Drug Transporter Function--Implications in CKD.

Drug transporters typically move substrates, including drugs, in an intracellular to extracellular direction and thus are efflux transporters. There is a small subset of transporters that move substrates in the opposite direction and are classified as influx transporters. Collectively, drug transporters contribute to the pharmacokinetic profile of a wide variety of drugs and other molecules including xenobiotics, metabolites, and endogenous solutes. Identification of genetic variants in the genes that encode these transporters is an emerging area of pharmacogenomics. Many polymorphisms of the multitude of genes that code for the transporters within the 2 major superfamilies (ATP-binding cassette transporters and solute carrier transporters) have been identified. Studies have shown that many single-nucleotide polymorphisms are associated with changes in protein expression, functionality, and drug exposure; however, there are limited data for most single-nucleotide polymorphisms and impact on clinical end points. Preliminary data suggest that patients with CKD may have reduced transporter function that may have effects on exposure and toxicity profiles. Additional research translating the functional significance of polymorphisms on clinical pharmacokinetics and relevant disease-specific end points will provide further understanding of the role of genetic variations in transporter genes.

Aldosterone blockade in CKD: emphasis on pharmacology.

Besides its epithelial effect on sodium retention and potassium excretion in the distal tubule, aldosterone promotes inflammation and fibrosis in the heart, kidneys, and blood vessels. As glomerular filtration rate falls, aldosterone is inappropriately elevated relative to extracellular fluid expansion. In addition, studies in CKD patients on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or direct renin inhibitors have shown that aldosterone levels paradoxically rise in approximately 30% to 40% of patients on these renin-angiotensin system-blocking drugs. Hence, there is interest in using mineralocorticoid receptor blockers that directly target the inflammatory and fibrotic effects of aldosterone in CKD patients. This interest, however, is tempered by a number of unresolved issues, including the safety of using such drugs in advanced CKD and ESRD populations, and the potential for differences in drug efficacy according to race and ethnicity of patient populations. A better understanding of mineralocorticoid receptor blocker pharmacology should help inform future research directions and clinical practice decisions as to how best to use these agents in CKD.

Should mycophenolate mofetil replace cyclophosphamide as first-line therapy for severe lupus nephritis?

Available treatments for severe (class III, IV, and V) lupus nephritis (LN) have expanded greatly over the last 40 years. In the 1970s and 1980s, cyclophosphamide (CYC), in combination with glucocorticoids, gained favor as induction and maintenance therapy for severe LN. However, the adverse event profile of CYC led to the search for other medications for severe LN. Beginning in the late 1990 s, mycophenolate mofetil (MMF) was introduced as induction and maintenance therapy for severe LN. This review discusses the clinical trial results, pharmacology, cost-effectiveness, and adverse effect profiles of CYC compared to MMF for induction and maintenance therapy for severe LN. The authors conclude that MMF should be considered first-line induction and maintenance treatment therapy for severe LN, although CYC may have a place under specific clinical and economic circumstances.

Ferumoxytol: a new intravenous iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease.

Ferumoxytol is an intravenous iron preparation for treatment of the anemia of chronic kidney disease (CKD). It is a carbohydrate-coated, superparamagnetic iron oxide nanoparticle. Because little free iron is present in the preparation, doses of 510 mg have been administered safely in as little as 17 seconds. Two prospective, randomized studies compared two doses of ferumoxytol 510 mg given in 5 +/- 3 days with 3 weeks of oral iron 200 mg/day (as ferrous fumarate) in anemic patients with CKD. One study enrolled 304 patients with stages 1-5 CKD (predialysis), and the other study enrolled 230 patients with stage 5D CKD (undergoing hemodialysis). In both studies, a greater increase in hemoglobin level from baseline to end of study (day 35) was noted in patients who received ferumoxytol compared with those who received oral iron (mean +/- SD 0.82 +/- 1.24 vs 0.16 +/- 1.02 g/dl in patients with stages 1-5 CKD and 1.02 +/- 1.13 vs 0.46 +/- 1.06 g/dl in patients with stage 5D CKD, p<0.001). A greater proportion of both predialysis and hemodialysis patients who received ferumoxytol had hemoglobin level increases from baseline of 1 g/dl or more compared with those who received oral iron (p<0.001). In a prospective, double-blind, crossover study of more than 700 patients with CKD stages 1-5D that compared the safety of ferumoxytol with normal saline injection, the rates of treatment-related adverse events were 5.2% and 4.5%, respectively. Serious treatment-related adverse events were seen in one patient in each treatment group. The most common adverse events with ferumoxytol occurred at the injection site (bruising, pain, swelling, erythema). Dizziness, nausea, pruritus, headache, and fatigue occurred in less than 2% of patients receiving ferumoxytol, with a similar frequency noted after administration of normal saline. In short-term studies, intravenous ferumoxytol was safely and rapidly administered, and was more effective than oral iron therapy in increasing hemoglobin levels in anemic patients with CKD. Long-term clinical trials with clinical outcomes and studies comparing ferumoxytol with other parenteral iron agents will help define the role of ferumoxytol in treating the anemia of CKD.

