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 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.

Acute kidney injury in neurocritical care.

Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients.

Critical Appraisal of Limitations in the Current Definition/Classification of Uremic Toxins.

Progress in the identification and characterization of uremic retention solutes has refined our understanding of the pathophysiology of the uremic syndrome. Furthermore, the evolution of dialysis and other techniques designed to remove uremic retention solutes offers opportunities to provide a more personalized and targeted treatment for patients with chronic kidney disease (CKD) with an aim to improve outcomes. Considering these developments, a consensus report was recently published that readdressed the 2003 definition and classification of uremic toxins and formulated recommendations for future research to enhance the understanding of uremic retention solutes. In the present work, the authors of a work group that contributed to the consensus report provide a more detailed rationale for the recommendations related to their theme "Critical appraisal of limitations in the current definition/classification of uremic toxins." In summary, the authors propose that the current definition of uremic toxins should remain organized on hemodialysis strategies, membranes, and removal patterns since hemodialysis is the most frequently applied therapeutic strategy to reduce their concentration in advanced CKD. Nevertheless, the work group also acknowledges that any classification based on cutoff values and/or molecular spatial configurations is arbitrary and will likely need to be changed with therapeutic advancements. Furthermore, the current physicochemical classification might be extended to reflect the degree of toxicity of a specific toxin that is likely to support more personalized and targeted dialysis prescriptions and improve the outcomes for patients with CKD.

Proposal for a New Classification of Solutes of Interest in Uremia and Hemodialysis.

Uremic toxins contribute to clinical manifestations of kidney dysfunction. These toxins include organic and inorganic elements or compounds. While the kidney typically clears uremic toxins, gut dysbiosis, and tissue inflammation could lead to increased production of substances that can further the clinical manifestations of uremia. The uremic toxins are quantitatively measurable in biological fluids and have an established relationship with azotemia signs and symptoms. Their elimination is associated with mitigated uremic manifestations, while their administration to the uremic levels leads to uremic signs in animal or human models or in vitro studies. Besides, the uremic toxins have an established and plausible pathophysiologic relationship with uremic manifestations. The previous classification of uremic toxins was mainly focused on the physicochemical characteristics of these substances to divide them into three categories, (1) free water-soluble low-molecular-weight (<500 Da) solutes, (2) protein-bound, water-soluble, low molecular weight (<500 Da), (3) middle molecular weight (>500 Da and <12,000 Da), and (4) high molecular weight (>12,000 Da). Unfortunately, the classification named above was not centered around patient outcomes and quality of life among those with severe kidney failure. Therefore, a panel of experts convened virtually to provide additional insights into the current state and propose a new uremic toxin classification. This article describes the group's consensus recommendations regarding the new classification of uremic toxins into more clinically oriented categories.

Rationale for a New Classification of Solutes of Interest in Chronic Kidney Disease and Hemodialysis.

A hallmark of chronic kidney disease is the retention of solutes that normally are eliminated by the kidneys. The current classification defines uremic toxins based on molecular weight and protein affinity. The retention of solutes is already detected in the early stages of the disease when patients are pauci-symptomatic or asymptomatic but the role of therapies to retard the loss of kidney function in patients with chronic kidney disease (e.g., modulators of the renin-angiotensin-aldosterone system, sodium-glucose cotransporter inhibitors) in reducing uremic toxins is poorly understood. Most of the research evaluating the impact of therapies to lower serum concentrations of those toxic compounds is carried out in patients with kidney failure already undergoing kidney replacement therapy. The removal of those molecules relies in physicochemical mass transfer phenomena, i.e., adsorption, diffusion, and convection. In the past 2 decades, the rise and broad adoption of blood purification strategies with enhanced convective properties, such as high-volume online hemodiafiltration and expanded hemodialysis, considerably amplified the ability to mechanically extract middle molecules (molecular weight >0.5 kDa) from the blood compartment. Nonetheless, the classification of uremic toxins has not evolved in parallel with dialysis advancements. Mounting evidence demonstrates the link between middle molecules with uremic symptoms, cardiovascular and mortality risks. An urgent need for updating the classification exists. Defining the causative relationship between specific solutes and specific clinical outcomes will promote the development of targeted therapies. In parallel, the inclusion of new pertinent dimensions to the classification like the influence of new dialysis membranes, sorbents, and intestinal chelators in the concentration of uremic toxins would improve the understanding of the pathogenesis of chronic kidney disease, setting the pace for future research in nephrology.

Standardization of Nomenclature for the Mechanisms and Materials Utilized for Extracorporeal Blood Purification.

