Kidney Health Plan 2033 in Korea: bridging the gap between the present and the future

In response to the increase in the prevalence of chronic kidney disease (CKD) in Korea, the growth of patients requiring renal replacement therapy and the subsequent increase in medical costs, the rapid expansion of patients with end-stage kidney disease (ESKD), and the decrease in patients receiving home therapy, including peritoneal dialysis, the Korean Society of Nephrology has proclaimed the new policy, Kidney Health Plan 2033 (KHP 2033). KHP 2033 would serve as a milestone to bridge the current issues to a future solution by directing the prevention and progression of CKD and ESKD, particularly diabetic kidney disease, and increasing the proportion of home therapy, thereby reducing the socioeconomic burden of kidney disease and improving the quality of life. Here, we provide the background for the necessity of KHP 2033, as well as the contents of KHP 2033, and enlighten the Korean Society of Nephrology’s future goals. Together with patients, healthcare providers, academic societies, and national policymakers, we need to move forward with goal-oriented drive and leadership to achieve these goals.

Serum interferon-γ and urinary monocyte chemoattractant peptide-1 are important factors in the pathogenesis of immunoglobulin A nephropathy

Background@#Imbalance of T helper (Th) 1/2 cells has been shown to contribute to the development of immunoglobulin A nephropathy (IgAN). To address the inconsistent results on the role of Th1/Th2 polarization, we evaluated the levels of Th1/Th2 cytokines in various samples from patients with IgAN. @*Methods@#Thirty-one patients with biopsy-proven IgAN (age, 34.48 ± 12.10 years) and 25 healthy controls (age, 44.84 ± 13.72 years) were enrolled. We evaluated the relationship between the levels of Th1/Th2 cytokines and the response to glucocorticoid treatment. @*Results@#The levels of serum interferon-gamma (IFNγ) and urinary monocyte chemoattractant peptide (MCP)-1 were higher in the IgAN group than in the control group. The levels of MCP-1 in urine and secreted by peripheral blood mononuclear cells (PBMCs) were significantly different among three groups categorized based on daily proteinuria. The level of urinary MCP-1 was significantly correlated with proteinuria. The levels of urinary MCP-1, serum interleukin (IL)-4, IFNγ, and IL-2 secreted by PBMCs and intrarenal IL-1 messenger RNA (mRNA) were significantly correlated with the ratio of proteinuria at 6 months to baseline proteinuria in patients undergoing glucocorticoid treatment. MCP-1 mRNA and protein levels were significantly upregulated in mesangial cells stimulated with IFNγ among representative Th1/Th2 cytokines. @*Conclusion@#IFNγ was shown to be a key cytokine in the pathogenic processes underlying IgAN, and its upregulation induced an increase in urinary MCP-1 production. These findings suggest that Th1 cytokines may play an important role in the development of IgAN.

Serum interferon-γ and urinary monocyte chemoattractant peptide-1 are important factors in the pathogenesis of immunoglobulin A nephropathy

Background@#Imbalance of T helper (Th) 1/2 cells has been shown to contribute to the development of immunoglobulin A nephropathy (IgAN). To address the inconsistent results on the role of Th1/Th2 polarization, we evaluated the levels of Th1/Th2 cytokines in various samples from patients with IgAN. @*Methods@#Thirty-one patients with biopsy-proven IgAN (age, 34.48 ± 12.10 years) and 25 healthy controls (age, 44.84 ± 13.72 years) were enrolled. We evaluated the relationship between the levels of Th1/Th2 cytokines and the response to glucocorticoid treatment. @*Results@#The levels of serum interferon-gamma (IFNγ) and urinary monocyte chemoattractant peptide (MCP)-1 were higher in the IgAN group than in the control group. The levels of MCP-1 in urine and secreted by peripheral blood mononuclear cells (PBMCs) were significantly different among three groups categorized based on daily proteinuria. The level of urinary MCP-1 was significantly correlated with proteinuria. The levels of urinary MCP-1, serum interleukin (IL)-4, IFNγ, and IL-2 secreted by PBMCs and intrarenal IL-1 messenger RNA (mRNA) were significantly correlated with the ratio of proteinuria at 6 months to baseline proteinuria in patients undergoing glucocorticoid treatment. MCP-1 mRNA and protein levels were significantly upregulated in mesangial cells stimulated with IFNγ among representative Th1/Th2 cytokines. @*Conclusion@#IFNγ was shown to be a key cytokine in the pathogenic processes underlying IgAN, and its upregulation induced an increase in urinary MCP-1 production. These findings suggest that Th1 cytokines may play an important role in the development of IgAN.

