The kidney and the brain play a major role in maintaining normal homeostasis of the extracellular fluid by neuroendocrine regulation of sodium and water balance. Therefore, disturbances of sodium balance are common in patients with central nervous system (CNS) disorders and clinicians should focus not only on the CNS lesion, but also on the potentially deleterious complications. Hyponatremia is the most common and important electrolyte disorder affecting patients with critical neurologic diseases. In these patients, the maladaptation to hyponatremia by impaired osmoregulation in pathologic lesions of brain may cause more aggressive cerebral edema and increased intracranial pressure due to hypoosmolality induced by hyponatremia. Furthermore, hyponatremia accompanied by CNS disorders has shown to increase delayed cerebral ischemia and mortality rates. Two main pathophysiologies of hyponatremia, excluding iatrogenic causes, are inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting (CSW) syndrome. Differential diagnosis between these two entities can be difficult due to considerable overlap in the laboratory findings and clinical situations. SIADH is in a volume expanded status due to inappropriately secreted arginine vasopressin (AVP) and requires water restriction. However, CSW syndrome is characterized by renal sodium wasting mainly due to increased natriuretic peptides resulting in volume depletion and follows appropriate secretion of AVP. Therefore, maintenance of volume status and sodium replacement is the mainstay of treatment in CSW syndrome. In this review, we aimed to describe the regulation of sodium and water balance, and pathophysiology, diagnosis and treatment of hyponatremia in neurologic patients, especially focusing on SIADH and CSW syndrome.
hyponatremia; inappropriate ADH syndrome; cerebral salt wasting syndrome; nervous system diseases
Inhibition of renal prostaglandin synthesis by non-steroidal anti-inflammatory drugs (NSAIDs) causes various electrolyte and acid-base disturbances including sodium retention (edema, hypertension), hyponatremia, hyperkalemia, and decreased renal function. Decreased sodium excretion can result in weight gain, peripheral edema, attenuation of the effects of antihypertensive agents, and rarely aggravation of congestive heart failure. Although rare, NSAIDs can cause hyponatremia by reducing renal free water clearance. Hyperkalemia could occur to a degree sufficient to cause cardiac arrhythmias. Renal function can decline sufficiently enough to cause acute renal failure. NSAIDs associated electrolyte and acid-base disturbances are not uncommon in some clinical situations. Adverse renal effects of NSAIDs are generally associated with prostaglandin dependent states such as volume-contracted states, low cardiac output, or other conditions that tend to compromise renal perfusion. All NSAIDs seem to share these adverse effects. In view of many NSAIDs users' susceptibility to renal adverse effects due to their underlying disease or condition, physicians should be cautious in prescribing NSAIDs to susceptible patients.
Edema; Hyponatremia; Renal tubular acidosis; Non-steroidal anti-inflammatory agents; Acute renal failure
Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a long-half life. This study investigated the efficacy of CERA for correcting anemia in Korean patients on dialysis. Patients (≥18 yr) who were not receiving any ESAs for more than 8 weeks were randomly assigned to either intravenous CERA once every 2 weeks (n=39) or epoetin beta thrice-weekly (n=41) during a 24-week correction phase. Hemoglobin (Hb) response was defined as increase of Hb by at least 1 g/dL and Hb≥11 g/dL without red blood cell (RBC) transfusion. Median dialysis duration was 1.7 (0.3-20.8) and 1.6 (0.4-13.8) yr in CERA and epoetin beta group, respectively. Hemoglobin response rate of CERA was 79.5% (95% confidence interval [CI], 63.5-90.7). As the lower limit of 95% CI was higher than pre-specified 60% response rate, it can be concluded that CERA corrected anemia (P<0.05). Hb response rate of epoetin beta was 87.8% (95% CI, 73.8-95.9) (P=0.37). Median time to response was 12 weeks in CERA and 10.3 weeks in epoetin beta (P=0.03). It is suggested that once every 2 weeks administration of CERA is effective for correcting anemia in Korean patients on long-term hemodialysis with longer time-to-response than thrice weekly epoetin beta. (ClinicalTrials.gov registry No. NCT00546481)
Anemia Correction; Continuous Erythropoietin Receptor Activator; Kidney Failure, Chronic; Renal Dialysis
