Management of Psychiatric Disorders in Patients with Chronic Kidney Diseases.

Abstract

INTRODUCTION Chronic kidney disease (CKD) is a common public health problem involving all ages and significantly affects the body’s overall homeostasis. It involves almost all organ systems and causes significant impairment in the quality of life. CKD is commonly caused by diabetes mellitus, hypertension, tubulointerstitial diseases, glomerulonephritis, polycystic kidney diseases, obstructive uropathy, and congenital malformations of the kidney. In CKD, there is a progressive decline in kidney function. CKD often present with appetite loss, nausea, vomiting, easy fatigability, lethargy, muscle cramps, edema of the extremities, itching, disturbed sleep, increase in blood pressure, dyspnea, chest pain, alteration of urine output. There are five stages of CKD, and a significant number of cases do reach the advanced stage of CKD called end-stage renal disease (ESRD). At this stage, patients need renal replacement therapy (RRT), maintenance dialysis (peritoneal and/or hemodialysis), and/or renal transplantation (RT). As CKD affects the individual’s functioning and produces significant disability, patients go through psychological distress. Evidence support that psychiatric comorbidities are common among patients with CKD.[1] The presence of psychiatric comorbidities in CKD affects the outcome of renal diseases as due to psychiatric comorbidity, these patients’ help-seeking behavior, lifestyle, and medication adherence becomes poor, which attribute to poor outcomes. The psychiatric comorbidities associated with CKD are summarized in Table 1.Table 1: Psychiatric comorbidities associated with chronic kidney diseasePatients with CKD often present with various psychiatric disorders. The psychiatric disorders commonly seen in patients with renal diseases are depression, anxiety disorders, and delirium.[4] Patients with ESRD go through enormous distress due to their compromised health, dependence on others, regular, frequent dialysis, continued cost of treatment, the uncertainty of renal transplant, which increases their vulnerability for mental illness. Metabolic derangements (electrolyte imbalance), anemia, renal bone disease, and hypertension associated with renal diseases also contribute to psychiatric morbidities such as depression and anxiety.[4] Similarly, several medications such as amantadine, aspirin, ciprofloxacin, steroids, phenytoin may contribute to the development of psychiatric manifestations ranging from anxiety, depression, insomnia to psychosis and delirium.[4] The use of these medications (whenever indicated) in patients with CKD and RRT needs absolute caution. Evidence supports that comorbid depression adversely affects the attitude toward medication compliance and compromises sleep quality.[5] Similarly, research suggests that patients with ESRD undergoing peritoneal dialysis and hemodialysis have deficits in cognitive function compared to the general population.[67] The deficits in cognition are evident in the domains of attention, concentration, orientation, and executive functions.[7] Similarly, reduced serum albumin level in patients with dialysis is associated with a decline in delayed memory, visuospatial skills, language ability, and general cognitive function.[6] This paper focuses on the management of psychiatric disorders in CKD with a specific focus on pharmacological management. Prescribing treatments to patients with renal diseases and those with RRT need certain careful considerations [Table 2].Table 2: Considerations while prescribing psychotropic medications in patients with renal diseases and those with renal replacement therapyRENAL PHYSIOLOGY RELEVANT FOR PSYCHIATRY Optimal renal function is required for maintaining homeostasis in the body. Renal function is required for the excretion of waste products from the body. Glomerular filtration rate (GFR) gives an estimation of renal function. GFR can be measured by checking ideal filtration markers, creatinine clearance, and Cystatin C protein.[8] Creatinine clearance test is considered as a marker of renal functioning. In a normally functioning kidney, the creatinine clearance is >60 ml/min; but, there are variations in the normal value of GFR among males and females (males >females), across different age groups and among different races.[910] Due to the cumbersome nature of the measurement of GFR, GFR is now more commonly estimated by using various formulas, which have been validated in many ethnic groups. The two most commonly used formulas for estimated GFR (eGFR) are modification of diet in renal disease and CKD-epidemiology collaboration (CKD-EPI).[1112] The severity of renal disease is broadly classified into five stages based on GFR; stage 1-eGFR ≥90 ml, stage 2-60-89 ml/min, stage 3-30-59 ml/min, stage 4-15-29 ml/min and stage 5-<15 ml/min.