Childhood cancer therapy carries a high risk of treatment-related toxicities and complications that can impact kidney function. Although many of these adverse effects in the acute setting are well described, less is know...Childhood cancer therapy carries a high risk of treatment-related toxicities and complications that can impact kidney function. Although many of these adverse effects in the acute setting are well described, less is known about the latent effects of childhood cancer treatments on long-term kidney health. With decades of advancements in treatment protocols for many pediatric malignancies, more children than ever before are surviving into adulthood after being cured of their disease and with lower long-term morbidity. Although there is decreased prevalence of many chronic health conditions in cancer survivors, including gastrointestinal, endocrine, and musculoskeletal disorders, the long-term risk of kidney dysfunction has increased. In this review, we summarize the epidemiology of kidney disease in survivors of childhood cancer and describe the treatment-related risk factors associated with long-term impairment of kidney health. We organize this review by specific kidney disease-related outcomes of interest (chronic electrolyte abnormalities, CKD, proteinuria, and hypertension) to highlight what specific aspects of cancer treatment have been associated with these outcomes. Finally, we conclude by comparing different clinical practice guidelines that exist for long-term kidney function monitoring and include recommendations for when a childhood cancer survivor would benefit from long-term nephrology care.
Cancer is one of the leading causes of death worldwide. With the introduction of newer chemotherapeutic agents, targeted therapies, and immunotherapy, the prognosis and survival of patients with cancer has remarkably imp...Cancer is one of the leading causes of death worldwide. With the introduction of newer chemotherapeutic agents, targeted therapies, and immunotherapy, the prognosis and survival of patients with cancer has remarkably improved. As a result, patients are living longer and experiencing long-term cardiovascular complications. Hypertension is an important risk factor for cardiovascular diseases. Patients with malignancy have multiple etiologies of hypertension development, worsening, or association. This is because of the complex interplay between cancer type, chemotherapeutic agent, patient age, antihypertensive agent, and preexisting comorbidities in the etiology and pathogenesis of hypertension. Management of hypertension in patients with cancer requires accurate blood pressure measurement and considering factors such as adjuvant therapy and cancer-related pain. There are no set guidelines for management of hypertension in this unique cohort, and the therapy should be individualized based on the treatment guidelines for the general population. Onco-hypertension is an emerging subspeciality and entails a multidisciplinary approach between oncology, primary care physicians, nephrology, and cardiology.
As breakthroughs in cancer care are leading to improved long-term outcomes in a subset of advanced cancers, there is a growing population of long-term cancer survivors that are at risk of long-term complications. In this...As breakthroughs in cancer care are leading to improved long-term outcomes in a subset of advanced cancers, there is a growing population of long-term cancer survivors that are at risk of long-term complications. In this review, we summarize what is known about chronic kidney disease in cancer survivors, focusing on the following high-risk groups: survivors of childhood cancers, stem cell transplant recipients, patients with renal cell carcinoma, patients exposed to cisplatin and other nephrotoxic chemotherapies, and patients receiving immunotherapy for cancer. As new anticancer therapies are developed, more research is needed to understand the long-term risks of kidney function decline and to devise methods to prevent chronic kidney disease.
The association between chronic kidney disease (CKD) and renal cell carcinoma (RCC) is bidirectional and multifactorial. Risk factors such as hypertension, diabetes mellitus, obesity, and smoking increase the risk of bot...The association between chronic kidney disease (CKD) and renal cell carcinoma (RCC) is bidirectional and multifactorial. Risk factors such as hypertension, diabetes mellitus, obesity, and smoking increase the risk of both CKD and RCC. CKD can lead to RCC via an underlying cystic disease or oxidative stress. RCC can cause CKD because of the tumor itself, surgical reduction of renal mass (either partial or radical nephrectomy), and perioperative acute kidney injury. Medical therapies such as immune checkpoint inhibitors and vascular endothelial growth factor inhibitors can lead to acute kidney injury and resultant CKD. Clinicians need to be aware of the complex, bidirectional interplay between both diseases.
Disorders of the divalent ions (magnesium, calcium, and phosphorous) are frequently encountered in patients with cancer. Of these, hypomagnesemia, hypocalcemia, hypercalcemia, and hypophosphatemia are seen most commonly....Disorders of the divalent ions (magnesium, calcium, and phosphorous) are frequently encountered in patients with cancer. Of these, hypomagnesemia, hypocalcemia, hypercalcemia, and hypophosphatemia are seen most commonly. These electrolyte disturbances may be related to the underlying malignancy or due to side effects of anticancer therapy. When caused by a paraneoplastic process, these abnormalities may portend a poor prognosis. Importantly, the development of severe electrolyte derangements may be associated with symptoms that negatively impact quality of life, preclude the administration of critical chemotherapeutic agents, or lead to life-threatening complications that require hospitalization and emergent treatment. In accordance, prompt recognition and treatment of these disorders is key to improving outcomes in patients living with cancer. This review will discuss selected derangements of the divalent ions seen in this population, with a focus on paraneoplastic and therapy-associated etiologies.
