Drug Dosing in Chronic Kidney Disease

Acute kidney injury (AKI) is defined as an injury to the renal parenchyma, with or without a decrease in kidney function, as reflected by accumulation of uremic toxins or altered urine production (i.e., increased or decreased). AKI might result from any of several factors, including ischemia, inflammation, nephrotoxins, and infectious diseases. AKI can be community- or hospital-acquired. The latter was not previously considered a common cause for AKI in animals; however, recent evidence suggests that the prevalence of hospital-acquired AKI is increasing in veterinary medicine. This is likely due to a combination of increased recognition and awareness of AKI, as well as increased treatment intensity (e.g., ventilation and prolonged hospitalization) in some veterinary patients and increased management of geriatric veterinary patients with multiple comorbidities.

Advancements in the management of AKI, including the increased availability of renal replacement therapies, have been made; however, the overall mortality of animals with AKI remains high. Despite the high prevalence of AKI and the high mortality rate, the body of evidence regarding the diagnosis and the management of AKI in veterinary medicine is very limited. Consequently, the International Renal Interest Society (IRIS) constructed a working group to provide guidelines for animals with AKI. Recommendations are based on the available literature and the clinical experience of the members of the working group and reflect consensus of opinion. Fifty statements were generated and were voted on in all aspects of AKI and explanatory text can be found either before or after each statement

The novel nucleoside analog, 4′-cyano-2′-deoxyguanosine (CdG), possesses inhibitory activity against both the wild-type and resistant hepatitis B virus. Since the dosage of the currently available nucleoside analog preparations needs to be adjusted, depending on renal function, we investigated the effect of renal dysfunction on the pharmacokinetics of CdG in a rat model of chronic kidney disease (CKD).

CKD model rats were either intravenously or orally administered CdG at a dose of 1 mg/kg. The concentration of CdG in plasma, organs (liver and kidney) and urine samples were determined by means of a UPLC system interfaced with a TOF-MS system.

Following intravenous administration, the plasma retention of CdG was prolonged in CKD model rats compared to healthy rats. In addition, the clearance of CdG was well correlated with plasma creatinine levels in CKD model rats. Similar to the results for intravenous administration, the plasma concentration profiles of CdG after oral administration were also found to be much higher in CKD model rats than in healthy rats. However, the results for the organ distribution and urinary excretion of CdG, the profiles of which were similar to that of healthy rats, indicated that CdG did not accumulate to a significant extent in the body.

The extent of renal dysfunction has a direct influence on the pharmacokinetics (plasma retention) of CdG without a significant accumulation, indicating that the dosage of CdG will be dependent on the extent of renal function. .

In ENDEAVOR, carfilzomib (56 mg/m²) and dexamethasone (Kd56) demonstrated longer progression-free survival (PFS) over bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (RRMM). Here we evaluated Kd56 vs Vd by baseline renal function in a post hoc exploratory subgroup analysis. The intent-to-treat population included 929 patients (creatinine clearance [CrCL] ≥15 to <50 mL/min, n = 85 and n = 99; CrCL 50 to <80 mL/min, n = 186 and n = 177; and CrCL ≥80 mL/min, n = 193 and n = 189 for Kd56 and Vd arms, respectively). In these respective subgroups, median PFS was 14.9 vs 6.5 months (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.320-0.757), 18.6 vs 9.4 months (HR, 0.48; 95% CI, 0.351-0.652), and not reached (NR) vs 12.2 months (HR, 0.60; 95% CI, 0.434-0.827) for those receiving Kd56 vs Vd, respectively; median overall survival (OS) was 42.1 vs 23.7 months (HR, 0.66; 95% CI, 0.443-0.989), 42.5 vs 32.8 months (HR, 0.83; 95% CI, 0.626-1.104), and NR vs 42.3 months (HR, 0.75; 95% CI, 0.554-1.009). Complete renal response (ie, CrCL improvement to ≥60 mL/min in any 2 consecutive visits if baseline CrCL <50 mL/min) rates were 15.3% (95% CI, 8.4-24.7) and 14.1% (95% CI, 8.0-22.6) for those receiving Kd56 vs Vd, respectively. In a combined Kd56 and Vd analysis, complete renal responders had longer median PFS (14.1 vs 9.4 months; HR, 0.805; 95% CI, 0.438-1.481) and OS (35.3 vs 29.7 months; HR, 0.91; 95% CI, 0.524-1.577) vs nonresponders. Grade ≥3 adverse event rates in the respective subgroups were 87.1% vs 79.4%, 84.4% vs 71.8%, and 77.1% vs 65.9% for those receiving Kd56 vs Vd, respectively. Thus, Kd56 demonstrated PFS and OS improvements over Vd in RRMM patients regardless of their baseline renal function. The ENDEAVOR trial was registered at www.clinicaltrials.gov as #NCT01568866.