In order to develop a standardized nomenclature for the mechanisms and materials utilized during extracorporeal blood purification, a consensus expert conference was convened in November 2022. Standardized nomenclature serves as a common language for reporting research findings, new device development, and education. It is also critically important to support patient safety, allow comparisons between techniques, materials, and devices, and be essential for defining and naming innovative technologies and classifying devices for regulatory approval. The multidisciplinary conference developed detailed descriptions of the performance characteristics of devices (membranes, filters, and sorbents), solute and fluid transport mechanisms, flow parameters, and methods of treatment evaluation. In addition, nomenclature for adsorptive blood purification techniques was proposed. This report summarizes these activities and highlights the need for standardization of nomenclature in the future to harmonize research, education, and innovation in extracorporeal blood purification therapies.

Uremic encephalopathy.

Uremic encephalopathy encompasses a wide range of central nervous system abnormalities associated with poor kidney function occurring with either progressive chronic kidney disease or acute kidney injury. The syndrome is likely caused by retention of uremic solutes, alterations in hormonal metabolism, changes in electrolyte and acid-base homeostasis, as well as changes in vascular reactivity, blood-brain barrier transport, and inflammation. There are no defining clinical, laboratory, or imaging findings, and the diagnosis is often made retrospectively when symptoms improve after dialysis or transplantation. The diagnosis is also made difficult because of the many confounding and overlapping conditions seen in patients with chronic kidney disease and acute kidney injury. Thus, institution of kidney replacement therapy should be considered as a trial to improve symptoms in the right clinical context. Neurological symptoms that do not improve after improvement in clearance should prompt a search for other explanations. Further knowledge linking possible uremic retention solutes with neurological symptoms is needed to better understand this syndrome as well as to develop more tailored treatments that aim to improve cognitive function.

Management of dysnatremias with continuous renal replacement therapy.

Disorders of serum sodium concentration are common in critically ill patients who may have concomitant acute kidney injury, chronic kidney disease, or end-stage kidney disease. Many of these patients may require customized serum sodium level management with dialysis which, if not strictly controlled, can lead to significant complications. Thus, controlled correction of the serum sodium level is necessary to avoid the development of osmotic demyelination syndrome in hyponatremic patients and dialysis disequilibrium syndrome in hypernatremic patients. Continuous renal replacement therapy offers unique benefits through the ability to slowly and safely correct dysnatremias that can be tailored to specific patient needs and should be considered in select patients.

Chronic Kidney Disease of Undetermined Etiology around the World.

BACKGROUND: Epidemics of chronic kidney disease of uncertain etiology (CKDu) are occurring on the Pacific coast of Central America, in Sri Lankan and Indian agricultural communities, and in other hotspots around the world. CKDu primarily affects male agricultural workers, and traditional risk factors such as diabetes and hypertension are not involved in the pathogenesis. Although a causal factor has not yet been identified, culprits include repeated volume depletion-induced kidney injury, as well as exposure to agrichemicals, heavy metals and nephrotoxins contained in drugs, beverages, and traditional medications. Multiple risk factors may interact in a synergistic fashion thus resulting in chronic kidney damage. The absence of undefined protective factors may amplify the risk. SUMMARY: This review focuses on the current understanding of CKDu by analyzing epidemiology, potential risk factors, and clinical and pathological features as well as geographical peculiarities of each disease. We also focus our attention on the etiology of these conditions in which multiple factors may synergistically contribute to the development and progression of the disease. The last part of the manuscript is dedicated to the research agenda and practical recommendations. Key Messages: Since renal replacement therapy is not extensively available in areas where CKDu is widespread, prevention by avoiding all known potential risk factors is crucial. Innovative healthcare solutions and social policies in endemic areas along with collaborative clinical research projects are needed to better identify factors involved in disease promotion and progression.

Technique Failure in Peritoneal Dialysis: Etiologies and Risk Assessment.

Technique failure (TF) is a well-recognized challenge encountered in patients undergoing peritoneal dialysis (PD). Identification of patients at risk for this complication is of utmost importance. Early detection of patients at risk and development of preventative strategies can improve technique survival that may lead to an increased utilization of PD. It will also promote a safe and planned transfer to hemodialysis once a patient identified with TF. The aim of this review is to summarize risk factors and scenarios associated with TF focusing on prevention of remediable factors at their earliest stage. Furthermore, integration of this knowledge into quality improvement initiatives should be entertained in an effort to improve outcomes.

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.

New drugs for acute kidney injury.