[13] In renal diseases, the protein binding ability of the psychotropic medications is decreased. As the unbound (free) forms of medications are responsible for the therapeutic effect and side effects, there is a need for dose adjustment in renal diseases, depending on the decrease in renal function.[9] Renal diseases also cause impairment in the excretion of certain psychotropic drugs and their metabolites that have renal excretion.[8] The formula for estimating the GFR[12] are as follows: The modification of diet in renal disease formula GFR (mL/min/1.73 m2) =175× (Scr)-1.154× (Age)-0.203× (0.742 if female) × (1.212 if African American) The chronic kidney disease-epidemiology collaboration formula GFR = 141× min (Scr/k, 1) a × max (Scr/k, 1)-1.209 × 0.993 age ×1.018 [if female] × 1.159 [if black] where: Scr: Serum creatinine in mg/dL, k: 0.7 (for females); 0.9 (for males) a:-0.329 (for females);-0.411 (for males) Min: Minimum of Scr/k or 1 Max: Maximum of Scr/k or 1 ASSESSMENT OF PSYCHIATRIC DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY Patients with CKD and RRT having psychiatric illnesses need to be assessed thoroughly. A thorough history taking is required in patients with CKD and RRT, who have a psychiatric illness. It is important to explore about the duration of illness, nature of psychopathology, severity of psychopathology, associated psychosocial issues (if any), medical comorbidities including CKD and RRT, drug history, degree of adherence to treatment, any side effects to medications, and response to treatment. Detailed physical examination (general and systemic) and appropriate investigations for medical condition (particularly kidney disease: Renal function test, GFR, urine routine and microscopic examination, serum electrolytes, serum albumin, 24-hour urine protein, and ultrasonogram of abdomen to see kidney size) and psychiatric condition (serum B12, folate, Vitamin D3 level, serum lithium [if the patient is receiving lithium], etc.) need to be done. It is important to take information about the medications prescribed for medical condition, as there is a possibility of drug-drug interaction with psychotropic medications. Figure 1 demonstrates the sequential clinical assessment that is relevant for considering appropriate psychotropic medications.Figure 1: Flow diagram showing assessment of patients with psychiatric illnesses with renal diseasesPSYCHIATRIC DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY Psychiatric disorders are commonly seen in patients with CKD, on dialysis, and renal transplants [Table 3].Table 3: Common psychiatric disorders in patients with chronic kidney disease and renal replacement therapyPrescribing antipsychotic drugs in patients with chronic kidney disease and renal replacement therapy Antipsychotic medications are the mainstay treatment modality for the management of psychosis. Although the kidney excretes few first-generation antipsychotic medications as inactive metabolites, most first-generation antipsychotics are safe in CKD and do not require dose adjustment.[9] Among the first-generation antipsychotic medications, haloperidol is safest. The phenothiazine group of antipsychotic medication increases the risk of hypotension in patients with CKD.[9] Similarly, most second-generation (atypical) antipsychotic medications are also considered safe in renal diseases as most of them are metabolized in the liver.[9] Among the atypical antipsychotics, paliperidone is excreted by the kidney in unchanged form, whereas olanzapine, risperidone, quetiapine, clozapine, and iloperidone are excreted by the kidney as their metabolites.[9] Amisulpride needs to be avoided in ESRD.[8] There is little evidence regarding any risk of worsening renal impairment or toxicity due to the metabolite with the use of aripiprazole in patients with CKD. However, it is recommended to avoid using depot preparations of aripiprazole in ESRD.[8] No evidence suggests dose reduction of asenapine till severe renal impairment; however, the use of asenapine in ESRD is poorly studied, hence better to be avoided in this condition[8] Most antipsychotic medications are safe in mild-to-moderate renal dysfunction. Dose adjustment may be required in severe to ESRD.[9] Caution needs to be exercised while using antipsychotic medications such as chlorpromazine, clozapine, flupentixol, haloperidol, lurasidone, olanzapine, risperidone, quetiapine, paliperidone, ziprasidone, pimozide, trifluoperazine, and zuclopenthixol.[8] In renal impairments, long-acting (depot) preparations of all typical and atypical antipsychotic medications need to be avoided.