Tumor lysis syndrome (TLS) is an oncologic emergency due to massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Clinical presentation is ch...Tumor lysis syndrome (TLS) is an oncologic emergency due to massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Clinical presentation is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. Acute kidney injury due to tumor lysis is potentiated by the precipitation of uric acid and calcium phosphate as well as renal vasoconstriction. Early recognition of tumor lysis can help prevent cardiac arrhythmias, seizures, and death. Management includes intravenous hydration to maintain urine flow, medications targeting hyperuricemia including rasburicase and allopurinol and in severe cases renal replacement therapy may be required.
Nephrotoxicity associated with immunotherapy is increasingly being encountered in clinical practice. Drugs that augment the immune system to eradicate cancer are revolutionary in the field of oncology. Older generation i...Nephrotoxicity associated with immunotherapy is increasingly being encountered in clinical practice. Drugs that augment the immune system to eradicate cancer are revolutionary in the field of oncology. Older generation immunotherapies such as high-dose interleukin and interferon-alpha are now being replaced with more effective immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies, which have shown promising results in numerous clinical trials. Unfortunately, these treatments come with a unique baggage of adverse effects including nephrotoxicity. This onconephrology review summarizes the immunotherapies currently in use and their kidney-related toxicities, pathophysiology, and their management.
The introduction of novel molecularly targeted therapies in the last 2 decades has significantly improved the patient survival compared to standard conventional chemotherapies. However, this improvement has been accompan...The introduction of novel molecularly targeted therapies in the last 2 decades has significantly improved the patient survival compared to standard conventional chemotherapies. However, this improvement has been accompanied by a whole new spectrum of kidney adverse events. Although known as "targeted," many of these agents lack specificity and selectivity, and they have a tendency to inhibit multiple targets including those in the kidneys. Early detection and correct management of kidney toxicities is crucial to preserve kidney functions. The knowledge of these toxicities helps guide optimal and continued utilization of these potent therapies. The incidence, severity, and pattern of nephrotoxicity may vary depending on the respective target of the drug. Here, we review the mechanism of action, clinical findings of kidney adverse events, and their proposed management strategies.
Conventional chemotherapies remain the mainstay of treatment for many malignancies. Kidney complications of these therapies are not infrequent and may have serious implications for future kidney function, cancer treatmen...Conventional chemotherapies remain the mainstay of treatment for many malignancies. Kidney complications of these therapies are not infrequent and may have serious implications for future kidney function, cancer treatment options, eligibility for clinical trials, and overall survival. Kidney adverse effects may include acute kidney injury (via tubular injury, tubulointerstitial nephritis, glomerular disease and thrombotic microangiopathy), long-term kidney function loss and CKD, and electrolyte disturbances. In this review, we summarize the kidney complications of conventional forms of chemotherapy and, where possible, provide estimates of incidence, and identify risk factors and strategies for kidney risk mitigation. In addition, we provide recommendations regarding kidney dose modifications, recognizing that these adjustments may be limited by available supporting pharmacokinetic and clinical outcomes data. We discuss management strategies for kidney adverse effects associated with these therapies with drug-specific recommendations. We focus on frequently used anticancer agents with established kidney complications, including platinum-based chemotherapies (cisplatin, carboplatin, oxaliplatin), cyclophosphamide, gemcitabine, ifosfamide, methotrexate and pemetrexed, among others.
Over the past 2 decades, significant research and advancements have been made in oncology and its therapeutics. Thanks to novel diagnostic methods, treatments, and supportive measures, patients with cancer live longer an...Over the past 2 decades, significant research and advancements have been made in oncology and its therapeutics. Thanks to novel diagnostic methods, treatments, and supportive measures, patients with cancer live longer and have a better quality of life. However, an unforeseen consequence of this progress has been increasing medical complications, including acute kidney injury. The purpose of this review is to provide an overview of the epidemiology and most common causes of acute kidney injury in patients with cancer unrelated to oncological treatment.