PURPOSE OF REVIEW: To describe recent advances in the development of therapeutic agents for acute kidney injury (AKI). RECENT FINDINGS: Traditional care for AKI is mostly supportive. At present, no specific therapy has been developed to prevent or treat AKI. However, based on a better understanding of the pathophysiology of AKI, various potential compounds have been recently identified and tested. A variety of pathways has been targeted, including oxidative and mitochondrial stress, cellular metabolism and repair, inflammation, apoptosis and hemodynamics. Many of these potential agents are currently ongoing early-phase clinical trials, and the purpose of this review is to provide a summary of those with the most potential. SUMMARY: Despite the lack of therapies specifically approved for AKI, many interesting potential agents are entering clinical trials, with the potential to transform the care of patients with AKI.

Mitochondria in Sepsis-Induced AKI.

AKI is a common clinical condition associated with the risk of developing CKD and ESKD. Sepsis is the leading cause of AKI in the intensive care unit (ICU) and accounts for nearly half of all AKI events. Patients with AKI who require dialysis have an unacceptably high mortality rate of 60%-80%. During sepsis, endothelial activation, increased microvascular permeability, changes in regional blood flow distribution with resulting areas of hypoperfusion, and hypoxemia can lead to AKI. No effective drugs to prevent or treat human sepsis-induced AKI are currently available. Recent research has identified dysfunction in energy metabolism as a critical contributor to the pathogenesis of AKI. Mitochondria, the center of energy metabolism, are increasingly recognized to be involved in the pathophysiology of sepsis-induced AKI and mitochondria could serve as a potential therapeutic target. In this review, we summarize the potential role of mitochondria in sepsis-induced AKI and identify future therapeutic approaches that target mitochondrial function in an effort to treat sepsis-induced AKI.

Wilderness Medical Society Clinical Practice Guidelines for the Management of Exercise-Associated Hyponatremia: 2019 Update.

Exercise-associated hyponatremia (EAH) is defined by a serum or plasma sodium concentration below the normal reference range of 135 mmol·L-1 that occurs during or up to 24 h after prolonged physical activity. It is reported to occur in individual physical activities or during organized endurance events conducted in environments in which medical care is limited and often not available, and patient evacuation to definitive care is often greatly delayed. Rapid recognition and appropriate treatment are essential in the severe form to increase the likelihood of a positive outcome. To mitigate the risk of EAH mismanagement, care providers in the prehospital and in hospital settings must differentiate from other causes that present with similar signs and symptoms. EAH most commonly has overlapping signs and symptoms with heat exhaustion and exertional heat stroke. Failure in this regard is a recognized cause of worsened morbidity and mortality. In an effort to produce best practice guidelines for EAH management, the Wilderness Medical Society convened an expert panel in May 2018. The panel was charged with updating the WMS Practice Guidelines for Treatment of Exercise-Associated Hyponatremia published in 2014 using evidence-based guidelines for the prevention, recognition, and treatment of EAH. Recommendations are made based on presenting with symptomatic EAH, particularly when point-of-care blood sodium testing is unavailable in the field. These recommendations are graded on the basis of the quality of supporting evidence and balanced between the benefits and risks/burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians.

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.

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.

Exploring Barriers and Potential Solutions in Home Dialysis: An NKF-KDOQI Conference Outcomes Report.

Home dialysis therapy, including home hemodialysis and peritoneal dialysis, is underused as a modality for the treatment of chronic kidney failure. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative sponsored a home dialysis conference in late 2017 that was designed to identify the barriers to starting and maintaining patients on home dialysis therapy. Clinical, operational, policy, and societal barriers were identified that need to be overcome to ensure that dialysis patients have the freedom to choose their treatment modality. Education of patients and patient partners, as well as health care providers, about home dialysis therapy, if offered at all, is often provided in a cursory manner. Lack of exposure to home dialysis therapies perpetuates a lack of familiarity and thus a hesitancy to refer patients to home dialysis therapies. Patient and care partner support, both psychosocial and financial, is also critical to minimize the risk for burnout leading to dropout from a home dialysis modality. Thus, the facilitation of home dialysis therapy will require a systematic change in chronic kidney disease education and the approach to dialysis therapy initiation, the creation of additional incentives for performing home dialysis, and breakthroughs to simplify the performance of home dialysis modalities. The home dialysis work group plans to develop strategies to overcome these barriers to home dialysis therapy, which will be presented at a follow-up home dialysis conference.

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.

EXERCISE-ASSOCIATED HYPONATREMIA.

Exercise-associated hyponatremia (EAH) is defined by an acute fall in the serum or plasma sodium concentration to below 135 mmol/L that occurs during or up to 24 hours after prolonged physical activity. EAH has been reported in nearly every form of endurance activity and has a common pathogenic feature of excessive water intake which is usually coupled with elevated vasopressin levels. Symptomatic EAH is uncommon but can be a cause of mortality in otherwise healthy adults and children. Rapid recognition and appropriate treatment with hypertonic saline are essential to maximizing outcomes and preventing death.