Association between Serum Uric Acid Level and ESRD or Death in a Korean Population

Background@#Serum uric acid (SUA) is recognized as a risk factor for chronic kidney disease (CKD) and mortality. However, there is controversy as to whether a high or low level of SUA is related to the risk of CKD progression or death, and whether it differs between males and females. @*Methods@#We included 143,762 adults who underwent voluntary health screening between 1995 and 2009 in Korea. For each sex, we divided participants into sex-specific quintiles according to SUA levels and compared end-stage renal disease (ESRD) incidence and mortality between the groups with low and high SUA levels and those with middle SUA levels. Sex-specific Cox proportional hazard analyses were performed for ESRD and all-cause mortality. @*Results@#Among the 143,762 participants, 0.2% (n = 272) developed ESRD. The hazard ratio (HR) of ESRD was higher in the highest (adjusted HR, 2.13; 95% confidence interval [CI], 1.18–3.84) and lowest (adjusted HR, 1.90; 95% CI, 1.02–3.51) SUA quintiles than in the middle SUA quintile in males and the highest SUA quintile in females (adjusted HR, 2.31; 95% CI, 1.10–4.84). Four-point three percent (n = 6,215) of participants died during a mean follow-up period of 157 months. The hazard ratio (HR) of all-cause mortality was higher in the highest SUA quintile than in the middle SUA quintile in males (adjusted HR, 1.15; 95% CI, 1.03–1.28) and females (adjusted HR, 1.17; 95% CI, 1.01–1.35). @*Conclusion@#Elevated levels of SUA are associated with increased risk for ESRD and all-cause mortality in both sexes. Low levels of SUA might be related to ESRD and death only in males, showing U-shaped associations. Our findings suggest sex-specific associations between SUA levels and ESRD development and mortality.

Erratum: Changes in bioimpedance analysis components before and after hemodialysis Volume 37, Issue 4, December 2018, Pages 393–403

The authors would like to publish this corrigendum to correct the data in Table 2 of the above article.

Effects of colchicine on renal fibrosis and apoptosis in obstructed kidneys

BACKGROUND/AIMS: Colchicine is an established drug for microtubule stabilization that may reduce tissue injury. No data were available that its effects may depend on the dosage of colchicine. We investigated the anti-fibrotic and apoptotic effects of various dose of colchicine in a unilateral ureteral obstruction (UUO) model. METHODS: Thirty-six Sprague-Dawley rats were randomly assigned into six groups. Two sham groups were divided into a vehicle-treated or colchicine-treated group (100 μg/kg/day). Four UUO groups were treated with either vehicle or three different doses of colchicine for 7 days (30, 60, and 100 μg/kg/day, intraperitoneally). All of the animals were sacrificed on day 7. RESULTS: Colchicine treatment diminished acetylated α-tubulin and tumor growth factor-β immunoreactivities in the cortical area of the 7-day obstructed kidneys, which was in dose dependent manner. Colchicine attenuated tubulointerstitial damage and apoptosis in both cortical and medullary area, and beneficial effects of colchicine therapy were dramatically shown at the higher dosage of colchicine. The expression levels of cleaved caspase-3, ED-1, and fibronectin were decreased in UUO animals. CONCLUSIONS: We found that the proper dosage of colchicine may have anti-fibrotic and anti-apoptotic effects in obstructed kidneys. For clinical applications, an optimal dose of colchicine should be evaluated to maximize the prevention of renal disease progression.

Changes in bioimpedance analysis components before and after hemodialysis

BACKGROUND: This study compared nutritional parameters in hemodialysis (HD) subjects and controls using bioimpedance analysis (BIA) and investigated how BIA components changed before and after HD. METHODS: This cross-sectional study included 147 subjects on maintenance HD from two hospitals and 298 propensity score-matched controls from one healthcare center. BIA was performed pre- and post-HD at mid-week dialysis sessions. RESULTS: Extracellular water/total body water (ECW/TBW) and waist-hip ratio were higher in the HD patients; the other variables were higher in the control group. The cardiothoracic ratio correlated best with overhydration (r = 0.425, P < 0.01) in HD subjects. Blood pressure, hemoglobin, creatinine, and uric acid positively correlated with the lean tissue index in controls; however, most of these nutritional markers did not show significant correlations in HD subjects. Normal hydrated weight was predicted to be higher in the pre-HD than post-HD measurements. Predicted ultrafiltration (UF) volume difference based on pre- and post-HD ECW/TBW and measured UF volume difference showed a close correlation (r 2 = 0.924, P < 0.01). Remarkably, the leg phase angle increased in the post-HD period. CONCLUSION: The estimated normal hydrated weight using ECW/TBW can be a good marker for determining dry weight. HD subjects had higher ECW/TBW but most nutritional indices were inferior to those of controls. It was possible to predict UF volume differences using BIA, but the post-HD increase in leg phase angle, a nutritional marker, must be interpreted with caution.

Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome

Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.

Alkali Therapy Attenuates the Progression of Kidney Injury via Na/H Exchanger Inhibition in 5/6 Nephrectomized Rats

Metabolic acidosis is a cause of renal disease progression, and alkali therapy ameliorates its progression. However, there are few reports on the role of renal acid-base transporters during alkali therapy. We evaluated the effect of sodium bicarbonate therapy and the role of acid-base transporters on renal disease progression in rats with a remnant kidney. Sprague-Dawley rats consumed dietary sodium bicarbonate (NaHCO3) or sodium chloride (NaCl) with 20% casein after a 5/6 nephrectomy. After being provided with a casein diet, the NaHCO3-treated group had higher levels of serum bicarbonate than the control group. At week 4, the glomerular filtration rate in the NaHCO3 group was higher than that in the NaCl group, and the difference became prominent at week 10. The glomerulosclerosis and tubulointerstitial damage indices in the NaHCO3 group were less severe compared with controls at week 4 and 10. The expression of the Na/H exchanger (NHE) was decreased, and apical reactivity was decreased in the NaHCO3 group, compared with the NaCl group. Endothelin-1 levels in the kidney were also decreased in the NaHCO3 group. Dietary sodium bicarbonate has the effects of ameliorating renal disease progression, which may be related to the altered expression of NHE in the remaining kidney.

Effects of Sodium Citrate on Salt Sensitivity and Kidney Injury in Chronic Renal Failure

Metabolic acidosis, which is observed in salt-sensitive hypertension, is also associated with kidney injury. Alkali therapy in chronic renal failure (CRF) may ameliorate the progression of kidney disease; however, few studies have examined the effects of alkali therapy on salt sensitivity and kidney injury in CRF. We randomly administered standard diet (SD), sodium chloride with 20% casein diet (NACL), or sodium citrate with 20% casein diet (NACT) to Sprague-Dawley rats after a CRF or a sham operation. Four weeks after 5/6 nephrectomy, serum bicarbonate levels were higher in the NACT-treated group. On the pressure-natriuresis curve, NACT-treated CRF rats were more salt-resistant than NACL-treated CRF rats. Additionally, the NACT-treated CRF group showed less tubulointerstitial damage than the NACL-treated CRF group. The expression and immunoreactivity of NHE3 in the kidney in the NACT-treated CRF group were lower than those in the NACL-treated CRF group. We observed that dietary NACT as alkali therapy in CRF might improve the altered salt-sensitivity and ameliorate the progression of kidney injury compared to the NACL diet, which may be related to reduced renal NHE3 expression.

Significance of Microalbuminuria in Relation to Subclinical Coronary Atherosclerosis in Asymptomatic Nonhypertensive, Nondiabetic Subjects

We aimed to investigate the significance of microalbuminuria and its relationship with subclinical atherosclerosis in nonhypertensive and nondiabetic patients, by using coronary artery computed tomography (CT). A total of 1,318 nonhypertensive and nondiabetic subjects who had taken coronary artery CT and measured spot urine albumin to creatinine ratio (UACR) were evaluated. The atherosclerotic changes of coronary arteries were greater in subjects with microalbuminuria, reflected by coronary artery calcium score (CACS) and significant coronary artery stenosis (CACS > or = 100 in 15.3% vs 7.6% and stenosis > or = 50% in 11.5% vs 4.9% of patients with vs without microalbuminuria, P = 0.008 and P = 0.011, respectively). Among various parameters that are known as a risk factor or possible biomarkers of coronary artery disease, presence of microalbuminuria, age and Framingham risk score were significantly related to coronary artery stenosis. Among them the presence of microalbuminuria showed stronger correlation than others to the coronary artery stenosis detected by CT, even after adjusting confounding factors (OR 3.397, 95% confidence interval 1.138 to 10.140, P = 0.028). The presence of microalbuminuria by UACR was significantly associated with presence of coronary artery stenosis > or = 50% in asymptomatic, nonhypertensive and nondiabetic general population. Our study suggests that the presence of microalbuminuria may imply subclinical coronary artery disease, even in asymptomatic population.

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.

Effects of Thiazide on the Expression of TRPV5, Calbindin-D28K, and Sodium Transporters in Hypercalciuric Rats

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.

