Role of IL-1alpha in Cisplatin-Induced Acute Renal Failure in Mice

BACKGROUND/AIMS: For unknown reasons, caspase-1 -/- mice, protected against cisplatin-induced acute renal failure (ARF), are deficient in interleukin (IL)-1alpha. We thus asked whether IL-1alpha deficiency underlies the mechanism of protection against cisplatin-induced ARF in these mice. METHODS: Cisplatin (30 mg/kg) was injected intraperitoneally into wild-type C57BL/6 mice to produce a cisplatin-induced model of ARF. IL-1alpha was measured in control vehicle- and cisplatin-treated wild-type animals. We also examined whether IL-1alpha -/- mice were similarly protected against cisplatin-induced ARF. Additionally, infiltration of CD11b- and CD49b-positive cells, as markers of macrophages, natural killer, and natural killer T cells (pan-NK cells), was investigated in wild-type and IL-1alpha -/- mice. RESULTS: Compared with vehicle-treated mice, renal IL-1alpha increased in cisplatin-treated wild-type mice beginning on day 1. IL-1alpha -/- mice were shown to be protected against cisplatin-induced ARF. No significant difference in the infiltration of neutrophils or CD11b- and CD49b-positive cells were observed between wild-type and IL-1alpha -/- mice. CONCLUSIONS: Mice deficient in IL-1alpha are protected against cisplatin-induced ARF. The lack of IL-1alpha may explain, at least in part, the protection against cisplatin-induced ARF observed in caspase-1 -/- mice. Investigation of the protective mechanism (s) in IL-1alpha -/- mice in cisplatin-induced ARF merits further study.

Isolated Pancreatic Tuberculosis in a Patient with End-Stage Renal Disease / 대한신장학회지

Tuberculosis (Tb) is a common disease in the developing world and its incidence is slowly increasing in developed countries, where a resurgence has occurred subsequent to the acquired immunodeficiency syndrome epidemic. In addition, patients with end-stage renal disease who are on maintenance hemodialysis carry a high risk for Tb; reported incidence varies from 6-16 times that of the general population. Extrapulmonary Tb constitutes a major part of Tb in dialysis patients. Isolated pancreatic Tb is a very rare occurrence in the setting of extrapulmonary Tb. It usually occurs as a complication of miliary Tb in immunodeficient individuals, particularly those with human immunodeficiency virus infection. There is no isolated pancreatic Tb in patients with end-stage renal disease. We recently experienced a case of isolated pancreatic Tb diagnosed by acid fast bacilli culture, Tb polymerase chain reaction from ultrasound-guided fine needle aspiration, and an excellent response after anti-Tb treatment in a 72-year-old patient with end-stage renal disease.

Fluid and Electrolyte Disturbances in Critically Ill Patients

Disturbances in fluid and electrolytes are among the most common clinical problems encountered in the intensive care unit (ICU). Recent studies have reported that fluid and electrolyte imbalances are associated with increased morbidity and mortality among critically ill patients. To provide optimal care, health care providers should be familiar with the principles and practice of fluid and electrolyte physiology and pathophysiology. Fluid resuscitation should be aimed at restoration of normal hemodynamics and tissue perfusion. Early goal-directed therapy has been shown to be effective in patients with severe sepsis or septic shock. On the other hand, liberal fluid administration is associated with adverse outcomes such as prolonged stay in the ICU, higher cost of care, and increased mortality. Development of hyponatremia in critically ill patients is associated with disturbances in the renal mechanism of urinary dilution. Removal of nonosmotic stimuli for vasopressin secretion, judicious use of hypertonic saline, and close monitoring of plasma and urine electrolytes are essential components of therapy. Hypernatremia is associated with cellular dehydration and central nervous system damage. Water deficit should be corrected with hypotonic fluid, and ongoing water loss should be taken into account. Cardiac manifestations should be identified and treated before initiating stepwise diagnostic evaluation of dyskalemias. Divalent ion deficiencies such as hypocalcemia, hypomagnesemia and hypophosphatemia should be identified and corrected, since they are associated with increased adverse events among critically ill patients.

