New Insight Concerning Therapeutic Drug Monitoring—The Importance of the Concept of Psychonephrology—

Abstract

Recently, the concept of psychonephrology was developed and has been recognized as a field of study that focuses on nephrology and mental health fields, such as psychiatry and psychosomatic medicine. Indeed, patients with chronic kidney disease frequently suffer from mental problems as the disease stage progresses. Most psychotropic drugs are hepatically metabolized, but some are unmetabolized and eliminated renally. However, renal disease may affect the pharmacokinetics of many psychotropic drugs, as the decreased renal function not only delays the urinary excretion of the drug and its metabolites but also alters various pharmacokinetic factors, such as protein-binding, enterohepatic circulation, and activity of drug-metabolizing enzymes. Therefore, when prescribing drug therapy for patients with both renal disease and mental issues, we should consider reducing the dosage of psychotropic drugs that are eliminated mainly via the kidney and also carefully monitor the blood drug concentrations of other drugs with a high extrarenal clearance, such as those that are largely metabolized in the liver. Furthermore, we should carefully consider the dialyzability of each psychotropic drug, as the dialyzability impacts the drug clearance in patients with end-stage renal failure undergoing dialysis. Therapeutic drug monitoring (TDM) may be a useful tool for adjusting the dosage of psychotropic drugs appropriately in patients with renal disease. We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis and offer new insight concerning TDM in the field of psychonephrology.

1. INTRODUCTION

In recent years, the effect of the renal function on pharmacokinetics has received much attention from both perspectives of clinical and basic. The kidney plays an important role in drug excretion, so a decrease in the renal function may lead to increased drug exposure in the body.

Drug excretion via the kidney is mediated by three processes: (1) glomerular filtration (simple filter system), (2) tubular secretion (“active” transport of drugs into the urine by transporters), and (3) tubular reabsorption (mainly “passive” transport of drugs into the blood vessels).¹⁾ Most psychotropic drugs, i.e., drugs targeting the central nervous system (CNS), are highly lipid-soluble and thus metabolized in the liver.²⁾ However, several drugs, including the antiepileptic drug gabapentin, which is highly water-soluble, are mainly excreted from the kidney as an unchanged form, regardless of the fact that the drugs are distributed to the CNS.²⁾ Therefore, when considering prescribing psychotropic drugs to psychiatric patients with renal dysfunction or renal failure, monitoring the blood drug concentrations may provide useful information for determining the appropriate dosage.

The administration of renally excreted drugs in patients with renal diseases can give rise to delayed urinary excretion, thus resulting in an increased blood concentration of the drug.¹⁾ Patients suffering from renal disease are thus more likely to develop poisoning by the administration of renally excreted drugs than others. Typical examples of adverse effects that are likely to occur in patients with renal failure (or dialysis) include neuropsychiatric symptoms caused by the anti-Parkinson’s agent amantadine, the antiviral agents acyclovir and valacyclovir, and the H₂ blocker famotidine; hearing impairment caused by aminoglycosides; and anorexia and arrhythmia caused by the cardiac glycoside digoxin. Therefore, the dosage and usage of drugs should be evaluated in patients with renal failure from the viewpoint of pharmacokinetics.

For renally excreted drugs in particular, the dosage adjustment is usually based on the patient’s glomerular filtration rate.³⁾ However, renal disease alters a number of factors related to pharmacokinetics, such as the protein-binding, enterohepatic circulation, and activity of transporters and drug-metabolizing enzymes; we should therefore also note that some drugs do not follow the dose adjustment based on the patient’s kidney function only.

Nephrotoxicity caused by psychotropic drugs has also recently been reported.^4,5) Such drug-induced kidney injury is classified by the site of injury into glomerular, tubular/interstitial, and vascular injuries.^6,7) Based on the pathogenic mechanism, injuries are further classified into (1) direct renal impairment, (2) allergic mechanism, (3) indirect toxicity via electrolyte abnormalities and decreased renal blood flow, and (4) urinary tract obstructive renal injury. Most drug-induced kidney injuries are associated with tubular and interstitial disorders, and many involve allergic mechanisms. However, these drug-induced kidney injuries in some cases are likely to be preventable to some extent if the drug pharmacokinetics are understood.

We herein review the pharmacokinetic considerations for psychotropic drugs in patients with renal disease as well as those undergoing dialysis. Based on this information, we provide new insight and highlight the importance of therapeutic drug monitoring (TDM) in the field of psychonephrology (Fig. 1).

Fig. 1. Schematic Concept of the Importance of Therapeutic Drug Monitoring in Psychonephrology

2. OUTLINE OF PSYCHONEPHROLOGY

Psychonephrology is a field of study that focuses on nephrology and mental health fields such as psychiatry and psychosomatic medicine.^8,9) Chronic kidney disease (CKD) is a serious health problem affecting approximately 10–15% of the world’s population. It is a life-threatening disease and requires life-long treatment.^10,11) As the stage of CKD progression, patients further suffer from anxiety and stress, as the remarkable physical symptoms related to the CKD progression may alter and reduce their QOL and limit their lifestyle.^12,13) Specifically, patients with end-stage renal disease (ESRD) need renal replacement therapy, which limits their participation in occupational activities and social roles and forces them to receive rigorous diet therapy.¹²⁾ To address these issues, the concept of psychonephrology, which comprises psychosomatic medicine, psychiatry, psychology, and nursing, in patients with renal disease was established recently.^11,14)

2.1. Psychiatric Symptoms in Patients with CKD or ESRD

Psychonephrology was started in 1978 when Levy and two other liaison psychiatrists started a study group in the field of liaison and consultation psychiatry¹⁵⁾; a similar study group was also established in Japan in 1990.¹⁶⁾ Many studies have pointed out that the prevalence of anxiety disorders and depression in CKD patients is higher than that in the general population, and these psychiatric disorders potentially worsen the renal function in patients with CKD or ESRD, suggesting the importance of psychological care for CKD patients.¹⁷⁾ Indeed, CKD patients frequently experience psychiatric symptoms, such as cognitive impairment and depression.¹⁸⁾ Overall, the prevalence of anxiety disorders and elevated anxiety symptoms among CKD patients is high, at 19 and 43% respectively.¹⁸⁾ The prevalence of anxiety symptoms in hemodialysis or peritoneal dialysis patients has also been shown to be twice that in healthy individuals.¹⁹⁾ High levels of anxiety symptoms in CKD patients with pre-dialysis phase were shown to increase the risk for death/dialysis events by 60% compared to those without such symptoms.²⁰⁾ Only 6 studies have explored anxiety prevalence in ESRD, and the range of the prevalence was 12 to 52%,^21–26) whereas the lifetime risk of depression has been estimated to be 5–10% in the general population.^27,28) Surprisingly, the prevalence of depression in patients with CKD or ESRD is reported to range from 21 to 37%, which is 3 to 4 times higher than in the general adult population and 2 to 3 times higher than in patients with other chronic diseases.^29–33)