Research on the prognosis of IgA nephropathy (IgAN) has focused on renal survival, with little information being available on patient survival. Hence, this investigation aimed to explore long-term patient outcome in IgAN patients. Clinical and pathological characteristics at the time of renal biopsy were reviewed in 1,364 IgAN patients from 1979 to 2008. The outcomes were patient death and end stage renal disease (ESRD) progression. Overall, 71 deaths (5.3%) and 277 cases of ESRD (20.6%) occurred during 13,916 person-years. Ten-, 20-, and 30-year patient survival rates were 96.3%, 91.8%, and 82.7%, respectively. More than 50% patient deaths occurred without ESRD progression. Overall mortality was elevated by 43% from an age/sex-matched general population (GP) (standardized mortality ratio [SMR], 1.43; 95% confidence interval [CI], 1.04–1.92). Men had comparable mortality to GP (SMR, 1.22; 95% CI, 0.82–1.75), but, in women, the mortality rate was double (SMR, 2.17; 95% CI, 1.21–3.57). Patients with renal risk factors such as initial renal dysfunction (estimated glomerular filgration rate <60 ml/min per 1.73m2; SMR, 1.70; 95% CI, 1.13–2.46), systolic blood pressure ≥140 mmHg (SMR, 1.88; 95% CI, 1.19–2.82) or proteinuria ≥1 g/day (SMR, 1.66; 95% CI, 1.16–2.29) had an elevated mortality rate. Patients with preserved renal function, normotension, and proteinuria <1 g/day, however, had a similar mortality rate to GP. When risk stratification was performed by counting the number of major risk factors present at diagnosis, low-risk IgAN patients had a mortality rate equal to that of GP, whereas high-risk patients had a mortality rate higher than that of GP. This investigation demonstrated that overall mortality in IgAN patients was higher than that of GP. Women and patients with renal risk factors had a higher mortality than that of GP, Therefore, strategies optimized to alleviate major renal risk factors are warranted to reduce patient mortality.
Recent studies reported that early initiation of hemodialysis may increase mortality. However, studies that assessed the influence of early initiation of peritoneal dialysis (PD) yielded controversial results. In the present study, we evaluated the prognosis of early initiation of PD on the various outcomes of end stage renal failure patients by using propensity-score matching methods. Incident PD patients (n = 491) who started PD at SNU Hospital were enrolled. The patients were divided into 'early starters (n = 244)' and 'late starters (n = 247)' on the basis of the estimated glomerular filtration rate (eGFR) at the start of dialysis. The calculated propensity-score was used for one-to-one matching. After propensity-score-based matching (n = 136, for each group), no significant differences were observed in terms of all-cause mortality (P = 0.17), technique failure (P = 0.62), cardiovascular event (P = 0.96) and composite event (P = 0.86) between the early and late starters. Stratification analysis in the propensity-score quartiles (n = 491) exhibited no trend toward better or poorer survival in terms of all-cause mortality. In conclusion, early commencement of PD does not reduce the mortality risk and other outcomes. Although the recent guidelines suggest that initiation of dialysis at higher eGFR, physicians should not determine the time to initiate PD therapy simply rely on the eGFR alone.
Peritoneal Dialysis; End Stage Renal Failure; Dialysis Initiation; Propensity Score Match; Outcome; Survival
We retrospectively evaluated demographic and biochemical parameters associated with depression and health-related quality of life (HRQOL) in maintenance peritoneal dialysis (PD) patients. This study included 105 patients maintaining PD at Seoul National University Hospital. Data were collected from electronic medical record. Korean Beck's Depression Inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 were used to evaluate depression and HRQOL, respectively. Moderate to severe depression was found in 24.8% of patients. Patients with lower normalized protein equivalent of nitrogen appearance (nPNA) (< 1.2 g/kg/day), lower weekly renal Kt/Vurea (< 0.2), and lower serum albumin level (≤ 4.0 g/dL) were associated with depression (P < 0.05). Among them, lower weekly renal Kt/Vurea was the only independent risk factor associated with depression (OR = 3.1, P = 0.007). Depressed patients showed significantly lower scores in every dimension of HRQOL (P < 0.001). Lower weekly renal Kt/Vurea (β = 0.24, P = 0.005) and lower nPNA (β = 0.15, P = 0.03) were the independent risk factors associated with lower kidney dialysis component summary, whereas lower plasma hemoglobin level was the consistent risk factor for lower physical component summary (β = 0.22, P = 0.03) and mental component summary (β = 0.22, P = 0.01). Depression is a prevalent psychological problem in PD population. Residual renal function is the most important factor associated with depression and impaired HRQOL in PD patients.