The safety and efficacy of ferumoxytol therapy in anemic chronic kidney disease patients.

BACKGROUND: Administration of safe and effective iron therapy in patients with chronic kidney disease is a time consuming process. This phase II clinical trial studied ferumoxytol, a semi-synthetic carbohydrate-coated iron oxide administered by rapid intravenous injection to anemic chronic kidney disease patients (predialysis or undergoing peritoneal dialysis). METHODS: Inclusion criteria included hemoglobin < or =12.5 g/dL and transferrin saturation < or =35%. Twenty-one adult patients were randomized to receive ferumoxytol in a regimen of 4 doses of 255 mg iron in 2 weeks or 2 doses of 510 mg iron in 1 to 2 weeks. Ferumoxytol was administered at a rate of up to 30 mg iron/sec. RESULTS: The maximum hemoglobin response following ferumoxytol administration occurred at 6 weeks, increasing from a baseline of 10.4 +/- 1.3 g/dL to 11.4 +/- 1.2 g/dL (P < 0.05). Ferritin increased from a baseline of 232 +/- 216 ng/mL to a maximum of 931 +/- 361 ng/mL at 2 weeks (P < 0.05), while the baseline transferrin saturation increased from 21 +/- 10% to 37 +/- 22% at 1 week (P < 0.05). Seven adverse events in 5 patients during this trial were deemed possibly related to ferumoxytol, none serious. These events included constipation, chills, tingling, a gastrointestinal viral syndrome, delayed pruritic erythematous rash, and transient pain at the injection site. CONCLUSION: Although larger studies are required, this small study demonstrates that ferumoxytol can be safe and effective in increasing iron stores, is associated with an increased hemoglobin response, and is well tolerated at a rapid infusion rate.

Safety of iron sucrose in hemodialysis patients intolerant to other parenteral iron products.

BACKGROUND/AIMS: This report summarizes the data gathered in four prospective studies of intravenous iron sucrose therapy administered to iron-deficient hemodialysis patients with a history of intolerance to other parenteral iron preparations. METHODS: A total of 130 iron dextran- and/or sodium ferric gluconate-sensitive patients received intravenous iron sucrose therapy to correct iron deficiency, and/or maintain body iron stores. A history of intolerance to iron dextran alone was reported in 109 patients, to ferric sodium gluconate alone in 6 patients, and to both iron dextran and ferric sodium gluconate in 15 patients. Therapy with iron sucrose consisted of 100- or 200-mg doses administered undiluted intravenously over 2-5 min, or diluted in normal saline and infused over 15-30 min. Test doses of iron sucrose were not administered. The median cumulative dose was 1,000 mg, with a range of 100-5,000 mg. RESULTS: There were no serious adverse events related to iron sucrose therapy in the 130 patients intolerant to other iron preparations. There were 14 nonserious drug-related adverse events in 8 patients attributed to iron sucrose, none of which resulted in discontinuation of therapy. These events were classified as either of severe (diarrhea), moderate (hypotension, nausea, vomiting), or mild severity (constipation, dry mouth, skin irritation). CONCLUSION: Iron sucrose therapy is safe and well tolerated in hemodialysis patients intolerant to iron dextran and/or sodium ferric gluconate.