2.2. Aggravation of the Renal Function or a Poor Prognosis by Psychiatric Symptoms

Depression has adverse effects on patient behavior and may negatively impact clinical outcomes. One prospective observational study assessed the impact of depressive symptoms on the kidney prognosis.²⁸⁾ Follow-up for approximately two years indicated that depressive symptoms were associated with progression of CKD to ESRD or death.²⁸⁾ Therefore, depressive symptoms in CKD patients may accelerate the progression to ESRD, initiation of dialysis, death, and hospitalization. Another study showed that depression in CKD patients increased the risk for hospitalization and dialysis events by two- and three-fold, respectively, compared to patients without such symptoms.²⁹⁾

Non-adherence to self-care behaviors ultimately leads to adverse health outcomes, as depressive symptoms are a significant independent predictor of poor medication adherence, and worsening depressive symptoms correlate with worse adherence to total dialysis time.^34,35) In both the general population and chronically ill patients, treatment with antidepressants or psychotherapy significantly improves depressive symptoms and psychosocial outcomes, and the combination therapy of the two is more effective than either alone^36–39) Therefore, it is important to use psychotropic drugs to control anxiety and depressive symptoms in CKD or ESRD patients with comorbid psychiatric disorders.

2.3. Psychiatric Disorder- or Psychotropic Drug-Induced Renal Dysfunction

A cohort study reported that schizophrenia itself, independent of the use of typical and atypical antipsychotics, increased the risk of CKD by 25% over a 3-year follow-up period.⁴⁰⁾ Patients with schizophrenia have higher rates of an unhealthy diet, smoking habits, physical inactivity, socioeconomic disadvantages, and metabolic syndrome than those without it,⁴¹⁾ which may contribute to the high incidence of CKD.⁴⁰⁾ In addition, nephrotoxicity caused by psychotropic drugs has also been reported. A recent report suggested that second-generation antipsychotics increased the risk of developing CKD in a cumulative dose-dependent manner.^42,43) Furthermore, lithium carbonate, a drug for bipolar disorder, has been suggested to induce tubular and glomerular damage,^44,45) and its long-term use has been reported to cause CKD.

3. CHANGES IN PHARMACOKINETICS DUE TO DECREASED RENAL EXCRETION

3.1. The Accumulation of Renally Excreted Drugs

Renally excreted drugs (e.g. drugs less susceptible to metabolism) are prone to induce toxic side effects due to their accumulation in the body following a decrease in the renal function. Most package inserts for drugs show the urinary excretion rate based on the total value for both metabolites and the unchanged form. Therefore, it is important to consider the urinary excretion rate of the “unchanged form” when planning the administration of drugs for renal disease patients.

3.2. The Accumulation of Active Metabolites

An active metabolite, which is a metabolite produced by the metabolism of a drug, possesses a similar pharmacological effect or toxicity to the parent compound. In some cases, there are various changes in the activity of the metabolite compared with the parent (e.g. some have stronger or weaker pharmacological effects than the parent compound). In renal disease patients, including dialysis patients, active metabolites accumulate and cause unexpected side effects.^46,47) For example, morphine⁴⁸⁾ and midazolam⁴⁹⁾ cause prolonged somnolence due to the accumulation of active glucuronide conjugates by metabolism in vivo. Therefore, in dialysis patients, we should avoid the use of these drugs.⁵⁰⁾ Regarding drugs for psychiatric disorders, paliperidone (9-hydroxyrisperidone), the active metabolite of the antipsychotic drug risperidone, has a 59% urinary excretion rate in its unchanged form, resulting in an increased maximum blood concentration (C_max) and area under the plasma concentration versus time curve (AUC) in patients with severe renal impairment compared with those with mild or moderate renal impairment (from the interview form for INVEGA^® tablets). Therefore, in psychiatric pharmacotherapy, even in the case of drugs with hepatic metabolism, we should pay close attention to the development of adverse effects depending on the urinary excretion rate of the active metabolite.

3.3. The Accumulation of Conjugated Drug Due to Intestinal Circulation

The enterohepatic circulation is a cycle in which drugs and endogenous substances are secreted into the duodenum through the bile ducts with bile, reabsorbed from the intestinal tract, and returned to the liver through the portal vein. Conjugates are highly polar and easily excreted in the urine as well as in the intestinal tract under conditions of a normal renal function. However, in end-stage renal failure, these conjugates that accumulate in the body are actively excreted in bile by excretory transporters in the bile duct.^51,52) Furthermore, in the process of moving from the duodenum to the small intestine and colon, these conjugates are assumed to become active substances (parent compound) again by the action of β-glucuronidase or deconjugating enzymes in the intestine. Among psychotropic drugs, zonisamide, an antiepileptic and antiparkinsonian drug, is excreted into the bile after glucuronidation in liver⁵³⁾ and is assumed to be reabsorbed by enterohepatic circulation (based on the information from Excegran^®, Torelief^® Tablets Interview Form). Therefore, the accumulation of zonisamide should be monitored in patients with ESRD.

4. CHANGES IN PHARMACOKINETICS OTHER THAN EXCRETION CAPACITY ASSOCIATED WITH RENAL FAILURE

4.1. Change in the Protein Binding Rate

In renal failure, the protein-binding of acidic drugs tends to decrease.⁵⁴⁾ Possible causes of this decrease are (1) hypoalbuminemia, (2) competition for the binding of drugs to albumin by uremic toxins, and (3) structural changes in albumin that prevent the binding of drugs properly. However, a decrease in protein-binding in patients with renal failure is unlikely to enhance drug efficacy. The reason for this is that the increasing distribution of drugs to tissues or decreasing total drug concentration in the blood, both of which are caused by decreases in protein-binding, have little effect on the unbound drug concentration in plasma.^55,56) In the steady state, the total drug concentration in the blood decreases, but the concentration of the free form remains unchanged. This is because the free form, which increases with decreasing protein-binding rate, is quickly metabolized. Therefore, the measurement of the total drug concentration in patients with decreased protein-binding is an important clinical issue. For instance, phenytoin and valproic acid have high binding to serum albumin.⁵⁷⁾ In patients with hypoalbuminemia, e.g., those with renal failure, there is a possibility that a large amount of unbound phenytoin or valproic acid might be distributed to the tissues and cause symptoms of poisoning if the dosage were adjusted to maintain the total blood drug concentration within the effective therapeutic range in patients with renal failure. Therefore, when administering such drugs to patients with renal failure, we should consider the dosage based on the concentration of serum albumin and unbound drug concentration in plasma.⁵⁸⁾

Some clinically used drugs, such as chlorpromazine, imipramine, lidocaine, and disopyramide, mainly bind to α₁-acid glycoprotein.^59,60) In renal failure, especially in dialysis patients, serum α₁-acid glycoprotein concentrations often increase.⁶¹⁾ Therefore, the expected effect may not be achieved due to decreases in the unbound drug concentration in plasma, even if the total drug concentration in the blood is within the therapeutic range. Furthermore, we should carefully interpret the results of TDM for drugs with high protein-binding. In patients with renal failure, it is particularly useful to measure the unbound drug concentration and it is important to carefully monitor the patient’s symptoms after administration of a drug with a high protein-binding rate.

