Advances in Chronic Kidney Disease
Volume 17, Issue 5 , Pages 381-383, September 2010

CKD: Pharmacotherapy in a House of Mirrors

Article Outline

 

This issue of Advances in Chronic Kidney Disease addresses current challenges and new knowledge relevant to pharmacotherapy in patients with CKD. Although drug discovery and therapeutic frontiers have contributed greatly to the advancement of treatment for diseases, such as cardiovascular disease and diabetes mellitus, CKD continues to impose a high level of physiologic, pharmacologic, pharmacodynamic, and pharmacokinetic (PK) complexity that makes optimal use of drug therapy challenging for the clinician. This issue seeks to provide insight into these complex therapeutic challenges.

Decreased renal drug elimination, a common consequence of reduced kidney function, has traditionally taken center stage when evaluating pharmacokinetic nuances in CKD patients. However, emerging data now indicate that the nonrenal clearance of drugs is altered in CKD and can have a prominent role in drug disposition. Dr. Nolin provides insight into the influence of CKD on the factors involved in intestinal and hepatic metabolism and transport, and how these may influence drug disposition in CKD patients. In fact, the Food and Drug Administration recently issued a draft for new guidance in evaluating the pharmacokinetics of investigational drugs, which supports the study of nonrenally cleared medications in CKD patients.1 A review of the draft guidance by both the American Society of Nephrology and Kidney Disease: Improving Global Outcomes (KDIGO) Foundation have also called for additional focus on patients with acute kidney injury or those undergoing other modalities of dialysis including short daily ambulatory hemodialysis, extended daily dialysis, or sustained low-efficiency dialysis.2 In fact, KDIGO recently launched an initiative for improved drug dosing in CKD and a position statement is expected this year.3

Drug dosing in special populations continues to be a vexing issue for clinicians. Over the last several decades, obesity rates have soared in the United States, with approximately one-third of Americans now classified as obese.4 However, most pharmacokinetic studies have focused on only normal-weight subjects, with little investigation regarding body weight descriptors and appropriate estimations of glomerular filtration rate. With the rates of obesity reaching epidemic proportions in the United States, clinicians face a multitude of unknowns in their attempts to estimate renal function in obese patients. Accordingly, very little is known about appropriate drug dosing in obesity, particularly in the setting of CKD. Dr. Pai provides evidence and insight into this rapidly growing population to illuminate the necessary considerations for determining a drug-dosing regimen that is both efficacious and safe.

Infections are common in CKD and a major cause of morbidity and mortality. Traditionally, dosing of antimicrobials in patients with CKD has solely focused on pharmacokinetic considerations. Dr. Mueller explores the key pharmacodynamic principles that predict an optimal antibiotic dosing regimen. When considered together with dosing antimicrobials, pharmacodynamic and pharmacokinetic drug characteristics help ensure optimal treatment of the broad spectrum of infections that occur in CKD patients.

Antimicrobials are certainly not the only drugs that require careful consideration in patients with CKD. As CKD progresses, increasing complexity in the patient’s prescribed medication regimen (e.g., stage 3/4 CKD: 6 to 8 medications/day; stage 5D CKD: 12 medications/day) leads to an increased prevalence of medication-related problems (MRPs). It is estimated that in CKD stage 5D alone, over US $10 billion is spent annually on MRPs.5 Studies have shown that identifying and resolving MRPs in the CKD population (particularly stage 5D) can improve quality of life and reduce hospitalizations, length of stay, mortality, and costs to the healthcare system. Dr. Manley reviews the effect of MRPs in CKD and offers strategies that clinicians can implement to resolve MRPs.

Three characteristics of medication use in CKD patients create the “perfect storm” for a drug misadventure; these include increased prevalence of polypharmacy, multiple healthcare providers, and frequent hospitalizations and/or transitions of care. In fact, the Institute for Healthcare Improvement, Institute of Safe Medication Practices, and the Joint Commission all recognize that gaps in medication knowledge occurring during transitions of care are responsible for up to 50% of medication errors in the hospital and up to 20% of adverse drug events.6, 7, 8 Often, what is “prescribed” for the patient, and what the patient actually takes, can be 2 completely discordant pieces of medical history. This gap in what information is accepted at face value, and what information is carefully gleaned from the patient, carves out a critical role for thorough medication reconciliation. A list of medications that accurately reflects what the patient is taking should be the cornerstone of every patient’s treatment plan and should be communicated and effectively disseminated to all clinicians involved in caring for the patient. Dr. St. Peter describes compelling data to accelerate initiatives to properly reconcile patient’s medication histories. She offers several pragmatic strategies that have been shown to improve the medication reconciliation process in CKD patients.