High Dose Vitamin D3 Attenuates the Hypocalciuric Effect of Thiazide in Hypercalciuric Rats

Thiazide is known to decrease urinary calcium excretion. We hypothesized that thiazide shows different hypocalciuric effects depending on the stimuli causing hypercalciuria. The hypocalciuric effect of hydrochlorothiazide (HCTZ) and the expression of transient receptor potential vanilloid 5 (TRPV5), calbindin-D(28K), and several sodium transporters were assessed in hypercalciuric rats induced by high calcium diet and vitamin D3. Urine calcium excretion and the expression of transporters were measured from 4 groups of Sprague-Dawley rats; control, HCTZ, high calcium-vitamin D, and high calcium-vitamin D with HCTZ groups. HCTZ decreased urinary calcium excretion by 51.4% in the HCTZ group and only 15% in the high calcium-vitamin D with HCTZ group. TRPV5 protein abundance was not changed by HCTZ in the high calcium-vitamin D with HCTZ group compared to the high calcium-vitamin D group. Protein abundance of NHE3, SGLT1, and NKCC2 decreased in the hypercalciuric rats, and only SGLT1 protein abundance was increased by HCTZ in the hypercalciuric rats. The hypocalciuric effect of HCTZ is attenuated in high calcium and vitamin D-induced hypercalciuric rats. This attenuation seems to have resulted from the lack of HCTZ's effect on protein abundance of TRPV5 in severe hypercalciuric condition induced by high calcium and vitamin D.

Renal Dysfunction in Patients with Chronic Liver Disease

Renal dysfunction in patients with chronic liver disease encompasses a clinical spectrum of hyponatremia, ascites, and hepatorenal syndrome. Clinical observation has suggested that patients with cirrhosis have hyperdynamic circulation, and recent studies strongly suggest that peripheral arterial vasodilatation and subsequent development of hyperdynamic circulation are responsible for disturbances in renal function. Arterial vasodilatation predominantly occurs in the splanchnic vascular bed, and seems to precede an increase in blood flow in the splanchnic circulation. Nitric oxide plays a central role in progressive vasodilatation, as evidenced by in vivo and in vitro studies. Renal dysfunction negatively affects the prognosis of patients with cirrhosis, as hyponatremia, ascites, and azotemia are associated with increased rate of complications and mortality. Recent advances in understanding the pathophysiology of renal dysfunction have enabled clinicians to develop new diagnostic criteria and therapeutic recommendations. Hepatorenal syndrome is regarded as a potentially reversible disorder, as systemic vasoconstrictors with concomitant albumin administration are emerging as a promising management option, especially in terms of providing bridging therapy for patients awaiting liver transplantation.

Altered Regulation of Renal Sodium Transporters in Salt-Sensitive Hypertensive Rats Induced by Uninephrectomy

Uninephrectomy (uNx) in young rats causes salt-sensitive hypertension (SSH). Alterations of sodium handling in residual nephrons may play a role in the pathogenesis. Therefore, we evaluated the adaptive alterations of renal sodium transporters according to salt intake in uNx-SSH rats. uNx or sham operations were performed in male Sprague-Dawley rats, and normal-salt diet was fed for 4 weeks. Four experimental groups were used: sham-operated rats raised on a high-salt diet for 2 weeks (CHH) or on a low-salt diet for 1 week after 1 week's high-salt diet (CHL) and uNx rats fed on the same diet (NHH, NHL) as the sham-operated rats were fed. Expression of major renal sodium transporters were determined by semiquantitative immunoblotting. Systolic blood pressure was increased in NHH and NHL groups, compared with CHH and CHL, respectively. Protein abundances of Na+/K+/2Cl- cotransporter (NKCC2) and Na+/Cl- cotransporter (NCC) in the CHH group were lower than the CHL group. Expression of epithelial sodium channel (ENaC)-gamma increased in the CHH group. In contrast, expressions of NKCC2 and NCC in the NHH group didn't show any significant alterations, compared to the NHL group. Expressions of ENaC-alpha and ENaC-beta in the NHH group were higher than the CHH group. Adaptive alterations of NKCC2 and NCC to changes of salt intake were different in the uNx group, and changes in ENaC-alpha and ENaC-beta were also different. These altered regulations of sodium transporters may be involved in the pathogenesis of SSH in the uNx rat model.

