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Nephrotic syndrome is an important clinical condition affecting both children and adults. Studies suggest that the pathogenesis of edema in individual patients may occur via widely variable mechanisms, i.e., intravascular volume underfilling versus overfilling. Managing edema should therefore be directed to the underlying pathophysiology. Nephrotic syndrome is also associated with clinically important complications related to urinary loss of proteins other than albumin. This educational review focuses on the pathophysiology and management of edema and secondary complications in patients with nephrotic syndrome. Keywords Nephrotic syndrome * Edema * Secondary complications * Underfill * Overfill, Introduction Nephrotic syndrome is defined by proteinuria (>3-3.5 g/day in adults or >1 g/[m.sup.2]/day in children), hypoalbuminemia ( Pathogenesis of edema in nephrotic syndrome Two major pathophysiologic mechanisms have been [...]

The study was undertaken to examine the potential cross talk between vasopressin and angiotensin II (ANG II) intracellular signaling pathways. We investigated in vivo and in vitro whether vasopressin-induced water reabsorption could be attenuated by ANG II AT1 receptor blockade (losartan). On a low-sodium diet (0.5 meq/day) dDAVP-treated animals with or without losartan exhibited comparable renal function [creatinine clearance 1.2 [+ or -] 0.1 in dDAVP + losartan (LSDL) vs. 1.1 [+ or -] 0.1 ml x 100 [g.sup.-1] x [day.sup.-1] in dDAVP alone (LSD), P > 0.05] and renal blood flow (6.3 [+ or -] 0.5 in LSDL vs. 6.8 [+ or -] 0.5 ml/min in LSD, P > 0.05). The urine output, however, was significantly increased in LSDL (2.5 [+ or -] 0.2 vs. 1.8 [+ or -] 0.2 ml x 100 [g.sup.-l] x [day.sup.-1], P < 0.05) in association with decreased urine osmolality (2,600 [+ or -] 83 vs. 3,256 [+ or -] 110 mosmol/kg[H.sub.2]O, P < 0.001) compared with rats in LSD. Immunoblotting revealed significantly decreased expression of medullary AQP2 (46 [+ or -] 6 vs. 176 [+ or -] 10% in LSD, P < 0.01), p-AQP2 (177 [+ or -] 13 vs. 214 [+ or -] 12% in LSD, P < 0.05), and AQP3 (134 [+ or -] 14 vs. 177 [+ or -] 11% in LSD, P < 0.05) in LSDL compared with LSD. The expressions of AQP1, the [[alpha].sub.1]- and [gamma]-subunits of Na-K-ATPase, and the Na-K-2Cl cotransporter were not different among groups. In vitro studies showed that ANG II or dDAVP treatment was associated with increased AQP2 expression and cAMP levels, which were potentiated by cotreatment with ANG II and dDAVP and were inhibited by AT1 blockade. In conclusion, ANG II AT1 receptor blockade in dDAVP-treated rats on a low-salt diet was associated with decreased urine concentration and decreased inner medullary AQP2, p-AQP2, and AQP3 expression, suggesting that AT1 receptor activation plays a significant role in regulating aquaporin expression and modulating urine concentration in vivo. Studies in collecting duct cells were confirmatory. aquaporin; urine concentration; cAMP doi: 10.1152/ajprenal.00168.2010.

The article discusses the pathophysiology of renal failure and cirrhosis and the clinical interventions that can help in the prevention and management of the ailment. The main types of renal failure in patients with cirrhosis and the different treatment methodologies are highlighted.

