Pharmacokinetic process
Changes in hemodialysis
Absorption
Increased absorption mediated by:
• Paracellular leakage
• Decreased efflux transporter activity
• Decreased P450 activity
Distribution
Increased free drug concentration mediated by:
• Decreased albumin concentration
• Uremic toxin-mediated decreases in protein binding
Metabolism
• Decreased Phase I metabolism
• Decreased Phase II metabolism
Excretion
• Decreased renal drug excretion
• Decreased biliary drug excretion
Hemodialysis
• Dialytic drug clearance leading to decreased plasma concentration
• Normalization of non-renal drug clearance pathways
The medication in patients with CKD needs to be made according to the characteristics of the specific drugs and their metabolites, as well as the degree of renal function. Drugs in patients with CKD should be selected and adjusted appropriately. Drug adjustments could be carried out through the following common ways: (1) Dosing adjustment: the initial dose of the drug and the drug interval remain unchanged, while the maintenance amount is reduced. (2) Interphase extension: the dosage of the drug remains unchanged, but the interphase is prolonged. Individualized medication regimens are implemented according to the specific conditions of patients. For special drugs, the regimen needs to be adjusted by monitoring the serum drug concentration. It should be emphasized that drugs with a high risk of renal damage might be banned or used with caution in patients with CKD. Several publications have focused specifically on recommendations for drug dosing and monitoring of patients with CKD, patients with ESRD who are on renal replacement therapy, and patients on continuous renal replacement therapy.
15.3 Challenge of Evidence-Based Prescribing in CKD
Increasingly, more and more evidence concerning medication in general populations has accumulated and may guide the treatment decisions. The types of patients selected for experimental treatments in clinical trials must be considered. It is worth noting that CKD, especially ESRD, is often an important clinical feature excluded by clinical trials [3]. For example, CKD patients were definitely excluded from approximately 50% of RCTs of interventions in chronic heart failure or acute coronary syndrome. Exclusions of patients with CKD were usually common in the clinical trials of inhibitors of the renin angiotensin-aldosterone system and anticoagulants.
Thus, because most evidence is derived from the trials in the general population, whether such evidence and the resulting guidelines for therapies could be used to guide treatment of patients with CKD or ESRD still need to be confirmed. Whether such extrapolations are appropriate is unclear, and in some instances extrapolation is appropriate, whereas in others it is not. More RCT studies are needed to support medication use in patients with CKD or ESRD.
15.4 Medication Use in Patients with CKD
Commonly used medicines in CKD or ESRD are described in detail below, according to the therapeutic types [4].
15.4.1 Adrenal Glucocorticoids
Characteristics of glucocorticoids used in CKD
Equivalent dose (mg) | Anti-inflammatory properties | Water sodium retention | T1/2 (h) | Plasma binding protein | Duration of efficacy (h) | |
|---|---|---|---|---|---|---|
Cortisone acetate | 25 | 0.8 | 2 | 0.5 | CBG/Alb | 8–12 |
Hydrocortisone | 20 | 1 | 2 | 1.7–2.1 | CBG/Alb | 8–12 |
Prednisone | 5 | 4 | 1 | 2.9–4.1 | CBG/Alb | 18–36 |
Prednisolone | 5 | 4 | 1 | 2.7–4.1 | CBG/Alb | 18–36 |
Methyl prednisolone | 4 | 5 | 0 | 1.6–3.4 | Alb | 18–36 |
Dexamethasone | 0.75 | 27 | 0 | 4.1–5.4 | Alb | 36–54 |
Indications and contraindications should be strictly evaluated before using a glucocorticoid. The dosage, duration, and adverse drug reactions must be closely monitored. Glucocorticoid resistance is defined as a nephrotic syndrome without improvement following sufficient glucocorticoid treatment (e.g. prednisone 1 mg/kg/day) for more than 3 months. The common reasons for glucocorticoid resistance are as follows: co-existing complications, such as infections, thrombosis, and embolism; severe edema leading to abnormalities of the digestive and absorptive functions of the gastrointestinal tract; concurrent drug use that reduces glucocorticoid concentrations; and primary kidney disease types which have poor responsiveness to glucocorticoids.
Adverse reactions to glucocorticoids are closely related to dosage and treatment duration. Common adverse reactions include infection; adverse reactions of the skin and soft tissues, such as acne; water and sodium retention; adverse reactions of the cardiovascular system, such as hypertension; adverse reactions of the digestive system, such as peptic ulcers and gastrointestinal bleeding; osteoporosis; elevated blood sugar; adverse reactions of the central nervous system, such as insomnia and euphoria; adverse reactions of the reproductive system, such as menstrual disorders and decreased fertility; and adrenocortical insufficiency such as that seen in patients upon withdrawal of long-term use of glucocorticoids.
