Assessment of GFR in Patients with Cancer: A Statement from the American Society of Onco-Nephrology.

Accurate assessment of GFR is crucial to guiding drug eligibility, dosing of systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. Up to 32% of patients with cancer have baseline CKD, and both malignancy and treatment may cause kidney injury and subsequent CKD. To date, there has been lack of guidance to standardize approaches to GFR estimation in the cancer population. In this two-part statement from the American Society of Onco-Nephrology, we present key messages for estimation of GFR in patients with cancer, including the choice of GFR estimating equation, use of race and body surface area adjustment, and anticancer drug dose-adjustment in the setting of CKD. These key messages are based on a systematic review of studies assessing GFR estimating equations using serum creatinine and cystatin C in patients with cancer, against a measured GFR comparator. The preponderance of current data involving validated GFR estimating equations involves the CKD Epidemiology Collaboration (CKD-EPI) equations, with 2508 patients in whom CKD-EPI using serum creatinine and cystatin C was assessed (eight studies) and 15,349 in whom CKD-EPI with serum creatinine was assessed (22 studies). The former may have improved performance metrics and be less susceptible to shortfalls of eGFR using serum creatinine alone. Since included studies were moderate quality or lower, the American Society of Onco-Nephrology Position Committee rated the certainty of evidence as low. Additional studies are needed to assess the accuracy of other validated eGFR equations in patients with cancer. Given the importance of accurate and timely eGFR assessment, we advocate for the use of validated GFR estimating equations incorporating both serum creatinine and cystatin C in patients with cancer. Measurement of GFR via exogenous filtration markers should be considered in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials.

Cancer therapy in patients with reduced kidney function.

Chronic Kidney Disease (CKD) and cancer constitute two major public health burdens and are on the rise. Moreover, the number of patients affected simultaneously by both conditions is growing. Potential nephrotoxic effect of cancer therapies is particularly important for patients with CKD, as they are also affected by several comorbidities. Therefore, administering the right therapy at the right dose for patients with decreased kidney function can represent a daunting challenge. We review in detail the renal toxicities of anti-cancer therapies i.e. conventional chemotherapy, targeted therapy, immune checkpoint inhibitors, and radioligand therapies, issue recommendations for patient monitoring along with guidance on when to withdraw treatment and suggest dosage guidelines for select agents in advanced stage CKD. Various electrolytes disturbances can occur as the result of the administration of anti-cancer agents in the patient with decreased kidney function. These patients are prone to developing hyponatremia, hyperkalemia, and other metabolic abnormalities because of a decreased GFR. Therefore, all electrolytes, minerals and acid base status should be checked at baseline and before each administration of chemotherapeutic agents. Moreover, studies on patients on kidney replacement therapy (KRT) are very limited and only single cases or small case series are published. Therefore, clinical therapeutical decisions in cancer patients with decreased function should be made by multidisciplinary teams constituted of medical oncologists, nephrologists, and other specialists. Onconephrology is an evolving and expanding subspecialty. It is crucial to consider anticancer drug treatment in these patients and offer them a chance to be treated effectively.

Improving Cancer Care for Patients With CKD: The Need for Changes in Clinical Trials.

Chemotherapeutic agents used to treat cancer generally have narrow therapeutic indices along with potentially serious adverse toxicities. Many cancer drugs are at least partially excreted through the kidney and, thus, the availability of accurate data on safe and effective dosing of these drugs in patients with chronic kidney disease (CKD) is essential to guide treatment decisions. Typically, during drug development, initial clinical studies only include patients with normal or only mildly impaired kidney function. In subsequent preregistration studies, a limited number of patients with more severe kidney dysfunction are included. Data obtained from patients with either severe kidney dysfunction (here defined as an estimated glomerular filtration rate [eGFR] < 30 ml/min or stage 4G CKD) or end-stage kidney disease (ESKD) requiring kidney replacement treatment are particularly limited before drug registration and only a minority of new drug applications to the US Food and Drug Administration (FDA) include data from this population. Unfortunately, limited data and/or other safety concerns may result in a manufacturer statement that the drug is contraindicated in patients with advanced kidney disease, which hinders access to potentially beneficial drugs for these patients. This systemic exclusion of patients with CKD from cancer drug trials remains an unsolved problem, which prevents provision of optimal clinical care for these patients, raises questions of inclusion, diversity, and equity. In addition, with the aging of the population, there are increasing numbers of patients with CKD and cancer who face these issues. In this review, we evaluate the scientific basis to exclude patients with CKD from cancer trials and propose a comprehensive strategy to address this problem.