The interaction of tumor necrosis factor (TNF)-[alpha] with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-[kappa]B and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-[kappa]B activation during sepsis may be beneficial to the microvasculature. In addition, the phosphatidylinositol-3-kinase/Akt signaling pathway (PI3-kinase/Akt) has been shown to be cytoprotective. In this study, we examined the effect of inhibition of NF-[kappa]B and PI3-kinase/ Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF-[alpha]-treated cultured microvascular endothelial cells. TNF-[alpha] induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-[kappa]B inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF-[alpha]-induced cytotoxicity. TNF-[alpha] also caused PI3-kinase/Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002. Inhibition of PI3-kinase/Akt also significantly potentiated TNF-[alpha]-mediated cytotoxicity. LY294002 treatment resulted in the appearance of increased apoptosis, compatible with the known antiapoptotic properties of PI3-kinase/Akt. The present results therefore demonstrate a cytotoxic effect of TNF-[alpha] in microvascular endothelial cells which can be attenuated by NF-KB inhibition. In addition, PI3kinase/Akt activation during TNF-[alpha] exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-[kappa]B inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock. endotoxemia; sepsis; cell culture; PDTC; LY294002

The effect of endotoxemia (lipopolysaccharide, 2.5 mg/kg ip) was investigated in aquaporin (AQP) 1 knockout (KO) compared with wild-type (WT) mice. At baseline, KO mice exhibited higher water intake (WI) and urine output (UO). After endotoxemia, WI and UO remained higher in the KO than WT mice, and urine osmolality was lower. The higher serum osmolality in AQP1-KO mice during endotoxemia was associated with higher AQP2 (133 [+ or -] 8 vs. 100 [+ or -] 3%, P < 0.01), AQP3 (140 [+ or -] 8 vs. 100 [+ or -] 4%, P < 0.001) and [Na.sup.+]-[K.sup.+]-2[Cl.sup.-] cotransporter type 2 (NKCC2; 152 [+ or -] 14 vs. 100 [+ or -] 15%, P < 0.05) expression than that in WT mice. These responses during endotoxemia in the AQP1-KO mice compared with WT were associated with lower glomerular filtration rate (GFR) (69 [+ or -] 8 vs. 96 [+ or -] 8 mi/min, P < 0.05) and renal blood flow (0.77 [+ or -] 0.1 vs. 1.01 [+ or -] 0.1 ml/min, P < 0.01). Urinary sodium excretion and fractional sodium excretion were higher in KO compared with WT mice in endotoxemia and were accompanied by more severe tubular injury. With water repletion and comparable serum osmolalities, GFR was still lower in KO (57 [+ or -] 13 vs. 120 [+ or -] 6 ml/min, P < 0.01) compared with WT during endotoxemia. The abundance of AQP2 and AQP3 protein in KO mice was not different from WT mice; however, NKCC2, [Na.sup.+]/[H.sup.+] exchanger type 3, and fractional sodium excretion remained higher in KO compared with WT. Thus the polyuria in AQP1-KO mice does not protect against endotoxemia-induced acute kidney injury but rather absence of AQP1 predisposed to enhanced endotoximic renal injury. lipopolysaccharide; sepsis; glomerular filtration rate; polyuria; aquaporin-1

Autosomal dominant polycystic kidney disease (ADPKD) is a highly prevalent genetic disease that results in cyst formation in kidney and liver. Cytokines and growth factors secreted by the cyst-lining epithelia are positioned to initiate autocrine/paracrine signaling and promote cyst growth. Comparative analyses of human kidney and liver cyst fluids revealed disparate cytokine/growth factor profiles. CXCR2 agonists, including IL-8, epithelial neutrophil-activating peptide (ENA-78), growth-related oncogene-[alpha] (GRO-[alpha]), are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids. Liver cysts are lined by epithelial cells derived from the intrahepatic bile duct (i.e., cholangiocytes). In polarized pkd2(WS25/-) mouse liver cyst epithelial monolayers, CXCR2 agonists were released both apically and basally, indicating that they may act both on the endothelial and epithelial cells within or lining the cyst wall. IL-8 and human liver cyst fluid induced cell proliferation of HMEC-1 cells, a human microvascular endothelial cell line, and Mz-ChA1 cells, a human cholangiocyte cell model. IL-8 expression can be regulated by specific stresses. Hypoxia and mechanical stretch, two likely stressors acting on the liver cyst epithelia, significantly increased IL-8 secretion and promoter activity. AP-1, c/EBP, and NF-[kappa]B were required but not sufficient to drive the stress-induced increase in IL-8 transcription. An upstream element between -272 and -1,481 bp allowed for the stress-induced increase in IL-8 transcription. These studies support the hypothesis that CXCR2 signaling promotes ADPKD liver cyst growth. interleukin-8; cholangiocytes; endothelium; cytokines; growth factors; autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening hereditary disease and is the fourth most common cause of end-stage kidney disease. Preclinical studies to identify effective interventions to prevent or slow progression of PKD nephropathy are therefore direly needed. Heterozygous Han:SPRD rats are an autosomal dominant PKD model with many of the characteristics of ADPKD in humans. In the present study, parameters known to antedate the decrease in renal function, namely, renal structure, renal blood flow (RBF), and mean arterial pressure (MAP), were evaluated with three different interventions, namely, HMG-CoA reductase inhibition with lovastatin, angiotensin-converting enzyme (ACE) inhibition with enalapril, and a combination of these two treatments. The statin therapy demonstrated structural and functional benefits, including increased RBF and decreased BUN, independently of a change in MAP, while the ACE inhibition therapy demonstrated structural benefit in association with a decrease in MAP. An enhancement of these protective interventions in this autosomal dominant PKD model was not demonstrated with the combined treatment. renal blood flow; renal structure; blood pressure