4.2. Change in the Volume of Distribution

The volume of distribution (V_d) is used as an indicator of tissue distribution and predicts the overall extent of distribution.⁶²⁾ A small V_d indicates that the drug stays in the blood vessels, while a large V_d indicates that the drug is distributed into the areas outside the blood vessels, such as the target tissue. The V_d of water-soluble drugs is generally small and susceptible to the factors that change V_d. For example, in the case of renal disease with edema, V_d increases with the overflow into extracellular fluid.^1,63) Therefore, we should increase the initial dose of water-soluble drugs depending on the increase in V_d.

4.3. Changes in Extrarenal Clearance

Extrarenal clearance refers to the metabolism and disappearance of drugs in organs other than kidneys. It had previously been thought that extrarenal clearance was not changed in patients with renal failure or dialysis. However, recent reports have shown that uremic toxins affect the functions of CYP and transporters.^64–66) Therefore, we need to pay attention to inhibition related to extrarenal clearance, such as via CYP-mediated metabolism, transporter-mediated inhibition of gastrointestinal secretion, and the hepatic uptake.⁶⁷⁾ The further accumulation of clinical information is expected in the future.

4.4. Metabolic Changes in the Kidney

The kidney is also a site of drug metabolism, such as oxidation and conjugation. Specifically, glucuronidation, glutathione conjugation, and sulfate conjugation, as well as oxidation reactions by CYP, all take place in kidney.^1,67) Therefore, we should carefully consider the metabolic changes undergone by psychotropic drugs in the kidneys of psychiatric patients with renal diseases.

5. CHANGES IN PHARMACOKINETICS DURING DIALYSIS

In the case of hemodialysis, represented by blood purification therapy, we should consider the extracorporeal removal of drugs by dialyzers in addition to the renal excretion of drugs depending on the patient’s renal function, as described above, via the following formula:

  

Therefore, it is important to understand the dialyzability of drugs by a dialyzer. The factors that affect the dialyzability of a drug can be divided into three categories: (1) drug factors, (2) dialysis factors, and (3) patient factors.

5.1. Changes in the Dialyzability of Drugs Due to Drug Factors

Regarding the removal efficiency of drugs by dialysis, drugs are generally judged to be “easily removed” or “dialyzable” when the removal efficiency is more than 70%. We can estimate to some extent the removal efficiency of drugs by dialysis based on several factors, most notably the (1) molecular weight, (2) protein-binding, and (3) V_d.^68,69) The molecular weight of a drug serves as a factor in determining whether or not it can pass through the pores of the dialysis membrane.^68,69) Since most drugs used in clinical practice are 100–2000 kDa in size, they can pass through the dialysis membrane. High-performance membranes, such as polysulfone and polyethersulfone membranes, both of which are currently widely used in clinical practice, are still permeable to materials with a rather high molecular weight. Therefore, almost all drugs, except for antibody drugs and protein drugs, can theoretically pass through them.^70–73)

In general, albumin and α₁-acid glycoprotein are not removed by dialysis membranes, so drugs with high protein-binding are difficult to remove by dialysis. It is thought that drugs with high protein-binding (>90%) are considered to be non-dialyzable. However, regardless of their protein-binding, drugs present in their free form in the blood can still be eliminated. As mentioned above, a small V_d (e.g. <0.2 L/kg) indicates that the drug is present only in the blood vessels, while a large V_d indicates that the drug is distributed to the extracellular and intracellular fluids or tissues. Assuming an adult of 50–60 kg body weight with all of the body weight being liquid, we would have a V_d of 1 L/kg. Therefore, the authors empirically consider a drug to have a high tissue distribution if it has a V_d exceeding 1 L/kg.

It is important to note that hemodialysis can only purify a portion of the blood or interstitium (extracellular fluid) and can only remove drugs present there. Drugs with a high tissue distribution (e.g. large V_d) can exist in areas (organs, etc.) beyond the range of removal by hemodialysis, so the removal efficiency by hemodialysis tends to low. For example, amitriptyline has a V_d of 15 L/kg, which means that only a small amount is removed from the body, no matter how much dialysis is performed. Therefore, in general, drugs with V_d >2.0 L/kg are considered non-dialyzable. Among these parameters, drugs with a protein-binding of >80% and V_d of >1.0 L/kg are also considered less dialyzable than others, whereas drugs that are highly water-soluble are easily excreted form kidney and also tend to be easily removed by dialysis.

5.2. Changes in the Dialyzability of Drugs Due to Dialysis Factors

The dialysis efficiency is affected by the performance of the dialyzer, i.e., the membrane material or area.^74–77) In addition, the efficiency of drug removal increases depending on the dialysis time and blood flow rate (QB), dialysate flow rate (QD),⁷⁸⁾ and ultrafiltration volume by extracorporeal ultrafiltration method.⁷⁹⁾

5.3. The Comparison of Various Dialysis Conditions

It is also important to note that the efficiency of dialysis depends on the type of hemodialysis regimen performed, such as intermittent hemodialysis and continuous renal replacement therapy (CRRT), which is represented by continuous hemodiafiltration (CHDF). Basically, the clearance of a drug is defined as the amount of solution that can be purified per unit time, so the clearance depends on the flow rate or velocity.^78,80) In hemodialysis, QB defines the clearance when QB ≪ QD. In contrast, in CRRT, (QD + replacement) fluid defines the clearance when QB ≫ (QD + replacement fluid). When comparing only QB and QD, hemodialysis shows by far the greater value. However, it is important to focus on the differences in dialysis duration between hemodialysis (4 h) and CRRT (24 h). Taking into account the dialysis time and converting it into a full week, the clearance of hemodialysis and CRRT is 14 mL/min and 12–18 mL/min, respectively, which are almost the same values and are about 15% of the removal capacity in individuals with normal renal function. In the case of CRRT, the removal efficiency for drugs with a small V_d may be decreased, as inflammation and acute kidney injury increase the extracellular fluid volume (edema, ascites, etc.). In addition, CRRT is a slow and steady blood purification process performed over a long time, decreasing the intra-patient’s variability in drug distribution due to the rebound phenomenon. Drugs with a V_d of 1–2 L/kg may therefore be eliminated. We should be mindful when using data from overseas studies, as the conditions for blood purification therapy differ and the clearance tends to be greater than in Japan.