[8] Some evidence supports that severe mental illnesses (e.g., schizophrenia and bipolar affective disorder) increase CKD risk, and the antipsychotic medications and mood-stabilizing anticonvulsants also increase the chance of renal impairment.[8] Hence, adequate caution needs to be exercised while treating these patients. Prescribing anticholinergic drugs in patients with chronic kidney disease and renal replacement therapy Patients with psychotic illnesses receiving antipsychotic medications often have extrapyramidal side effects. Anticholinergic medications such as trihexyphenidyl and procyclidine are commonly used for the treatment of extrapyramidal side effects. However, using these anticholinergic medications may cause urinary retention and need to be avoided in conditions with obstructive genitourinary conditions.[14] Prescribing antidepressant drugs in patients with chronic kidney disease and renal replacement therapy Patients with renal diseases with depression need to be treated with special precaution. Antidepressant treatment, psychotherapy, and somatic treatments are commonly used in the treatment of depression. Cognitive behavior therapy (CBT) is a commonly practiced and evidence-based psychological treatment for the management of depression. A recent meta-analysis supports the efficacy of CBT in the management of depression in patients with renal diseases on dialysis.[15] Antidepressant medications are often metabolized in the liver and excreted by the kidney.[9] Among the selective serotonin reuptake inhibitors, fluoxetine level remains unchanged irrespective of the severity of renal impairment, whereas paroxetine concentration goes high in patients with severe renal impairment requiring dose adjustment.[9] Citalopram use increases the risk of sudden cardiac arrest when used in patients undergoing hemodialysis. The risk is significantly higher in comparison to other selective serotonin reuptake inhibitors.[8] Among the serotonin-norepinephrine reuptake inhibitors, venlafaxine and desvenlafaxine excretion are affected by renal impairment. In severe renal impairment, the plasma concentration of these medications may increase up to 50%; hence, there is a need for dose reduction.[9] However, duloxetine is safe in mild-to-moderate renal impairment. Severe renal impairment increases the blood level of duloxetine multi-folds requiring dose reduction.[9] Although the safety profile is acceptable for tricyclic antidepressants, monoamine oxidase inhibitors and bupropion in mild to moderate renal diseases, dose reduction, and slow titration is required for severe renal impairment.[9] Approximately three-fourth of the mirtazapine is excreted by kidneys in unchanged form, and renal impairment causes a decrease in the excretion of the drug, increasing plasma concentration.[8] Therefore, dose reduction is required in CKD. Vortioxetine is safe in renal disorders as the existing evidence suggests that it is minimally excreted by the kidney; however, caution needs to be followed during its use in patients with ESRD.[8] Vortioxetine is a new molecule and requires extensive research for safety. Hence, the clinician should exercise adequate caution and need to be watchful for all possible side effects, while recommending vortioxetine in patients with CKD and RRT. Tricyclic antidepressants such as amitriptyline, nortriptyline, imipramine, clomipramine, due to their anticholinergic property, may cause urinary retention, postural hypotension, sedation, and confusion like state.[8] Agomelatine has negligible renal excretion, so believed to be safe in early renal diseases; however, caution needs to be exercised in moderate to severe renal impairments.[8] Likewise, caution needs to be exercised while using dosulepin (Dothiepin) as the majority of the active metabolites of the drug are excreted through the kidney, and renal impairment causes accumulation of the metabolites resulting in excess sedation.[8] Therefore, it has been recommended that patients with GFR <20 ml/min need to be given low doses with slow escalation.[8] Trazodone also needs to be used in low doses to manage depression in patients with CKD.[8] Prescribing mood stabilizers in patients with chronic kidney disease and renal replacement therapy Mood stabilizers are the mainstay of treatment in the management of bipolar affective disorder. Mood stabilizers that are effective in managing manic episodes are lithium, valproate, carbamazepine, and oxcarbazepine, whereas for the management of depressive episodes in bipolar affective disorder, lithium and lamotrigine are found to be useful. There is a need for dose adjustment for lithium in mild-to-moderate renal impairment. Lithium use needs to be avoided, preferably in patients with severe renal diseases and ESRD.