A study was conducted to investigate the effect of tolvaptan, an orally active vasopressin [V.sub.2]-receptor antagonist on predicting acute and chronic hyponatremia, which is used to predict death among patients with chronic heart failure and cirrhosis. The results show that tolvaptan, when added to standard therapy, despite consistent side effects, is of great help in raising and maintaining serum sodium concentrations in the patients.

Urinary diluting ability and protein abundance of renal aquaporins (AQPs) and ion transporters in glucocorticoid-deficient (GD) rats were examined at baseline and in response to oral water loading. Rats underwent bilateral adrenalectomy followed by aldosterone (GD) or aldosterone + dexamethasone (CTL) replacement. Before oral water loading, urinary output was significantly decreased and urinary osmolality ([U.sub.osm]) was increased in GD compared with CTL rats. Protein abundance of inner medullary AQP2 (148 [ + or -] 18%), phosphorylated AQP2 (pAQP2, 156 [ + or -] 13%), and AQP3 (145 [ + or -] 8%) was significantly upregulated in GD compared with CTL rats (all P < 0.05). GD rats also demonstrated a marked reduction in urinary [Na.sup.+] excretion compared with pair-led CTL rats. [Na.sup.+]-[K.sup.+]-[2C1.sup.]cotransporter, [Na.sup.+/[H.sup.+] exchanger type 3, and cortical [beta]- and [gamma]-subunits of the epithelial [Na.sup.+] channel were significantly upregulated in GD rats. At 1 h after an acute water load (40 ml/kg by oral gavage), GD rats demonstrated a decrease in percent water excretion (5 [ + or -] 1 vs. 33 [ + or -] 9%, P < 0.01) and urinary output (33 [ + or -] 12 vs. 250 [ + or -] 65 [micro]*[kg.sup.-]*[min.sup.1] , P < 0.05) and an increase in [U.sub.osm ] (1,894 [ + or -] 292 vs. 316 [ + or -] 92 mosmol/kg[H.sup.2 O], P < 0.001) compared with CTL rats. Plasma AVP was increased (1.6 [ + or -] 0.2 vs. 0.9 [ + or -] 0.2 pg/ml, P < 0.05), as was protein expression of inner medullary AQP2 (149 [ + or -] 5%) and pAQP2 (177 [ + or -] 9%, P < 0.01), in GD compared with CTL rats; apical expression of AQP2 was maintained in GD rats. The vasopressin V2 receptor antagonist OPC-31260 increased percent water excretion and urinary output and reduced [U.sub.osm] compared with vehicle-treated GD rats. OPC-31260 also reversed the increased abundance and apical trafficking of inner medullary AQP2 and pAQP2 protein in GD rats. In conclusion, enhanced protein abundance of [Na.sup.+] transporters and [Na.sup.+] channels with Nan retention occurred with GD. OPC-31260 reversed upregulation and apical trafficking of AQP2 and pAQP2 in association with improved urinary diluting capacity and increased water excretion after oral water loading. arginine vasopressin; aquaporin; impaired urinary dilution