Altered Renal Sodium Transporter Expression in an Animal Model of Type 2 Diabetes Mellitus

Hemodynamic factors play an important role in the development and/or progression of diabetic nephropathy. We hypothesized that renal sodium transporter dysregulation might contribute to the hemodynamic alterations in diabetic nephropathy. Otsuka Long Evans Tokushima Fatty (OLETF) rats were used as an animal model for type 2 diabetes. Long Evans Tokushima (LETO) rats were used as controls. Renal sodium transporter regulation was investigated by semiquantitative immunoblotting and immunohistochemistry of the kidneys of 40-week-old animals. The mean serum glucose level in OLETF rats was increased to 235+/-25 mg/dL at 25 weeks, and the hyperglycemia continued up to the end of 40 weeks. Urine protein/ creatinine ratios were 10 times higher in OLETF rats than in LETO rats. At 40th week, the abundance of the epithelial sodium channel (ENaC) beta-subunit was increased in OLETF rats, but the abundance of the ENaC gamma-subunit was decreased. No significant differences were observed in the ENaC alpha-subunit or other major sodium transporters. Immunohistochemistry for the ENaC beta-subunit showed increased immunoreactivity in OLETF rats, whereas the ENaC gamma-subunit showed reduced immunoreactivity in these rats. In OLETF rats, ENaC beta-subunit upregulation and ENaC gamma-subunit downregulation after the development of diabetic nephropathy may reflect an abnormal sodium balance.

A case of chinese herb nephropathy induced by aristolochia fangchi / 대한내과학회지

Chinese herb nephropathy (CHN) is characterized by progressive tubulointerstitial nephritis and development of renal failure in a couple of years after diagnosis. Aristolochic acid (AA) is believed to be associated with the development of CHN. The authors report a case of CHN in which AA in the herb regimen was identified by high-performance liquid chromatography (HPLC). A 32-year-old female presented with nausea, vomiting and generalized weakness. She had been taking Chinese herbs for symptomatic care. Clinical and laboratory examinations revealed Fanconi syndrome, renal failure, and severe anemia. Renal biopsy showed severe tubulointerstitial nephritis with moderate tubular atrophy and interstitial fibrosis. She developed end-stage renal failure 4 months after diagnosis. The herb she had been taking was Aristolochia fangchi. HPLC technique was used to identify AA and to measure its concentration in the herb. From the clinical and laboratory data, the patient was diagnosed with CHN caused by aristolochic acid.

Absence of intact thiazide-sensitive sodium-chloride cotransporter in the renal tissue of a Gitelman's syndrome patient / 대한내과학회지

BACKGROUND: Gitelman's syndrome is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. It is known to be caused by a mutation of SLC12A3 gene coding the sodium-chloride cotransporter (NCCT) in the distal tubule. The defect of NCCT in human renal tissues has not been investigated, and we tested whether the defect of NCCT can be detected in renal tissue of a patient with Gitelman's syndrome by using immunohistochemistry. METHODS: In an adult patient with Gitelman's syndrome, blood and urine samples were collected for measurement of biochemical parameters. Renal clearance study and gene analysis were performed. Immunohistochemistry was performed on the renal tissue of the patient using a rabbit polyclonal antibody directed against a synthetic peptide corresponding to a portion in the amino terminal tail for human NCCT. Normal human renal tissues from surgical nephrectomy due to renal cell carcinoma and renal biopsy tissues from patients with glomerulonephritis but without any electrolyte disturbance were used as controls. RESULTS: The patient had hypokalemic metabolic alkalosis, hypocalciuria and hypomagnesemia. Renal clearance study revealed a decrease in distal fractional chloride reabsorption after the administration of furosemide. SLC12A3 gene mutation (S967F) was found by direct sequencing method. Immunohistochemistry showed the absence of NCCT staining in the renal tissue of the patient. On the other hand, the immunostaining of other transporters was all positive in renal tissues from both Gitelman's syndrome patients and controls. CONCLUSIONS: We report the absence of intact NCCT in the renal tissue of a Gitelman's syndrome patient.