Peritoneal Dialysis; Depression; Health-Related Quality of Life; Residual Renal Function; Beck's Depression Inventory; KDQOL-SF
We conducted a multi-center randomized double-blind study to determine the effects of 6-month therapy with sulodexide on urinary protein excretion in patients with idiopathic Immunoglobulin A (IgA) nephropathy.
Materials and Methods
A total of seventy-seven patients participated in the study. They were randomly allocated to one of three groups: sulodexide 75 mg or 150 mg daily or the placebo for 6 months. The primary end point was the achievement, at 6 months, of at least 50% reduction in urine protein/creatinine ratio (UPCR) from the baseline value.
At 6 months, the primary end point was achieved by 12.5% of the patients assigned to the placebo, 4.0% of the patients assigned to sulodexide 75 mg daily and 21.4% of those assigned to 150 mg (p=0.308). Treatment with sulodexide 150 mg daily for 6 months significantly reduced log UPCR from 6.38±0.77 at baseline to 5.98±0.94 at 6 months (p=0.045), while treatment with sulodexide 75 mg daily and placebo did not.
A 6-month treatment with sulodexide did not achieve 50% reduction of urinary protein excretion in IgA nephropathy patients, but showed a tendency to increase the time-dependent anti-proteinuric effect. Therefore, long-term clinical trials on a larger scale are warranted to elucidate the hypothesis that sulodexide affords renal protection in IgA nephropathy patients.
IgA nephropathy; sulodexide; proteinuria
Anti-erythropoietin antibodies usually cross-react with all kinds of recombinant erythropoietins; therefore, erythropoiesis-stimulating agent (ESA)-induced pure red-cell aplasia (PRCA) is not rescued by different ESAs. Here, we present a case of ESA-induced PRCA in a 36-yr-old woman with chronic kidney disease, whose anemic condition improved following reintroduction of darbepoetin-α. The patient developed progressive, severe anemia after the use of erythropoietin-α. As the anemia did not improve after the administration of either other erythropoietin-α products or erythropoietin-β, all ESAs were discontinued. Oxymetholone therapy failed to improve the transfusion-dependent anemia and a rechallenge with ESAs continuously failed to obtain a sustained response. However, her anemia improved following reintroduction of darbepoetin-α at 3 yr after the initial diagnosis. Interestingly, anti-erythropoietin antibodies were still detectable, although their concentration was too low for titration. In conclusion, darbepoetin-α can improve ESA-induced PRCA when the anti-erythropoietin antibody titer declines and its neutralizing capacity is lost.
Red-Cell Aplasia, Pure; Kidney Failure, Chronic; Erythropoietin, Recombinant; Darbepoetin-alfa
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-D28K, 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.
Hypercalciuria; TRPV5; Sodium Transporters; Cholecalciferol; Thiazides
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)-γ 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-α and ENaC-β 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-α and ENaC-β were also different. These altered regulations of sodium transporters may be involved in the pathogenesis of SSH in the uNx rat model.
salt-sensitive hypertension; nephrectomy; sodium-potassium-chloride symporters; sodium chloride symporters; epithelial sodium channel
Nephrotic syndrome is an unusual manifestation of IgA Nephropathy (IgAN). Some cases respond to steroid treatment. Here we describe a case-series of IgAN patients with steroid-responsive nephrotic syndrome. Twelve patients with IgAN with steroid-responsive nephrotic syndrome were evaluated and followed up. All patients presented with generalized edema. Renal insufficiency was found in two patients. The renal biopsy of eight patients revealed wide foot process effacement in addition to the typical features of IgAN. They showed complete remission after steroid therapy. Seven relapses were reported in five patients; six of the relapsed cases responded to steroid therapy. Compared with steroid-non-responsive patients, the patients with steroid-responsive nephrotic syndrome had shorter symptom duration, more weight gain, more proteinuria, and lower histologic grade than did those that had steroid-non-responsive nephrotic syndrome at presentation. None of the responders progressed to end stage renal disease, whereas five (38%) non-responders required dialysis or renal transplantation. Patients with IgAN who have steroid-responsive nephrotic syndrome likely have both minimal change disease and IgAN. The clinical features of sudden onset of generalized edema, initial heavy proteinuria and initial severe hypoalbuminemia might help identify the subset of patients, especially in low grade IgAN.