The purpose of this study was to examine protein expression of renal aquaporins (AQP) and ion transporters in hypothyroid (HT) rats in response to an oral water load compared with controls (CTL) and HT rats replaced with L-thyroxine (HT+T). Hypothyroidism was induced by aminotriazole administration for 10 wk. Body weight, water intake, urine output, solute and urea excretion, and serum and urine osmolality were comparable among the three groups at the conclusion of the 10-wk treatment period. One hour after oral gavage of water (50 ml/kg body wt), HT rats demonstrated significantly less water excretion, higher minimal urinary osmolality, and decreased serum osmolality compared with CTL and HT+T rats. Despite the hyposmolality, plasma vasopressin concentration was elevated in HT rats. These findings in HT rats were associated with an increase in protein abundance of renal cortex AQP1 and inner medulla AQP2. AQP3, AQP4, and the Na-K-2Cl cotransporter were also increased. Moreover, 1 h following the oral water load, HT rats demonstrated a significant increase in the membrane-to-vesicle fraction of AQP2 by Western blot analysis. The defect in urinary dilution in HT rats was reversed by the [V.sub.2] vasopressin antagonist OPC-31260. In conclusion, impaired urinary dilution in HT rats is primarily compatible with the nonosmotic release of vasopressin and increased protein expression of renal AQP2. The impairment of maximal solute-free water excretion in HT rats, however, appears also to involve diminished distal fluid delivery. water transport; solute-free water excretion; thyroid disease

Caspase-1-deficient (-/-) mice are protected against sepsis-induced hypotension and mortality. We investigated the role of caspase-1 and its associated cytokines in a nonhypotensive model of endotoxemic acute renal failure (ARF). Mice were injected intraperitoneally with 2.5 mg of LPS that induces endotoxemic ARF. On immunoblot analysis of whole kidney, there was an increase in caspase-1 protein in LPS-treated mice compared with vehicle-treated controls. In LPS-treated mice, the glomerular filtration rate (GFR) was significantly higher in caspase-1 -/- vs. wild-type mice at 16 and 36 h after LPS. To determine the mechanism of this protection, the caspase-1-activated cytokines IL-1[beta] and IL-18 were investigated. IL-1[beta] and IL-18 protein were significantly increased in the kidneys of LPS- vs. vehicle-treated mice. To determine the role of these cytokines, mice were treated with recombinant IL-1 receptor antagonist (IL-1Ra) or IL-18-neutralizing antiserum. In LPS-treated mice, GFR was not different in IL-1Ra-treated or IL-18-neutralizing antiserum-treated or combination therapy (IL-1Ra plus IL-18-neutralizing antiserum-treated) compared with control mice. In addition, tubular cell apoptosis, neutrophil infiltration, myeloperoxidase activity, caspase-3 activity, and calpain activity were not different between wild-type and caspase-1 -/- mice with endotoxemic ARF. In LPS- vs. vehicle-treated wild-type mice, renal IL-1[alpha] was significantly increased. In both LPS- and vehicle-treated caspase-1 -/- mice, renal IL-1[alpha] was very low. In summary, caspase-1 -/- mice are functionally protected against endotoxemic ARF. Neutralization of IL-1[beta] and IL-18 is not functionally protective. The role of the intracellular proinflammatory cytokine IL-1[alpha] in endotoxemic ARF merits further study. glomerular filtration rate; multiorgan failure; cytokine

Various studies show that sepsis is associated with high incidence of acute renal failure. Persons with acute renal failure who do not have sepsis have lower mortality than those with sepsis related acute renal failure.