[9] Lithium is also known to produce renal disease, primarily tubulointerstitial damage. Therefore, patients receiving lithium treatment need to be regularly monitored for serum lithium levels and renal function tests in regular intervals. Valproate (or Valproic acid) is a commonly used antiepileptic medication, which also has significant mood-stabilizing properties.[16] However, valproate needs to be used cautiously in patients with renal impairment and urea cycle disorders.[1617] Evidence suggests that valproate may cause renal tubular injury and Fanconi’s syndrome.[17] Lamotrigine is another mood stabilizer commonly recommended in the management of bipolar depression. Inactive metabolites of lamotrigine are excreted by the kidney; hence there is no need for dose adjustment.[9] The data regarding the use of lamotrigine in severe renal diseases and ESRD are sparse. Dose titration may be required in such a group of patients and patients on dialysis.[9] Oxcarbazepine is metabolized by glucuronidation. Its subsequent metabolites are excreted through the kidney. Mild to moderate renal impairment does not require dose adjustment for oxcarbazepine; however, for severe renal impairment and ESRD, dose reduction of oxcarbazepine (maybe by 50% of the recommended dose) is required.[9] Prescribing anxiolytic drugs (benzodiazepines and nonbenzodiazepine anxiolytics) in patients with chronic kidney disease and renal replacement therapy Anxiety is a common comorbidity among patients with CKD, patients on dialysis, and following renal transplant. Persistent anxiety that is significantly impairing and lasts beyond a specific time period is considered an anxiety disorder. Various pharmacological and non-pharmacological treatment options are considered in patients with anxiety disorders. Among the pharmacological treatment options, antidepressants, benzodiazepines, beta-blockers, and buspirone are commonly used.[18] The active metabolites of buspirone are excreted by the kidney. In mild-to-moderate renal impairment, it should be started in a low dose with slow escalation; but, it needs to be avoided in severe renal impairment.[8] Among the benzodiazepines, chlordiazepoxide, diazepam, clonazepam, lorazepam, nitrazepam, oxazepam need to be used with caution as their active metabolite may accumulate in renal impairment, causing excessive sedation.[8] Gabapentin and pregabalin are excreted by the kidney in unchanged form; hence, dose reduction is required in renal impairment.[8] Promethazine is an antihistaminic agent with anxiolytic properties. Therefore, it needs to be used with caution as it may produce excessive sedation in renal impairment.[8] Antidepressant medications are commonly used in the management of anxiety disorders. The precautions that needed to be exercised have been discussed in detail under the section on the treatment of mood disorders in renal impairment (above). Prescribing pro-cognitive drugs in patients with chronic kidney disease and renal replacement therapy Neurocognitive disorders like dementia are commonly seen in the elderly population. Alzheimer’s disease is a common neurocognitive disorder in the elderly. Medications with anticholine esterase properties such as donepezil, rivastigmine, and galantamine are commonly used in patients with dementia. Memantine is an antiglutamatergic drug also used in the treatment of dementia. The commonly used antidementia medication, donepezil, is partially excreted by the kidney in unchanged form; however, its clearance is not much affected in renal impairment.[8] Galantamine gets excreted by the kidney, partially. Dose reduction is recommended beyond severe renal impairment.[8] ESRD is a contraindication for the use of galantamine.[8] It has been recommended to start with a low dose and go slow to use memantine and rivastigmine to manage dementia in CKD.[8] Prescribing drugs used in addiction management in patients with chronic kidney disease and renal replacement therapy Patients with CKD may have comorbid substance use disorders. Anti-craving agents like acamprosate, naltrexone, and baclofen are used in the management of alcohol use disorder. Benzodiazepines remain the mainstay of treatment of withdrawal symptoms of alcohol. Disulfiram is used as a deterrent in the management of alcohol use disorder. Similarly, buprenorphine and methadone are commonly used in the management of opioid use disorders. Naltrexone is used as a treatment modality for relapse prevention, being an opioid receptor antagonist. Bupropion is used as an anti-craving agent for tobacco. The precautions regarding the use of bupropion and benzodiazepines have been mentioned earlier in this article. The kidney excretes Acamprosate in an unchanged form. However, CKD may cause impairment of excretion of acamprosate and an increase in its plasma concentration.