5.4. Patient-Related Factors

An increased extracellular fluid volume due to recovery of the patient’s residual renal function or inflammation, such as systemic inflammatory response syndrome (SIRS), increases V_d through a temporary increase in the blood vessel permeability. In addition, an increase in the cardiac output causes augmented renal clearance (ARC), which is an increase in the renal clearance through an increase in the renal blood flow. This increases the intrinsic clearance of antibacterial agents used for SIRS.

6. PSYCHIATRIC PHARMACOTHERAPY IN PATIENTS WITH RENAL FAILURE AND DIALYSIS

Table 1 shows the information related to the pharmacokinetics and TDM of typical psychotropic drugs. Drugs used in psychiatry are characterized by their high distribution to the CNS due to their ability to cross the blood-brain barrier. Although they generally have properties, e.g. highly lipophilic⁵⁰⁾ and high basicity,⁸¹⁾ they rarely eliminated renally in an unchanged form (Table 1). However, some drugs require a dosage adjustment due to renal failure (Table 2). Therefore, it is important to understand the drugs that require such special attention. In this section, we describe three typical psychotropic drugs whose pharmacokinetics are altered by renal dysfunction or renal failure.

Table 1. Information Related to the Pharmacokinetics and Therapeutic Drug Monitoring of Typical Psychotropic Drugs^a)

	Molecular weight	Protein-binding rate (%)	Vd	Tmax (h)	t1/2 (h)	Enzymes and transporters involved in drug disposition	Therapeutic reference range	Laboratory alert level
Antidepressants
Escitalopram	324.4	56	−	3.8–4.3	27–33	CYP2C19, CYP2D6, CYP3A4, P-gp	15–80 ng/mL	160 ng/mL
Sertraline	306.2	98	−	6.7–8.7	24–36	CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, UGT1A1, P-gp	10–150 ng/mL	300 ng/mL
Paroxetine	329.4	95	−	approximately 5	10–25	CYP2D6, CYP3A4, P-gp	20–65 ng/mL	120 ng/mL
Fluvoxamine	318.3	77	−	approximately 4–5	8–28	CYP2D6, CYP1A2, P-gp	60–230 ng/mL	500 ng/mL
Duloxetine	297.4	>90	−	6.9–7.8	8–17	CYP1A2, CYP2D6, P-gp (ABCB1)	30–120 ng/mL	240 ng/mL
Venlafaxine	277.4	<30	−	6	4–5	CYP2C19, CYP2D6, CYP2C9, CYP3A4, P-gp	100–400 ng/mL	800 ng/mL
Milnacipran	246.3	−	−	2–3	12	CYP3A4, P-gp, renal excretion	100–150 ng/mL	300 ng/mL
Mirtazapine	265.4	85	−	1.1–1.4	31.6	CYP3A4, CYP1A2, CYP2D6	30–80 ng/mL	160 ng/mL
Mood stabilizers
Lithium	6.9	0	0.7–1.0 L/kg	2.6	18–36	Renal excretion	4–8 µg/mL	4–8 µg/mL
Valproic acid	144.2	90	−	0.92	−	UGT1A3, UGT1A6, UGT2B7, CYP2A6, CYP2B6, CYP2C9, CYP219, β-oxidation	50–100 µg/mL	120 µg/mL
Carbamazepine	236.3	75	0.8 kg	4–24	9–15	CYP1A2, CYP2C8, CYP3A4, UGT2B7, P-gp, BCRP, epoxide hydrolase	4–12 µg/mL	20 µg/mL
Topiramate	339.4	15–20	−	2	−	UGTs, P-gp	2–10 µg/mL	16 µg/mL
Antipsychotics
Risperidone	410.5	90	−	approximately 1	3–30	CYP2D6, CYP3A4, P-gp, BCRP	20–60 ng/mL	120 ng/mL
Paliperidone	426.5	−	−	approximately 24	19	60% excreted unmetabolized, CYP3A4, UGT, P-gp, BCRP	20–60 ng/mL	120 ng/mL
Olanzapine	312.4	93	16 ± 5 L	4.8	32–38	UGT1A4, UGT2B10, FMO, CYP1A2, CYP2D6, P-gp	20–80 ng/mL	100 ng/mL
Quetiapine	383.5	83	593 L	approximately 2.6	5–6	CYP3A4, CYP2D6, P-gp	100–500 ng/mL	1000 ng/mL
Clozapine	326.8	95–97	2–7 L/kg	3.1	9–17	CYP1A2, CYP2C19, CYP3A4, P-gp	350–600 ng/mL	1000 ng/mL
Aripiprazole	448.4	>99	4.9 L/kg	3.6	47–68	CYP2D6, CYP3A4, P-gp	100–350 ng/mL	1000 ng/mL

UGT, UDP-glucuronosyltransferase; P-gp, P-glycoprotein; BCRP, Breast Cancer Resistance Protein; FMO, Flavin-containing monooxygenase. a) This table is prepared based on the previous review articles^2,97) with modifications and the package insert in Japan.

Table 2. Psychotropic Drugs to Be Considered for Dose Reduction in Case of Renal Failure Based on the Interview Form in Japan

Drug class	Drug	Typical product name	Dose reduction for patients with conservative CKD	Dose reduction for patients with HD	Dialyzability
Antidepressants (SSRIs)	Escitalopram	Lexapro®	CCr <10: approx. 10 mg q.d.		No
	Paroxetine	Paxil®	CCr <60: 5–30 mg q.d.	5–20 mg q.d.	No
Antidepressants (SNRIs)	Venlafaxine	Effexor®	CCr 30–60: Reduce the dose to 50–75% of the usual dose	Contraindications	No
			CCr <30: Reduce the dose to 50% or less of the usual dose
	Duloxetine	Cymbalta®	CCr <30: Contraindications		No
Antidepressant (NaSSA)	Mirtazapine	Remeron®	CCr <60: Reduce the dose to 2/3		No
		Reflex®	CCr <15 (Including HD): Reduce the dose to 1/2 of the usual dose
Mood stabilizers	Lithium carbonate	Limas®	CCr 15–60: Reduce the dose to 50–75% of the usual dose		Yes
			CCr <15 (Including HD): Reduce the dose to 25–50% of the usual dose
			※Contraindicated in patients with renal impairment because lithium tends to accumulate in the body.
Typical antipsychotics	Sulpiride	Dogmatyl®	CCr 15–60: 25-300 mg t.i.d.< CCr 15: 25 mg once a day	25 mg q.d.	Yes
Atypical antipsychotics	Risperidone	Risperdal®	First dose: 1 mg b.i.d., Maintenance dose: 2–6 mg (The active metabolite accumulates.)		No
		Risperdal consta intramuscular injection	First dose: 25 mg, after 2 weeks: Reduce the dose to 1/2 (The active metabolite accumulates.)		No
	Paliperidone	Invega®	CCr 50–80: Start with 3 mg/d and do not exceed 6 mg/d.		No
			CCr <50 (Including HD): Contraindications (The excretion of the drug may be delayed and the blood concentration may increase.)
		Xeplion aqueous suspension for IM injection ®	CCr 50–80: First dose 100 mg, second dose 75 mg after 1 week, then 50 mg once every 4 weeks		No
			CCr <50 (Including HD): Contraindications (The excretion of the drug may be delayed and the blood concentration may increase.)
Atypical antipsychotics	Clozapine	Clozaril ®	CCr <60: Careful administration (There is a risk of deterioration in renal function.)		No
			CCr <15 (Including HD): Contraindications (There is a risk of deterioration in renal function.)