The safety and efficacy of an accelerated iron sucrose dosing regimen in patients with chronic kidney disease.

BACKGROUND: Provision of adequate iron to support erythropoiesis in patients with chronic kidney disease (CKD) is time consuming and may present adherence problems for patients in the outpatient setting. We studied an accelerated regimen of high-dose intravenous iron sucrose therapy in a cohort of iron-deficient, anemic CKD patients. METHODS: Intravenous iron sucrose 500 mg was infused over three hours on two consecutive days in 107 CKD patients (glomerular filtration rate, 32.3 +/- 19.6 mL/min/1.73m2, baseline hemoglobin 10.2 +/- 1.7 g/dL). Iron indices (transferrin saturation, ferritin) were measured at baseline and at two and seven days after completion of the iron regimen. Blood pressures were monitored immediately prior to, and hourly throughout the iron sucrose infusions. RESULTS: Transferrin saturation and serum ferritin increased from 18.5 +/- 8.5% and 177 +/- 123.8 ng/mL at baseline to 40.2 +/- 22.3% and 811 +/- 294.1 ng/mL in 102 evaluated patients (P < 0.015). In 55 patients with additional measurements at 7 days post-dosing, the transferrin saturation and ferritin had fallen to 26.3 +/- 10.6% and 691 +/- 261.8 ng/mL (P < 0.015 compared to two days' post-dose). Blood pressure rose slightly, but not significantly, throughout the infusions, and altering the infusion rate was not necessary. Two patients had seven adverse events that were considered related to iron sucrose. CONCLUSION: An accelerated regimen of high-dose intravenous iron sucrose therapy in CKD patients is safe and effective in restoring iron stores, and may potentially save time and improve patient adherence.

Prediction of single-pool Kt/v based on clinical and hemodialysis variables using multilinear regression, tree-based modeling, and artificial neural networks.

The impact of clinical and other variables on single-pool Kt/V (spKt/V) is unclear. The goal of this study was to identify clinical and hemodialysis treatment related predictors of spKt/V and use multilinear regression (LM), tree-based modeling (TBM), and artificial neural networks (ANN) to predict actual spKt/V. When 602 hemodialysis records were analyzed, spKt/V correlated with urea reduction ratio (URR) (r=0.91) and weakly with other variables. When URR was excluded, both LM and TBM identified normalized protein equivalent of total nitrogen appearance (nPNA), prehemodialysis (HD) and post-HD weights, blood flow rate, and dialyzer surface area as predictors of spKt/V. LM identified sex, height, dialyzer ultrafiltration coefficient (Kuf), and duration of dialysis, while TBM identified the dialysis nurse code. Prediction algorithms were developed from a "training" dataset, and validated on a separate ("testing") dataset. Correlation coefficients of predicted spKt/V with measured spKt/V with and without nPNA respectively were 0.745 and 0.679 for LM, 0.6 and 0.512 for TBM, and 0.634 for ANN, which performed better without using nPNA.

New empiric expressions to calculate single pool Kt/V and equilibriated Kt/V.

Most formulae used for Kt/V computations are cumbersome and require variables that are not always available. Even the simplest models involve urea distribution volume or patient postdialysis weight. Calculating urea reduction ratio (URR) is easier and does not require additional variables, but it fails to account for residual renal function or for the removal of urea when urea levels do not change, e.g., during ultrafiltration. The goal of this study was to derive new expressions to calculate Kt/V based on URR using bivariate and multivariate linear and nonlinear models, with the URR adjusted for ultrafiltration volume and time on dialysis. Models were derived from a database of 598 dialysis records with a mean spKt/V of 1.6 (range 0.74-2.8). Models were validated on the same dataset that they were derived from and a separate dataset consisting of 17,190 dialysis records. The validation was made by comparing the empirically derived models with the Gotch and Daugirdas formulae. Among our empirically derived expressions, the closest approximation of the "gold standard," Kt/V, is the multivariate linear model of URR adjusted for ultrafiltration volume. When information about ultrafiltration is not available, the bivariate exponential formula can be successfully used to estimate Kt/V.