Glomerulonephritis, IGA; Nephrosis, Lipoid; Nephrotic Syndrome; Steroids
TRPV5 is believed to play an important role in the regulation of urinary calcium excretion. We assessed the effects of hydrochlorothiazide (HCTZ) on the expression of TRPV5, calbindin-D28K, and several sodium transporters in hypercalciuric rats. Sprague-Dawley rats were divided into 4 groups; control, HCTZ, high salt, and high salt with HCTZ group in experiment 1; control, HCTZ, high calcium (Ca), and high Ca with HCTZ group in experiment 2. To quantitate the expression of TRPV5, calbindin-D28K, and sodium transporters, western blotting was performed. In both experiments, HCTZ significantly decreased urinary calcium excretion. TRPV5 protein abundance decreased in all hypercalciuric rats, and restored by HCTZ in both high salt with HCTZ and high Ca with HCTZ group. Calbindin-D28K protein abundance increased in the high salt and high salt with HCTZ groups, but did not differ among groups in experiment 2. Protein abundance of NHE3 and NKCC2 decreased in all hypercalciuric rats, and were restored by HCTZ in only high Ca-induced hypercalciuric rats. In summary, protein abundance of TRPV5, NHE3, and NKCC2 decreased in all hypercalciuric rats. The hypocalciuric effect of HCTZ is associated with increased protein abundance of TRPV5 in high salt or calcium diet-induced hypercalciuric rats.
Hypercalciuria; Thiazides; Transporters
Oxidative stress plays various roles in the development and progression of IgA nephropathy, while bilirubin is known as a potent antioxidant. We therefore hypothesized that serum bilirubin would be associated with renal prognosis in IgA nephropathy. The study subjects comprised 1,458 adult patients with primary IgA nephropathy in Korea. We grouped patients according to the following quartile levels of bilirubin: <0.4 mg/dL (Q1), 0.4-0.5 mg/dL (Q2), 0.6-0.7 mg/dL (Q3), and >0.8 mg/dL (Q4). The outcome data were obtained from the Korean Registry of end-stage renal disease (ESRD). Eighty patients (5.5%) contracted ESRD during a mean follow-up period of 44.9 months. The ESRD incidences were 10.7% in Q1, 8.2% in Q2, 2.8% in Q3, and 2.8% in Q4 (p<0.001). The relative risk of ESRD compared to that in Q1 was 0.307 (95% confidence interval [CI], 0.126-0.751) in Q3 and 0.315 (95% CI, 0.130-0.765) in Q4. The differences of ESRD incidence were greater in subgroups of males and of patients aged 35 yr or more, with serum albumin 4.0 g/dL or more, with normotension, with eGFR 60 mL/min/1.73 m2 or more, and with proteinuria less then 3+ by dipstick test. In conclusion, higher bilirubin level was negatively associated with ESRD incidence in IgA nephropathy.
Bilirubin; Glomerulonephritis, IGA; Kidney Failure, Chronic
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) β-subunit was increased in OLETF rats, but the abundance of the ENaC γ-subunit was decreased. No significant differences were observed in the ENaC α-subunit or other major sodium transporters. Immunohistochemistry for the ENaC β-subunit showed increased immunoreactivity in OLETF rats, whereas the ENaC γ-subunit showed reduced immunoreactivity in these rats. In OLETF rats, ENaC β-subunit upregulation and ENaC γ-subunit downregulation after the development of diabetic nephropathy may reflect an abnormal sodium balance.