CKD, chronic kidney disease; HD, hemodialysis; SSRIs, Selective Serotonin Reuptake Inhibitors; SNRIs, Serotonin Noradrenaline Reuptake Inhibitors; NaSSA, Noradrenergic and Specific Serotonergic Antidepressant; CCr, creatinine clearance (mL/min); q.d., one a day; t.i.d., three times a day; b.i.d., twice a day.

6.1. Risperidone and Paliperidone

Risperidone is a serotonin-dopamine antagonist that blocks dopamine D2 and serotonin 5-HT₂ receptors in the brain. Risperidone is a pharmacologically active and highly lipid-soluble drug that is metabolized mainly by CYP2D6 to 9-hydroxy risperidone (paliperidone), which also exerts serotonin-dopamine blockade activity.⁸²⁾ In normal volunteers, risperidone has a half-life of 4 h, whereas paliperidone has a longer half-life of 21 h, and the pharmacological activities of both are almost the same, thus paliperidone is responsible for the main pharmacological effect.

Of note, the administration of 1 mg risperidone to patients with moderate renal dysfunction (creatinine clearance (CCr): 30–60 mL/min/1.73 m²) and severe renal dysfunction (CCr: 10 to 29 mL/min/1.73 m²) resulted in a 35 and 55% increase in the t_1/2 of the active moiety (i.e., risperidone plus paliperidone) and 2.7- and 2.6-fold increases in the AUC, respectively,⁸³⁾ compared to individuals with a normal renal function. Administration of paliperidone also resulted in a two- and four-fold increase in the t_1/2 and AUC, respectively, in patients with severe renal impairment (from the package insert for INVEGA^® tablets). Paliperidone, which is metabolite form of risperidone, has high water-solubility, so the renal excretion rate of paliperidone may be higher than that of risperidone.

6.2. Duloxetine

Duloxetine is a serotonin-noradrenaline reuptake inhibitor (SNRI) that acts on the CNS and exerts a variety of effects, including antidepressant and analgesic effects. Once absorbed, duloxetine is almost completely metabolized (urinary excretion rate in unchanged form; 0%). The administration of duloxetine showed no significant difference in the t_1/2 between patients with severe renal impairment (CCr <30 mL/min/1.73 m²) and healthy volunteers, whereas both the C_max and AUC increased approximately 2-fold in patients with severe renal impairment.⁸⁴⁾ Since changes in the t_1/2 and delay of disappearance were not observed, the increased bioavailability, including increased gastrointestinal absorption, may be responsible for this phenomenon, although the detailed mechanism is still unknown.

Duloxetine is mainly metabolized by CYP1A2 and CYP2D6 but also inhibits the activity of CYP2D6 in vitro. Recently, uremic toxins have been attracting attention, as they impact the function of drug-metabolizing enzymes and transporters.^85–87) Therefore, uremic toxins may impact the disposition of duloxetine, although evaluation of this interaction will require further basic or clinical research.

6.3. Lithium Carbonate

Lithium carbonate is a relatively rare inorganic compound used to treat manic depression. According to the package insert for lithium, the serum lithium level should be measured about once a week in the initial phase of administration as well as during the dose-increase phase until the maintenance dose is fixed.^88,89) It should then be measured about once every two to three months during the maintenance dose phase.^88,89) Basically, the effective serum lithium concentration is around 0.3–1.2 mEq/L. If the serum lithium concentration exceeds 1.5 mEq/L, the clinical symptoms should be carefully monitored, and the dose should be reduced, or the drug should be withdrawn as necessary. If the serum concentration exceeds 2.0 mEq/L, the dose should be reduced, or the administration should be stopped altogether, as an overdose can cause poisoning.^2,90)

Lithium is 100% absorbed (V_d of 0.84 L/kg), is not protein-bound, is not metabolized, and is typically excreted in the urine as inorganic ions. In addition, renal clearance is unexpectedly small, around 30 mL/min, so the t_1/2 is relatively long (i.e., 18 h).^2,90) Therefore, lithium-induced acute kidney injury may also occur depending on the increase in the blood levels in patients with an impaired renal function.⁹¹⁾

According to a report by the Pharmaceuticals and Medical Devices Agency, TDM is not performed in half of patients prescribed lithium carbonate, so active intervention of TDM is desirable (https://www.pmda.go.jp/files/000145551.pdf). In addition, lithium therapy has been suggested to be associated with the development of CKD as well as acute kidney injury. According to previous findings, a low baseline renal function and history of type 2 diabetes mellitus are considered risk factors for CKD in patients treated lithium.⁹²⁾ However, even if lithium is discontinued after the development of CKD, the rate of decline in the renal function is similar to that in the continuous group, and discontinuation of lithium after the renal function decline may not contribute to the inhibition of CKD progression. Therefore, assessing the baseline renal function is important for lithium administration, and nephrotoxicity should be avoided by maintaining a low dose while conducting TDM.⁹³⁾ Since there is no specific antidote for lithium poisoning, we should cease the administration of lithium and promote excretion of the drug using replacement fluids and diuretics (mannitol, aminophylline, etc.).⁹⁴⁾ However, drugs that promote sodium excretion, such as furosemide, should be used with caution, as their use compensatively increases reabsorption of lithium, a monovalent cation, and may prolong the symptoms of poisoning due to delayed lithium excretion.^95,96) Therefore, regular monitoring of the renal function and serum lithium concentration, with attention to complications and concomitant medications, will optimize the lithium therapy. Drug-induced renal injury should be avoided, especially since it is an essential drug for treating bipolar disorder.

7. CONCLUSION

The kidneys are major organs that excrete drugs. When administrating drugs to patients with an impaired renal function, it is necessary to design drug administration in consideration of changes in pharmacokinetics due to a decreased renal excretion capacity and changes in pharmacokinetics other than excretion capacity, such as changes in the protein-binding and V_d. The concomitant mental problems are common in patients with CKD or ESRD. Additionally, some psychotropic drugs, such as lithium carbonate, have potential to cause nephrotoxicity. Taken together, these reports suggest that psychiatric disorders and CKD are likely to co-occur. Furthermore, psychiatric disorders and symptoms can be associated with the progression of renal disease, so drug therapy for psychiatric disorders is essential for ensuring the best prognosis possible in patients with CKD. However, the pharmacokinetics of psychotropic drugs may be altered by renal function and dialyzability. Therefore, when these drugs for psychiatric disorders are administered to patients with CKD or ESRD, it is important to design the dosing regimen by the renal function evaluation as well as TDM in order to support personalized medicine in the field of psychonephrology.