15.4.2 Immunosuppressants
Characteristics and therapeutic principles of cyclophosphamide
Cyclophosphamide |
|---|
• Alkylating agent |
• Gonadal toxicity depends on cumulative doses and increased age |
• Gastrointestinal and hematological system toxicities are common |
• Increases the risk of malignancy in the hematological system |
• Due to the risk of hemorrhagic cystitis and bladder neoplasms, patients should be hydrated during treatment |
• Oral dose: 1–2 mg/kg/day |
• Impact intravenous doses: 0.5–1.0 g/m2 surface area |
• Routine blood and liver function should be monitored and routine urine output monitored for life |
• Cystoscopy is required for non-glomerular-derived hematuria |
Characteristics and treatment principles of azathioprine
Azathioprine |
|---|
• Purine analog |
• Digestive and hematological system toxicity is common |
• Dose for kidney transplantation: 3–5 mg/kg/day • Dose for autoimmune disease: 1–2.5 mg/kg/day |
• Contraindicated with allopurinol and febuxostat |
• Routine blood and urine analyses and liver function should be monitored |
• Use with glucocorticoids to reduce glucocorticoid dosage or to maintain treatment |
Characteristics, treatment principles, and precautions of methotrexate
Methotrexate |
|---|
• An indirect agonist of adenosine |
• Dihydrofolate reductase inhibitor |
• Adverse reactions in the gastrointestinal, hematological system, and skin mucosa are common |
• The liver, hematological system, and lung can have rare but serious adverse reactions |
• Dose: 5–30 mg per week |
• Daily use of 1–2 mg of folic acid can partially reduce the incidence of adverse reactions or decrease their severity |
• Patients with decreased glomerular filtration rate (GFR) or concurrent alcohol use should receive a reduced dose |
• White blood cell counts and liver and kidney function should be measured every 4–8 weeks |
• Chest radiographs should be obtained before treatment |
Characteristics, treatment principles, and precautions of mycophenolate mofetil (MMF)
MMF |
|---|
• Inositol monophosphate dehydrogenase (IMPDH) inhibitors |
• Gastrointestinal and hemotological system toxicities are common |
• Dosage: 1–2 g/day, taken on a separate basis |
• Doses should be reduced according to renal function |
• Routine blood analyses should be monitored after administration |
• The efficacy of this class of drugs is superior to azathioprine in organ transplantation |
Characteristics, treatment principles and precautions of leflunomide
Leflunomide |
|---|
• Isoxazole derivatives |
• May be used in kidney transplantation, autoimmune disease, and primary renal disease |
• Active metabolites can inhibit dihydroorotate dehydrogenase (DHODH) |
• Gastrointestinal toxicity is common |
• Dosage: 50–100 mg/day for 3 days, 20–30 mg/day for maintenance |
• Dosage does not require adjustment in impaired renal function |
• Liver function should be monitored |
Treatment principles and precautions for calcineurin inhibitors
Calcineurin inhibitors |
|---|
• Cyclosporine A and tacrolimus (FK506) are commonly used |
• May be used in kidney transplantation, autoimmune disease, and primary renal disease |
• Inhibition of calcineurin |
• Nephrotoxicity and neurotoxicity are most common |
• Because the effective treatment concentration range is narrow, blood drug concentrations should be monitored during treatment |
• Liver function should be monitored |
15.4.3 Diuretics
Common diuretics and their functional characteristics
Classification | Representative drugs | Characteristics |
|---|---|---|
Loop diuretics | • Furosemide • Bumetanide • Butyric acid • Tolasemi | • Inhibits the active reabsorption of NaCl in the loop • Destruction of the intramedullary mass concentration gradient • Damage of renal dilution function • Damage of renal concentration function • Maximum diuretic effect can reach 20–50% of total Na+ filtration • Increases urinary potassium excretion • Dilated renal cortical vessels |
Thiazide diuretics | • Chlorothiazide • Hydrochlorothiazide • Indapamide | • Inhibition of cortical distal convoluted tubule Na+ reabsorption • Poor function when creatinine clearance is decreased • Limited renal dilution function • Does not affect the concentration function • Increases urinary potassium excretion • Constricts blood vessels |
Potassium-sparing diuretics | • Aldosterone antagonist: spironolactone • Inhibition of potassium extraction: amiloride, aminobenzene | • Potassium-sparing • The diuretic effect is weak and is not used alone |
15.4.3.1 Clinical Application Principles for Diuretics
First, the uses of diuretics must be based on dietary controls that limit Na+ intake and control of salt intake. Patients with mild and moderate edema require a low-salt diet, and patients with severe refractory edema require a salt-free diet. While edema is not the preferred indication for the use of diuretics, such medications are suitable for use in heart or respiratory function insufficiency, obvious ascites, or in patients with edema who cannot accept a strict salt restriction. A strong diuresis is necessary only in patients with acute pulmonary edema and acute renal failure, while other conditions should adhere to the principle of slow diuresis. Adverse reactions should be closely monitored during diuresis, especially abnormal blood volume, and electrolyte disturbances.
