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.

Baseline High Blood Pressure is Associated with Clinico-Pathologic Findings and Later Renal Progression in Chronic Glomerulonephritis

BACKGROUND@#Several factors had been suggested to contribute to the development of hypertension in chronic glomerulonephritis (GN). This study was conducted to find the association of baseline blood pressure (BP) with pathophysiologic findings and later renal progression in chronic GN.@*METHODS@#Clinico-pathological findings including serum creatinine (Cr), proteinuria, pathological findings, and urinary Na excretion were analyzed in a total of 233 patients with IgA nephropathy from The Kyung-Hee Cohort of GN. Glomerular surface area (GSA) was measured by imaging analysis and urine angiotensinogen (AGT) concentrations by human ELISA kits.@*RESULTS@#Systolic BP was ≥130mmHg in 124 patients (53%). Systolic BP was negatively correlated with follow-up eGFR (r=−0.32, p<0.0001) and positively serum uric acid concentrations, while it had no significant relationships with initial serum Cr and eGFR. As compared with patients with systolic BP<130 mmHg, those with ≥130 mmHg were older and showed higher serum Cr, proteinuria, 24 hr urinary Na excretion, mean GSA, and T-I fibrosis, lower follow-up eGFR, and steeper decline in slope of eGFR. The results in patients with normal serum Cr concentrations were comparable to those in whole group. Systolic BP was positively correlated with age, baseline and follow-up proteinuria, serum uric acid concentrations and IgM deposit and negatively with follow-up eGFR. In subgroup analysis, systolic BP was also positively correlated with mean GSA and urinary AGT concentrations.@*CONCLUSION@#This study showed that baseline systolic BP is related to urinary Na excretion, glomerulomegaly, T-I fibrosis and later renal progression in patients with IgA nephropathy.

Conversion from acetate dialysate to citrate dialysate in a central delivery system for maintenance hemodialysis patients

BACKGROUND: The objective of this study was to compare the impact of citrate dialysate (CD) and standard acetate dialysate (AD) in hemodialysis by central delivery system (CDS) on heparin demand, and clinical parameters. METHODS: We retrospectively evaluated 75 patients on maintenance hemodialysis with CDS. Patients underwent hemodialysis with AD over a six-month period (AD period), followed by another six-month period using CD (CD period). Various parameters including mean heparin dosage, high sensitivity C-reactive protein (hsCRP), calcium-phosphate product (CaxP), intact parathyroid hormone (iPTH), and urea reduction ratio (URR) were collated at the end of each period. RESULTS: Patients were 60.5 ± 14.7 years old, of whom 62.7% were male. Patients required less heparin when receiving CD (AD period: 1,129 ± 1,033 IU/session vs. CD period: 787 ± 755 IU/session, P < 0.001). After the CD period (Δ(CD)), pre-dialysis total CO₂ increased to 1.21 ± 2.80 mmol/L, compared to −2.44 ± 2.96 mmol/L (P < 0.001) after the AD period (Δ(AD)). After the CD period, concentrations of iPTH (Δ(AD): 73.04 ± 216.34 pg/mL vs. Δ(CD): −106.66 ± 251.79 pg/mL, P < 0.001) and CaxP (Δ(AD): 4.32 ± 16.63 mg²/dL² vs. Δ(CD): −4.67 ± 15.27 mg²/dL², P = 0.015) decreased. While hsCRP levels decreased after the CD period (Δ(AD): 0.07 ± 4.09 mg/L vs. Δ(CD): −0.75 ± 4.56 mg/L, P = 0.705), the change was statistically insignificant. URR remained above clinical guideline of 65% after both periods (Δ(AD): 72.33 ± 6.92% vs. Δ(CD) period: 69.20 ± 4.49%, P = 0.046). CONCLUSION: Our study confirmed that the use of CD in CDS required lower heparin doses compared to the use of AD. The use of CD also provided a more stable acid-base status.