Etiology and Clinical Outcomes of Renovascular Hypertension / 대한신장학회잡지

BACKGROUND: Renovascular hypertension has variable etiologic diseases and therapeutic outcomes. We performed a retrospective analysis of the causes and treatment results of renovascular hypertension to elucidate long-term prognosis with respect to blood pressure and renal function. METHODS: We reviewed patients who were admitted to Seoul National University Hospital for evaluation of renovascular hypertension in period from January, 1983 to December, 2002. Diagnosis of renovascular hypertension was made by combination of positive functional studies such as captopril renal scintigraphy and/or captopril test and angiographic demonstration of significant stenoses in one or both of renal arteries. Patients who were followed up for more than six months were included and classified according to the etiologic disease and treatment modalities. Responses of blood pressure and renal function in each patient were periodically evaluated. RESULTS: Of 74 patients included, 37 were male and 37 were female. The median age of the patients was 40. Atherosclerotic renal artery stenosis was the most common diagnosis (31, 41.9%), followed by Takayasu's arteritis (21, 28.4%) and fibromuscular dysplasia (14, 18.9%). Control of blood pressure and preservation of renal function were significant in medical, radiological, and surgical therapy group. There was no significant difference in response of blood pressure and renal function to treatment among treatment groups. Poor response of blood pressure and deterioration of renal function were observed more frequently in patients with atherosclerotic renal artery stenosis than in those with Takayasu's arteritis or fibromuscular dysplasia. CONCLUSION: Atherosclerosis was the most common etiologic diagnosis of renovascular hypertension. Medical treatment showed satisfactory treatment results as compared to radiologic and surgical revascularization. Patients with atherosclerotic renal artery stenosis showed poorer control of blood pressure and preservation of renal function.

Diversity of initial manifestations in renal tubular acidosis / 대한내과학회지

BACKGROUND: Diagnosis of RTA (renal tubular acidosis) is not easy due to its nonspecific and various manifestations. To find out the clues to diagnosis, we investigated initial manifestations, laboratory features and clinical course of RTA patients. METHODS: Thirty-seven patients with RTA type I or II, whose follow-up period was over 6 months were included in the study. We reviewed their medical records retrospectively. RESULTS: Male to female ratio was 5:32 and the average age at the time of diagnosis was 38.7 (15~60). Twenty-five patients had RTA type I, nine had type II, and three had both. The average follow-up period was 6.4 years. Initial manifestations were asthenia (54%), nausea (46%), urinary stone (24%), paresthesia (24%), lower extremity weakness (22%), and paralysis (11%). Underlying diseases at the time of diagnosis include Sjogren's syndrome (14%), SLE (8%), drug-induced nephropathy (11%), diabetic nephropathy (5.4%), Sjogren's syndrome combined with SLE (2.7%), and medullary sponge kidney (2.7%). Laboratory tests revealed acidosis with hypokalemia (59%), acidosis without hypokalemia (14%), and hypokalemia without acidosis (24%). The level of total CO2 was 22 mmol/L or lower in 27 patients. The Na:Cl ratio on the average was 1:1.26 and for 33 patients below 1:1.35. Renal function deteriorated in 8 patients and 7 of them had underlying diseases. Urinary stone developed in 2 patients with RTA type I. CONCLUSION: When patients with nonspecific symptoms show decreased levels of serum total CO2, potassium, or Na:Cl ratio, RTA should always be considered.