15.4.3.2 Indications of Diuretics
Nephrotic Syndrome
Diuretic treatment in nephrotic syndrome can improve the pathophysiological changes caused by H2O storage by the kidney, which is one of the basic steps in the treatment of nephrotic syndrome. However, there are two pathophysiological conditions associated with the occurrence of edema in nephrotic syndrome: insufficient circulating blood volume caused by fluid flow to the interstitial fluid, or due to excessive capacity due to kidney sodium. The former may exacerbate primary kidney damage by the use of diuretics. Therefore, it is necessary to carry out a careful assessment of the condition to give correct diuretic treatment.
Acute Kidney Injury (AKI)
A large number of RCTs showed no clinical benefit in the incidence of inpatient mortality and renal replacement therapy for AKI patients. Therefore, diuretics should not be used as preventive or therapeutic drugs when AKI occurs.
Chronic Renal Failure (CRF)
Diuretics can be helpful for the regulation of the total body water, electrolyte disorders, and hypertension in CRF patients.
Renal Tubular Acidosis
Loop diuretics can increase H2O and NaCl in the downstream nephron and stimulate the secretion of aldosterone and phosphorus excretion. Therefore, loop diuretics increase the discharge of acid.
Heart and Liver Diseases
Diuretics can be helpful for improvement of CKD with heart and liver disease, such as acute left heart failure and chronic cirrhosis.
Hypertension
Diuretics can be effective for controlling blood pressure by reducing the circulating blood volume. Thiazide diuretics might be beneficial in the treatment of hypertension; however, the metabolic side effects of thiazides are gradually attracting attention.
15.4.3.3 Adverse Reactions of Diuretics
Adverse reactions of diuretics, especially loop diuretics and thiazide diuretics, include metabolic abnormalities and allergic reactions. Blood volume, hyponatremia, and hypokalemia are the most significant adverse reactions. Therefore, the ensuing changes in volume and electrolytes should be closely monitored during treatment with diuretics.
15.4.4 Inhibitors of the Renin-Angiotensin-Aldosterone System (RAAS)
Among all oral prescription medications, inhibitors of RAAS have received the most attention in terms of their protective effects in CKD. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are recommended in CKD patients with hypertension and proteinuria, especially in those with diabetic nephropathy. Underuse of these drugs in CKD population seems to be especially common among the elderly and the patients with heart failure. Another topic often be discussed is the lower use of inhibitors of RAAS for secondary prevention after myocardial infarction. Patients discharged from hospitalization for myocardial infarction usually experienced a lower maintenance treatment of beta blockers, statins, and RAAS inhibitors in CKD patients. It is vital to point out that in patients with CKD who receive RAAS inhibitors, serum creatinine, and creatinine potassium should be monitored closely. If the level of serum creatinine exceeds more than 30% over the base value or hyperkalemia is detected, the use of RAAS inhibitors needed to be reassessed or discontinued if necessary.
15.4.5 Anticoagulation Agents
Patients with CKD often need anticoagulation, especially for those patients undergoing hemodialysis. The most widely used anticoagulant therapy for hemodialysis includes heparin and low-molecular weight heparin. In patients with ESRD, antiplatelet agents such as aspirin and clopidogrel together with thrombolytics do not require dose adjustment. Warfarin could be used for atrial fibrillation or venous thromboembolism in patients with CKD or ESRD, which needed to be dose adjusted according to the international normalized ratio (INR). However, it is important to emphasize that patients with CKD or ESRD might display a greater risk of bleeding with anticoagulation treatment. However, the direct oral anticoagulants still require more study to support their use in patients with CKD or ESRD, which are currently not recommended among such population.
15.4.6 Antibacterial Agents
Dose adjustment of antibacterial agents in CKD
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