Expression of Calcium Transporters According to Dietary Sodium in the Distal Tubule of Rat Kidneys / 대한신장학회지

PURPOSE: Hypercalciuria is a risk factor of renal calcium stone and proper initial management is dietary salt restriction. But the molecular mechanism responsible for this sodium calcium relationship remains unclear. The present study investigates the relationship between different amount of sodium intake and the expression level of transporters involved in the active calcium transport. METHODS: Sprague-Dawley rats were randomized into three groups: a normal salt group, a low salt group, and a high salt group. Expression of mRNA and protein of transient receptor potential vanilloid (TRPV) 5 and calbindin-D28K was determined by real-time quantitative PCR and western blots, respectively. RESULTS: Hematocrit and body weight showed no difference among the three groups. High salt diet led to significant increase in the amount of urinary calcium excretion and decreased mRNA expression of calbindin-D28K and TRPV5. Protein abundance of calbindin-D28K and TRPV5 was decreased but the result was statistically insignificant. Low salt diet decreased the amount of urinary calcium excretion without significant difference. Messenger RNA expression and protein abundance of calbindin-D28K and TRPV5 showed no difference, compared to those of normal salt group. CONCLUSION: These data suggest that high sodium intake increases urinary calcium excretion, which is accompanied by a decreased expression of calbindin-D28K mRNA.

The Risk Factors and Natural History of Chronic Kidney Disease in Liver Transplant Recipients / 대한신장학회잡지

BACKGROUND: With the increasing success of liver transplantation, more patients are developing renal dysfunction. The goal of the current study was to assess the natural history of renal dysfunction and to identify patients at risk for the development of chronic kidney disease in liver transplant recipients. METHODS: Cumulative incidence of chronic kidney disease (defined as a sustained decrease in estimated glomerular filtration rate of <60 mL/min/m2 for at least 3 months) was determined using the Kaplan - Meier method. Cox regression analysis was used to test the independent effect of potential risk factors on time to development of chronic kidney disease. In addition, mycophenolate mofetil was introduced in conjuncion with rapid reduction of calcineurin inhibitors (CNI) in some cases of patients with renal dysfunction, and the change of renal function was analyzed. RESULTS: The cumulative incidence of chronic kidney disease was 28.7% and the incidence of severe renal dysfunction was 2.3%. Pre - transplant renal dysfunction and older age are risk factors of chronic kidney disease. Renal dysfunction at 3 months after transplantation was a significant predictor for the development of chronic kidney disease. A significant improvement of renal function was seen in patients with rapid reduction of CNI. CONCLUSION: We have identified risk factors and the natural history of chronic kidney disease in liver transplant recipients. These observations may be useful in the development of less - nephrotoxic immunosuppressive regimens for liver transplant recipients at high - risk of renal dysfunction.

Tuberculous Pyomyositis in a Renal Transplant Patient / 대한신장학회잡지

Tuberculosis infection of skeletal muscle is rare, even in countries where tuberculosis is relatively prevalent. Because tuberculosis of muscle is usually secondary to underlying tuberculosis of the bone or adjacent joint, isolated tuberculosis of skeletal muscle is very rare. Moreover, tuberculosis pyomysitis shows nonspecific symptoms even in immuno-compromised hosts. Recently we experienced an isolated tuberculosis pyomysitis in renal allograft recipient and report here. A 57-year-old woman presented with pain and edema on right calf area. Sonographic imaging of right calf muscle showed large elongated fluid collection. Operative debridement was done and the histopathology of calf muscle showed granulomas surrounded by Langhans' giant cells. We diagnosed her as tuberculous polymyositis combining the data of histology and positive result of polymerase chain reaction for mycobacterium tuberculosis. We treated her with the anti-tuberculosis medication. After surgical debridement and medical management, calf muscle tuberculous polymyositis showed fair improvement.

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.

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.

Adult Minimal Change Nephrotic Syndrome: Treatment Response and Relapse / 대한신장학회잡지

BACKGROUND: Minimal change nephrotic syndrome (MCNS) is the most common cause of idiopathic nephrotic syndrome in Korea, not only in children but also in adults. METHODS: We reviewed the medical records of patients older than 16 years who were diagnosed MCNS by percutaneous renal biopsy between 1979 and 2002 and followed more than 6 months there after. RESULTS: Of total 94 patients enrolled, there were 58 men and 36 women (male to female 1.6: 1), the mean age of onset was 30.5 (16-73) years, and the mean follow-up period was 66 (6-297) months. Of 81 patients who were initially given corticosteroid, complete remission (CR) was observed in 68 (84%), partial remission in 7 (8.6%), and failure to remission in 6 (7.4%). In comparison of the 47 patients who showed CR by the 4th week with the group who showed CR after 4 weeks plus who did not show CR after all, male (p=0.04) and renal insufficiency (p=0.01) were more dominant in the latter group. All of 10 patients who were initially given the combination of cyclophosphamide and corticosteroid showed CR. The mean number of relapse per patient per year was 0.37 in 79 patients who achieved CR with initial treatment, 0.44 in 61 patients younger than 40 years, and 0.15 in 18 patients older than 40 years (p=0.02). Remission was maintained longer in patients older than 40 years (p=0.005), and in those with proteinuria less than 10 grams per day (p=0.04). CONCLUSION: Among patients with MCNS, those who presented with initial renal insufficiency show a less favorable response to corticosteroid. Patients older than 40 years show less frequent relapse and longer duration of remission.