Renal Tubular Acidosis in Patients with Primary Sjögren's Syndrome

Primary Sjögren's syndrome (pSS) is characterized by lymphocytic infiltration of the exocrine glands resulting in decreased saliva and tear production. It uncommonly involves the kidneys in various forms, including tubulointerstitial nephritis, renal tubular acidosis, Fanconi syndrome, and rarely glomerulonephritis. Its clinical symptoms include muscle weakness, periodic paralysis, and bone pain due to metabolic acidosis and electrolyte imbalance. Herein, we describe the cases of two women with pSS whose presenting symptoms involve the kidneys. They had hypokalemia and normal anion gap metabolic acidosis due to distal renal tubular acidosis and positive anti-SS-A and anti-SS-B autoantibodies. Since one of them experienced femoral fracture due to osteomalacia secondary to renal tubular acidosis, an earlier diagnosis of pSS is important in preventing serious complications.

Syndrome of inappropriate antidiuretic hormone secretion associated with seronegative neuromyelitis optica spectrum disorder

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a potential cause of hyponatremia of the central nervous system (CNS). Although SIADH has been reported to be associated with many other central nervous disorders, its association with neuromyelitis optica (NMO) or NMO spectrum disorders are rare. NMO is a demyelinating disorder characterized by optic neuritis and transverse myelitis. Aquaporin-4 (AQP4), which is the target antigen for a NMO autoantibody, is the predominant CNS water channel. However, some NMO patients show seronegative AQP4 antibody results. The spectrum of NMO has been changed, and new findings about the disease have been reported. Here, we report a case of seronegative NMO spectrum disorder associated with SIADH.

Elevated serum immunoglobulin E level as a marker for progression of immunoglobulin A nephropathy

BACKGROUND: Immunoglobulin E (IgE) has traditionally been associated with anaphylaxis and atopic disease. Previous studies reported that serum IgE levels are elevated in nephrotic syndrome and suggested IgE levels as a prognostic indicator in glomerular diseases. The aim of this study was to explore the association between serum IgE levels and renal outcome in patients with immunoglobulin A nephropathy (IgAN). METHODS: We included 117 patients with biopsy-proven IgAN. Renal progression was defined if a patient meets one of these criteria: (1) a negative value of delta estimated glomerular filtration rate (mL/min/1.73 m²/mo) or (2) a rise in serum creatinine to an absolute level of ≥ 1.3 mg/dL (male) or 1.2 mg/dL (female). We defined delta changes in serum creatinine, estimated glomerular filtration rate, and proteinuria as a difference of values during the follow-up period. RESULTS: A total of 117 patients with IgAN were included. The serum IgE level was significantly high in the renal progressive group compared with the nonprogressive group. Sex and history of gross hematuria were significantly different between the high-IgE group and the low-IgE group. Regression analysis showed that a male sex, initial proteinuria, and change of proteinuria were significantly associated with serum IgE levels. CONCLUSION: The serum IgE level is potentially associated with disease progression and pathogenesis of IgAN.

Plasma endocan level and prognosis of immunoglobulin A nephropathy

BACKGROUND: Endocan, previously called endothelial cell–specific molecule-1, is a soluble proteoglycan that is secreted from vascular endothelial cells. Elevated plasma endocan levels were shown to be associated with poor cardiovascular outcomes in patients with chronic kidney disease (CKD). We investigated the clinical relevance of plasma and urine endocan levels in patients with immunoglobulin A nephropathy (IgAN). METHODS: Sixty-four patients with IgAN and 20 healthy controls were enrolled in this study. Plasma and urine endocan levels were measured. Clinical parameters, pathologic grades, and renal outcomes were compared among subgroups with different plasma and urine endocan levels. RESULTS: Both plasma and urine endocan levels were significantly higher in patients with IgAN than in controls. Elevated serum phosphorus and C-reactive protein were independent determinants for plasma endocan, and elevated C-reactive protein was also an independent determinant for urine endocan levels in multivariate analysis. Plasma endocan level was not significantly different across CKD stages, but patients with higher plasma endocan levels showed adverse renal outcome. Urine endocan levels were also elevated in patients with poor renal function. Cox proportional hazard models showed that high plasma endocan was an independent risk factor for CKD progression after adjusting for the well-known predictors of outcome in patients with IgAN. CONCLUSION: This study suggested that plasma endocan might be useful as a prognostic factor in patients with IgAN.

Genetic Variations of Tyrosine Hydroxylase in the Pathogenesis of Hypertension

One of the major pathophysiological features of primary hypertension is an inappropriate activation of the sympathetic nervous system, which is mediated by excessive synthesis and secretion of catecholamine into the blood. Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine, has been highlighted because genetic variations of TH could alter the activity of the sympathetic nervous system activity and subsequently contribute to the pathogenesis of hypertension. Here, we discuss the role of TH as a regulator of sympathetic activity and review several studies that investigated the relationship between genetic variations of TH and hypertension.

