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The need for kidney supportive care in all active treatments for people with advanced chronic kidney disease
Globally, incident kidney failure (KF) patients (defined as estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2) are becoming older and are presenting with complex comorbidities and substantial physical and cognitive dysfunction.1 Mortality rates remain high without the progress in preventing mortality that has been seen from other non-communicable diseases such as cardiovascular disease, chronic obstructive pulmonary disease, and cancer.1 Symptom burden for people with advanced chronic kidney disease (CKD) is also very high across age, sex, race, and geographic location. By the time a person reaches KF and requires kidney replacement therapy (KRT), they will have on average 6-20 symptoms.2-5 The five most prevalent symptoms across advanced CKD stages and KF tend to be fatigue or lack of energy 81% (49–100%), feeling drowsy 75% (49–82%), pain 65% (38–90%), pruritus 61%, (33–84%) and decreased appetite 57% (9-83%).4 These symptoms are often multifactorial in etiology, caused by complications of CKD, side effects of medications used to treat these complications, comorbidity, and effects of aging. They increase in prevalence and severity as kidney function declines.

Syndromes such as malnutrition, protein energy wasting, and frailty are also common, leading to muscle and fat loss and cachexia.6 These factors exacerbate symptom burden and together with navigating challenging and shifting family dynamics, end-of-life issues, and a burdensome treatment such as dialysis, they profoundly compromise patients functional capacity and health-related quality of life (HRQOL).7 Symptom burden has been shown to account for up to 46% of dialysis patients’ reduction in HRQOL.2,3 While dialysis may address some uremic symptoms, especially for more robust individuals with limited comorbidity, it appears to do little to address symptoms in older more frail patients or those with multimorbidity. In this subset of patients, dialysis does not necessarily improve HRQOL.8-12 Rather, for some, dialysis may add to overall symptom burden while chronic inflammation, malnutrition, and frailty continue to progress regardless of whether dialysis is started or not. The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study investigated HRQOL and symptoms at initiation of dialysis and 1 year later.13 At 1 year, 20%-31% of patients had worsening, 42%-60% had no changes, and 19%-28% had improvement in the eight HRQOL domains of the SF- 36.

Similarly, 19%-30% had worsening, 50%-65% had no changes, and 16%-24% had improvement in the dialysis-specific symptom domains of assessment after 1 year of dialysis. 101 of 928 (10.9%) of patients had died. Only 24% of patients reported an improvement in energy one year after starting dialysis while 27% reported worsening. The incidence of pruritus is 19% across all pre-dialysis stages of CKD9 but is reported in up to 84% of people on hemodialysis.10 Problems with sleep also become more common and severe compared with pre-dialysis; only 19% reported an improvement of sleep symptoms while 24% reported a worsening after 1 year of dialysis.1 Dialysis had no positive impact on pain and sexual dysfunction became more prevalent.13 The patients that tend to do the best are those with limited comorbidity; they tend to have low symptom burden until shortly before needing dialysis and experience the more typical uremic symptoms of anorexia, nausea, vomiting, fatigue, and these can quickly improve after starting dialysis. However, at a population level, starting dialysis does not result in an improvement in overall symptom burden or HRQOL. Dialysis withdrawal due to poor HRQOL remains one of the leading causes of death in patients with KF in high‐ income countries (HICs), where dialysis is readily available.14 In these high resource settings, older patients are much more likely to withdraw from dialysis compared to younger patients.

Given the high mortality rate and symptom burden associated with advanced CKD and KF, kidney supportive care (KSC) is recognized as a core component of integrated kidney care. Kidney supportive care is an approach that aims to improve the HRQOL for people for whom kidney disease, either directly or indirectly, substantially impacts their wellbeing, treatment options, or access to care, and that of their families, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual. This definition has its roots in the World health Organizations (WHOs) definition for palliative care and it should be available for all people with advanced CKD according to need, both those receiving KRT (dialysis or kidney transplantation) and those not receiving it. Kidney supportive care should not be reserved solely for people who have withdrawn from dialysis or who are actively dying. It prioritizes the components of care most important to the individual patient and therefore must integrate culturally sensitive shared decision-making and ensure that it guides clinical decisions, even when treatment options are limited. Kidney supportive care involves skilled communication and meticulous and timely attention to symptom management, crisis planning, advance care planning, integration of community services, terminal/end-of-life care, and bereavement. Many countries are placing increased emphasis on the provision of KSC by nephrologists, generalists, and community providers as a component of usual care.