End stage renal disease (ESRD) is increasing in the U.S., and these patients demonstrate greater all-cause mortality, cardiovascular events, and hospitalization rates when compared to those with normal renal function. These patients may experience significant complications associated with loss of renal function and dialysis.

This review evaluates complications of ESRD including cardiopulmonary, neurologic, infectious disease, vascular, and access site complications, as well as medication use in this population.

ESRD incidence is rapidly increasing, and patients commonly require renal replacement therapy including hemodialysis (HDS) or peritoneal dialysis (PD), each type with specific features. These patients possess greater risk of neurologic complications, cardiopulmonary pathology, infection, and access site complications. Focused history and physical examination are essential. Neurologic issues include uremic encephalopathy, cerebrovascular pathology, and several others. Cardiopulmonary complications include pericarditis, pericardial effusion/tamponade, acute coronary syndrome, sudden cardiac death, electrolyte abnormalities, pulmonary edema, and air embolism. Infections are common, with patients more commonly presenting in atypical fashion. Access site infections and metastatic infections must be treated aggressively. Access site complications include bleeding, aneurysm/pseudoaneurysm, thrombosis/stenosis, and arterial steal syndrome. Specific medication considerations are required for analgesics, sedatives, neuromuscular blocking agents, antimicrobials, and anticoagulants.

Consideration of renal physiology with complications in ESRD can assist emergency providers in the evaluation and management of these patients. ESRD affects many organ systems, and specific pharmacologic considerations are required.

Critically ill patients present a challenge in drug management because their clinical condition can change quite rapidly. In addition, acute pathophysiology may have a transient impact on pharmacokinetics for certain drugs that are difficult to predict. Conditions such as uremia or hypoproteinemia can significantly impact free drug concentrations for drugs such as valproic acid, leading to toxic effects at standard doses. This chapter discusses pathophysiologic changes associated with critically ill patients and opportunities for therapeutic drug monitoring to be used in the management of these patients.

Patients with kidney disease frequently experience adverse effects from medication exposure, even when drugs are cleared by nonrenal pathways. Although many studies suggest that nonrenal drug clearance is decreased in chronic kidney disease (CKD), there remains a paucity of in vivo studies in patients with varying degrees of decreased kidney function and those comparing the impact of dialysis modality (eg, hemodialysis [HD] and peritoneal dialysis [PD]).

We performed in vivo clinical pharmacokinetic studies of midazolam, a nonrenally cleared specific probe for CYP3A4, and fexofenadine, a nonspecific probe for hepatic and intestinal transporters.

Healthy controls (n = 8), patients with non−dialysis-dependent (NDD)-CKD (n = 8), and patients receiving HD (n = 10) or PD (n = 8).

Exposure to midazolam and fexofenadine were quantified using area under the curve (AUC). Comprehensive pharmacokinetic parameters also were calculated for both probes.

Midazolam AUC was significantly higher in the HD group (382.8 h·ng/mL) than in the healthy-control (63.0 h·ng/mL; P < 0.001), NDD-CKD (84.5 h·ng/mL; P = 0.002), and PD (47.4 h·ng/mL; P < 0.001) groups. Fexofenadine AUC was significantly higher in each of the NDD-CKD (2,950 h·ng/mL; P = 0.003), HD (2,327 h·ng/mL; P = 0.01), and PD (2,095 h·ng/mL; P = 0.04) groups compared with healthy controls (1,008 h·ng/mL).

Small study groups had different proportions of diabetic patients, early stages of CKD not available.

Our data suggest that selection of dialysis modality is a major determinant of exposure to the CYP3A4 probe midazolam. Exposure to the intestinal and hepatic transporter probe fexofenadine is altered in patients with NDD-CKD and PD and HD patients. Thus, drug development and licensing of nonrenally cleared drugs should include evaluation in these 3 patient groups, with these results included in approved product information labeling. This reinforces the critical need for more in vivo studies of humans that evaluate the exposure to drugs cleared by these pathways.