Transforming growth factor-beta receptor 2 gene polymorphisms are associated with end-stage renal disease

BACKGROUND: Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine involved in immune disorders, cancer, asthma, lung fibrosis, and chronic kidney disease, and its signal pathways are considered crucial mediators of a variety of cellular processes. In addition, several recent studies have reported that TGF-beta receptor (TGF-betaR) gene polymorphism is associated with chronic kidney disease. However, the association between end-stage renal disease (ESRD) and the TGF-beta gene polymorphism has not been sufficiently investigated. In this study, we hypothesized that polymorphisms of the TGF-beta ligands or their receptors may be related to ESRD. METHODS: We assessed the relationship between four single-nucleotide polymorphisms (SNPs) in the TGF-betaR2 and TGF-beta2 genes and ESRD, in 312 patients with ESRD and 258 controls. RESULTS: Compared with the control participants, the frequencies of the TGF-betaR2 (rs764522*C) and TGF-betaR2 (rs3087465*G) alleles were significantly higher in the patients with ESRD. Genotyping analysis demonstrated that two SNPs in TGF-betaR2 of the four SNPs included in the study were significantly associated with ESRD in the codominant 1 [rs764522, odds ratio (OR)=1.65; rs3087465, OR=1.63], dominant (rs764522, OR=1.63; rs3087465, OR=1.57), and log-additive (rs764522, OR=1.54; rs3087465, OR=1.39) models after adjusting for age and sex. CONCLUSION: We suggest that TGF-betaR2 polymorphisms (rs764522 and rs3087465) increase the risk of development of ESRD.

Hypertension in Chronic Glomerulonephritis

Chronic glomerulonephritis (GN), which includes focal segmental glomerulosclerosis and proliferative forms of GN such as IgA nephropathy, increases the risk of hypertension. Hypertension in chronic GN is primarily volume dependent, and this increase in blood volume is not related to the deterioration of renal function. Patients with chronic GN become salt sensitive as renal damage including arteriolosclerosis progresses and the consequent renal ischemia causes the stimulation of the intrarenal renin-angiotensin-aldosterone system(RAAS). Overactivity of the sympathetic nervous system also contributes to hypertension in chronic GN. According to the KDIGO guideline, the available evidence indicates that the target BP should be or =30mg/24 h (i.e., those with both micro-and macroalbuminuria), a lower target of or =30mg/ 24 h. The combination of a RAAS blockade with a calcium channel blocker and a diuretic may be effective in attaining the target BP, and in reducing the amount of urinary protein excretion in patients with chronic GN.

A Case Report of Familial Renal Hypouricemia Confirmed by Genotyping of SLC22A12, and a Literature Review

A 24-year-old male visited our hospital because of pain in both flanks. His biochemistry profile showed an elevated serum creatinine level and low serum uric acid level. History taking revealed that he had undertaken exercise prior to the acute kidney injury (AKI) event, and he stated that family members had a history of urolithiasis. His renal profile improved after hydration and supportive care during hospitalization. Although the patient was subsequently admitted again due to AKI, his status recovered with similar treatment. Since the diagnosis of the patient was familial renal hypouricemia with exercise-induced AKI, we performed genotyping of SLC22A12, which encodes human urate transporter 1. The diagnosis was confirmed by the detection of a homozygous mutation of W258X. We herein, report a case of familial renal hypouricemia confirmed by genotyping of SLC22A12, and review the relevant literature.

A case of Ramsay Hunt syndrome diagnosed after kidney transplantation

We report the first case of Ramsay Hunt syndrome (RHS) diagnosed after kidney transplantation in Korea. RHS is a disease caused by latent varicella-zoster characterized to involve geniculate ganglion of the seventh cranial nerve. Patients who have undergone kidney transplantation can be easily affected by viral infections because of their immune-compromised status. A 35-year-old man with hypertensive end-stage renal disease underwent kidney transplantation. Two months after surgery, the recipient was diagnosed with RHS and treated with antivirals and steroids. However, after using the antiviral agents for the recommended duration, facial paralysis occurred as a new presentation and he required further treatment. Otalgia and periauricular vesicles improved, but the facial palsy remained.

