Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).

Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases. The Health and Environmental Sciences Institute (HESI) - Immuno-Safety Technical Committee (ITC) organized a project to address this issue through two complementary approaches: (i) an industry survey on FIH dose selection strategies and (ii) detailed case studies for immunomodulators in oncology and non-oncology indications. Key messages from the industry survey responses highlighted a preference toward more dynamic PK/PD approaches as in vitro assays are seemingly not representative of true physiological conditions for immunomodulators. These principles are highlighted in case studies. To address the above themes, we have proposed a revised decision tree, which expands on the guidance by the IQ MABEL Working Group (Leach et al. 2021). This approach facilitates a more refined recommendation of FIH dose selection for immunomodulators, allowing for a nuanced consideration of their mechanisms of action (MOAs) and the associated risk-to-benefit ratio, among other factors.

Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Our dementia challenge: arise palliative care.

While many of the maladies of the 20th century are steadily coming under control, the march of neurodegenerative disorders continues largely unchecked. Dementias are an exemplar of such disorders; their incidence and prevalence continue to rise, in large part due to a steadily ageing population worldwide. They represent a group of chronic, progressive and, ultimately, fatal neurodegenerative diseases. Dementia has remained therapeutically recalcitrant. It is not a single disease, and because of that, we cannot expect a single panacea. While primary prevention rightly gains prominence, those with established disease currently require a shift in focus from curative intent towards improved quality of life. Enter palliative care. The sheer number and complexity of needs of patients with dementia, from the physical to the psychosocial and spiritual, necessitates the engagement of a wide range of medical disciplines, nursing and allied health professionals. One of those disciplines, as highlighted in the recent Australian Royal Commission into Aged Care Quality and Safety, is palliative care. This paper shall expand upon that role in the overall context of care for those with dementia.

Kidney failure end-of-life care: impact of advance care planning - retrospective observational study.

OBJECTIVES: Patients with kidney failure (KF) have poor prognosis yet receive aggressive medical interventions at the end of life. Advance care planning (ACP) aims to respect patients' treatment preference and facilitate good death, though whether these are achieved in KF is unknown.This study examines the utility of ACP for end-of-life care in KF patients. METHODS: A retrospective observational study of KF patients who completed an ACP document 2012-2019 and died in an Australian hospital. Medical records were reviewed to assess treatment concordance to the ACP document and quality of end-of-life care received. RESULTS: 65 KF patients (29 dialysis, 36 conservative) had a median age of 84 years and 57% males. 86% of deaths followed an emergency admission. ACP documents recorded patients' preference to avoid cardiopulmonary resuscitation (91%) and forego dialysis (86%). 95% patients received treatment concordant with ACP. One patient was resuscitated, and one conservative patient dialysed. A good quality death was achieved for most, including dialysis withdrawal (80%), palliative care referral (88%), discussion of prognosis (95%), rationalised medications (89%) and anticipatory end-of-life medications (92%). CONCLUSION: ACP documents are useful facilitating treatment concordant with KF patients' preferences. Most patients avoided aggressive medical interventions and received good quality end-of-life care.

Current nonclinical approaches for immune assessments of immuno-oncology biotherapeutics.

Harnessing the immune system to kill tumors has been revolutionary and, as a result, has had an enormous benefit for patients in extending life and resulting in effective cures in some. However, activation of the immune system can come at the cost of undesirable adverse events such as cytokine release syndrome, immune-related adverse events, on-target/off-tumor toxicity, neurotoxicity and tumor lysis syndrome, which are safety risks that can be challenging to assess non-clinically. This article provides a review of the biology and mechanisms that can result in immune-mediated adverse effects and describes industry approaches using in vitro and in vivo models to aid in the nonclinical safety risk assessments for immune-oncology modalities. Challenges and limitations of knowledge and models are also discussed.

The neuropalliative multidisciplinary team-Members and their roles.

Neurodegenerative conditions are prominent contributors to both morbidity and mortality worldwide. They pose a significant challenge to health professionals, health systems, and the often unpaid, untrained family members and carers. The many and varied challenges encountered are best managed by a multidisciplinary neuropalliative team, as it is impossible for a single clinician to possess and deliver the wide range of skills and services required to optimally care for these patients. This chapter discusses the assembly, maintenance, and care of such a team, as well as potential difficulties and solutions in domains such as funding, training, geographical remoteness, as well as the potential lack of awareness and acceptance by colleagues. A comprehensive description of the role of all possible team members is discussed. The chapter outlines the concept, content, and potential benefits of a multidisciplinary team in neuropalliative care. Its thesis is twofold: that multidisciplinary care is vital and, second, that the sum of the whole of a team can be greater than the individual parts with respect to organization, planning, experience, and creativity of approach. With all these factors considered, and implemented wherever possible, we may all move closer to optimizing the comfort and care of our shared neuropalliative patients.

Feasibility, acceptability, and utility of a nurse-led survivorship program for people with metastatic melanoma (MELCARE).