Glomerular Filtration Rate Measurement and Chemotherapy Dosing.

Many chemotherapeutic drugs used to treat malignancies undergo renal clearance. Thus, accurate knowledge of kidney function is critical to ensure proper dosing, maximize efficacy, and minimize toxicity of drugs that often have a narrow therapeutic index. Making this issue more salient is the fact that impaired kidney function, as assessed by glomerular filtration rate (GFR), is encountered commonly in patients with cancer. Recent data and expert guidelines recommend the use of the Chronic Kidney Disease-Epidemiology Collaboration equation to guide the assessment of kidney function, except when directly measured GFR is clinically necessary. Controversies regarding the measurement of kidney function include the use of race in this equation, indexing to body surface area, and dosing of medications based on stages of chronic kidney disease versus more discrete values of estimated GFR. The development of accurate, real-time GFR measures may hold great promise in allowing for more accurate dosing of these important drugs.

The effect of high-flow arteriovenous fistulas on systemic haemodynamics and brain oxygenation.

AIMS: High-flow arteriovenous fistula (AVF) for haemodialysis leads to profound haemodynamic changes and sometimes to heart failure (HF). Cardiac output (CO) is divided between the AVF and body tissues. The term effective CO (COef) represents the difference between CO and AVF flow volume (Qa) and better characterizes the altered haemodynamics that may result in organ hypoxia. We investigated the effects of Qa reduction on systemic haemodynamics and on brain oxygenation. METHODS AND RESULTS: This is a single-centre interventional study. Twenty-six patients on chronic haemodialysis with high Qa (>1500 mL/min) were indicated for surgical Qa reduction for HF symptoms and/or signs of structural heart disease on echocardiography. The included patients underwent three sets of examinations: at 4 months and then 2 days prior and 6 weeks post-surgical procedure. Clinical status, echocardiographical haemodynamic assessment, Qa, and brain oximetry were recorded. All parameters remained stable from selection to inclusion. After the procedure, Qa decreased from 3.0 ± 1.4 to 1.3 ± 0.5 L/min, P < 0.00001, CO from 7.8 ± 1.9 to 6.6 ± 1.5 L/min, P = 0.0002, but COef increased from 4.6 ± 1.4 to 5.3 ± 1.4 L/min, P = 0.036. Brain tissue oxygen saturation increased from 56 ± 11% to 60 ± 9%, P = 0.001. CONCLUSIONS: Qa reduction led to increased COef. This was explained by a decreased proportion of CO running through the AVF in patients with Qa > 2.0 L/min. These observations were mirrored by higher brain oxygenation and might explain HF symptoms and improved haemodynamics even in asymptomatic high Qa patients.

Disorders of Divalent Ions (Magnesium, Calcium, and Phosphorous) in Patients With Cancer.

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.

Onconephrology: The intersections between the kidney and cancer.

Onconephrology is a new subspecialty of nephrology that recognizes the important intersections of kidney disease with cancer. This intersection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, paraneoplastic glomerulonephritis, and the interactions of chronic kidney disease with cancer. Data clearly demonstrate that, when patients with cancer develop acute or chronic kidney disease, outcomes are inferior, and the promise of curative therapeutic regimens is lessened. This highlights the imperative for collaborative care between oncologists and nephrologists in recognizing and treating kidney disease in patients with cancer. In response to this need, specific training programs in onconephrology as well as dedicated onconephrology clinics have appeared. This comprehensive review covers many of the critical topics in onconephrology, with a focus on acute kidney injury, chronic kidney disease, drug-induced nephrotoxicity, kidney disease in stem cell transplantation, and electrolyte disorders in patients with cancer.

Cancer Screening in Patients Undergoing Maintenance Dialysis: Who, What, and When.