Chronic low-grade inflammation, now coined by the new paradigm as "metaflammation" or "metainflammation", has been linked to chronic kidney disease and its progression. In diabetes, altered metabolism denotes factors ass...Chronic low-grade inflammation, now coined by the new paradigm as "metaflammation" or "metainflammation", has been linked to chronic kidney disease and its progression. In diabetes, altered metabolism denotes factors associated with the metabolic syndrome and hyperglycemia, among others. The interplay among hyperglycemia, oxidative stress, and inflammation in the pathogenesis of diabetic kidney disease (DKD) has been broadly explored. Identification of mediators of inflammatory processes involving macrophage infiltration, production of inflammasomes, release of cytokines, and activation of pertinent signaling pathways including mitogen-activated protein kinase, Jun N-terminal kinase, Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (JAK/STAT), and apoptosis signal-regulating kinase 1 signaling mechanisms have enabled the development of therapeutic agents for DKD. This review describes the evidence supporting the contribution of the inflammatory response and fibrotic changes and focuses on selected, novel, promising drugs as well as repurposed drugs that have made it to phase 2, 3, or 4 of clinical trials in adults with type 2 diabetes mellitus and their potential to become an important part of our armamentarium to improve the management of DKD. Importantly, drugs that solely target inflammatory processes may be insufficient to fully optimize care of patients with DKD because of the complex nature of the disease.
The area of aldosterone blockade has exploded in the last decade with the development of four new compounds of a different class referred to as nonsteroidal mineralocorticoid receptor antagonists (MRAs). Their chemistry...The area of aldosterone blockade has exploded in the last decade with the development of four new compounds of a different class referred to as nonsteroidal mineralocorticoid receptor antagonists (MRAs). Their chemistry and clinical charatcteristics are distinctly different from their steroidal cousins. Apart from blocking aldosterone activity, albeit in a different way than the steroidal MRAs, they have much less blood pressure (BP) effects and are better tolerated. The spectrum of nonsteroidal MRAs includes one agent with significant BP reduction, KBP-5074, to agents with minimal BP effects yet have demonstrated significant cardiorenal risk reduction in diabetic kidney disease, finerenone. The paper reviews the development and pharmacology of these different agents and tries to provide a perspective as to their place in the spectrum of aldosterone excess disorders.
Post-transplant diabetes mellitus is a frequent consequence of or a pre-existing comorbidity in solid organ transplantation (SOT) that is associated with greater morbidity and mortality. Novel glucose-lowering agents tha...Post-transplant diabetes mellitus is a frequent consequence of or a pre-existing comorbidity in solid organ transplantation (SOT) that is associated with greater morbidity and mortality. Novel glucose-lowering agents that have been shown to have cardiovascular morbidity/mortality benefit and renal protective effects such as sodium glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are being incorporated into new standard of care for diabetes mellitus. There is a paucity of data regarding the use of these agents in SOT. In this article, we will aim to review available literature on newer glucose-lowering therapeutics in SOT, mainly sodium glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, their mechanism of action, benefits, risks, and safety profiles.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective in reducing glycemia in patients with type 2 diabetes (T2D). These medications effectively reduce cardiovascular (CV) risk in patients with T2D a...Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective in reducing glycemia in patients with type 2 diabetes (T2D). These medications effectively reduce cardiovascular (CV) risk in patients with T2D and established CV disease or with multiple risk factors. In addition, treatment with GLP-1 RA may exert protective effects on the diabetic kidney. Herein, we summarize the findings regarding the kidney safety and efficacy of GLP-1 RAs in patients with T2D. We review data from GLP-1 RAs phase 3 kidney studies, CV outcome trials, as well as real-world evidence. The accumulating data show that treatment with GLP-1 RAs is safe, well-tolerated, and effective in patients with different levels of kidney dysfunction. Furthermore, CV outcome trials suggest that GLP-1 RAs reduce albuminuria and may attenuate the decline in kidney function over time. The ongoing FLOW trial studying the effects of semaglutide in patients with diabetic kidney disease is expected to shed light on the effects of GLP-1 RAs on kidney outcomes and clarify their role in the management of patients with T2D and kidney disease.
Adv Chronic Kidney Dis
· 2021 Jul · PMID 34922690
·
Full text
The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent...The worldwide prevalence of type 2 diabetes (T2D) is steadily increasing, and it remains a challenging public health problem for populations in both developing and developed countries around the world. Despite the recent advances in novel antidiabetic agents, diabetic kidney disease and cardiovascular disease remain the leading causes of morbidity and mortality in T2D. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), incretin hormones that stimulate postprandial insulin secretion, serve as a promising avenue for treatment of T2D as they result in a variety of antihyperglycemic effects including increased endogenous insulin secretion, decreased gluconeogenesis, inhibition of pancreatic α-cell glucagon production, decreased pancreatic β-cell apoptosis, and increased β-cell proliferation. GLP-1RAs have also been found to delay gastric emptying, promote weight loss, increase satiety, decrease hypertension, improve dyslipidemia, reduce inflammation, improve albuminuria, induce natriuresis, improve cardiovascular function, and prevent thrombogenesis. In this review, we will present risk factors for the development of cardiac and kidney disease in individuals with T2D and discuss possible mechanisms for the cardiorenal protective effects seen with GLP-1RAs. We will also present the possibility of dual- and tri-receptor agonist therapies with GLP-1, gastric inhibitory peptide, and glucagon RAs as an area of possible mechanistic synergy in the treatment of T2D and the prevention of cardiorenal complications.