Several drug classes are burdened with unique pharmacologic, pharmacodynamic, and PK challenges that complicate their use in CKD. Systemic anticoagulation continues to be a challenging therapeutic issue, because CKD patients frequently have coagulopathies that increase their propensity for both thrombosis and bleeding. Making anticoagulation even more difficult in clinical practice is the lack of data on efficacy of these agents in CKD. Most clinical trials of anticoagulant therapy have excluded CKD patients. Thus, developing effective yet safe anticoagulation regimens poses a formidable challenge in CKD. Dr. Dager reviews important CKD-related considerations regarding therapy with widely used anticoagulants such as warfarin, unfractionated heparin, low-molecular weight heparin, fondaparinux and direct thrombin inhibitors. The authors also enlighten clinicians regarding anticoagulants that are in the late stages (e.g., phases 2 and 3) of the drug development process.

In addition to problems associated with widely used drug classes in CKD, certain rare but devastating disease states present pharmacotherapeutic challenges that are complicated by a lack of strong clinical trial evidence. Although calcemic uremic arteriolopathy (i.e., calciphylaxis) occurs in a small proportion of CKD patients, its consequences can yield a bleak prognosis for the affected patient. A lack of randomized controlled trials leaves clinicians to rely almost solely on case reports of nonpharmacologic and pharmacologic treatments. Recently, use of sodium thiosulfate has been increasing and Dr. Mason reviews this potential treatment, as well as bisphosphonates, cinacalcet, and tissue plasminogen activator for treatment of calciphylaxis.

Another cumbersome challenge for the healthcare provider caring for CKD patients is optimizing glycemic control. In the past 5 years, 2 new classes of incretin-based therapies (glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase-IV inhibitors) have broadened the treatment options for diabetes mellitus; however, the role of these agents in CKD remains less established. The efficacy and safety of these agents, along with special considerations for their use in CKD, are reviewed by Dr. Pinelli in this issue.

A kidney transplant changes the life and ultimately the mortality risk for the patient with ESRD. Optimizing immunosuppressive regimens after kidney transplant poses many challenges, most importantly finding that delicate balance between over- and under-suppression of the immune system. Dr. Fleming explores both the strengths and limitations of therapeutic drug monitoring of the calcineurin inhibitors and mycophenolate mofetil in kidney transplant patients. He also explores the use of biomarkers, including FOXP3 (forkhead box P3), urine proteomic analysis, soluble CD30, intracellular ATP, and the enzyme-linked immunosorbent spot assay, that may offer advanced sophistication to the art of monitoring of immunosuppression.

In summary, CKD imparts numerous challenges that require a multifaceted approach to optimizing pharmacotherapy. Emerging paradigms for optimal drug dosing include incorporation of nonrenal clearance, consideration of evidence-based data in special populations in CKD, optimizing pharmacodynamic properties of drugs, expanding our knowledge of new drugs in the CKD population, and increasing focus on the complexity of medication regimens used in these patients. These facets are critical to advancing pharmacotherapy in CKD and realizing the goal of improved life expectancy.

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References 

  1. Guidance for Industry: Pharmacokinetics in patients with impaired renal function—Study design, data analysis, and impact on dosing and labeling. Available at: http://www.asn-online.org/policy_and_public_affairs/docs/Draft%20FDA%20Guidance%20for%20PK%20Studies%20in%20Renal%20Failure%203%2010.pdf. Accessed June 7, 2010
  2. Letter from ASN to FDA dated 5/21/10. Available at: http://www.asn-online.org/policy_and_public_affairs/docs/ASN%20Letter%20on%20FDA%20PK%20Draft%20Guidelines.pdf. Accessed June 7, 2010
  3. KDIGO Controversies Conference: Drug Prescribing in Kidney Disease: Initiative for Improved Dosing, Baltimore, MD, May 2010. Available at: http://www.kdigo.org/meetings_events/drug_Prescribing_in_KD-Initiative_for_Improved_Dosing.php. Accessed June 10, 2010
  4. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303:235–241
  5. Kaplan B, Mason NA, Shimp LA, et al. Chronic hemodialysis patients. Part I: Characterization and drug-related problems. Ann Pharmacother. 1994;28:316–318
  6. Institute for Healthcare Improvement: Prevent Adverse Drug Events (Medication Reconciliation). Institute for Healthcare Improvement (IHI) website. Available at: http://www.ihi.org/IHI/Programs/Campaign/ADEsMedReconciliation.htm. Accessed June 9, 2010
  7. Institute for Safe Medication Practices: ISMP Medication Safety. Institute for Safe Medication Practices website. Available at: http://www.ismp.org/newsletters/acutecare/articles/20050421.asp. Accessed June 9, 2010
  8. The Joint Commission: Sentinel Event Alert #35. Using medication reconciliation to prevent errors. The Joint Commission website. Available at: http://www.jointcommission.org/SentinelEvents/SentinelEventAlert/sea_35.htm. Accessed June 9, 2010

PII: S1548-5595(10)00116-3

doi:10.1053/j.ackd.2010.06.005

Advances in Chronic Kidney Disease
Volume 17, Issue 5 , Pages 381-383, September 2010

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