Circulating renalase predicts all-cause mortality and renal outcomes in patients with advanced chronic kidney disease

BACKGROUND/AIMS@#Patients with chronic kidney disease (CKD) have been found to show markedly increased rates of end-stage renal disease, major adverse cardiovascular and cerebrovascular events (MACCEs), and mortality. Therefore, new biomarkers are required for the early detection of such clinical outcomes in patients with CKD. We aimed to determine whether the level of circulating renalase was associated with CKD progression, MACCEs, and all-cause mortality, using data from a prospective randomized controlled study, Kremezin STudy Against Renal disease progression in Korea (K-STAR; NCT 00860431).@*METHODS@#A retrospective analysis of the K-STAR data was performed including 383 patients with CKD (mean age, 56.4 years; male/female, 252/131). We measured circulating renalase levels and examined the effects of these levels on clinical outcomes.@*RESULTS@#The mean level of serum renalase was 75.8 ± 34.8 μg/mL. In the multivariable analysis, lower hemoglobin levels, higher serum creatinine levels, and diabetes mellitus were significantly associated with a higher renalase levels. Over the course of a mean follow-up period of 56 months, 25 deaths and 61 MACCEs occurred. Among 322 patients in whom these outcomes were assessed, 137 adverse renal outcomes occurred after a mean follow-up period of 27.8 months. Each 10-μg/mL increase in serum renalase was associated with significantly greater hazards of all-cause mortality and adverse renal outcomes (hazard ratio [HR] = 1.112, p = 0.049; HR = 1.052, p = 0.045). However, serum renalase level was not associated with the rate of MACCEs in patients with CKD.@*CONCLUSIONS@#Our results indicated that circulating renalase might be a predictor of mortality and adverse renal outcomes in patients with CKD.

Mineralocorticoid receptor blockade for renoprotection

No abstract available.

Erratum: Sustained uremic toxin control improves renal and cardiovascular outcomes in patients with advanced renal dysfunction: post-hoc analysis of the Kremezin Study against renal disease progression in Korea Volume 36, Issue 1, March 2017, Pages 68–

The values of y axis in Fig. 3 should be corrected. The authors would like to apologize for any inconvenience this has caused.

Long-term study of the association of adipokines and glucose variability with diabetic complications

BACKGROUND/AIMS: Recent studies have suggested an important role of adipokines in the development of insulin resistance and diabetes mellitus. The clinical relevance of adipokines on long-term outcomes in patients with diabetes and chronic kidney disease is uncertain. The purpose of this study was to identify a predictable factor in patients with long-term diabetic complications. METHODS: A total of 161 diabetic individuals were followed-up from 2002 to 2013. Circulating plasma levels of adiponectin, glypican-4, irisin, visfatin, and visit-to-visit glucose variability were measured in diabetic patients. Associations among adipokines and variable metabolic parameters and microvascular, and macrovascular complications were evaluated. RESULTS: Plasma adiponectin and glypican-4 levels were significantly increased in patients with renal insufficiency. These adipokines were negatively associated with estimated glomerular filtration rate and positively associated with urinary albumin excretion. The relative risk of renal progression to dialysis increased independently with increasing level of adiponectin. Glypican-4 and visfatin were not predictive of any microvascular or macrovascular complications. Glucose variability increased the risk of diabetic nephropathy and cerebrovascular complications. CONCLUSIONS: Adiponectin and glypican-4 were associated with renal function and might be able to predict renal progression. Glucose variability was a predictable factor for diabetic nephropathy and cerebrovascular complications.

Sustained uremic toxin control improves renal and cardiovascular outcomes in patients with advanced renal dysfunction: post-hoc analysis of the Kremezin Study against renal disease progression in Korea

BACKGROUND: We investigated the long-term effect of AST-120, which has been proposed as a therapeutic option against renal disease progression, in patients with advanced chronic kidney disease (CKD). METHODS: We performed post-hoc analysis with a per-protocol group of the K-STAR study (Kremezin study against renal disease progression in Korea) that randomized participants into an AST-120 and a control arm. Patients in the AST-120 arm were given 6 g of AST-120 in three divided doses, and those in both arms received standard conventional treatment. RESULTS: The two arms did not differ significantly in the occurrence of composite primary outcomes (log-rank P = 0.41). For AST-120 patients with higher compliance, there were fewer composite primary outcomes: intermediate tertile hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.38 to 1.01, P = 0.05; highest tertile HR 0.436, 95% CI 0.25 to 0.76, P = 0.003. The estimated glomerular filtration rate level was more stable in the AST-120 arm, especially in diabetic patients. At one year, the AST-120-induced decrease in the serum indoxyl sulfate concentration inversely correlated with the occurrence of composite primary outcomes: second tertile HR 1.59, 95% CI 0.82 to 3.07, P = 0.17; third tertile HR 2.11, 95% CI 1.07 to 4.17, P = 0.031. Furthermore, AST-120 showed a protective effect against the major cardiovascular adverse events (HR 0.51, 95% CI 0.26 to 0.99, P = 0.046). CONCLUSION: Long-term use of AST-120 has potential for renal protection, especially in diabetic patients, as well as cardiovascular benefits. Reduction of the serum indoxyl sulfate level may be used to identify patients who would benefit from AST-120 administration.

Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy

The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria.

Interleukin-6 signaling in podocyte hypertrophy

No abstract available.

Corrigendum: Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet Volume 33, Issue 1, March 2014, Pages 33-44

The authors apologize for a wrong unit in the table 1.

A case of primary aldosteronism combined with acquired nephrogenic diabetes insipidus

Aldosterone-producing adrenal adenoma can induce various clinical manifestations as a result of chronic exposure to aldosterone. We report a rare case of a 37-year-old man who complained of general weakness and polyuria. He was diagnosed with aldosterone-producing adrenal adenoma and nephrogenic diabetes insipidus. Aldosterone enhances the secretion of potassium in the collecting duct, which can lead to hypokalemia. By contrast, nephrogenic diabetes insipidus, which manifests as polyuria and polydipsia, can occur in several clinical conditions such as acquired tubular disease and those attributed to toxins and congenital causes. Among them, hypokalemia can also damage tubular structures in response to vasopressin. The patient's urine output was > 3 L/d and was diluted. Owing to the ineffectiveness of vasopressin, we eventually made a diagnosis of nephrogenic diabetes insipidus. Laparoscopic adrenalectomy and intraoperative kidney biopsy were subsequently performed. The pathologic finding of kidney biopsy revealed a decrease in aquaporin-2 on immunohistochemical stain.

Serum calcium and phosphorus levels in patients undergoing maintenance hemodialysis: A multicentre study in Korea

BACKGROUND: In many countries, nephrologists follow clinical practice guidelines for mineral bone disorders to control secondary hyperparathyroidism (SHPT) associated with abnormal serum calcium (Ca) and phosphorus (P) levels in patients undergoing maintenance hemodialysis (MHD). The Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines have long been used in Korea, and this study was undertaken to investigate the current status of serum Ca and P control in MHD patients. METHODS: Data were collected from a total of 1,018 patients undergoing MHD without intercurrent illness, in 17 hemodialysis centers throughout the country. Serum levels of Ca, P, and intact parathyroid hormone (iPTH) were measured over 1 year, and the average values were retrospectively analyzed. RESULTS: Serum levels of Ca, P, and the CaxP product were 9.1+/-0.7mg/dL, 5.3+/-1.4mg/dL, and 48.0+/-13.6mg2/dL2, respectively. However, the percentages of patients with Ca, P, and Ca x P product levels within the KDOQI guideline ranges were 58.7%, 51.0%, and 70.7%, respectively. Of the 1,018 patients, 270 (26.5%) had iPTH >300pg/mL (uncontrolled SHPT), whereas 435 patients (42.7%) showed iPTH <150pg/mL. Patients with uncontrolled SHPT had significantly higher values of serum Ca, P, and CaxP product than those with iPTH < or =300pg/mL. CONCLUSION: Despite the current clinical practice guidelines, SHPT seems to be inadequately controlled in many MHD patients. Uncontrolled SHPT was associated with higher levels of serum Ca, P, and Ca x P product, suggestive of the importance of SHPT management.

Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet

BACKGROUND: Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor alpha [as well as interleukin (IL)-1beta, IL-10, and interferon gamma]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). METHODS: Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). RESULTS: Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. CONCLUSION: TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

Pseudomyxoma Peritonei: A Rare Cause of Oliguric Acute Kidney Injury / 전남의대학술지

Pseudomyxoma peritonei is a rare clinical condition that causes the accumulation of mucinous ascites, which gradually results in the compression of intra-abdominal organs. Most published reports of pseudomyxoma peritonei concern the mass effect of the resulting ascites, which presents as abdominal pain or intestinal ileus in severe cases. However, few reports of renal complications of the disease have been published. Here, we present a case of oliguric acute kidney injury caused by external compression by pseudomyxoma peritonei. After decompression with external drainage, the patient's renal function rapidly improved.

Pseudomyxoma Peritonei: A Rare Cause of Oliguric Acute Kidney Injury / 전남의대학술지

Pseudomyxoma peritonei is a rare clinical condition that causes the accumulation of mucinous ascites, which gradually results in the compression of intra-abdominal organs. Most published reports of pseudomyxoma peritonei concern the mass effect of the resulting ascites, which presents as abdominal pain or intestinal ileus in severe cases. However, few reports of renal complications of the disease have been published. Here, we present a case of oliguric acute kidney injury caused by external compression by pseudomyxoma peritonei. After decompression with external drainage, the patient's renal function rapidly improved.