Cancer screening guidelines were developed for the general population with the aim of improving health outcomes through early detection. However, these screening recommendations are not generalizable to patients undergoing maintenance dialysis given that their life expectancy is often less than 5 years. In addition, the performance characteristics of screening tests in patients treated by dialysis may not be the same as in the general population, leading to differences in these tests' sensitivity and specificity in detecting cancer. Survival benefits in patients receiving dialysis may also be tempered by increased risks of curative therapies. Given the uncertainties of cancer screening in patients treated by maintenance dialysis, an individualized approach to cancer screening is warranted. This approach should balance the patient's life expectancy and the potential benefits from screening with its potential costs and harm. The special circumstance of renal cell carcinoma in patients treated by dialysis is also discussed.

Creatinine: From physiology to clinical application.

Estimating static kidney function accurately and detecting changes in kidney function in a timely fashion are challenging but critically important tasks. Serum creatinine is the most widely used functional biomarker of the kidney. However, its use is associated with substantial shortcomings. Understanding these shortcomings is critical in allowing accurate interpretation of creatinine values and translating them into changes in kidney function. In this review, the pathways involved in creatinine generation and metabolism as well as the techniques involved in measuring creatinine concentrations are discussed. This allows for the discussion of the value and pitfalls in using creatinine as a marker of kidney function. In addition, information regarding alternative functional biomarkers of the kidney is provided.

GFR Measurement and Chemotherapy Dosing in Patients with Kidney Disease and Cancer.

Chemotherapeutic agents require precise dosing to ensure optimal efficacy and minimize complications. For those agents that are removed from the body by the kidney, accurate knowledge of GFR is critical. In addition, GFR needs to be determined rapidly, easily, and, if possible, with little additional cost. The ability to easily measure GFR also allows for rapid detection of nephrotoxicity. Current methodologies include direct clearance measurement of an indicator substance or estimation of creatinine clearance or GFR through regression equations that use a serum marker, such as creatinine or cystatin C. These methodologies all have shortfalls and limitations, some of which are specific to the patient with cancer. Newer methodologies that directly measure GFR are in clinical trials and offer the ability to rapidly and noninvasively provide accurate estimates of drug clearance as well as detection of nephrotoxicity. These methods offer the opportunity to refine drug dosing and improve outcomes.

Summary of the International Conference on Onco-Nephrology: an emerging field in medicine.

Onco-nephrology is an emerging field in medicine. Patients with cancer may suffer from kidney diseases because of the cancer itself and cancer-related therapy. It is critical for nephrologists to be knowledgeable of cancer biology and therapy in order to be fully integrated in the multidisciplinary team and optimally manage patients with cancer and kidney diseases. In a recent international meeting, the key issues in this challenging clinical interface were addressed, including many unresolved basic science questions, such as the high tumor incidence in kidney transplant recipients. To this end, 70 highly qualified faculty members were gathered from all over the world to discuss these issues in 8 plenary sessions, including 5 keynote lectures. In addition, 48 young nephrologists and oncologists were invited to present their original observations that were highlighted in 2 large poster sessions.

Acute kidney injury in the patient with cancer.

Dramatic advances in the care of patients with cancer have led to significant improvement in outcomes and survival. However, renal manifestations of the underlying cancer as well as the effects of anti-neoplastic therapies leave patients with significant morbidity and chronic kidney disease risks. The most common renal manifestations associated with cancer include acute kidney injury (AKI) in the setting of multiple myeloma, tumor lysis syndrome, post-hematopoietic stem cell therapy, and AKI associated with chemotherapy. Knowledge of specific risk factors, modification of risk and careful attention to rapid AKI diagnosis are critical for improving outcomes.

Hyponatremia in patients with cancer.

PURPOSE OF REVIEW: Hyponatremia is seen commonly in patients with cancer and is associated with increased mortality and morbidity. Understanding the proper diagnosis and therapy of cancer-associated hyponatremia is critical to ensure improved outcomes. RECENT FINDINGS: The most common cancers associated with hyponatremia are the various forms of lung cancer with incidences approaching 25-45%. The most common causes of hyponatremia in cancer patients are the syndrome of inappropriate antidiuretic hormone secretion [syndrome of inappropriate antidiuretic hormone (ADH)] and volume depletion. Proper diagnosis rests on clinical information supplemented by laboratory studies and is critical to ensure appropriate therapy. In recent years, the development of drugs that specifically antagonize the vasopressin type 2 receptor in the distal tubule have offered targeted and highly effective therapies for syndrome of inappropriate ADH. SUMMARY: Hyponatremia in cancer patients generally indicates advanced or severe disease but proper therapy that targets the underlying process can improve outcomes.