The Changes of Aquaporin-2 Expression in Rats with Lithium Induced Nephrogenic Diabetes Insipidus after Hydrochlorothiazide Administration / 대한신장학회잡지

BACKGROUND: Thiazides have been used in nephrogenic diabetes insipidus (NDI) patients to decrease urine volume, but the mechanism of antidiuretic effect is not known yet. Recently, it has been demonstrated that abundance of aquaporin-2 (AQP2) was decreased in lithium induced NDI. We performed this study to investigate the effect of hydrochlorothiazide (HCTZ) in lithium induced NDI rats and the change of AQP2 expression. METHODS: NDI was induced in 7 male Spraque- Dawley rats by feeding lithium carbonate containing rat chow (40 mmol/kg) for 5 weeks. 4 rats were control group. HCTZ 3.75 mg/day (n=3 among lithium treated; Li+TZ) or vehicle (n=4 among lithium treated and control; Li and Control, respectively) was infused to the rats through osmotic minipump for the last 7 days. Urine volume and urine osmolality were measured. Kidneys were processed for immunohistochemistry and immunoblotting using antibody to AQP2. RESULTS: Li+TZ showed decreased urine volume (46+/-11 mL/day for Li+TZ vs. 127+/-1 mL/day for Li, p<0.05) and higher urine osmolality (557+/-139 mmol/kgH2O for Li+TZ vs. 207+/-9 mmol/kgH2O for Li, p<0.05) comparing to Li. In semi-quantitative immunoblotting using whole kidney homogenate, Li+TZ showed increase in AQP2 expression comparing to Li (39+/-2% for Li+TZ vs. 20+/-9% for Li, p<0.05, % of normal controls). In immunohistochemistry, AQP2 expression in cortex was markedly decreased after lithium treatment. But, AQP2 expression was slightly increased after HCTZ treatment. CONCLUSION: HCTZ treatment partially increased urine concentrating ability and AQP2 expression in rats with lithium induced NDI. We concluded that partial improvement in urine concentrating ability might be associated with upregulation of AQP2.

Contributory Roles of Distal Renal Sodium Transporters in NSAID-induced Sodium Retention / 대한신장학회잡지

BACKGROUND: Sodium retention occurs in some patients taking NSAIDs (nonsteroidal anti-inflammatory drugs). Although the renal effects of NSAIDs are predominantly mediated through the inhibition of prostaglandins synthesized by cyclooxygenase-2 (COX-2), the mechanisms of sodium retention are not clear at the sodium transporter levels in the kidney. Previous studies have shown that compensatory upregulation of COX-2 is induced in renal medulla by high salt intake and that NSAID-induced sodium retention may be transitory. METHODS: To investigate whether renal sodium transporter abundances are altered by NSAID administration and whether renal sodium transporter abundances are affected by high salt intake or chronic NSAID administration, we performed an acute study treated with a single injection of diclofenac and another chronic study treated with 7 days' administration of DFU, a selective COX-2 inhibitor, using semiquantitative immunobotting from rat kidneys. Male Sprague-Dawley rats were divided into three groups in each study: controls, NSAID treatment, and high-salt intake plus NSAID treatment. The control diet contained sodium 1 mmol/200 g BW/day, and the high-salt diet 10 mmol/200 g BW/day. RESULTS: The acute study using diclofenac (100 mg/kg BW) increased the abundances of NKCC2 (by 73%) and ENaC-alpha (by 60%) in cortex and of NKCC2 (by 165%) and ENaC-alpha (by 91%) in outer medulla, in association with a significant decrease in urinary sodium excretion. The increased ENaC-alpha abundance was reversed by addition of high salt intake in both cortex and outer medulla. The chronic study using DFU (40 mg/kg/d for 7 days) showed no significant changes in distal renal sodium transporters except a decreased abundance of Na-K- ATPase alpha1-subunit (by 24%) in outer medulla. The addition of high salt intake decreased the abundances of ENaC-alpha (by 35%) and ENaC-beta (by 47 %) in outer medulla. CONCLUSION: The abundances of thick ascending limb NKCC2 and collecting duct ENaC are altered in response to NSAID administration. It is suggested that NKCC2 & ENaC are contributory to NSAID- induced sodium retention and also have a compensatory role in high salt intake and chronic NSAID administration.

