Bacteremia in hemodialysis patients

Infection is a common complication and is the second leading cause of death in hemodialysis patients. The risk of bacteremia in hemodialysis patients is 26-fold higher than in the general population, and 1/2-3/4 of the causative organisms of bacteremia in hemodialysis patients are Gram-positive bacteria. The ratio of resistant bacteria in hemodialysis patients compared to the general population is unclear. Several reports have indicated that hemodialysis patients have a higher risk of methicillin-resistant Staphylococcus aureus infection. The most common site of infection causing bacteremia is internal prostheses; the use of a hemodialysis catheter is the most important risk factor for bacteremia. Although antibiotic lock of hemodialysis catheters and topical antibiotic ointment can reduce catheter-related blood stream infection(CRBSI), their use should be limited to necessary cases because of the emergence of resistant organisms. Systemic antibiotic administration and catheter removal is recommended for treating CRBSI, although a study indicated the advantages of antibiotic lock and guidewire exchange of catheters over systemic antibiotic therapy. An infection control bundle recommended by the Center for Disease Control and Prevention succeeded in reducing bacteremia in hemodialysis patients with either a catheter or arteriovenous fistula. Appropriate infection control can reduce bacteremia in hemodialysis patients.

Regulatory roles of nitric oxide and angiotensin Ⅱ on renal tubular transport

Renal tubules regulate blood pressure and humoral homeostasis.Mediators that play a significant role in regulating the transport of solutes and water include angiotensin Ⅱ(AngⅡ) and nitric oxide(NO).AngⅡ can significantly raise blood pressure via effects on the heart,vasculature,and renal tubules.AngⅡ generally stimulates sodium reabsorption by triggering sodium and fluid retention in almost all segments of renal tubules.Stimulation of renal proximal tubule(PT) transport is thought to be essential for AngⅡ-mediated hypertension.However,AngⅡ has a biphasic effect on in vitro PT transport in mice,rats,and rabbits:stimulation at low concentrations and inhibition at high concentrations.On the other hand,NO is generally thought to inhibit renal tubular transport.In PTs,NO seems to be involved in the inhibitory effect of AngⅡ.A recent study reports a surprising finding:AngⅡ has a monophasic stimulatory effect on human PT transport.Detailed analysis of signalling mechanisms indicates that in contrast to other species,the human NO/guanosine3',5'-cyclic monophosphate/extracellular signal-regulated kinase pathway seems to mediate this effect of AngⅡ on PT transport.In this review we will discuss recent progress in understanding the effects of AngⅡ and NO on renal tubular transport.

Functional coupling of V-ATPase and CLC-5

Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria,hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl^-/H^+ antiporter chloride channel 5(CLC-5),which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H^+-ATPase(V-ATPase). Initially identified as a member of the CLC family of Cl- channels,CLC-5 was presumed to provide Cl- shunt into the endosomal lumen to dissipate H^+ accumulation by V-ATPase,thereby facilitating efficient endosomal acidification. However,recent findings showing that CLC-5 is in fact not a Cl-channel but a 2Cl^-/H^+ antiporter challenged this classical shunt model,leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis,as illustrated in mice carrying an artificial Cl- channel mutation E211 A that developed defective endocytosis but normal endosomal acidification. Conversely,a recent functional analysis of a newly identified disease-causing Cl^- channel mutation E211 Q in a patient with typical Dent's disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification,lending support to the classical shunt model. In this editorial,we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.

The Effects of Insulin Resistance and Inflammation on Renal Proximal Tubule Sodium Transport and Hypertension

Insulin resistance, closely linked to inflammation, is recognized as a key factor in the onset and aggravation of diabetes, cardio-renal syndrome, hypertension, and obesity. In the renal proximal tubule, insulin resistance may increase renal sodium reabsorption, leading to hypertension, edema and sometimes heart failure. Recently some anti-diabetic agents have been shown to have effects on the transporters in renal proximal tubule. Because renal proximal tubule mediates about 70% of sodium reabsorption, it is quite important to clarify the function of renal proximal tubule under insulin resistance and inflammation.