Diabetic Nephropathies; Rats, Inbred OLETF; Sodium-Hydrogen Exchanger 3; Bumetanide Sensitive NaK2Cl Cotransporter; Thiazide Sensitive Nacl Cotransporter; Epithelial Sodium Channel
Macrophage infiltration has been observed in the renal biopsy specimens of diabetic nephropathy (DN), and hyperglycemic state stimulates the renal expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) and MCP-1 (monocyte chemoattractant protein-1). Upregulation of RANTES and MCP-1 with infiltrating macrophages may play a crucial role in the development and progression of DN. Genetic polymorphisms of RANTES and its receptors were reported to be independent risk factors for DN. We genotyped single nucleotide polymorphism (SNPs) in the MCP-1 G-2518A, CCR2 G46295A, RANTES C-28G and G-403A in 177 diabetic end-stage renal disease (ESRD) patients and 184 patients without renal involvement (controls) in order to investigate the effects of these SNPs on DN in Korean patients with type 2 DM. There were no differences in the frequencies of SNPs and the distribution of haplotypes of RANTES promoter SNPs between two groups. In conclusion, there were no associations of MCP-1, CCR2 and RANTES promoter SNPs with diabetic ESRD in Korean population. Prospective studies with clearly-defined, homogenous cohorts are needed to confirm the effect of these genetic polymorphisms on DN.
Diabetic Nephropathies; Kidney Failure, Chronic; Monocyte Chemoattractant Proteins; RANTES; Polymorphism, Single Nucleotide Polymorphisms; Diabetes Mellitus, Type 2
Anemia and vitamin D deficiency are both important health issues; however, the nature of the association between vitamin D and either hemoglobin or anemia remains unresolved in the general population.
Data on 11,206 adults were obtained from the fifth Korean National Health and Nutritional Examination Survey. A generalized additive model was used to examine the threshold level for relationship between serum 25-hydroxyvitamin D [25(OH)D] and hemoglobin levels. A multivariate logistic regression for anemia was conducted according to 25(OH)D quintiles. All analyses were stratified according to sex and menstrual status.
The generalized additive model confirmed a threshold 25(OH)D level of 26.4 ng/mL (male, 27.4 ng/mL; premenopausal females, 11.8 ng/mL; postmenopausal females, 13.4 ng/mL). The threshold level affected the pattern of association between 25(OH)D and anemia risk: the odds ratio of the 1st quintile but not the 2nd, 3rd, and 4th quintiles were significantly different from the 5th quintile in both premenopausal and postmenopausal females, however there was no obvious trend in males.
This population-based study demonstrated a non-linear relationship with a threshold effect between serum 25(OH)D and hemoglobin levels in females. Further interventional studies are warranted to determine whether the appropriate level of hemoglobin can be achieved by the correction of vitamin D deficiency.
Only a few large-scale studies have investigated the association between health-related quality of life (HRQOL) and renal function. Moreover, the HRQOL of patients with moderate renal dysfunction is frequently underestimated by healthcare providers. This study assessed the impact of renal function on preference-based HRQOL in Korean adult population.
We analyzed data for 5,555 adults from the 3rd Korean National Health and Nutritional Examination Survey 2005. The EuroQol-5D (EQ-5D) utility score was used to evaluate HRQOL. The study subjects were stratified into three groups based on their estimated glomerular filtration rates (eGFRs): ≥ 90.0, 60.0-89.9 and 30.0-59.9 mL/min/1.73 m2. Individuals with advanced renal dysfunction were excluded from the analysis.
The proportions of participants who reported problems in each of the five EQ-5D dimensions increased significantly with decreasing eGFR. However, a significant decrease in the EQ-5D utility score was observed among participants with an eGFR of 30.0-59.9 mL/min/1.73 m2. Participants with an eGFR of 30.0-59.9 mL/min/1.73 m2 had an almost 1.5-fold higher risk of impaired health utility (the lowest quartile of EQ-5D utility score) compared with those participants with eGFRs ≥ 90.0 mL/min/1.73 m2, after adjustment for age, gender, health-related behaviors, socioeconomic and psychological variables, and other comorbidities. Among the five dimensions of the EQ-5D, an eGFR of 30.0-59.9 mL/min/1.73 m2 was an independent determinant of self-reported problems in the mobility and pain/discomfort dimensions.
Although age affects the association between renal dysfunction and the EQ-5D, moderate renal dysfunction seems to be an important determinant of impaired health utility in a general population and may affect the mobility and pain/discomfort dimensions of health utility.
Chronic kidney disease; EuroQol-5D; Preference-based health utility