Acknowledgments

This work was supported in part by JSPS KAKENHI (Grant Nos. 20K07134, 21K07486).

Conflict of Interest

The authors declare no conflict of interest.

REFERENCES

• 1) Lea-Henry TN, Carland JE, Stocker SL, Sevastos J, Roberts DM. Clinical pharmacokinetics in kidney disease: fundamental principles. Clin. J. Am. Soc. Nephrol., 13, 1085–1095 (2018).
• 2) Hiemke C, Bergemann N, Clement HW, et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: update 2017. Pharmacopsychiatry, 51, 9–62 (2018).
• 3) Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur. J. Clin. Pharmacol., 65, 757–773 (2009).
• 4) Hsu CW, Lee Y, Lee CY, Lin PY. Neurotoxicity and nephrotoxicity caused by combined use of lithium and risperidone: a case report and literature review. BMC Pharmacol. Toxicol., 17, 59 (2016).
• 5) Hayes JF, Marston L, Walters K, Geddes JR, King M, Osborn DP. Adverse renal, endocrine, hepatic, and metabolic events during maintenance mood stabilizer treatment for bipolar disorder: a population-based cohort study. PLoS Med., 13, e1002058 (2016).
• 6) Pazhayattil GS, Shirali AC. Drug-induced impairment of renal function. Int. J. Nephrol. Renovasc. Dis., 7, 457–468 (2014).
• 7) Usui J, Yamagata K, Imai E, et al. Clinical practice guideline for drug-induced kidney injury in Japan 2016: digest version. Clin. Exp. Nephrol., 20, 827–831 (2016).
• 8) Finnegan-John J, Thomas VJ. The psychosocial experience of patients with end-stage renal disease and its impact on quality of life: findings from a needs assessment to shape a service. ISRN Nephrol., 2013, 308986 (2013).
• 9) Fradelos EC, Alikari V, Tsaras K, Papathanasiou IV, Tzavella F, Papagiannis D, Zyga S. Assessment of psychological distress in end stage renal disease: is it spirituality related? Med. Pharm. Rep., 94, 79–87 (2021).
• 10) Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, Van Lente F, Levey AS. Prevalence of chronic kidney disease in the United States. JAMA, 298, 2038–2047 (2007).
• 11) Cukor D, Cohen SD, Peterson RA, Kimmel PL. Psychosocial aspects of chronic disease: ESRD as a paradigmatic illness. J. Am. Soc. Nephrol., 18, 3042–3055 (2007).
• 12) Simoes ESAC, Miranda AS, Rocha NP, Teixeira AL. Neuropsychiatric disorders in chronic kidney disease. Front. Pharmacol., 10, 932 (2019).
• 13) Goh ZS, Griva K. Anxiety and depression in patients with end-stage renal disease: impact and management challenges-a narrative review. Int. J. Nephrol. Renovasc. Dis., 11, 93–102 (2018).
• 14) Perez Dominguez TS, Rodriguez Perez A, Buset Rios N, Rodriguez Esparragon F, Garcia Bello MA, Perez Borges P, Parodis Lopez Y, Rodriguez Perez JC. Psychonephrology: psychological aspects in autosomal dominant polycystic kidney disease. Nefrologia, 31, 716–722 (2011).
• 15) Levy NB. What is psychonephrology? J. Nephrol., 21 (Suppl. 13), S51–S53 (2008).
• 16) Haruki S. Psychonephrology in Japan. Adv. Psychosom. Med., 23, 37–57 (2001).
• 17) Cukor D, Fruchter Y, Ver Halen N, Naidoo S, Patel A, Saggi SJ. A preliminary investigation of depression and kidney functioning in patients with chronic kidney disease. Nephron Clin. Pract., 122, 139–145 (2012).
• 18) Huang CW, Wee PH, Low LL, Koong YLA, Htay H, Fan Q, Foo WYM, Seng JJB. Prevalence and risk factors for elevated anxiety symptoms and anxiety disorders in chronic kidney disease: A systematic review and meta-analysis. Gen. Hosp. Psychiatry, 69, 27–40 (2021).
• 19) Oyekcin DG, Gulpek D, Sahin EM, Mete L. Depression, anxiety, body image, sexual functioning, and dyadic adjustment associated with dialysis type in chronic renal failure. Int. J. Psychiatry Med., 43, 227–241 (2012).
• 20) Loosman WL, Rottier MA, Honig A, Siegert CE. Association of depressive and anxiety symptoms with adverse events in Dutch chronic kidney disease patients: a prospective cohort study. BMC Nephrol., 16, 155 (2015).
• 21) Weisbord SD, Carmody SS, Bruns FJ, Rotondi AJ, Cohen LM, Zeidel ML, Arnold RM. Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients. Nephrol. Dial. Transplant., 18, 1345–1352 (2003).
• 22) Martin CR, Thompson DR. Prediction of quality of life in patients with end—stage renal disease. Br. J. Health Psychol., 5, 41–55 (2000).
• 23) Farmer CJ, Snowden SA, Parsons V. The prevalence of psychiatric illness among patients on home haemodialysis. Psychol. Med., 9, 509–514 (1979).
• 24) McCann K, Boore JR. Fatigue in persons with renal failure who require maintenance haemodialysis. J. Adv. Nurs., 32, 1132–1142 (2000).
• 25) Curtin RB, Bultman DC, Thomas-Hawkins C, Walters BA, Schatell D. Hemodialysis patients’ symptom experiences: effects on physical and mental functioning. Nephrol. Nurs. J., 29, 562, 567–574 (2002).
• 26) Kutner NG, Fair PL, Kutner MH. Assessing depression and anxiety in chronic dialysis patients. J. Psychosom. Res., 29, 23–31 (1985).
• 27) Waraich P, Goldner EM, Somers JM, Hsu L. Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can. J. Psychiatry, 49, 124–138 (2004).
• 28) Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin. Neurosci., 13, 7–23 (2011).
• 29) Hedayati SS, Minhajuddin AT, Afshar M, Toto RD, Trivedi MH, Rush AJ. Association between major depressive episodes in patients with chronic kidney disease and initiation of dialysis, hospitalization, or death. JAMA, 303, 1946–1953 (2010).
• 30) Shirazian S, Grant CD, Aina O, Mattana J, Khorassani F, Ricardo AC. Depression in chronic kidney disease and end-stage renal disease: similarities and differences in diagnosis, epidemiology, and management. Kidney Int. Rep., 2, 94–107 (2017).
• 31) Chiang HH, Guo HR, Livneh H, Lu MC, Yen ML, Tsai TY. Increased risk of progression to dialysis or death in CKD patients with depressive symptoms: a prospective 3-year follow-up cohort study. J. Psychosom. Res., 79, 228–232 (2015).