Hyperphosphatemia is associated with patency loss of arteriovenous fistula after 1 year of hemodialysis

BACKGROUND: The patency of arteriovenous access is important for stable and effective hemodialysis, and long-term technical survival is best achieved with a native arteriovenous fistula (AVF). However, maintaining AVF patency remains a challenge. This study was designed to determine the independent prognostic factors for AVF patency according to hemodialysis duration. METHODS: The primary study end point was unassisted patency of the AVF, which was defined as the time from the first fistula surgery to the first AVF failure. AVF failure was defined as an event that required percutaneous intervention or surgery to revise or replace the fistula, which occurred at least 2 months after fistula formation. RESULTS: We enrolled 478 patients with a mean age of 55.5+/-14.0 years, and mean duration of dialysis was 2.5+/-2.1 years. There were 109 cases (22.8%) of AVF failure. The factors related to AVF patency differed according to hemodialysis duration. Using a Cox-adjusted model, we observed a significant correlation between the incidence of AVF failure and diabetes within the initial 12 months of hemodialysis. Uncontrolled hyperphosphatemia (mean serum phosphorus>5.5 mg/dL during hemodialysis) was associated with patency loss of AVF after 1 year of hemodialysis. CONCLUSION: Various factors were associated with the development of patency loss of AVF as hemodialysis duration differed, and a preventive role of hyperphosphatemia control in AVF survival needs further clinical study.

Clinicopathological role of kidney injury molecule-1 in immunoglobulin A nephropathy

BACKGROUND: Urinary kidney injury molecule-1 (KIM-1) is an early and sensitive biomarker of acute kidney injury, but it is unclear if it is a biomarker of chronic glomerulonephritis. We evaluated whether urinary KIM-1 levels in patients with immunoglobulin A (IgA) nephropathy can be a marker to reflect clinicopathological severity and predict the prognosis. METHODS: We measured urinary KIM-1 levels in 40 patients (15 males; mean age 36.67+/-12.9 years) with IgA nephropathy and 10 healthy people (5 males; mean age 37.37+/-9.6 years) as controls. The correlation of urinary KIM-1 levels with patients' clinical parameters, histological grades, and follow-up data were analyzed using the modified H. S. Lee grading system and tubulointerstitial change scores. RESULTS: Urinary KIM-1 levels were higher in patients with IgA nephropathy than healthy controls (P=0.001). Univariate and multivariate regression analyses showed that urinary KIM-1 levels had a direct correlation with H. S. Lee grade and tubulointerstitial inflammation (P=0.004 and P=0.011, respectively). CONCLUSION: In patients with IgA nephropathy, urinary KIM-1 has a significant correlation with histopathologic severity.

Urinary excretion of beta2-microglobulin as a prognostic marker in immunoglobulin A nephropathy

BACKGROUND/AIMS: beta2-microglobulin (beta2-MG) is freely filtered at the glomerulus and subsequently reabsorbed and catabolized by proximal renal tubular cells. Urinary beta2-MG is an early and sensitive biomarker of acute kidney injury; however, its utility as a biomarker of immunoglobulin A nephropathy (IgAN) is unclear. METHODS: We included urinary beta2-MG levels in the routine laboratory examination of all inpatients with biopsy-proven IgAN at our hospital from 2006 to 2010. We retrospectively analyzed the correlation between beta2-MG levels and clinical parameters as a prognostic biomarker of IgAN. RESULTS: A total of 51 patients (30 males, 21 females; mean age, 33.01 +/- 12.73 years) with IgAN were included in this study. Initial demographic, clinical, and laboratory data for all patients are listed. The mean initial estimated glomerular filtration rate and 24-hour urine protein levels were 94.69 +/- 34.78 mL/min/1.73 m2 and 1.28 +/- 1.75 g/day, respectively. The mean level of urinary beta2-MG was 1.92 +/- 7.38 microg/mg creatinine. There was a significant correlation between initial serum creatinine (iSCr), urine protein creatinine ratio (UPCR), and the level of beta2-MG (r = 0.744, r = 0.667, p < 0.01). There was also a significant correlation between renal function tests and the level of urinary beta2-MG (p < 0.01). Cox regression analysis showed that albumin, beta2-MG, iSCr, and UPCR were significant predictors of disease progression in IgAN. CONCLUSIONS: Urinary beta2-MG levels showed a significant correlation with renal function and proteinuria in IgAN. Thus, we propose that urinary beta2-MG may be an additional prognostic factor in patients with IgAN.

