Chronic kidney disease (CKD) is the silent epidemic. It often follows hypertension, diabetes, and obesity. Patients with CKD are not seen exclusively in a nephrology practice. Often, they are not referred to a nephrologist until their glomerular filtration rate (GFR) is less than 60 mL/min/1.73m2.
CKD affects 11.5% of the US population ages 20 and older,1 which translates to some 23 million people. According to the National Institute of Diabetes and Digestive and Kidney Diseases, more than 382,000 people were receiving dialysis in 2008,1 and this number is expected to more than double by 2020. It is essential for the practitioner in any specialty to be aware of their patients’ renal status and any adjustments that may entail.
Q: In my primary care office, I saw a dialysis patient with peripheral neuropathy caused by her diabetes. I treated her with gabapentin 300 mg qd with an increase of 100 mg each week until her symptoms resolved. I received a note from the nephrology group that the dose I ordered was way too high, and they adjusted it down to 100 mg/d. Is that right? Would it have been better for me to prescribe pregabalin? I was trying to use an inexpensive medication because this patient has to take so many.
Gabapentin has been used for years in the dialysis unit to treat patients with diabetes-related peripheral neuropathy.2 It is one of the most commonly prescribed drugs for this population of patients due to its effectiveness and low adverse-effect profile. However, because gabapentin is cleared solely by renal excretion, it is recommended that patients on dialysis receive 200 to 300 mg after each four-hour hemodialysis session. This dose should be reached with gradual titration to avoid adverse effects, which include dizziness, ataxia, sedation, euphoria, ankle edema, and weight gain.
The risk for altered consciousness and myoclonus associated with gabapentin is increased in the dialysis population. When these adverse effects occur, the drug should be stopped. Doses above the recommended 200 to 300 mg per dialysis session have not been shown to provide any added analgesic effect and may increase adverse effects, putting patients at greater risk for falls, in addition to other side effects. Gabapentin has a much longer half-life in patients on dialysis, compared with those who have normal kidney function. These patients will benefit from a minimal dosing schedule as well as the prolonged pain control with gabapentin.
The efficacy of pregabalin (Lyrica®) in the management of painful diabetic neuropathy has been established in several controlled clinical trials.3 Because it has not been in use as long as gabapentin, its safety profile has not yet been established. Pregabalin has better gastrointestinal absorption than gabapentin and offers more rapid pain relief; it can be administered twice daily. Pregabalin is cleared rapidly by dialysis and has a short half-life; therefore, an extra dose is required after each dialysis session. Pregabalin dosing must also be adjusted for creatinine clearance.*
Pregabalin is a Schedule V controlled substance because of its potential for abuse. It cannot be prescribed by advanced practitioners in all states.
Dawn McCombs, CRNP, Nephrology Associates, PC, Birmingham, AL
* Several sources are available on the Internet to determine creatinine clearance or stage of kidney disease if your lab does not calculate it for you.
Q: In diabetic patients with incipient nephropathy (microalbuminuria, but GFR > 90 mL/min, more specifically), do evidence-based recommendations exist that suggest renal dosing parameters be followed in order to protect against progressive nephropathy? This, of course, would constitute a secondary prevention strategy, since (as most clinicians know) glycemic and blood pressure control are the most important primary steps toward prevention.
A patient with microalbuminuria and preserved renal function, according to the estimated GFR (eGFR), would be classified as having CKD stage 2. Currently, no medication dosing guidelines are available for patients at this stage of CKD; however, as providers, we should be aware that the presence of microalbuminuria has important clinical implications.
Microalbuminuria is associated with increased risk for cardiovascular disease and progression of CKD.4 Accordingly, medication selection should be targeted at avoiding renal insult, limiting progression of nephropathy through the use of ACE inhibitors or angiotensin receptor blockers (ARBs), and promptly addressing and modifying the risk factors for cardiovascular disease.
Blood pressure (BP), glycemic control, and lipids should all be managed aggressively. The JNC7 (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure)5 and the K/DOQI (Kidney Disease Outcomes Quality Initiative) guidelines6 recommend a target BP below 130/80 mm Hg for CKD patients with proteinuria of less than 1 g/24 h; and below 120/80 mm Hg for patients with proteinuria greater than 1 g/24 h. Unpublished guidelines from “Kidney Disease: Improving Global Outcomes” (see www.kdigo.org) are encouraging practitioners to give nonhypertensive diabetic patients with proteinuria an ACE inhibitor or an ARB.
Nephrotoxins, such as NSAIDs and aminoglycosides, should be avoided. Contrast dye and nephrotoxic chemotherapeutic agents should be used with caution and only if clinically justified. If they are used, renal precautions should be taken, including preprocedure and postprocedure hydration.7
Whenever possible, an ACE inhibitor or an ARB should be initiated early, as the greatest benefit in slowing the progression of nephrosclerosis is realized when these medications are initiated before irreversible scarring has occurred.5,6 Initiating one of these agents is preferable while the serum creatinine level is below 1.2 mg/dL.8 Creatinine and potassium should be checked within two weeks of initiating or increasing ACE inhibitor or ARB dosing.
As CKD progresses, patients are at risk for acidemia and hyperkalemia. Typically, these concerns are greater in CKD stages 4 to 5 but can be seen as early as CKD stage 3. Metformin should be prescribed with caution in patients with CKD stage 2 and changed to an alternate antihyperglycemic agent for men whose serum creatinine exceeds 1.5 mg/dL and for women with serum creatinine greater than 1.4 mg/dL.8
Clinically, it is recommended that metformin be avoided in patients whose eGFR is below 60 to 70 mL/min.9 The eGFR is a better indicator of CKD stage than serum creatinine; using serum creatinine alone to calculate the CKD stage could lead to a very wrong result. For example, a thin, elderly white woman can have a very low eGFR but a serum creatinine of 1.4 mg/dL or less (which is essentially normal).
Diabetic patients in particular are susceptible to hyperkalemia, so spironolactone, potassium, and sulfamethoxazole should be prescribed with caution. Potassium levels should be monitored in patients receiving b-blockers, ACE inhibitors, or ARBs.
Renal medication dosing guidelines, as noted in the FDA information in each drug’s package insert, generally offer recommendations for adjustment in CKD stage 4 or 5, which correspond to an eGFR of < 30 mL/min or < 15 mL/min, respectively. FDA renal dosing guidelines are often based on serum creatinine, but eGFR can vary widely for a particular serum creatinine level, depending upon patient variables such as age, weight, race, and gender (as in the example above).
In summary, although no specific published guidelines exist for patients with CKD stage 2, the presence of microalbuminuria is an important clinical indicator that should inform the provider’s approach to patient management.
Alexis Chettiar, ACNP, East Bay Nephrology Medical Group, Oakland, CA
1. National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). http://kidney.niddk.nih.gov. Accessed November 18, 2011.
2. Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis. 2001;38(1):104-108.
3. Blommel ML, Blommel AL. Pregabalin: an antiepileptic agent useful for neuropathic pain. Am J Health-System Pharm. 2007;64(14):1475-1482.
4. Gerstein HC, Mann JF, Yi Q, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001;286(4):421-426.
5. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.
6. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004; 43(5 suppl 1):S1-290.
7. National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI™). www.kidney.org/professionals/kdoqi. Accessed November 18, 2011.
8. Post TW, Rose BD. Overview of management of chronic kidney disease in adults. www.uptodate.com/contents/overview-of-the-management-of-chronic-kidney-disease-in-adults/contributors. Accessed November 18, 2011.
9. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131(4):281-303.