Angiotensin-converting enzyme inhibition (ACEI) with captopril has been shown to increase water intake and urine output in rats, but the mechanism is unknown. ACEI impairs the conversion of ANG I to ANG 11, a dipsogenic hormone, and impairs the degradation of bradykinin. The goal of this study was to examine the role of bradykinin in the polydipsia and polyuria associated with ACEI. Male Sprague-Dawley rats received captopril (CPT; 20 mg x [kg.sup.-1] x [day.sup.-1]) in ground chow for 48 h. Water intake, food intake, and urine output were monitored and compared with control rats (CTL), rats receiving captopril treatment with limited water intake (CPT-LIM), and rats receiving captopril treatment with ad libitum water intake plus 24-h treatment with the bradykinin antagonist B-9430 (CPT-BK1). CPT rats consumed significantly more water and produced more urine vs. CTL. Urine osmolality was significantly decreased in CPT rats vs. CTL. Inner medullary aquaporin-2 (AQP2) protein abundance was also markedly decreased in CPT rats vs. CTL. These findings were reversed in CPT-LIM rats, suggesting captopril-induced primary polydipsia. CPT-BKI rats demonstrated parameters no different from CTL despite ad libitum water intake. Mean arterial pressure and 24-h creatinine clearance did not differ among groups. We conclude that ACEI with captopril induces primary polydipsia despite impaired production of the dipsogen ANG II and that this primary increase in water intake is likely the cause of the decreased protein abundance of inner medullary AQP2. Furthermore, this dipsogenic effect was reversed by antagonism of bradykinin, thus implicating this hormone in thirst regulation in the rat. angiotensin-converting enzyme inhibition; aquaporin

Cadnapaphornchai, Melissa A., Sandra N. Summer, Sandor Falk, Joshua M. Thurman, Mark A. Knepper, and Robert W. Schrier. Effect of primary polydipsia on aquaporin and sodium transporter abundance. Am J Physiol Renal Physiol 285: F965-F971, 2003. First published July 22, 2003; 10.1152/ajprenal.00085.2003.--Chronic primary polydipsia (POLY) in humans is associated with impaired urinary concentrating ability. However, the molecular mechanisms responsible for this finding have not been elucidated. The purpose of this study was to examine the effect of chronic primary POLY on water metabolism and renal aquaporin (AQP) water channels and sodium and urea transporter abundance in rats. Primary POLY was induced in male Sprague-Dawley rats by daily administration of 15 g powdered rat chow mixed in 100 ml water for 10 days. Control rats (CTL) received 15 g powdered rat chow per day and ad libitum drinking water. Rats were studied following this period before further intervention and with a 36-h period of water deprivation to examine maximal urinary concentrating ability. At baseline, POLY rats demonstrated significantly greater water intake (100[+ or -]1 vs. 22[+ or -]2 ml/day, P < 0.0001) and urinary output (80[+ or -]1 vs. 11[+ or -]1 ml/day, P < 0.0001) and decreased urinary osmolality (159[+ or -]13 vs. 1,365[+ or -]188 mosmol/kg[H.sub.2]O, P < 0.001) compared with CTL rats. These findings were accompanied by decreased inner medulla AQP-2 protein abundance in POLY rats compared with CTL rats before water deprivation (76[+ or -]2 vs. 100[+ or -]7% CTL mean, P < 0.007). With water deprivation, maximal urinary osmolality was impaired in POLY vs. CTL rats (2,404[+ or -]148 vs. 3,286[+ or -]175 mosmol/kg[H.sub.2]O, P < 0.0005). This defect occurred despite higher plasma vasopressin concentrations and similar medullary osmolalities in POLY rats. In response to 36-h water deprivation, inner medulla AQP-2 protein abundance was decreased in POLY rats compared with CTL rats (65[+ or -]5 vs. 100[+ or -]5% CTL mean, P < 0.0006). No significant differences were noted in renal protein abundance of either AQP-3 or AQP-4 or sodium and urea transporters. We conclude that the impaired urinary concentrating ability associated with primary POLY in rats is due to impaired osmotic equilibration in the collecting duct that is mediated primarily by decreased AQP-2 protein abundance. urinary concentrating ability