PURPOSE: Immune checkpoint inhibitors (ICIs) and targeted therapy (TT) have improved the survival of people with metastatic melanoma. We assessed the feasibility, acceptability, and utility of a novel model of nurse-led, telehealth-delivered survivorship care (MELCARE) for this survivor group. METHODS: People ≥ 18 years diagnosed with unresectable stage III or stage IV melanoma who were ≥ 6 months post initiation of ICI/TT with a radiological response suggestive of a long-term response to ICI/TT were recruited from a specialist melanoma centre in Australia. All participants received MELCARE, a nurse-led survivorship program involving two telehealth consultations 3 months apart, needs assessment using the Distress Thermometer (DT) and Problem List, and creation of a survivorship care plan. Feasibility, acceptability, and utility were assessed using rates of consent and study completion, time taken to complete each component of MELCARE, the Acceptability of Intervention Measure (AIM), and a customised utility survey. RESULTS: 31/54 (57%) people consented. Participants were male (21, 68%), with a median age of 67 (range: 46-82). Eleven (35%) were receiving/had received ipilimumab and nivolumab and 27 (87%) had ceased treatment. Feasibility was demonstrated with 97% completing MELCARE. Utility was demonstrated on a customised survey and supported by a reduction in the mean DT score (initial: 5.6, SD: 2.9; follow-up: 1.5, SD: 1.2). Acceptability was demonstrated on 3/4 AIM items. CONCLUSION: MELCARE was feasible and acceptable with high levels of utility. However, the consent rate was 57% indicating some people do not require support. Future studies should consider MELCARE's optimal timing, resourcing, and cost-effectiveness.

Motor neuron disease: The last 12 months.

BACKGROUND: For patients with motor neuron disease (MND), the final 12 months of life can be a tumultuous period, with rapid and significant losses in function and independence, regular contact with the health system and carer stress. OBJECTIVE: The aim of this article is to provide an outline of the challenges encountered during the last 12 months of life and the role of the specialised multidisciplinary team in managing the challenges that may arise. DISCUSSION: While MND remains rare overall, it is likely that most general practitioners (GPs) will encounter at least one patient with MND during their career. An understanding of the complexity of this group of diseases, including management in the terminal phase, is important given the GP is a valuable member of the multidisciplinary team.

Cannabinoids for Symptom Management in Patients with Kidney Failure: A Narrative Review.

People with kidney failure can experience a range of symptoms that lead to suffering and poor quality of life. Available therapies are limited, and evidence for new treatment options is sparse, often resulting in incomplete relief of symptoms. There is growing interest in the potential for cannabinoids, including cannabidiol and tetrahydrocannabinol, to treat symptoms across a wide range of chronic diseases. As legal prohibitions are withdrawn or minimized in many jurisdictions, patients are increasingly able to access these agents. Cannabinoid receptors, CB1 and CB2, are widely expressed in the body, including within the nervous and immune systems, and exogenous cannabinoids can have anxiolytic, antiemetic, analgesic, and anti-inflammatory effects. Considering their known physiologic actions and successful studies in other patient populations, cannabinoids may be viewed as potential therapies for a variety of common symptoms affecting those with kidney failure, including pruritus, nausea, insomnia, chronic neuropathic pain, anorexia, and restless legs syndrome. In this review, we summarize the pharmacology and pharmacokinetics of cannabinoids, along with what is known about the use of cannabinoids for symptom relief in those with kidney disease, and the evidence available concerning their role in management of common symptoms. Presently, although these agents show varying efficacy with a reasonable safety profile in other patient populations, evidence-based prescribing of cannabinoids for people with symptomatic kidney failure is not possible. Given the symptom burden experienced by individuals with kidney failure, there is an urgent need to understand the tolerability and safety of these agents in this population, which must ultimately be followed by robust, randomized controlled trials to determine if they are effective for symptom relief.

A human rights-based approach to improve access to insulin and other aspects of diabetes care.

Many nations struggle to provide adequate diabetes care. Legal as well as moral obligations may facilitate access. International human rights law places obligations on governments to ensure the accessibility and affordability of insulin (a World Health Organization essential medicine), and other components of diabetes care. Despite this obligation, the global reality is that access remains deficient. A human rights approach facilitating the improvement of diabetes services and equitable access to insulin provides a strong framework, theoretically and practically, for advocacy and policymaking changes. This approach links governments to their international obligations, fosters the ideal of, and adherence to, national essential medicine lists, complements the pursuit of international goals in non-communicable diseases, and should influence the actions of pharmaceutical and device companies. This approach empowers patients, families, and communities living with diabetes, and grounds actions by governments, clinicians, and non-government organisations in the principles of dignity, non-discrimination, and equity of access.

A Novel Clinical Tool for the Management of Taste Changes in Patients With Chronic Kidney Disease: The Chronic Kidney Disease Taste Plate.

Taste alteration is a common, but poorly understood, symptom in end-stage kidney disease. The pathophysiology of taste alteration is complex; to date, management has been largely empirical. As our understanding of pathophysiology grows so does the evidence base for its management. This article introduces a clinical tool-the CKD Taste Plate-to assist clinicians in directing management to the underlying pathophysiology of taste alterations in chronic kidney disease.