Severe Hyponatremia Associated with the Use of Angiotensin II Receptor Blocker/thiazide Combinations

There are several widely used combinations of angiotensin II receptor blocker (ARB)/thiazide. The complimentary mechanism of action for such anti-hypertensive therapies is that, while ARB inhibits the vasoconstricting and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and increases excretion of sodium and chloride in the distal tubule, consequently promoting water excretion. In addition, hypokalemia, which may be triggered by a hydrochlorothiazide-induced increase in urinary potassium loss, is resisted by the use of ARB. Hence, the ARB/thiazide combination is safe in terms of potassium imbalance. For these reasons, fixed-dose ARB/thiazide combination anti-hypertensive drugs have been widely used for the treatment of hypertension. However, there have not been many studies done regarding cases where patients under such regimens showed severe hyponatremia, even when the amount of thiazide included was low. Here we report two cases in which severe hyponatremia occurred following treatment with the ARB/thiazide combinations. Upon discontinuation of the regimen, both patients showed recovery from hyponatremia.

Treatment of Primary Glomerulonephritis / 대한내과학회지

Much progress has been made in the elucidation of potential pathogenetic mechanisms of glomerulonephritis such as anti-PLA2R autoantibody in membranous nephropathy and under-galactosylated IgA1 in IgA nephropathy as well as in the fields of treatment. This knowledge is, hopefully in the future, being applied in the development of the creation of rational therapeutic approaches. Current treatment strategies for glomerular diseases recommended by many clinical studies include high-dose glucocorticoids, calcineurin inhibitors, cyclophosphamide, mycophenolate mofetil, and rituximab. Although these therapies have been effective in treating immune-mediated glomerular diseases, they all have potentially serious side effects.

Renal outcomes and clinical course of nondiabetic renal diseases in patients with type 2 diabetes

BACKGROUND/AIMS: In several recent studies, renal biopsies in patients with type 2 diabetes and renal disease have revealed a heterogeneous group of disease entities. Our aim was to study the prognosis and clinical course of nondiabetic renal disease (NDRD) and to determine risk factors for NDRD in patients with type 2 diabetes. METHODS: Renal biopsy reports of 110 patients with type 2 diabetes who were seen at Kyung Hee University Medical Center and Kyung Hee University Hospital at Gangdong, Seoul, Korea between January 2000 and December 2011 were retrospectively analyzed. RESULTS: Of 110 patients with type 2 diabetes, 41 (37.3%) had diabetic nephropathy (DN), 59 (53.6%) had NDRD, and 10 (9.1%) had NDRD superimposed on DN. Immunoglobulin A nephropathy (43.5%) was the most common NDRD. Patients with NDRD had a shorter duration of diabetes, lower frequency of diabetic retinopathy, and better renal outcomes, which might have resulted from the use of aggressive disease-specific treatments such as steroids and immunosuppressants in patients with NDRD. CONCLUSIONS: Compared with DN, NDRD was associated with better renal outcomes in patients with type 2 diabetes, as evidenced by a higher cumulative renal survival rate and lower rate of end-stage renal disease (ESRD). Shorter duration of diabetes and absence of retinopathy were independent predictors of NDRD in patients with type 2 diabetes and renal involvement. Renal biopsy is recommended for patients with type 2 diabetes and risk factors for NDRD, to obtain an accurate diagnosis, prompt initiation of disease-specific treatment, and ultimately better renal outcomes with the avoidance of ESRD.

A Case of Linezolid-Associated Lactic Acidosis / 대한내과학회지

Linezolid has been used for treatment of vancomycin-resistant Enterococcus faecium infection, nosocomial pneumonia caused by Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus or Streptococcus pneumoniae, and complicated and uncomplicated skin and skin structure infections. Lactic acidosis is an adverse effect associated with drugs, including metformin, the nucleoside reverse-transcriptase inhibitors and, rarely, linezolid. We report a case in which severe lactic acidosis developed as an adverse effect of linezolid in a 75-year-old woman who had been on linezolid for 30 days for treatment of a wound infection caused by methicillin-resistant coagulase-negative Staphylococcus. Discontinuation of linezolid and hemodialysis improved her lactic acidosis.