[19] Therefore, Acamprosate may be used in lower doses for patients with mild to moderate renal impairment and avoided in severe renal impairments and ESRD.[20] For moderate renal impairment, the recommended starting dose of acamprosate is 333 mg, one tablet thrice in a day.[21] Naltrexone has an important role in the management of alcohol use disorder and opioid use disorder. The kidney majorly excretes naltrexone and its primary metabolite. There is a lack of adequate studies on naltrexone in severe renal impairment; however, caution needs to be taken while prescribing naltrexone in severe renal impairment and ESRD.[22] Buprenorphine is primarily metabolized and excreted by the liver. There is no alteration of pharmacokinetics of buprenorphine in patients on hemodialysis. Hence, dose alteration of buprenorphine is not required in patients with CKD, irrespective of their severity.[23] Methadone and its metabolites are excreted by the kidney to some extent. However, the safety of methadone use among patients with renal impairment is not systematically studied. Hence, it is recommended to use methadone cautiously in renal impairment patients. It is advisable to start with a low dose and give methadone with less frequent dosing.[24] The pharmacokinetics of baclofen in CKD is not well studied. It has been suggested for dose reduction of baclofen in renal impairment. Dose reduction is required more as the severity of renal impairment increases.[25] Similarly, dose reduction is also recommended for disulfiram used to manage alcohol use disorder with renal impairment.[26] Prescribing drugs in the management of childhood psychiatric disorders in patients with chronic kidney disease and renal replacement therapy Children and adolescents are also affected by CKD. Many psychiatric disorders such as autism, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder are commonly diagnosed at an early age (childhood and adolescence). The pharmacological management in autism, oppositional defiant disorder, and conduct disorder has a limited role. If pharmacotherapy is recommended for the aggressive and disruptive behavior due to the above condition, mostly mood stabilizers, antipsychotic medications, or antidepressant medications are prescribed. The precaution to these medications in CKD has been mentioned in the above sections. The same strategy of start low and go slow should be followed with regular monitoring for the side effects. Patients with ADHD are often treated with stimulants like methylphenidate, atomoxetine, dextroamphetamine, and modafinil. No data is available regarding the use of dextroamphetamine and modafinil in CKD and patients on dialysis.[27] However, caution must be exercised with close monitoring for side effects when these medications are given in severe renal impairment and ESRD. Though no dose adjustment is suggested for the use of methylphenidate in CKD, adequate caution must be taken while prescribing it to patients on dialysis.[27] The kidney excretes the metabolites of atomoxetine, and cautious use of atomoxetine is recommended in treating ADHD in CKD.[28] Prescribing sedative and hypnotic drugs in patients with chronic kidney disease and renal replacement therapy Sleep disturbances are common among patients with CKD. Conventionally, benzodiazepines, zolpidem, eszopiclone, tricyclic antidepressants, mirtazapine, and melatonin are used to treat insomnia. Adequate precaution needs to be exercised while using benzodiazepines, tricyclic antidepressants, and mirtazapine in patients with CKD, as mentioned above (under antidepressant and anxiolytic section). The kidney minimally excretes eszopiclone and zopiclone; so, no dose adjustment is required. Similarly, though the clearance of zolpidem is moderately reduced for zolpidem, dose reduction is not usually required in patients with renal impairment.[8] Prescribing drugs used in the management of psychosexual disorders in patients with chronic kidney disease and renal replacement therapy Men with CKD may have sexual dysfunctions like premature ejaculation and erectile dysfunction. Selective serotonin reuptake inhibitors are commonly used in the treatment of premature ejaculation. Adequate precautions need to be exercised (as mentioned above under the mood disorder section) while using selective serotonin reuptake inhibitor for premature ejaculation. Phosphodiesterase inhibitors like sildenafil and tadalafil are used in the management of erectile dysfunction. Sildenafil is to be used with caution in patients with renal impairment. Severe renal impairment warrants a dose reduction of sildenafil. A low dose (25 mg) may be considered the starting dose of sildenafil for erectile dysfunction in severe renal impairment.[29] Research evidence is poor concerning tadalafil, though theoretically, it seems to be a safer option than sildenafil.