• 32) Fischer MJ, Xie D, Jordan N, Kop WJ, Krousel-Wood M, Kurella Tamura M, Kusek JW, Ford V, Rosen LK, Strauss L, Teal VL, Yaffe K, Powe NR, Lash JP, Investigators CSG. Factors associated with depressive symptoms and use of antidepressant medications among participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC studies. Am. J. Kidney Dis., 60, 27–38 (2012).
• 33) Kop WJ, Seliger SL, Fink JC, Katz R, Odden MC, Fried LF, Rifkin DE, Sarnak MJ, Gottdiener JS. Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes. Clin. J. Am. Soc. Nephrol., 6, 834–844 (2011).
• 34) Cukor D, Rosenthal DS, Jindal RM, Brown CD, Kimmel PL. Depression is an important contributor to low medication adherence in hemodialyzed patients and transplant recipients. Kidney Int., 75, 1223–1229 (2009).
• 35) Kimmel PL, Peterson RA, Weihs KL, Simmens SJ, Alleyne S, Cruz I, Veis JH. Psychosocial factors, behavioral compliance and survival in urban hemodialysis patients. Kidney Int., 54, 245–254 (1998).
• 36) Cuijpers P, Dekker J, Hollon SD, Andersson G. Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis. J. Clin. Psychiatry, 70, 1219–1229 (2009).
• 37) Rayner L, Price A, Evans A, Valsraj K, Higginson IJ, Hotopf M. Antidepressants for depression in physically ill people. Cochrane Database Syst. Rev., CD007503 (2010).
• 38) Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane Database Syst. Rev., 12, CD008381 (2012).
• 39) Kupfer DJ, Frank E, Phillips ML. Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet, 379, 1045–1055 (2012).
• 40) Tzeng NS, Hsu YH, Ho SY, Kuo YC, Lee HC, Yin YJ, Chen HA, Chen WL, Chu WC, Huang HL. Is schizophrenia associated with an increased risk of chronic kidney disease? A nationwide matched-cohort study. BMJ Open, 5, e006777 (2015).
• 41) Harris LW, Guest PC, Wayland MT, Umrania Y, Krishnamurthy D, Rahmoune H, Bahn S. Schizophrenia: metabolic aspects of aetiology, diagnosis and future treatment strategies. Psychoneuroendocrinology, 38, 752–766 (2013).
• 42) Wang HY, Huang CL, Feng IJ, Tsuang HC. Second-generation antipsychotic medications and risk of chronic kidney disease in schizophrenia: population-based nested case-control study. BMJ Open, 8, e019868 (2018).
• 43) Hojlund M, Lund LC, Herping JLE, Haastrup MB, Damkier P, Henriksen DP. Second-generation antipsychotics and the risk of chronic kidney disease: a population-based case-control study. BMJ Open, 10, e038247 (2020).
• 44) Gitlin M. Lithium and the kidney: an updated review. Drug Saf., 20, 231–243 (1999).
• 45) Bendz H, Aurell M, Balldin J, Mathe AA, Sjodin I. Kidney damage in long-term lithium patients: a cross-sectional study of patients with 15 years or more on lithium. Nephrol. Dial. Transplant., 9, 1250–1254 (1994).
• 46) Coluzzi F, Caputi FF, Billeci D, Pastore AL, Candeletti S, Rocco M, Romualdi P. Safe use of opioids in chronic kidney disease and hemodialysis patients: tips and tricks for non-pain specialists. Ther. Clin. Risk Manag., 16, 821–837 (2020).
• 47) Prescott LF, Speirs GC, Critchley JA, Temple RM, Winney RJ. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur. J. Clin. Pharmacol., 36, 291–297 (1989).
• 48) Janicki PK. Pharmacology of morphine metabolites. Curr. Pain Headache Rep., 1, 264–270 (1997).
• 49) Bauer TM, Ritz R, Haberthur C, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G, Haefeli WE. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet, 346, 145–147 (1995).
• 50) Dean M. Opioids in renal failure and dialysis patients. J. Pain Symptom Manage., 28, 497–504 (2004).
• 51) Nolin TD, Naud J, Leblond FA, Pichette V. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin. Pharmacol. Ther., 83, 898–903 (2008).
• 52) Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin. Drug Metab. Toxicol., 4, 1065–1074 (2008).
• 53) Peters DH, Sorkin EM. Zonisamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs, 45, 760–787 (1993).
• 54) Koch-Weser J, Sellers EM. Drug therapy. Binding of drugs to serum albumin (second of two parts). N. Engl. J. Med., 294, 526–531 (1976).
• 55) Giacomini KM, Blaschke TF. Effect of concentration-dependent binding to plasma proteins on the pharmacokinetics and pharmacodynamics of disopyramide. Clin. Pharmacokinet., 9 (Suppl. 1), 42–48 (1984).
• 56) Greenblatt DJ. Hepatic clearance of drugs in patients with renal insufficiency. Clin. Pharmacol. Drug Dev., 2, 295–297 (2013).
• 57) Patsalos PN, Spencer EP, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs in epilepsy: a 2018 update. Ther. Drug Monit., 40, 526–548 (2018).
• 58) Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology, 34, 395–397 (1984).
• 59) Valdes R Jr, Jortani SA, Gheorghiade M. Standards of laboratory practice: cardiac drug monitoring. Clin. Chem., 44, 1096–1109 (1998).
• 60) Kornguth ML, Hutchins LG, Eichelman BS. Binding of psychotropic drugs to isolated α1-acid glycoprotein. Biochem. Pharmacol., 30, 2435–2441 (1981).
• 61) Piafsky KM, Borgå O, Odar-Cederlöf I, Johansson C, Sjöqvist F. Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1 acid glycoprotein. N. Engl. J. Med., 299, 1435–1439 (1978).
• 62) Freitas AA, Limbu K, Ghafourian T. Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients. J Cheminform, 7, 6 (2015).
• 63) Roberts DM, Sevastos J, Carland JE, Stocker SL, Lea-Henry TN. Clinical pharmacokinetics in kidney disease: application to rational design of dosing regimens. Clin. J. Am. Soc. Nephrol., 13, 1254–1263 (2018).
• 64) Masereeuw R, Russel FG. Mechanisms and clinical implications of renal drug excretion. Drug Metab. Rev., 33, 299–351 (2001).
• 65) Sugimoto R, Watanabe H, Ikegami K, Enoki Y, Imafuku T, Sakaguchi Y, Murata M, Nishida K, Miyamura S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T. Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism. Kidney Int., 91, 658–670 (2017).
