Carbon dioxide: Global warning for nephrologists.

The large prevalence of respiratory acid-base disorders overlapping metabolic acidosis in hemodialysis population should prompt nephrologists to deal with the partial pressure of carbon dioxide (pCO2) complying with the reduced bicarbonate concentration. What the most suitable formula to compute pCO2 is reviewed. Then, the neglected issue of CO2 content in the dialysis fluid is under the spotlight. In fact, a considerable amount of CO2 comes to patients' bloodstream every hemodialysis treatment and "acidosis by dialysate" may occur if lungs do not properly clear away this burden of CO2. Moreover, vascular access recirculation may be easy diagnosed by detecting CO2 in the arterial line of extracorporeal circuit if CO2-enriched blood from the filter reenters arterial needle.

The First Report of Bayés Syndrome in Hemodialysis Patient.

A chronic hemodialysis patient-known to have advanced interatrial block (IAB)-had reported symptoms suggesting arrhythmias, hence she underwent hemodialysis treatment while on the cardiac monitor. This allowed us to recognize the occurrence of paroxysmal atrial fibrillation and, in turn, disclose the first case of Bayés syndrome. Even though atrial fibrillation and IAB are very frequent in hemodialysis patients, Bayés syndrome, that comprehends both, has never been described, likely because the IAB is often overlooked and undiagnosed. This case could improve the awareness of IAB and of the Bayés syndrome in hemodialysis population.

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice.

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 (rBAT) and SLC7A9 (b(0,+)AT). Gene targeting of the catalytic subunit (Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b(0,+). No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b(0,+)AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

Kidney-specific inactivation of Ofd1 leads to renal cystic disease associated with upregulation of the mTOR pathway.

The oral-facial-digital type I syndrome (OFDI; MIM 311200) is a rare syndromic form of inherited renal cystic disease. It is transmitted as an X-linked dominant, male lethal disorder and is caused by mutations in the OFD1 gene. Previous studies demonstrated that OFDI belongs to the growing number of disorders ascribed to dysfunction of primary cilia. We generated a conditional inactivation of the mouse Ofd1 gene using the Ksp-Cre transgenic line, which resulted in a viable model characterized by renal cystic disease and progressive impairment of renal function. The study of this model allowed us to demonstrate that primary cilia initially form and then disappear after the development of cysts, suggesting that the absence of primary cilia is a consequence rather than the primary cause of renal cystic disease. Immunofluorescence and western blotting analysis revealed upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin, a specific inhibitor of the mTOR pathway, resulted in a significant reduction in the number and size of renal cysts and a decrease in the cystic index compared with untreated mutant animals, suggesting that dysregulation of this pathway in our model is mTOR-dependent. The animal model we have generated could thus represent a valuable tool to understand the molecular link between mTOR and cyst development, and eventually to the identification of novel drug targets for renal cystic disease.

Female ROMK null mice manifest more severe Bartter II phenotype on renal function and higher PGE2 production.

ROMK null mice with a high survival rate and varying severity of hydronephrosis provide a good model to study type II Bartter syndrome pathophysiology (26). During the development of such a colony, we found that more male than female null mice survived, 58.7% vs. 33.3%. To investigate the possible mechanism of this difference, we compared the survival rates, renal functions, degree of hydronephrosis, as well as PGE(2) and TXB(2) production between male and female ROMK wild-type and null mice. We observed that female ROMK Bartter's mice exhibited lower GFR (0.37 vs. 0.54 ml.min(-1).100 g BW(-1), P < 0.05) and higher fractional Na(+) excretion (0.66% vs. 0.48%, P < 0.05) than male Bartter's. No significant differences in acid-base parameters, urinary K(+) excretion, and plasma electrolyte concentrations were observed between sexes. In addition, we assessed the liquid retention rate in the kidney to evaluate the extent of hydronephrosis and observed that 67% of male and 90% of female ROMK null mice were hydronephrotic mice. Urinary PGE(2) excretion was higher in both sexes of ROMK null mice: 1.35 vs. 1.10 ng/24 h in males and 2.90 vs. 0.87 ng/24 h in females. TXB(2) excretion was higher in female mice in both wild-type and ROMK null mice. The increments of urinary PGE(2) and TXB(2) were significantly higher in female null mice than males, 233.33% vs. 22.74% of PGE(2) and 85.67% vs. 20.36% of TXB(2). These data demonstrate a more severe Bartter phenotype in female ROMK null mice, and higher PGE(2) and TXB(2) production may be one of the mechanisms of this manifestation.

