1. Introduction
Chronic kidney disease (CKD) is a growing and important clinical entity, and is often encountered by community and family physicians during screening and management of other concomitant medical problems [1-3]. For instance, common chronic medical illnesses such as diabetes mellitus and hypertension are leading causes of CKD [3]. Also, the presence of renal impairment is an independent risk factor for important clinical outcomes such as cardiovascular disease [2]. The kidneys assume crucial homeostatic functions which include the handling of fluid and electrolytes, secretion of hormones like erythropoietin and vitamin D, regulation of blood pressure, excretion of uremic wastes and elimination of medicinal compounds. Patients with chronic kidney diseases often have altered pharmacokinetics and pharmacodynamics. More importantly, CKD patients exhibited heightened susceptibility to renal toxicities of nephrotoxic drugs. Furthermore, some common medications used in CKD patients are teratogenic and should be avoided or discontinued should pregnancy be contemplated. Without careful consideration in prescription and appropriate dosage modification, disastrous clinical outcomes can ensue. The following review elaborated on the changes in drug metabolism and pitfalls of prescription in CKD patients.
2. Changes in pharmacokinetics and pharmacodynamics in patients with chronic kidney disease
Impaired absorption of drugs is observed in CKD patients. The frequent use of phosphate-binders and proton pump inhibitors in CKD patients caninfluence absorption of other acidic medicinal compounds. Furthermore, patients with severe uremia exhibit nausea and repeated vomiting, which can substantially decrease the absorption of other oral medications. The significant decrease of serum albumin in patients with nephrotic syndrome can influence the distribution of highly protein-bound drugs and also the absorption of drugs due to gut edema.These drugs include warfarin and furosemide. As a result, the clotting profile has to be closely monitoring in nephrotic patients who receive warfarin treatment [4]. Also, high dose intravenous furosemide might be required to achieve the desired diuretic effects in patients with significant proteinuria [5]. Many drugs undergo oxidation/reduction and hydrolysis in the kidney before they are eliminated and these mechanisms might be impaired in patients with renal failure. More important, the excretion of drugs and its metabolites are diminished in patients with decreased glomerular filtration rate (GFR). The elimination of drugs constitutes a significant problem in dialysis patients. In hemodialysis patients, the clearance of drugs is dependent on the pore size of dialyzer as well as blood and dialysate flow rates during hemodialysis6. As for peritoneal dialysis, drug elimination is generally poor although drugs with small molecular size and high volume of distribution might assume slight advantage in clearance7. Protein loss in peritoneal dialysis fluid might also facilitate the elimination of highly protein-bound substances [7].
3. Dosage adjustment in patients with chronic kidney disease
In general, the modification of drug dosages should be based on GFR measurement (Table 1). In daily clinical practice, serum creatinine (Cr) level remains a widely accepted and convenient indicator of renal function. However, the measurement of serum Cr can be problematic in CKD subject who are often elderly with shrunken muscle mass or significant peripheral edema. Another major drawback in applying serum Cr to gaugekidneyfunction is related to itspredisposition to drug interaction. For instance, cimetidine and probenecid can inhibit tubular secretion of Cr whereas ascorbic acid and cephalosporins can interfere with Cr assays. The Cockcroft-Gault Equation represented another common and convenient way to estimate GFR. This formula, however, shows better accuracy in patients with stable renal function and might become less precise when there is rapidly varying clinical conditions and kidney function. The Modification of Diet in Renal Disease Study (MDRD) equation is another useful equation for the estimation of GFR and has been validated in Chinese patients8,9. The MDRD is most accurate in subjects with moderate renal impairmentyet can be imprecise at the extremes of kidney function. Other methods of eGFR measurement include Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations, which based on the same four variables in the MDRD equation, was reported to show better performance and with less bias especially in patients with higher GFR10. However, this equation is still not widely adopted in many laboratories. Drugs which rely on substantial renal clearance would need dosage adjustment in CKD. Renal adjustment of dosage can be achieved by decrease in individual doses or the frequency of administration, depending on the characteristics of the drug. Dosage optimization in CKD patients can sometimes be facilitated by therapeutic monitoring of blood levels of drugs (e.g. vancomycin and aminoglycoside). Careful review of the clinical indications and consideration of alternatives can also help avoid the use of nephrotoxic drugs in CKD patients.
4. Common pitfalls of prescription in patients with chronic kidney diseases
4.1 Drugs used in common infections
Bacterial infection is common medical problem encountered in the community and family care setting. Beta-lactam antibiotics such as penicillin, amoxicillin (including augmentin), cephalosporin and quinolones usually require dosage reduction in CKD patients [11,12]. Nitrofurantoin and cotrimoxazole which are commonly used in patients with urinary tract infection can lead to nephrotoxicity should generally be avoided(contraindicated when eGFR<60ml/ min/1.73m2 and <15ml/min/1.73m2 for nitrofurantoin and cotrimoxazole respectively). Other nephrotoxic antibiotics include vancomycin and aminoglycosides and therapeutic monitoring of their blood levels needs to be performed if these agents are to be used. Herpes zoster infection is also a common clinical problem in the community. The dose of acyclovir should be properly adjusted according to eGFRand the side effects (confusion, crystallization of drugs in renal tubules, etc.)are generally more common when eGFR is <60ml/min/1.73m2 and hence should be carefully monitored.The use of oseltamivir for influenza in renal failure patients is associated with increased gastrointestinal side effects and dose reduction would be needed(eGFR 31-60 ml/min/1.73m2: 30 mg bd for 5 days; eGFR11- 30 ml/min/1.73m2: 30mg daily for 5 days; avoid if eGFR<10 ml/ min/1.73m2).Conventional anti-fungal agent such as amphotericin B can accentuate renal deterioration, especially in patients with underlying CKD, and renal function and electrolytes should be closely monitored should these patients be treated with amphotericin. A liposomal form of amphotericin B might be associated with lower toxicity at the organ level and hence can be considered as a viable option if amphotericin needs to be used in CKD patients. Azole groups or newer anti-fungal agents such ecchinocandinsshould also be considered as alternatives in CKD patients.