Where do we stand on human diabetic nephropathy?

No abstract available.

Plasma leptin concentrations are greater in type II diabetic patients and stimulate monocyte chemotactic peptide-1 synthesis via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway

BACKGROUND: Leptin is an adipokine that is recently reported to be a biomarker of systemic inflammation. Although atherosclerosis causes cardiovascular diseases, it is not clear whether leptin contributes to the acceleration of this process. In this study, we investigated whether alterations of plasma leptin levels were related to diabetic nephropathy and systemic inflammation. In addition, we examined the physiologic action of leptin in cultured vascular smooth muscle cells (VSMCs). METHODS: A total of 126 type 2 diabetic participants and 37 healthy controls were studied. The diabetic participants were divided into three groups according to stage of nephropathy. We investigated whether leptin induced monocyte chemotactic peptide-1 (MCP-1) synthesis through the mitogen-activated protein kinase (MAPK) pathway using cultured VSMCs. RESULTS: Plasma leptin concentrations were significantly higher in the diabetic group than in the controls. Plasma leptin levels were positively correlated with body mass index, fasting and postprandial blood glucose, hemoglobin A1c, total cholesterol, urinary albumin excretion, high-sensitivity C-reactive protein (hsCRP), and MCP-1 plasma levels, and negatively correlated with creatinine clearance values. In cultured VSMCs, leptin increased MCP-1 production in a dose-dependent manner, and this stimulating effect of leptin on MCP-1 expression was reversed by the MAPK (MEK) inhibitor PD98059. In addition, leptin stimulated the phosphorylation of MEK, extracellular signal-regulated kinase, and E26-like transcription factor, which are components of the MAPK pathway. CONCLUSION: Overall, these findings suggest that activation of leptin synthesis may promote MCP-1 activation in a diabetic environment via the MAPK pathway in VSMCs and that it possibly contributes to the acceleration of atherosclerosis.

The Role of Visfatin in Diabetic Nephropathy / 전남의대학술지

As a result of the energy overload in obesity, insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together comprise the metabolic syndrome. Although the kidney becomes a victim of hyperglycemia in diabetes mellitus, recent work has shown that the abnormalities of lipid and glucose metabolism in the kidney are similarly important to those in adipose tissue. Interestingly, obesity triggers the release of adipokines such as leptin, resistin, and visfatin, and these can then be associated with the progression of diabetic nephropathy and other vascular complications. These adipokines, which are also synthesized in the kidney, appear to have an important role in renal injury associated with insulin resistance. Our studies found that visfatin is not only a surrogate marker of systemic inflammation in type 2 diabetic patients but is also up-regulated in diabetic kidney through the uptake of glucose into renal cells, which leads to the activation of the intracellular insulin signaling pathway and pro-inflammatory mechanisms. However, we also observed a beneficial effect of visfatin administration to type 2 diabetic mice. Visfatin injection improved diabetic nephropathy in vivo, in contrast to our previous in vitro study of cultured renal mesangial cells. These results suggest the possibility of multiple cross-talk between adipose tissue and kidney in the metabolic syndrome, particularly in diabetic nephropathy. Further study should be undertaken to understand the role of adipose tissue and kidney as major organs in the metabolic syndrome.

The Role of Visfatin in Diabetic Nephropathy / 전남의대학술지

As a result of the energy overload in obesity, insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together comprise the metabolic syndrome. Although the kidney becomes a victim of hyperglycemia in diabetes mellitus, recent work has shown that the abnormalities of lipid and glucose metabolism in the kidney are similarly important to those in adipose tissue. Interestingly, obesity triggers the release of adipokines such as leptin, resistin, and visfatin, and these can then be associated with the progression of diabetic nephropathy and other vascular complications. These adipokines, which are also synthesized in the kidney, appear to have an important role in renal injury associated with insulin resistance. Our studies found that visfatin is not only a surrogate marker of systemic inflammation in type 2 diabetic patients but is also up-regulated in diabetic kidney through the uptake of glucose into renal cells, which leads to the activation of the intracellular insulin signaling pathway and pro-inflammatory mechanisms. However, we also observed a beneficial effect of visfatin administration to type 2 diabetic mice. Visfatin injection improved diabetic nephropathy in vivo, in contrast to our previous in vitro study of cultured renal mesangial cells. These results suggest the possibility of multiple cross-talk between adipose tissue and kidney in the metabolic syndrome, particularly in diabetic nephropathy. Further study should be undertaken to understand the role of adipose tissue and kidney as major organs in the metabolic syndrome.