2.5 × 10
cells/kg;
=7 each) plus standardized medical treatment; the medical treatment only group (
=14) included subjects matched for age, kidney function, and stenosis severity. We measured cortical and medullary volumes, perfusion, and RBF using multidetector computed tomography. We assessed tissue oxygenation by blood oxygen level-dependent MRI and GFR by iothalamate clearance. MSC infusions were well tolerated. Three months after infusion, cortical perfusion and RBF rose in the STK (151.8-185.5 ml/min,
=0.01); contralateral kidney RBF increased (212.7-271.8 ml/min,
=0.01); and STK renal hypoxia (percentage of the whole kidney with R2*>30/s) decreased (12.1% interquartile range, 3.3%-17.8% to 6.8% interquartile range, 1.8%-12.9%,
=0.04). No changes in RBF occurred in medical treatment only subjects. Single-kidney GFR remained stable after MSC but fell in the medical treatment only group (-3% versus -24%,
=0.04). This first-in-man dose-escalation study provides evidence of safety of intra-arterial infusion of autologous MSCs in patients with RVD. MSC infusion without main renal artery revascularization associated with increased renal tissue oxygenation and cortical blood flow.
Abstract
Renovascular disease (RVD) remains a major cause of secondary and treatment-resistant hypertension. Most cases are related either to fibromuscular or atherosclerotic lesions, but a variety ...of other causes including arterial dissection, stent occlusion, and embolic disease can produce the same syndrome. Recent studies emphasize the kidney’s tolerance to moderate flow reduction during antihypertensive drug therapy and the relative safety of medical therapy to control blood pressure. Several prospective trials in moderate RVD fail to identify major benefits from endovascular revascularization for moderate atherosclerotic disease. However, high-risk and progressive renovascular syndromes are recognized to be relatively refractory to medical therapy only and respond better to combining renal revascularization with ongoing medical therapy. Clinicians caring for complex hypertension should be familiar with pathogenic pathways, imaging techniques, and a rational approach to managing renovascular hypertension in the current era.
The reported risks of hypertension (HTN) in rotating shift and night shift workers are controversial. The objective of this meta-analysis was to assess the association between shift work status and ...HTN.
A literature search was performed using MEDLINE, EMBASE and Cochrane Database from inception through October 2016. Studies that reported odds ratios (OR) comparing the risk of HTN in shift workers were included. A prespecified subgroup analysis by rotating shift and night shift statuses were also performed. Pooled OR and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. The protocol for this study is registered with International Prospective Register of Systematic Reviews; no. CRD42016051843.
Twenty-seven observational studies (nine cohort and 18 cross-sectional studies) with a total of 394 793 individuals were enrolled. The pooled ORs of HTN in shift workers in cohort and cross-sectional studies were 1.31 (95% CI, 1.07-1.60) and 1.10 (95% CI, 1.00-1.20), respectively. When meta-analysis was restricted only to cohort studies in rotating shift, the pooled OR of HTN in rotating shift workers was 1.34 (95% CI, 1.08-1.67). The data regarding night shift and HTN in cohort studies was limited. The pooled OR of HTN in night shift workers in cross-sectional studies was 1.07 (95% CI, 0.85-1.35).
Based on the findings of our meta-analysis, shiftwork status may play an important role in HTN, as there is a significant association between rotating shift work and HTN. However, there is no significant association between night shift status and risk of HTN.
Renal toxicities have been increasingly recognized as complications of the immune checkpoint inhibitors (ICIs). Recent studies have outlined the incidence and potential risk factors for ...nephrotoxicity. For clinicians, the key question is how to manage patients who develop these adverse renal effects. This is of paramount importance to providers as ICI use for cancer therapy becomes more widespread and nephrotoxicity increasingly develops. As clinicians encounter ICI-associated nephrotoxicity, an appropriate approach to management is required to facilitate the best outcomes in patients with cancer. Importantly, ICI rechallenge in patients who developed ICI-related acute kidney injury (AKI) is unclear and represents a conundrum for providers. Clinicians struggle with the “if, when, and how to” questions related to ICI rechallenge in this subset of patients. In addition, ICI use in the transplant population raises concerns for promoting acute rejection when treating cancer in these patients. We herein review current information on these various topics.
Immune checkpoint inhibitors (ICIs) are now established treatments for advanced cancer and their use is now ubiquitous. The high upside of ICIs is tempered by their toxicity profile affecting almost ...every organ, including the kidneys. Although acute interstitial nephritis is the major kidney-related adverse effect of checkpoint inhibitors, other manifestations such as electrolyte abnormalities and renal tubular acidosis have been described. With increasing awareness and recognition of these events, the focus has shifted to non-invasive identification of ICI-acute interstitial nephritis, with sophisticated approaches involving biomarkers and immunologic signatures being studied. Although the management of immune-related adverse events with corticosteroids is straightforward, there now are more data to help guide immunosuppressive regimens, ICI rechallenge, and delineate risk and efficacy in special populations such as individuals on dialysis or those who have received a transplant.
Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the ...most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.
ABSTRACT
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and outcomes, leading to an expanding use in millions of patients worldwide. However, they can cause a spectrum of ...immune-related adverse events (irAEs). Essentially, any organs can be affected by irAEs, which have emerged as therapy-limiting side effects. In the kidneys, ICI-associated acute interstitial nephritis (ICI-AIN) leads to acute kidney injury (AKI) in 2%–5% of patients on ICI therapy. AKI associated with ICI therapy pathologically presents with AIN in nearly 90% of the cases, but the pathophysiology of ICI-AIN remains to be defined. The generation of autoreactive T cells in patients receiving AIN-inducible drugs, such as proton pump inhibitors (PPIs), is one of the leading theories, supported by a higher incidence of ICI-AIN in patients on these AIN-inducible drugs. In this review, we will discuss our understanding of the incidence, potential pathophysiological mechanisms, clinical presentations, risk factors, diagnosis, and management of PPI-related AIN and its interaction with ICI therapy.
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