Acute renal failure (ARF) during sepsis is associated with increased nitric oxide (NO) and oxygen radicals, including superoxide ([O.sup.-.sub.2]). Because [O.sup.-.sub.2] reacts with NO in a rapid manner, it plays an important role in modulating NO levels. Therefore, scavenging of [O.sup.-.sub.2] by superoxide dismutase (SOD) may be critical for preserving NO bioavailability. In mice, substantial renal extracellular SOD (ECSOD) expression implies its important role in scavenging [O.sup.-.sub.2] in the kidney. We hypothesized that during endotoxemic ARF, EC-SOD is decreased in the kidney, resulting in increased [O.sup.-.sub.2] and thus decreased vascular NO bioavailability with resultant renal vasoconstriction and ARF. In the present study, normotensive endotoxemic ARF was induced in mice using lipopolysaccharide (LPS; 5 mg/kg ip). Sixteen hours after LPS, glomerular filtration rate (GFR; 50 [+ or -] 16 vs. 229 [+ or -] 21 [micro]l/min, n = 8, P < 0.01) and renal blood flow (RBF; 0.61 [+ or -] 0.10 vs. 0.86 [+ or -] 0.05 ml/min, n = 8, P < 0.05) were subsequently decreased. EC-SOD mRNA and protein expression in endotoxemic kidneys were decreased at 16 h compared with controls. A catalytic antioxidant, metalloporphyrin, reversed the deleterious effects of endotoxemia on renal function as GFR (182 [+ or -] 40 vs. 50 [+ or -] 16 [micro]l/min, n = 6, P < 0.01) and RBF (1.08 [+ or -] 0.10 vs. 0.61 [+ or -] 0.10 ml/min, n = 6, P < 0.05) were preserved. Similar results were obtained with tempol, a chemically dissimilar antioxidant. Specific inhibition of inducible nitric oxide synthase (iNOS), L-[N.sup.6]-(1-iminoethyl)-lysine, reversed the renal protective effect on GFR and RBF observed with antioxidant treatment during endotoxemia. In summary, renal EC-SOD expression is decreased during endotoxemia. Antioxidant therapy preserved GFR and RBF during endotoxemia. The reversal of this protective effect by inhibition of iNOS suggests the importance of the bioavailability of NO for preservation of renal function during early endotoxemia. sepsis; extracellular superoxide dismutase; lipopolysaccharide; kidney

Acute renal failure (ARF) contributes substantially to the high morbidity and mortality observed during endotoxemia. We hypothesized that selective blockade of the renal nerves would be protective against ARF during the early (16 h) stage of endotoxemia [5 mg lipopolysaccharide (LPS)/kg ip in mice]. At 16 h after LPS, there was no change in mean arterial pressure, but plasma epinephrine (4,604 [+ or -] 719 vs. 490 [+ or -] 152 pg/ml, P < 0.001), norepinephrine (2,176 [+ or -] 306 vs. 1,224 [+ or -] 218 pg/ml, P < 0.05), and plasma renin activity (40 [+ or -] 5 vs. 27 [+ or -] 2 ng*[ml-.sup.-1]*[h.sup.-1], P < 0.05) were higher in the LPS-treated vs. control mice. The high plasma renin activity level decreased to the control level with renal denervation in endotoxemic mice. After intravenous injection of phentolamine (200 [micro]g/kg), the decrement in mean arterial pressure was significantly greater in LPS-treated vs. control mice (19.4 [+ or -] 3.5 vs. 8.1 [+ or -] 1.5 mmHg, P < 0.01). Sixteen hours after LPS administration, there were significant decreases in glomerular filtration rate (52 [+ or -] 18 vs. 212 [+ or -] 23 [micro]l/min, P < 0.01) and renal blood flow (0.58 [+ or -] 0.08 vs. 0.85 [+ or -] 0.06 ml/min, P < 0.01) in sham-operated mice. The decrement in glomerular filtration rate during endotoxemia was significantly attenuated in mice with denervated kidneys (32 vs. 79%). Moreover, there was no change in renal blood flow during endotoxemia in mice with renal denervation. The present results therefore demonstrate a protective role of renal denervation during normotensive endotoxemia-related ARF in mice, an effect that may be, at least in part, due to a diminished activation of the renin-angiotensin system. glomerular filtration rate; renal blood flow; epinephrine; norepinephrine; sepsis