Physiological and pathophysiological roles of the electrogenic Na⁺-HCO₃^–cotransporter NBCe1

The electrogenic Na+-HCO3– cotransporter NBCe1 encoded by SLC4A4 gene plays essential roles in the regulation of intracellular/extracellular pH. Three NBCe1 variants are thought to mediate distinct physiological roles with different modes of transport stoichiometry. Homozygous inactivating mutations in NBCe1 cause the isolated proximal renal tubular acidosis (pRTA) invariably associated with ocular abnormalities. Functional analyses indicate that more than 50% reduction in NBCe1 activity may be required to induce severe acidemia. Some of the pRTA- related NBCe1 mutations, which show defective me-mbrane expression in mammalian cells, are also associated with migraine. Dysregulation of local pH in brain due to the loss of NBCe1 activity in astrocytes may underlie this association. Two types of NBCe1 deficient animals, NBCe1 knockout and W516X knockin mice, have been reported. Both of them show severe acidemia and early lethality unless they are treated with alkali. In isolated renal proximal tubules from W516X knockin mice, both NBCe1 activity and the rate of bicarbonate absorption are severely reduced, confirming the essential role of NBCe1 in bicarbonate absorption from this nephron segment. In this review, we summarize the recent data about physiological and pathophysiological roles of NBCe1 in health and diseases.

Species differences in regulation of renal proximal tubule transport by certain molecules

Renal proximal tubules(PTs) play important roles in the regulation of acid/base, plasma volume and blood pressure. Recent studies suggest that there are substantial species differences in the regulation of PT transport. For example, thiazolidinediones(TZDs) are widely used for the treatment of type 2 diabetes mellitus, but the use of TZDs is associated with fluid overload. In addition to the transcriptional enhancement of sodium transport in distal nephrons, TZDs rapidly stimulate PT sodium transport via a non-genomic mechanism depending on peroxisome proliferator activated receptor g/Src/epidermal growth factor receptor(EGFR)/MEK/ERK. In mouse PTs, however, TZDs fail to stimulate PT transport probably due to constitutive activation of Src/EGFR/ERK pathway. This unique activation of Src/ERK may also affect the effect of high concentrations of insulin on mouse PT transport. On the other hand, the effect of angiotensin Ⅱ(Ang Ⅱ) on PT transport is known to be biphasic in rabbits, rats, and mice. However, Ang Ⅱ induces a concentration-dependent, monophasic transport stimulation in human PTs. The contrasting responses to nitric oxide/guanosine 3',5'-cyclic monophosphate pathway may largely explain these different effects of Ang Ⅱ on PT transport. In this review, we focus on the recent findings on the species differences in the regulation of PT transport, which may help understand the species-specific mechanisms underlying edema formation and/or hypertension occurrence.

The acid-base regulation by renal proximal tubule

The kidney plays quite an important role in the regulation of acid-base homeostasis. The dysfunction of renal acid-base regulation causes diseases such as developmental disorder, bone malformation, calcification of eye and brain, etc. In the kidney, this regulation is performed, to a considerable part, in the proximal tubule of the nephron. In the luminal side the key player is sodium-proton exchanger type 3 (NHE3), whereas sodium-bicarbonate cotransporter (NBCe1) plays the critical role in the basolateral side. In the cytoplasm there is carbonic anhydrase type 2 (CAII) that intermediates the conversion of CO2/ . Interestingly, in human, mutations have been found in NBCe1 and CAII but not in NHE3 so far. Mutations of NBCe1 lead to severe proximal renal tubular acidosis (pRTA) and other systemic manifestations. In animal model studies, however, the relative contribution of NHE3 to proximal tubule functions remains controversial. Recently, V-ATPase with renal specific subunits is suggested to have some roles in the regulation of proximal tubule functions. In this review, we will discuss the regulation of acid-base transport in the proximal tubule and the updates.

Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

Thiazolidinediones(TZDs), pharmacological activators of peroxisome-proliferator-activated receptors γ(PPARγ), significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of controversy. Originally, PPARγ-mediated enhanced transcription of the epithelial Na channel(ENaC) γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from renal proximal tubule(PT) in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fibroblast cells confirmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-induced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signaling. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system(s) in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.