Conservative kidney management
Over the last two decades, the international nephrology community has increasingly recognized that the burden of KRT, whether that be dialysis or transplantation, will outweigh the benefits for some patients in whom KRT offers neither a survival nor a HRQOL advantage. These patients may live longer and/or better lives if cared for without KRT. International recommendations state clearly that KRT should not be the default. Where available, receiving KRT is a choice that requires the careful balance of risks and benefits, recognizing that the balance is preference sensitive and will likely involve both HRQOL and survival considerations. If a patient is unlikely to benefit from KRT, a positive alternative in the form of conservative kidney management (CKM) should be provided. Conservative kidney management is defined as care for people with KF that focuses predominantly on providing KSC to promote HRQOL but does not include KRT. Conservative kidney management is an active treatment that comes with its own set of recommendations and guidelines. It focuses on KSC, but also involves management of CKD progression and complications of CKD in so far as doing so aligns with the individuals priorities. Conservative kidney management should not be confused with pre- dialysis care where the choice for dialysis has been made but has yet to be started. Nor should CKM be bundled with withdrawal of dialysis, in which maintenance dialysis is stopped; these patients typically have only days to weeks to live and therefore require terminal/end-of-life care. Conservative kidney management should also not be defined solely by no KRT as these patients require active treatment that is highly individualized, often for many months or years.

The evidence for CKM and who will most benefit from it
Although there have been no randomized controlled trials in this area, there have been several systematic reviews of cohort studies. A systematic review and meta-analysis of 89 cohort studies published between 1976 and 2014 reported survival on 294 921 elderly patients with KF treated with either CKM or dialysis. Patients receiving CKM were older (79.2 v. 77.4 years).15 Although there was considerable heterogeneity amongst studies, the combined 1-yr survival rate was similar between those who were dialyzed and those receiving CKM at 73.0% (95% confidence interval (CI) 66.3-79.7%) v. 70.6% (95% CI 63.3- 78.0%). Subgroup analyses based on age less than or greater than 80 years, study design, cohort era, or study size made no impact on the main findings. Out of all these studies, only six directly compared survival between dialysis and CKM. All six of these comparative studies showed a small survival advantage with dialysis. Only four of these studies explored factors which predicted survival, three of which demonstrated loss of any survival advantage with high comorbidity (especially ischemic heart disease), deceased functional ability with activities of daily living, or age over 80 years. Of note, there was a difference in the 2-year survival; 62% for dialysis v. 44% for CKM. Limitations included lead- time bias for CKM and a paucity of data as only 724 patients (0.2% of the total patient population) were receiving CKM, most of which were from the United Kingdom.

Subsequently, a retrospective survival analysis of a single-center cohort in The Netherlands from 2004 to 2014 compared the survival of patients > 70 years at the time they made the decision for either dialysis (n = 204) or CKM (n = 107).16 Results were similar in that there was a survival advantage with dialysis which was no longer observed in patients over 80 years or in patients over 70 years with severe comorbidity. Also consistent was that many people receiving CKM survived several years on a CKM pathway. These cohort studies have also shown that patients receiving CKM spend less time in hospital and die there less often than people receiving dialysis.

A more recent systematic review included 41 cohort studies that documented HRQOL and/or the use of healthcare resources among 5102 patients who made the decision for CKM. Of the eight studies that described HRQOL, mental well- being improved over time, and physical well-being, symptoms, and overall HRQOL were stable until near the end of life. In places that had dedicated CKM and palliative care resources, symptom burden improved. Unfortunately, what is often missing is a coordinated approach and infrastructure to adequately provide CKM, and specifically a lack of coordinated crisis management. This resulted in common use of acute care services including emergency room visits and hospital admissions with a substantial disparity in access to KSC even near the end of life.17 

Choice-restricted CKM
The rise in CKD is of particular concern in many low- (LICs) and low to middle-income countries (LMICs), particularly in Africa, where there is either restricted or no option for KRT.18,19 These countries are experiencing an increasing burden of non- communicable diseases, particularly hypertension, heart failure, and diabetes mellitus, all of which are major contributors to KF. 20,21 The evolving epidemic of communicable diseases, particularly human immunodeficiency virus, malaria, tuberculosis, and an explosion of illicit drug use are also contributing to the increased incidence of KF. These factors, compounded by poor access to preventative care, are resulting in people reaching KF with multiple comorbidities and complex psycho-social needs at a much younger age than typically seen in HICs. For example, in Uganda only 4% of the dialysis population is older than 60 years.22 Priority setting is an essential component of providing healthcare in these low resource regions as kidney care programs work to balance the fundamental human right to health with scare resources due to the expensive nature of KRT.23,24,25 As a result, physicians and patients in LICs and LMICs face challenges that are significantly different from those experienced by their counterparts in well-resourced countries.26 Ethically endorsed, transparent criteria to allocate KRT in low resource settings typically use the accountability for reasonableness approach and the overarching ethical principle of utilitarianism.27