In the past 2 decades, eight glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the management of type 2 diabetes, each with its peculiar molecular structure, pharmacokinetics, and metabolic effe...In the past 2 decades, eight glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the management of type 2 diabetes, each with its peculiar molecular structure, pharmacokinetics, and metabolic effects. Along with their marked glucose-lowering actions, which occur both at fasting and in the postprandial phase without an increased risk of hypoglycemia, GLP-1RAs have provided marked reductions in body weight and ancillary improvements in blood pressure and lipid profile. Recent cardiovascular outcome trials have established the benefits of GLP-1RAs on major cardiovascular events and all-cause mortality, independent of glucose control, with minor effects on preventing hospitalization for heart failure. Novel evidence is also emerging on the protection of GLP-1RAs against diabetic kidney disease, mainly preventing the onset of macroalbuminuria. Several mechanisms have been proposed to explain the cardiorenal protective properties of GLP-1RAs, which may be direct or mediated by additional hemodynamic and anti-inflammatory/antioxidant effects. With their favorable cardiometabolic properties and safety profile, GLP-1RAs may offer an ideal pharmacological option for the management of diabetic kidney disease. In this review, we discuss pharmacokinetic properties, glucometabolic effects, and cardioprotective actions of GLP-1RAs, highlighting the available evidence for a kidney protective role and the proposed mechanisms.
As a result of the growing number of patients with type 2 diabetes mellitus, the prevalence of diabetic kidney disease (DKD) has proven to be one of the fastest growing health care challenges globally. Early detection an...As a result of the growing number of patients with type 2 diabetes mellitus, the prevalence of diabetic kidney disease (DKD) has proven to be one of the fastest growing health care challenges globally. Early detection and initiation of appropriate interventions to slow the progression of DKD are impeded by low awareness of the health consequences of DKD, high complexity of care that includes the need for lifestyle modifications, difficulties with adhering to increasingly complicated medication regimens, and low acceptance and application of guideline-directed management. After 2 decades of status quo in the care of patients with DKD, recently approved glucose-lowering agents are promising to transform care by demonstrating slowed DKD disease progression and improved survival. As has been learned over the last 2 decades, multiple barriers exist to the optimal integration and utilization of new therapies to improve kidney outcomes. The health care community, professional societies, and regulatory agencies must join efforts to develop implementation strategies for increasing DKD awareness, detection, and treatment.
Adv Chronic Kidney Dis
· 2021 Jul · PMID 34922687
·
Full text
Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due...Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due to associated weight loss, low risk of hypoglycemia, and improved cardiorenal outcomes seen in persons with type 2 diabetes mellitus. The increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA, has led many to be wary of their use in T1D, especially given limited pediatric data and data regarding cardiorenal protection in this population. The phase 3 trials of these agents in T1D have yielded lower HbA1c, decreased total daily insulin dose, and small but significant weight loss with no increase in hypoglycemia. These trials also reported increased risks of genital mycotic infection and DKA. SGLT inhibitors have been approved as adjunctive therapy to insulin in adults with T1D in Europe and Japan, but the United States Food and Drug Administration has rejected similar applications. Although approaches to mitigate the risk of DKA have been developed, no randomized trials using such tools have been conducted. More research is needed to minimize the risk of DKA and to better evaluate the cardiorenal impact of these agents in persons with T1D.
Large-scale randomized trials have demonstrated the remarkable capacity of sodium-glucose cotransporter 2 inhibitors to reduce the risk of cardiovascular outcomes and kidney disease progression, irrespective of the prese...Large-scale randomized trials have demonstrated the remarkable capacity of sodium-glucose cotransporter 2 inhibitors to reduce the risk of cardiovascular outcomes and kidney disease progression, irrespective of the presence or absence of type 2 diabetes mellitus. Although the results of these trials have transformed clinical practice guidelines, the mechanisms underpinning the wide-ranging benefits of this class of agents remain incompletely understood and subject to ongoing investigation. Improvements in cardiometabolic risk factors such as glucose, blood pressure, body weight, and albuminuria likely contribute. However, other direct effects on physiological and cellular function, such as restoration of tubuloglomerular feedback, improvements in kidney and cardiac oxygenation and energy efficiency, as well as restoration of normal autophagy are also likely to be important. This review summarizes the rationale and potential mechanisms for cardiorenal protection with sodium-glucose cotransporter 2 inhibitors in people with and without diabetes, their relative importance, and the experimental and clinical lines of evidence supporting these hypotheses.