Potassium: From Physiology to Clinical Implications.

BACKGROUND: Potassium (K(+)) is the major intracellular cation, with 98% of the total pool being located in the cells at a concentration of 140-150 mmol/l, and only 2% in the extracellular fluid, where it ranges between 3.5 and 5 mmol/l. A fine regulation of the intracellular-extracellular gradient is crucial for life, as it is the main determinant of membrane voltage; in fact, acute changes of K(+) plasma levels may have fatal consequences. SUMMARY: An integrated system including an 'internal' and 'external' control prevents significant fluctuations of plasma levels in conditions of K(+) loading and depletion. The internal control regulates the intra-extracellular shift, a temporary mechanism able to maintain a constant K(+) plasma concentration without changing the total amount of body K(+). The external control is responsible for the excretion of the ingested K(+), and it has the kidney as the major player. The kidney excretes nearly 90% of the daily intake. Along the proximal tubule and the thick ascending limb on Henle's loop, the amount of K(+) reabsorption is quite fixed (about 80-90%); conversely, the distal nephron has the ability to adjust K(+) excretion in accordance with homeostatic needs. The present review analyzes: (1) the main molecular mechanisms mediating K(+) reabsorption and secretion along the nephron; (2) the pathophysiology of the principal K(+) derangements due to renal dysfunction, and (3) the effect of ingested K(+) on blood pressure and renal electrolyte handling. KEY MESSAGES: Maintaining plasma K(+) levels in a tight range is crucial for life; thus, multiple factors are implicated in K(+) homeostasis, including kidney function. Recent studies have suggested that K(+) plasma levels, in turn, affect renal salt absorption in animal models; this effect may underlie the reduction of blood pressure observed in hypertensive subjects under K(+) supplementation.

[Inhibitors of intra-cystic secretion: novel therapies in ADPKD (Autosomal Dominant Polycystic Kidney Disease)]. / Gli inibitori della secrezione intracistica: nuove terapie nella ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human renal disorder. Progressive enlargement of the kidneys is due to aberrant proliferation of the cyst epithelial cells, together with accumulation of fluid within the cyst cavities due to transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) and specific basolateral transporters. Increased levels of cAMP, probably reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor, in mutant renal epithelia, play an important role in the pathogenesis of ADPKD and contribute to both transepithelial secretion of fluid and proliferation of cyst epithelia. For example, cAMP activates the CFTR leading to the stimulation of Cl- secretion into the cyst lumen. This review focuses on the pathophysiology and molecular mechanism of fluid secretion in ADPKD cysts examined during pre-clinical trials of potentially useful drugs for the treatment of this condition.

Unit dosing of darbepoetin alfa for thetreatment of anemia in patients with end-stage renal disease being switched from recombinant human erythropoietin: Results of a phase IIIb, 27-week, multicenter, open-label study in Greek patients.

BACKGROUND: Darbepoetin alfa is an erythropoietis-stimulating glycoprotein with a ∼3-fold longer t1/2 and greater biological activity compared with recombinant human erythropoietin (rHuEPO). OBJECTIVE: The objective of this study was to evaluate the efficacy andtolerability of long-term (24-week) darbepoetin alfa treatment in maintaining hemoglobin (Hb) concentrations in the target range of 10 to 13 g/dL in patients undergoing dialysis; the patients were switched from rHuEPO to a less-frequent dosing regimen of darbepoetin alfa without an increase in dose. METHODS: In this Phase IIlb, open-label, multicenter study, patients withend-stage renal disease (ESRD) undergoing dialysis who were receiving rHuEPO BIW or TIW at baseline were switched to darbepoetin alfa QW; patients receiving rHuEPO QW were switched to darbepoetin alfa Q2W Administration of darbepoetin alfa was by the same route as previous rHuEPO administration (IV or SC). Patients received darbepoetin alfa for 24 weeks, including a 20-week drug titration period followed by a 4-week, stable-dose evaluation period. The mode, dose, and frequency of administration of darbepoetin alfa were compared with those of baseline rHuEPO. Tolerability assessment was based on spontaneous reporting and laboratory tests (hematology, vital sign measurement, iron status, and biochemistry). RESULTS: The study comprised 173 patients who were divided into 2 groups by route of administration (IV group, n = 146; SC group, n = 27). Mean (SE) adjusted increases in Hb concentration from baseline to the evaluation period for patients receiving darbepoetin alfa QW were 0.94 (0.32) g/dL and 0.38 (0.30) g/dL for the IV or SC routes, respectively (P = 0.004 and NS, respectively). For patients receiving darbepoetin alfa Q2W the mean (SE) adjusted increases in Hb concentration were 0.08 (0.53) g/dL and 0.48 (0.35) g/dL for the IV and SC routes, respectively (both, P = NS). No significant differences in IV/SC dose ratio were observed between the 2 routes of administration. In addition, no increases in darbepoetin alfa dose were observed. The most commonly reported adverse events were hypertension (8 patients [5%]) and vascular access thrombosis (4 [2%]). The incidence of treatment-related adverse events was 6 (3%). CONCLUSIONS: Darbepoetin alfa effectively maintained Hb concentrations within the target range without an increase in dose, even at a reduced dosing frequency. Overall, darbepoetin alfa was well tolerated.