The development of these guidelines involve wide consultation with relevant stakeholders in an iterative process and has withstood the scrutiny of the Human Rights Commission.28 However, this is not without cost to both patients and decision-makers. As an example, in South Africa the overriding criteria to access KRT for those with irreversible KF is transplantability. Patients need to be assessed as medically and socially able to undergo transplantation before being accepted for dialysis. Dialysis is therefore seen as a bridge to transplantation. In government facilities, dialysis slots are always full, and a new patient can only be accommodated once an existing patient is transplanted or dies. The reality is that many are not accepted into KRT programmes and those that are accepted may die while waiting for an available space. In a retrospective study at Groote Schuur Hospital in South Africa, 54% of 564 patients with KF presenting between 2008- 2012 were deemed not eligible for KRT. Predictors of non-acceptance included age above 50 years (OR 0.3, p = 0.001), unemployment (OR 0.3,p<0.001), substance abuse (OR 0.2, p<0.001), diabetes (OR 0.4, p = 0.016), and a poor psychosocial assessment (OR 0.13, p<0.001).29

For patients who are unable to access KRT, the only active treatment option is CKM; when CKM is accessed due to a lack of KRT rather than choice it is referred to as choice restricted CKM. In an international cross-sectional survey to determine the global capacity to deliver KRT and CKM conducted by the International Society of nephrology (ISN), CKM was reported as available in 124 (81%) of the 154 surveyed countries.30 However, in 43% (66/154), CKM was associated with a choice- restricted- approach due to lack of resources. Furthermore, in low resource settings there is also limited palliative care capacity. In 2019, only 50% of countries reported having palliative care within their national noncommunicable diseases policy that was operational31; this leaves many people with KF untreated and unjustifiably suffering.32

The delivery of CKM
The intent of all medical interventions in people receiving CKM is to optimize HRQOL, and individualization is essential. The illness trajectory of people receiving CKM is highly variable; many with an eGFR of 10 – 15 ml/min per 1.73 m2 or even lower may remain functional and stable for years, although some may deteriorate over a few months. Treatment therefore needs to consider the patient’s general condition and prognosis. Earlier in the illness trajectory, maximizing HRQOL likely requires a careful balance between preserving kidney function, optimizing functional status, and reducing symptom burden while in the last weeks to months of life, control of symptoms and overall comfort generally take precedence.

Management of the metabolic complications of kidney failure in CKM
The approach to managing the complications of KF in people receiving CKM represents a shift from disease-focused treatment, which often takes years to accrue benefits such as with statin therapy, to shorter-term symptom- and patient-specific goal-focused interventions. Medications are therefore used primarily with the intention of improving symptoms and protecting kidney function. The recommendations for managing the complications of KF are summarized in Table 1. The full recommendations are available elsewhere.33,34 Many of these interventions involve dietary restrictions. For patients with significant anorexia and poor oral intake, it is reasonable to remove all dietary restrictions. It is crucial to adapt these recommendations to the specific local context and the resources available, especially in LICs and LMICs. For example, the use of erythropoiesis stimulating agents and intravenous or oral iron may not be available therefore limiting the need for regular monitoring of haemoglobin and iron studies. It may be feasible to administer a blood transfusion in some settings if the anaemia is very symptomatic and fluid overload is not an issue. As electrolyte monitoring may also be restricted, dietary advice should emphasize low potassium diets. These diets need to take into consideration local food availability and affordability. Educational materials in local languages can assist with the implementation of regional dietary advice. Blood monitoring should be directly in line with management plans. If no alterations in management are to be performed, then monitoring should cease.

Table 1. Summary of CKD Management Recommendations for People receiving CKM33,34

Abbreviations: CKM, conservative kidney management; HRQOL, health-related quality of life; RLS, restless legs syndrome. *Individualization is essential.

Symptom management in CKM
The aim of symptom management is to ameliorate symptoms that cause significant distress. Its typically not necessary nor possible to resolve symptoms completely. Its important to acknowledge this and negotiate with the patient and often the family an acceptable level of symptom control. Symptom management should ideally follow a stepped approach that first involves ruling out contributing factors, then maximizing the use of non-pharmacological interventions to avoid unnecessary polypharmacy and the adverse effects associated with many medications. Pharmacological interventions should only be considered if symptoms continue to adversely impact the patients HRQOL. For people with KF most medications should be started at a low dose and titrated slowly to effect while monitoring for adverse effects. Patients require ongoing reassessment for the impact of the treatment on the outcomes that are most important to them. The recommendations for managing symptoms in people receiving CKM are summarized in Table 2. The full recommendations are available elsewhere.33,34