Mouse model of type II Bartter's syndrome. I. Upregulation of thiazide-sensitive Na-Cl cotransport activity.

ROMK-deficient (Romk(-/-)) mice exhibit polyuria, natriuresis, and kaliuresis similar to individuals with type II Bartter's form of hyperprostaglandin E syndrome (HPS; antenatal Bartter's syndrome). In the present study, we utilized both metabolic and clearance studies to define the contributions of specific distal nephron segments to the renal salt wasting in these mice. The effects of furosemide, hydrochlorothiazide, and benzamil on urinary Na(+) and K(+) excretion in both wild-type (Romk(+/+)) and Romk(-/-) mice were used to assess and compare salt transport by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2)-expressing thick ascending limb (TAL), the Na(+)-Cl(-) cotransporter (NCC)-expressing distal convoluted tubule (DCT1/DCT2), and the epithelial Na(+) channel (ENaC)-expressing connecting segment (CNT) and collecting duct (CD), respectively. Whole kidney glomerular filtration rate was reduced by 47% in Romk(-/-) mice. Furosemide-induced increments in the fractional excretion rate of Na(+) and K(+) and absolute excretion of Na(+) and K(+) were significantly blunted in Romk(-/-) mice, consistent with a major salt transport defect in the TAL. In contrast, hydrochlorothiazide produced an exaggerated natriuresis in Romk(-/-) mice, indicating upregulation of salt absorption by the DCT. Benzamil resulted in a similar increment in absolute Na excretion in both Romk(-/-) and Romk(+/+), indicating no significant upregulation of Na(+) transport by ENaC in ROMK null mice. Moreover, hydrochlorothiazide increased the fractional K(+) excretion rate in Romk(-/-) mice, confirming our recent observation that maxi-K channels contribute to distal K(+) secretion in the absence of ROMK.

Channels, carriers, and pumps in the pathogenesis of sodium-sensitive hypertension.

Sodium-sensitive hypertension is thought to be dependent on primary alterations in renal tubular sodium reabsorption. The major apical plasma membrane Na(+) transporters include the proximal tubular Na(+)-H(+) exchanger, the thick ascending limb Na(+)-K(+)-2Cl(-) cotransport system, the distal tubular Na(+)-Cl(-) cotransporter, and the collecting duct epithelial sodium channel (ENaC). This article explores the role of each transporter in the pathogenesis of hypertension. Although the contribution of the proximal tubule Na(+)-H(+) exchanger is not yet defined completely, more convincing data have been generated about the importance of the Na(+)-K(+)-2Cl(-). Indeed at least 2 forms of hypertension appear to be related to the up-regulation of the transporter: the so-called programmed hypertension induced by low-protein diet during pregnancy and the early phase of hypertension in the Milan strain of rats. With respect to the Na(+)-Cl(-) cotransporter this may be overactive caused by inactivating mutation of WNK4 as in the Gordon syndrome, although it is the main actor for the maintenance phase of the hypertension found in the Milan strain of rats. Finally, the contribution of the ENaC has been established clearly; indeed, in the Liddle syndrome the mutation of the ENaC gene leads to a longer retention of the channel on the cell surface of collecting duct principal cells, thus inducing stronger sodium reabsorption along this segment. All these examples clearly indicate that renal sodium transporters may be responsible for various types of sodium-sensitive hypertension.