Temporal changes and risk factors for death from early withdrawal within 12 months of dialysis initiation-a cohort study.

BACKGROUND: Mortality risk is high soon after dialysis initiation in patients with kidney failure, and dialysis withdrawal is a major cause of early mortality, attributed to psychosocial or medical reasons. The temporal trends and risk factors associated with cause-specific early dialysis withdrawal within 12 months of dialysis initiation remain uncertain. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the temporal trends and risk factors associated with mortality attributed to early psychosocial and medical withdrawals in incident adult dialysis patients in Australia between 2005 and 2018 using adjusted competing risk analyses. RESULTS: Of 32 274 incident dialysis patients, 3390 (11%) experienced death within 12 months post-dialysis initiation. Of these, 1225 (36%) were attributed to dialysis withdrawal, with 484 (14%) psychosocial withdrawals and 741 (22%) medical withdrawals. These patterns remained unchanged over the past two decades. Factors associated with increased risk of death from early psychosocial and medical withdrawals were older age, dialysis via central venous catheter, late referral and the presence of cerebrovascular disease; obesity and Asian ethnicity were associated with decreased risk. Risk factors associated with early psychosocial withdrawals were underweight and higher socioeconomic status. Presence of peripheral vascular disease, chronic lung disease and cancers were associated with early medical withdrawals. CONCLUSIONS: Death from dialysis withdrawal accounted for >30% of early deaths in kidney failure patients initiated on dialysis and remained unchanged over the past two decades. Several shared risk factors were observed between mortality attributed to early psychosocial and medical withdrawals.

Chronic Kidney Disease-Associated Pruritus: A Review.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP), also known as uraemic pruritus, is a disabling symptom for patients and a challenging condition for clinicians. Despite being common amongst end-stage kidney disease (ESKD) patients, it remains underestimated and underdiagnosed. The exact pathogenesis remains largely elusive, which hampers the synthesis of a definite treatment approach. SUMMARY: Chronic pruritus (lasting 6 weeks or more in duration) is a common and potentially disabling symptom in patients with advanced CKD. A unified hypothesis of pathogenesis has not yet been concluded. Studies have shown changes in the immunochemical milieu of the skin in patients with CKD-aP with several inciting stimuli identified. However, other unrecognized factors are likely to be involved. This article will review the current observations and understanding of the postulated pathogenesis of CKD-aP, as well as the evidence for current management strategies. Key Messages: CKD-aP is a common and troubling symptom amongst ESKD patients that is associated with decreased quality of life and poor prognosis. Its exact pathogenesis, at the time of writing, is not well-understood. A stepwise approach is recommended for management. Systematic reviews show the largest body of evidence was found for the effectiveness of gabapentin. Comparison is needed between newly emerging pharmacological agents such as kappa-opioid receptor agonists and more established agents, such as the gabapentinoids. Finally, renal transplantation should be considered in severe and refractory cases who are suitable transplant candidates as it has shown an excellent outcome in most cases.

Moral Distress and Moral Injury in Nephrology During the COVID-19 Pandemic.

Across the world, challenges for clinicians providing health care during the coronavirus disease 2019 (COVID-19) pandemic are highly prevalent and have been widely reported. Perspectives of provider groups have conveyed wide-ranging experiences of adversity, distress, and resilience. In understanding and responding to the emotional and psychological implications of the pandemic for renal clinicians, it is vital to recognize that many experiences also have been ethically challenging. The COVID-19 pandemic has prompted rapid and extensive transformation of health care systems and widely impacted care provision, heightening the risk of barriers to fulfillment of ethical duties. Given this, it is likely that some clinicians also have experienced moral distress, which can occur if an individual is unable to act in accordance with their moral judgment owing to external barriers. This review presents a global perspective of potential experiences of moral distress in kidney care during the COVID-19 pandemic. Using nephrology cases, we discuss why moral distress may be experienced by health professionals when withholding or withdrawing potentially beneficial treatments owing to resource constraints, when providing care that is inconsistent with local prepandemic best practice standards, and when managing dual professional and personal roles with conflicting responsibilities. We argue that in addition to responsive and appropriate health system supports, resources, and education, it is imperative for health care providers to recognize and prevent moral distress to foster the psychological well-being and moral resilience of clinicians during extended periods of crisis within health systems.

End-stage kidney disease: The last 12 months.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent in Australia's ageing population. Over the past decade, there has been growing recognition that dialysis does not benefit every patient with end-stage kidney disease (ESKD). Patients with advanced age, significant comorbidities and poor functional status may not gain a survival benefit with dialysis when compared with being managed conservatively. These developments have implications for general practitioners (GPs). A further development has been the emergence of renal supportive care, a patient-centred approach that integrates the principles of palliative care into nephrology. OBJECTIVE: The aim of this article is to outline salient aspects in the care of patients with ESKD. DISCUSSION: Salient aspects throughout the trajectory of ESKD are discussed, including symptoms of CKD, relevant management, prognostication, advance care planning discussions and end-of-life care. The role of the GP is vital, and it is recommended that GPs are involved early in a patient's CKD trajectory.