[30] However, a recent trial suggests the safety of low-dose tadalafil in treating erectile dysfunction in ESRD patients undergoing hemodialysis.[31] Hence, caution and dose reduction need to be exercised, while using tadalafil in CKD patients, particularly those with ESRD. Similarly, behavioral and other psychological treatment measures need to be prioritized for patients to address their sexual difficulties, rather than relying more on pharmacotherapy.[32] SPECIFIC CONSIDERATIONS REGARDING THE USE OF PSYCHOTROPIC MEDICATIONS IN RENAL REPLACEMENT THERAPY There is some uniqueness with regards to patients on RRT, which are:[3334] Patients planned for RRT or who had undergone RRT have ESRD Patients who had undergone renal transplant remain on life-long immunosuppressants Patients with renal transplants receive immunosuppressant agents like prednisolone, tacrolimus, azathioprine, cyclosporine, mycophenolate, and rapamycin.[3334] Patients receiving immunosuppressants need to avoid monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. In addition, selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors need to be used with caution as drugs like fluoxetine, paroxetine, and fluvoxamine inhibit the CYP 3A4 enzyme in the liver and increase the plasma level of calcineurin inhibitors like tacrolimus and cyclosporine.[35] Antidepressants relatively safe to use in RT patients are escitalopram, sertraline, citalopram, venlafaxine, mirtazapine, and bupropion.[35] Valproate and carbamazepine are the CYP 3A4 enzyme inducers. The use of these medications decreases the concentration of sirolimus and everolimus, which can increase the risk of graft rejection.[36] Other drugs such as modafinil, armodafinil, phenobarbital, topiramate, and clobazam were also found to induce CYP 3A4 and therefore, reduce the activity of calcineurin inhibitors.[37] The use of mycophenolate along with antipsychotic medication clozapine increases the risk of blood dyscrasia.[37] Summary of the safety of common psychotropic medications in CKD is discussed in Table 4.Table 4: Summary of safety of common psychotropic medications in chronic kidney diseaseLOWER URINARY TRACT DISEASES AND USE OF PSYCHOTROPIC MEDICATIONS Lower urinary tract diseases include diseases of the bladder and beyond. Of these, benign prostatic hyperplasia (BPH) is a common age-related pathology of the prostate in males. BPH obstructs the bladder outflow by compressing the urethra. Psychotropic medications such as antipsychotics (e.g., chlorpromazine, quetiapine), antidepressants (e.g., tricyclic antidepressants, milnacipran, fluoxetine, citalopram), anticholinergic agents (e.g., trihexyphenidyl, procyclidine, promethazine), and anticonvulsants have the potential to cause urinary retention.[38] The safer psychotropic medications to be used in BPH are: Antipsychotics: Haloperidol, amisulpride, olanzapine, aripiprazole Antidepressants: Bupropion, sertraline, agomelatine, desvenlafaxine Mood stabilizer: Lithium, valproate, carbamazepine, lamotrigine. PRINCIPLES OF PSYCHOTROPIC DRUG MODIFICATION DURING CHRONIC KIDNEY DISEASE AND RENAL REPLACEMENT THERAPY Certain general recommendations have been prescribed while using psychotropic medications in patients with renal diseases and RT. Table 5 summarizes the recommendations.[8]Table 5: General recommendations for psychotropic use in chronic kidney diseaseIn addition to these general recommendations, patients on dialysis may need supplementation of drugs after dialysis for drugs which are dialysable. This area is out of the scope of this review. However, treating doctors should consult recommendations for specific drugs for a type of dialysis; hemodialysis, peritoneal dialysis, or continuous RRT and supplement drugs if required. Figure 2 summarizes the safety profile of various psychotropic medications in various stages of CKD.Figure 2: Safety profile of common psychotropic medications in various stages of chronic kidney diseaseCONCLUSION A collaborative work between the nephrologist and psychiatrist is required to better the patients of renal diseases with mental health issues. The use of non-pharmacological measures like psychotherapy (CBT, behavior therapy, relaxation techniques) and somatic treatments like electroconvulsive therapy, transcranial magnetic stimulation, and transcranial direct current stimulation may be helpful in patients with chronic renal diseases and those with RRT. Similarly, the clinician needs to consider the potential interactions of the psychotropic medications with the immunosuppressants used in patients with renal transplants. The selection of appropriate psychotropic agent in appropriate doses in patients with CKD and RRT will minimize the harm and maximize the benefit. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.