4.2 Drugs used in cardiovascular diseases
Renin-angiotensin-aldosterone blocking agents are commonly used in patients with CKD for renal protection, reduction of proteinuria and control of blood pressure. The use of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) can precipitate renal deterioration in patients with pre-existing renal artery stenosis or severe kidney dysfunction(e.g. Stage 4-5 CKD). Clinicians should look for renal bruits before embarking on ACEI/ ARB and closely monitor renal function tests after their initiation. A rise of serum Cr >15% above baseline would generally require discontinuation of these agents. Furthermore, hyperkalemia is also a common problem in the use of ACEI/ARB in CKD patients. Patients should be advised to consume low potassium diets to prevent these unwanted complications. Other anti-hypertensives such as alphablockers, beta-blockers, calcium channel blockers, hydralazine and methyldopa are generally safe in CKD patients. Digoxin is a commonly used rate-controlling agent in patients with atrial fibrillation. The use of digoxin in CKD patients can be complicated, especially in those with hypo/hyperkalemia and hence proper dosage reduction should be exercised.
4.3 Drugs used in cardiovascular diseases
Diabetes mellitus is one of the most common medical problems encountered in family physicians. Many oral hypoglycemic agents such as sulphonylurea and dipeptidyl peptidase-4 (DPP4) inhibitors (except linagliptin) require appropriate dosage modification [13,14]. The use of metformin can result in severe lactic acidosis and should be avoided in patients with moderate to severe kidney dysfunction (The author would generally avoid metformin in patients with serum Cr >150 μmol/L). Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists should not be used in CKD patients as they are associated with increased risk of cardiovascular events and fluid overload15. In general, switching to insulin therapy should be considered in patients with moderate to severe reduction in GFR(e.g. eGFR<30 ml/min/1.73m2). Gout and hyperuricemia is commonly associated with CKD. The dose of allopurinol should be adjusted according to renal function (eGFR 10-20 ml/min/1.73m2: 100-200mg/ day; eGFR<10 ml/min/1.73m2: 100mg daily)and colchicine should be used with caution in CKD patients in view of their potential to cause myopathy.
4.4 Drugs used in malignancy conditions and autoimmune diseases
Many cytotoxic agents and immunosuppressants require significant dosage modification in CKD patients. Examples include cyclophosphamide, methotrexate and mycophenolic acid (MPA) [16-18]. The failure to adjust dosage of these agents according to renal function might result in severe myelosuppression, and hence life-threatening infective complications. There are also some lethal drug-drug interaction for treatments commonly used in autoimmune kidney diseases such as allopurinol and azathioprine (AZA) [19]. Very often substitution with other immunosuppressive agents might be needed before initiation of allopurinol and patients should be referred to the relevant specialists. Caution should be also exercised during prescription of other medications for CKD patients who are receiving calcineurin inhibitors (CNI). Rifampicin will induce CYP450 to enhance CNI metabolism and lead to reduced efficacy of CNI [20]. Conversely, the use of macrolide antibiotics or azoles for fungal infection will inhibit CYP450 and hence increase the nephrotoxic and immunosuppressive effects of CNI [20].
4.5 Drugs used for analgesia
Non-steroidal anti-inflammatory drugs (NSAIDS) are wellrecognized nephrotoxic analgesics. NSAIDs can lead to acute renal failure, glomerulonephritis (e.g. membranous nephropathy), acute or chronic interstitial nephritis and papillary necrosis [21]. CKD patients are at increased risk of the NSAID-related nephrotoxic side effects and the risk correlated with the severity of CKD. Cyclo-oxygensase 2 (COX2) inhibitors cause less gastrointestinal problems, but their nephrotoxic effects appear to be similar to NSAIDs [22]. Other painkillers such as paracetamol, weak or strong opioids are generally safe in CKD patient, although previous studies have reported that opioids and its metabolites can accumulate in patients with advanced CKD [23].
4.6 Teratogenicity of drugs commonly used in CKD patients
Many drugs commonly used in CKD patients have teratogenic potential and have to be discontinued when pregnancy is contemplated. One good example is ACEI/ARB which can cause renal agenesis in the fetus [24]. Clinicians should take the initiative to enquire for pregnancy plans in female CKD patients in the reproductive age. ACEI/ARB should be discontinued and the blood pressure/proteinuria be closely monitored in patients who wish to get pregnant. MPA, a commonly used maintenance therapy in autoimmune glomerular diseases, can cause teratogenicity and might be replaced by AZA or CNI if pregnancy is considered [25]. The decision of changing immunosuppressive treatments should also take into consideration the past history of flare and current disease activity.
5. Conclusion
CKD patients have altered drug metabolism and increased susceptibility to nephrotoxic medications. Avoidance of nephrotoxic drugs and potential drug interactions, appropriate adjustment of dosage and vigilant monitoring of renal functioncan help minimize unwanted side effects of these agents in CKD patients.
Competing Interests
The authors declare that they have no competing interests.