MHC Expression in Human Embryonic Stem Cells and Embryoid Bodies / 대한이식학회지

PURPOSE: Human embryonic stem (ES) cell is pluripotent cell derived from a group of cells called the inner cell mass and has the ability to reproduce itself for long periods and give rise to types of cells that develop from the three germ layers. Due to its pluripotency, ES cell holds the promise of being able to replace cells that are damaged or destroyed by many devastating diseases. However, the potential for the recipient of an ES cell transplant to reject this cell as foreign is very high. Thus, it is essential to determine whether human ES cells express MHC antigens. The purpose of this study is to characterize the stem cell properties of our cell line (SNUhES1) and the expression profile of MHC antigens on the surface of these cells and their differentiated derivatives, embryoid bodies (EBs). METHODS: The ES cells were grown on STO fibroblast in DMEM-F12. The EBs were grown in the same medium with exception that it lacked LIF and bFGF. The expression of self-renewal-associated genes and three germ layer cell-specific genes in ES cells and EBs were measured by RT-PCR at varying time point of incubation (1, 7, 14 and 28 day). The expression of MHC molecules were measured by RT-PCR and FACS analysis. RESULTS: The SNUhES1 cells expressed all self-renewal- associated genes (Fgf4, FoxD3, Oct4, Sox2 and TERT) we tested. During the differentiation three germ layer cell-specific genes in EBs were expressed as following order: ecto-, meso- and endodermal cell-specific genes. MHC class I proteins (HLA-ABC and beta2m) on the surfaces of ES cells and EBs were expressed in very low levels. MHC class II proteins (HLA-DP, -DQ and -DR) and HLA-G were not expressed on the surface of these cells. However, the expression of MHC class II proteins were detected in 1% more or less cells of 28-day-old EBs which were hardly detected in the population of 1-day-old EBs. CONCLUSION: These data imply that SNUhES1 cells and EBs have stem cell properties. Although they express very low MHC antigens, further investigation determining whether the MHC expression in the ES cells and EBs may alter under inflammatory condition which can be occurred in damaged tissue or through surgical process.

Chronic Furosemide Administration Alters Abundance of Sodium Transporters in Rat Kidney / 대한신장학회잡지

BACKGROUND: Furosemide inhibit NaCl absorption in the thick ascending limb and produce an increase in distal delivery of Na+. We carried out semiquantitative immunoblotting and immunohistochemistry of rat kidneys to investigate whether chronic furosemide infusion is associated with compensatory increases in the abundance of Na+ transporters in distal nephron. METHODS: Osmotic minipumps were implanted into Sprague-Dawley rats to deliver 12 mg/day of furosemide(n=6) with simultaneous administration of 0.8% NaCl and 0.1% KCl in drinking water for 7 days. RESULTS: Compared with vehicle infused controls, urine volume and urine sodium amount were increased. However, there were no differences in body weight, serum aldosterone, and creatinine clearance. The abundance of Na+-K+-2Cl- cotransporter after furosemide infusion was increased in cortex (151+/-10 vs. 100+/-10%, p< 0.05) and outer medulla (122+/-5 vs. 100+/-3%, p< 0.01). In furosemide infusion group, the abundance of all three subunits of epithelial sodium channel (ENaC) was increased both in cortex (alpha: 187+/-25 vs. 100+/-17%, p< 0.05; beta: 155+/-8 vs. 100+/-15%, p< 0.05; gamma: 168+/-16 vs. 100+/-9%, p< 0.05) and outer medulla (alpha: 171+/-27 vs. 100+/-17%, p< 0.05; beta: 986+/-91 vs. 100+/-33%, p< 0.01; gamma: 242+/-24 vs. 100+/-22%, p< 0.01). Consistent with these results, ENaC beta-subuint immunohistochemistry showed a remarkable increase in immunoreactivity in the principal cells of collecting ducts with furosemide treatment. CONCLUSION: These increases in the abundance of ENaC protein may account for the generation of diuretic tolerance.