Persistent decrease of renal functional reserve in patients after cardiac surgery-associated acute kidney injury despite clinical recovery.

Background: Cardiac surgery is a leading cause of acute kidney injury (AKI). Such AKI patients may develop progressive chronic kidney disease (CKD). Others, who appear to have sustained no permanent loss of function (normal serum creatinine), may still lose renal functional reserve (RFR). Methods: We extended the follow-up in the observational 'Preoperative RFR Predicts Risk of AKI after Cardiac Surgery' study from hospital discharge to 3 months after surgery for 86 (78.2%) patients with normal baseline estimated glomerular filtration rate (eGFR), and re-measured RFR with a high oral protein load. The primary study endpoint was change in RFR. Study registration at clinicaltrials.gov Identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. Results: At 3 months, three patients developed new CKD. All remaining patients continued to have a normal eGFR (93.3 ± 15.1 mL/min/1.73 m2). However, when stratified by post-operative AKI and cell cycle arrest (CCA) biomarkers, AKI patients displayed a significant decrease in RFR {from 14.4 [interquartile range (IQR) 9.5 - 24.3] to 9.1 (IQR 7.1 - 12.5) mL/min/1.73 m2; P < 0.001} and patients without AKI but with positive post-operative CCA biomarkers also experienced a similar decrease of RFR [from 26.7 (IQR 22.9 - 31.5) to 19.7 (IQR 15.8 - 22.8) mL/min/1.73 m2; P < 0.001]. In contrast, patients with neither clinical AKI nor positive biomarkers had no such decrease of RFR. Finally, of the three patients who developed new CKD, two sustained AKI and one had positive CCA biomarkers but without AKI. Conclusions: Among elective cardiac surgery patients, AKI or elevated post-operative CCA biomarkers were associated with decreased RFR at 3 months despite normalization of serum creatinine. Larger prospective studies to validate the use of RFR to assess renal recovery in combination with biochemical biomarkers are warranted.

Acute Kidney Injury in Patients With Cancer.

Acute kidney injury (AKI) is a common complication in cancer patients and occurs in up to 30% of patients during their disease course. Multiple myeloma, leukemia/lymphoma, renal cell carcinoma, and hematopoietic stem cell transplantation are commonly associated with the development of AKI. Drugs used to treat various malignancies are also a common and notable cause of AKI in this population. Nephrology consultation is important to ensure proper and rapid diagnosis, as well as appropriate therapy and follow-up. In particular, knowledge of the nephrotoxicity of the various anticancer regimens employed is critical. This is a rapidly evolving area that requires continuous updating as new drugs are released into clinical practice and nephrotoxicity is observed.

Opening an onconephrology clinic: recommendations and basic requirements.

Onconephrology is a rapidly evolving subspeciality that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well-defined multidisciplinary management administered by a dedicated team. Since there is an increasing need to address the needs of this population in dedicated outpatient clinics, it is critical to highlight basic characteristics and to suggest areas of development. In this brief perspective article, we analyse the requirements of an onconephrology clinic in terms of logistics, critical mass of patients and building a multidisciplinary team. We will further discuss which patients to refer and which conditions to treat. The last part of the article is dedicated to education and performance indicators and to analysis of the potential advantages of applying the hub-and-spoke model to this field. The ultimate aim of this experience-based article is to initiate debate about what an onconephrology outpatient clinic might look like in order to ensure the highest quality of care for this growing population of patients.

Nephrotoxicity and Chinese Herbal Medicine.

Chinese herbal medicine has been practiced for the prevention, treatment, and cure of diseases for thousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening.

Renal cell carcinoma for the nephrologist.

Renal cell carcinoma (RCC), a malignancy whose incidence is increasing, is frequently encountered in general nephrology practice when acute and chronic kidney disease occurs in the course of disease. Importantly, when kidney disease develops in the setting of RCC, mortality is significantly increased with patients often dying of a non-cancer-related complication of kidney disease. As such, practicing nephrologists need to have a working knowledge of this cancer's biology, treatment, and complications. Nephrologists should be involved in all aspects of the care of patients with RCC including in the acute setting prior to nephrectomy and in the chronic setting for patients with post-nephrectomy chronic kidney disease and those receiving potentially nephrotoxic anti-cancer agents. This collaborative approach to RCC care will hopefully improve patient outcomes.