The management of pain for people with KF can be particularly challenging as most analgesics, including opioids and their active metabolites, are cleared by the kidneys. Ideally, analgesics should only be used in conjunction with non-pharmacologic therapies such as physical and behavioral therapies that address the psychosocial aspects of chronic pain. There is a very high prevalence of illicit drug use in people receiving CKM in LICs and LMICs. Healthcare workers often fear the divergence of prescribed medication and family support is complicated by previous drug addiction behaviour such as theft, abuse, or homelessness. These patients and their families require specific psycho-social support, which includes the realization that CKM is a palliative pathway, forgiveness of previous abuse, and sometimes containing ongoing addiction. An adapted WHO analgesic ladder has been advocated for the management of acute and chronic pain in patients with KF and in those receiving CKM.44-47 It involves the slow introduction and upward titration of analgesics, starting with non-opioids then progressing to opioids as required for pain relief. Table 2 outlines the recommended analgesics in CKM.46 There is no evidence that weak opioids such as codeine or tramadol are less risky than strong opioids at their lowest effective dose.48

Given the risks of using weak opioids such as codeine and tramadol in patients with KF, strong opioids at a low dose with careful titration when opioid therapy is required is recommended.46 For patients with a neuropathic component to their pain, the first step is to introduce an adjuvant. Many pains experienced by people with KF will be of mixed type e.g., pain associated with ischemia. It is important to target the neuropathic component first with an adjuvant to prevent inappropriate opioid use. Symptom management is complicated in low resource settings due to limited access to essential medications, healthcare facilities, and kidney care or palliative care personnel. For example, 83% of the world’s countries have low to non-existent access to opioids49 and access to even the simplest pain-relieving medication is often limited.50 Low-income countries and LMICs have the greatest need for CKM and palliative care in general yet these regions account for only 7% of global opioid use.51,52 Access to medication, particularly opioids, in LICs and LMICs is heavily influenced by national formularies, which are often highly restrictive, leading to overregulation in the prescribing of these medications.50 This issue becomes even more complex for people with KF who are limited in what they can safely use.

There are tremendous differences between the international pharmacological recommendations in KF and CKM and essential medications lists. The WHO lists acetaminophen, codeine, morphine, transdermal fentanyl, and amitriptyline as essential medications; methadone is on the complementary list but only for the management of cancer pain.53 This list is not fully aligned with the recommended analgesics for people with KF. Only codeine and morphine are typically on formulary across Africa and India with morphine being the preferred opioid for the management of moderate or severe pain. 50-52,54 However, the accumulation of morphine metabolites in KF poses a genuine concern. Despite this, it is important to recognize that leaving a patient in severe pain at the end of life is ethically unacceptable. The reality is that morphine will need to be used for people receiving CKM in low resource settings. In such cases, morphine should be initiated cautiously, starting with small doses of 1.25mg to 2.5mg twice daily and then titrated slowly with close monitoring for adverse effects. There is also a need to continue to advocate for other medications required for the safe and equitable care of people with KF. 

Table 2. Symptom Management For People Receiving CKM33,34

Additional considerations for delivering CKM in low resource settings
Delivering CKM in low resource settings requires a comprehensive approach that considers resource optimization. This includes the importance of screening for early detection, risk factor modification, and preservation of residual kidney function in high-risk individuals to reduce the burden of KF and the need for CKM. Most CKM is overseen in the community by primary care and provide by family members. Engagement with community leaders to strengthen primary care clinics and home-based care nursing is essential. A multidisciplinary approach is needed to optimize CKM delivery and prevent abandonment while acknowledging the unique cultural, religious, and system barriers.56 This can be very challenging in regions where there is a lack of physicians and allied healthcare professionals and most have little or no knowledge of the principles and practices of palliative care, which is the underpinning for KSC and CKM. Addressing this training gap for those delivering care is a matter of high importance. These care teams need to deal with not only those who have embarked on CKM (typically choice- restricted) but also those on the waiting list for dialysis, many of whom will die before treatment becomes available. Given the pivotal role of family in delivering CKM, they need to be involved in all management decisions and educational efforts, even when options for care are limited. This includes helping patients and families understand the disease trajectory and the importance of non- pharmacological interventions. Table 3 expands on these discussion points. While they are important for all people receiving CKM, they take on increased relevance in low resource settings. 

Table 3. Discussion points around non-pharmacological management of CKM in low resource settings

Abbreviations: CKD, chronic kidney disease; KF, kidney failure; CKM, conservative kidney management; KRT, kidney replacement therapy 
Conclusion
Kidney supportive care and CKM are essential treatments for KF but are poorly developed and/or poorly integrated with kidney care across LICs, LMIC, and HICs. For people with KF who are unlikely to derive a survival or HRQOL from KRT, a positive alternative in the form of CKM should be provided. Conservative kidney management is highly individualized active treatment that comes with its own set of recommendations that focus predominantly on providing KSC. In low resource settings, providing choice-restricted CKM should not excuse government bodies from investing in adequate kidney services, including KRT programs, exploring innovative thinking such as public-private partnerships.

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