Targeted knockdown of Kv1.3 channels in T lymphocytes corrects the disease manifestations associated with systemic lupus erythematosus.

Lupus nephritis (LN) is an autoimmune disease with substantial morbidity/mortality and limited efficacy of available therapies. Memory T (Tm) lymphocytes infiltrate LN kidneys, contributing to organ damage. Analysis of LN, diabetic nephropathy, and healthy donor kidney biopsies revealed high infiltration of active CD8+ Tm cells expressing high voltage-dependent Kv1.3 potassium channels-key T cell function regulators-in LN. Nanoparticles that selectively down-regulate Kv1.3 in Tm cells (Kv1.3-NPs) reduced CD40L and interferon-γ (IFNγ) in Tm cells from LN patients in vitro. Kv1.3-NPs were tested in humanized LN mice obtained by engrafting peripheral blood mononuclear cells (PBMCs) from LN patients into immune-deficient mice. LN mice exhibited features of the disease: increased IFNγ and CD3+CD8+ T cell renal infiltration, and reduced survival versus healthy donor PBMC engrafted mice. Kv1.3-NP treatment of patient PBMCs before engraftment decreased CD40L/IFNγ and prolonged survival of LN mice. These data show the potential benefits of targeting Kv1.3 in LN.

Converting to doxercalciferol capsules from intravenous paricalcitol or doxercalciferol.

OBJECTIVE: The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar intact parathyroid hormone control when converting from intravenous (IV) paricalcitol or doxercalciferol. DESIGN: Both studies were multicenter, open-label, randomized designs comprising the following 3 periods: a screening period, a 5-week run-in period, and a 5-week treatment period. SETTING: Dialysis centers in the United States. PATIENTS: Patients with stage 5 chronic kidney disease receiving dialysis 3 times weekly for a minimum of 6 months and with recent intact parathyroid hormone measurements between 15.9 and 63.7 pmol/L (150 to 600 pg/mL) were included. INTERVENTION: After a 5-week fixed-dose IV paricalcitol or doxercalciferol run-in period, subjects were randomized to doxercalciferol capsules for the 5-week treatment period. Conversion factors for the paricalcitol study were 0.5, 1.0, and 1.5 times the current paricalcitol dose. Conversion factors for the doxercalciferol study were 1.0, 1.5, and 2.0 times the current doxercalciferol injection dose. RESULTS: The predicted conversion factor for paricalcitol injection to doxercalciferol capsules was 0.92, whereas the factor for doxercalciferol injection to doxercalciferol capsules was 1.49. No statistically significant changes in serum calcium and phosphorus levels were found in either study. The nature of adverse events was consistent with the administration of an active vitamin D therapy to patients with chronic kidney disease receiving dialysis. CONCLUSION: The studies demonstrate patients on dialysis can be safely and effectively converted from IV paricalcitol or doxercalciferol to oral doxercalciferol.

Role of C-reactive protein, reticulocyte haemoglobin content and inflammatory markers in iron and erythropoietin administration in dialysis patients.

AIM: C-reactive protein (CRP) is an acute phase reactant protein, which becomes elevated in response to inflammation, infections or malignancies. These conditions are well known causes of bone marrow hyporesponsiveness and erythropoietin resistance in dialysis patients. The role of iron-deficiency as a cause of hyporesponsiveness under these conditions is not clear. Reticulocyte haemoglobin content (CHr) is one of several iron indices used to determine iron deficiency in dialysis patients. The aim of this study is to evaluate the role of CRP and CHr in iron administration and anaemia management in dialysis patients. METHODS: In 47 haemodialysis patients with ferritin levels of >500 ng/mL, CRP, CHr, transferrin saturation (TSAT), other markers and erythropoietin dose were evaluated. Patients with CRP < 5 mg/L (Group A) were compared to patients with CRP > 5 mg/L (Group B). RESULTS: Ferritin levels in the two groups were not different. Weekly erythropoietin was significantly different between the two groups. Group B required an average of 121% more erythropoietin than Group A to maintain similar haemoglobin levels of 11-12 g/dL 36% of Group B had CHr < 29 pg versus 7% of patients in Group A. 39% of patients in Group B also had TSAT < 20% versus 0% in Group A. Group A also had more arteriovenous (AV) fistulae as dialysis access than group B. CONCLUSION: Data indicate that low CHr, similar to low TSAT, could be associated with inflammatory process and erythropoietin resistance, but not necessarily with iron-deficiency. High CRP association with low CHr and low TSAT levels can explain the lack of response to further IV iron therapy. AV grafts, contrary to AV fistulae, are associated with high inflammatory markers and also with a higher erythropoietin requirement.

Parathyroid hormone suppression by intravenous calcitriol: role of phosphate, calcium, race and diabetes.

BACKGROUND: Parathyroid hormone (PTH) suppression in patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis is achieved largely by the use of intravenous calcitriol. Aspects of the utility and efficacy of this therapy remain controversial. It is debated whether oral versus intravenous therapy is more effective. Most existing studies examine the effect of calcitriol in isolation, without adjusting for other factors that might influence PTH levels. Thus, the simultaneous role of factors such as dosing, control of serum calcium and phosphorus, and demographic variables such as age, sex, race, and duration of ESRD is not well understood. METHODS: We examined the relationship between the administration of calcitriol and PTH suppression in a cohort of hemodialysis patients at a large urban dialysis facility over a period of 30 months. Hemodialysis patients (n = 155) who received at least 3 months of treatment in this facility were included. RESULTS: Using a time sensitive multiple linear regression modeling technique, we found that second and subsequent PTH levels were positively correlated with black race (P < 0.0001) and serum phosphate (P < 0.03) and strongly negatively correlated with serum calcium (P< 0.0001) and diabetes (P< 0.0039). Drug dose (in micrograms per kilogram per month) was weakly negatively correlated (P < 0.04). Unlike previous studies, we adjusted for the simultaneous confounding influence of demographic and laboratory variables, as well as for drug dose normalized for body weight. CONCLUSIONS: This analysis suggests that calcitriol therapy in hemodialysis patients is adversely affected by higher phosphate levels and needs to account for such patient characteristics as race and diabetes and such laboratory variables as calcium and phosphate control. Finally, as has been recently suggested by others, the patient's race may require us to aim for different PTH target levels with therapy.