• 66) Watanabe H, Sugimoto R, Ikegami K, Enoki Y, Imafuku T, Fujimura R, Bi J, Nishida K, Sakaguchi Y, Murata M, Maeda H, Hirata K, Jingami S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T. Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-kappaB signaling pathway in secondary hyperparathyroidism. Biochem. Pharmacol., 145, 192–201 (2017).
• 67) Yeung CK, Shen DD, Thummel KE, Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int., 85, 522–528 (2014).
• 68) Keller F, Wilms H, Schultze G, Offerman G, Molzahn M. Effect of plasma protein binding, volume of distribution and molecular weight on the fraction of drugs eliminated by hemodialysis. Clin. Nephrol., 19, 201–205 (1983).
• 69) Hirata S, Izumi S, Furukubo T, Ota M, Fujita M, Yamakawa T. Factors influencing the removal rate of drugs by hemodialysis. Nihon Toseki Igakkai Zasshi, 37, 1893–1900 (2004).
• 70) Sanaka T, Koremoto M. Selection guidelines for high-performance membrane. Contrib. Nephrol., 173, 30–35 (2011).
• 71) Bowry SK, Gatti E, Vienken J. Contribution of polysulfone membranes to the success of convective dialysis therapies. Contrib. Nephrol., 173, 110–118 (2011).
• 72) Krieter DH, Lemke HD. Polyethersulfone as a high-performance membrane. Contrib. Nephrol., 173, 130–136 (2011).
• 73) Mineshima M. The past, present and future of the dialyzer. Contrib. Nephrol., 185, 8–14 (2015).
• 74) Gautham A, Muhammed J, Manavalan M, Najeeb M. Hemodialysis membranes: Past, present and future trends. Int. Res. J. Pharm., 4, 16–19 (2013).
• 75) Twardowski ZJ. History of hemodialyzers’ designs. Hemodial. Int., 12, 173–210 (2008).
• 76) Pavlenko D, Van Geffen E, Van Steenbergen MJ, Glorieux G, Vanholder R, Gerritsen KG, Stamatialis D. New low-flux mixed matrix membranes that offer superior removal of protein-bound toxins from human plasma. Scientific Reports, 6, 1–9 (2016).
• 77) Pistolesi V, Morabito S, Di Mario F, Regolisti G, Cantarelli C, Fiaccadori E. A guide to understanding antimicrobial drug dosing in critically ill patients on renal replacement therapy. Antimicrob. Agents Chemother., 63, e00583-19 (2019).
• 78) Kashiwagi T, Sato K, Kawakami S, Kiyomoto M, Enomoto M, Suzuki T, Genei H, Nakada H, Iino Y, Katayama Y. Effects of reduced dialysis fluid flow in hemodialysis. J. Nippon Med. Sch., 80, 119–130 (2013).
• 79) Pedrini LA. Transmembrane pressure, ultrafiltration coefficient and the optimal infusion rate in haemodiafiltration. Nephrol. Dial. Transplant., 26, 1445–1446 (2011).
• 80) Bohler J, Donauer J, Keller F. Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage. Kidney Int. Suppl., 56, S24–S28 (1999).
• 81) Martin U, Temple RM, Winney RJ, Prescott LF. The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure. Eur. J. Clin. Pharmacol., 41, 43–46 (1991).
• 82) de Leon J, Wynn G, Sandson NB. The pharmacokinetics of paliperidone versus risperidone. Psychosomatics, 51, 80–88 (2010).
• 83) Snoeck E, Van Peer A, Sack M, Horton M, Mannens G, Woestenborghs R, Meibach R, Heykants J. Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man. Psychopharmacology (Berl.), 122, 223–229 (1995).
• 84) Lobo ED, Heathman M, Kuan HY, Reddy S, O’Brien L, Gonzales C, Skinner M, Knadler MP. Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials. Clin. Pharmacokinet., 49, 311–321 (2010).
• 85) Nigam SK, Bush KT. Uraemic syndrome of chronic kidney disease: altered remote sensing and signalling. Nat. Rev. Nephrol., 15, 301–316 (2019).
• 86) Barnes KJ, Rowland A, Polasek TM, Miners JO. Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins. Eur. J. Clin. Pharmacol., 70, 1097–1106 (2014).
• 87) Volpe DA, Tobin GA, Tavakkoli F, Dowling TC, Light PD, Parker RJ. Effect of uremic serum and uremic toxins on drug metabolism in human microsomes. Regul. Toxicol. Pharmacol., 68, 297–303 (2014).
• 88) Ooba N, Tsutsumi D, Kobayashi N, Hidaka S, Hayashi H, Obara T, Satoh M, Kubota K, Fukuoka N. Prevalence of therapeutic drug monitoring for lithium and the impact of regulatory warnings: analysis using japanese claims database. Ther. Drug Monit., 40, 252–256 (2018).
• 89) Yoshida K, Uchida H, Suzuki T, Watanabe M, Yoshino N, Houchi H, Mimura M, Fukuoka N. Prediction model of serum lithium concentrations. Pharmacopsychiatry, 51, 82–88 (2018).
• 90) Grandjean EM, Aubry JM. Lithium: updated human knowledge using an evidence-based approach. Part II: clinical pharmacology and therapeutic monitoring. CNS Drugs, 23, 331–349 (2009).
• 91) Davis J, Desmond M, Berk M. Lithium and nephrotoxicity: a literature review of approaches to clinical management and risk stratification. BMC Nephrol., 19, 305 (2018).
• 92) Pahwa M, Joseph B, Nunez NA, Jenkins GD, Colby CL, Kashani KB, Marin V, Moore KM, Betcher HK, Ozerdem A, Cuellar-Barboza AB, McElroy SL, Biernacka JM, Frye MA, Singh B. Long-term lithium therapy and risk of chronic kidney disease in bipolar disorder: a historical cohort study. Bipolar Disord., 23, 715–723 (2021).
• 93) Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int. J. Bipolar Disord., 4, 27 (2016).
• 94) Noormohamed FH, Lant AF. Renal handling of lithium and the effects of mannitol and arginine vasopressin in man. Clin. Sci. (Lond.), 89, 27–36 (1995).
• 95) Hedya SA, Avula A, Swoboda HD. Lithium toxicity. StatPearls. Treasure Island, FL (2021). https://www.ncbi.nlm.nih.gov/books/NBK499992/
• 96) Baird-Gunning J, Lea-Henry T, Hoegberg LCG, Gosselin S, Roberts DM. Lithium Poisoning. J. Intensive Care Med., 32, 249–263 (2017).
• 97) Baghdady NT, Banik S, Swartz SA, McIntyre RS. Psychotropic drugs and renal failure: translating the evidence for clinical practice. Adv. Ther., 26, 404–424 (2009).