Boonyarit Cheunsuchon

Prevalence and clinicopathologic findings of antiphospholipid syndrome nephropathy in Thai systemic lupus erythematosus patients who underwent renal biopsies.

Aim:  To determine the prevalence of antiphospholipid syndrome nephropathy (APSN) in Thai systemic lupus erythematosus (SLE) patients who underwent renal biopsy and to compare the relationship of renal histopathology and other significant clinical parameters between SLE patients with and without APSN.

Evaluating the Clinical Course and Prognostic Factors of Posttransplantation Immunoglobulin A Nephropathy

INTRODUCTION Previous reports have suggested that posttransplantation immunoglobulin (Ig) A nephropathy displays a relatively benign course, hardly ever affecting graft function. However, more recent studies with longer follow-up have shown that posttransplantation IgA nephropathy may be a significant contributor to graft loss. Additionally, there may be other clinical or pathological factors that affect long-term graft outcome. We retrospectively analyzed 30 kidney transplant recipients with biopsy-proven IgA nephropathy in their allografts to determine the clinical course and prognostic factors in posttransplantation IgA nephropathy. The median duration of follow-up was 36 months (range, 1 month-17 years). The median onset of IgA nephropathy was 33.6 months posttransplantation (range, 5 days-103 months). The most common presentation was an abnormal urine examination (96.6%). Fifteen (50%) displayed microscopic hematuria with proteinuria more than 1 g/d. Fifteen patients (50%) lost their grafts at a median time of 24 months after the onset of disease (range, 1-93 months). Allograft loss was associated with a high serum creatinine level at the time of diagnosis (3.68 +/- 2.23 vs 1.79 +/- 0.34 mg/dL; P = .006), a greater level of proteinuria at the time of diagnosis (2.43 +/- 0.76 vs 1.29 +/- 1.07 g/d; P = .003), and more than 50% extracapillary proliferation (P = .05). Fibrinoid necrosis on allograft pathology impacted 1-year allograft survival (P = .025). CONCLUSION Posttransplantation IgA nephropathy worsens allograft outcomes among patients with increased serum creatinine level or significant proteinuria at presentation or significant glomerular inflammation and/or tubulointerstitial damage.

Anti-CD20 monoclonal antibody (rituximab) for the treatment of membranous nephropathy after living-unrelated kidney transplantation: a case report.

A 41-year-old Thai male with end-stage renal disease of uncertain etiology started chronic hemodialysis in November 2001. Two years later, he underwent a living unrelated, four HLA mismatched, kidney transplantation from his wife. Pretransplant class I panel reactive antibody was 80% and the cross-match was positive for immunoglobulin (Ig)M. There was no complication until 30 months after transplantation, when he developed frank nephrotic syndrome with 12.9 g/day of proteinuria. Serum creatinine was 1.5 mg/dL. Allograft biopsy showed membranous nephropathy and mild acute cellular rejection with plasma cell infiltration. In addition to enalapril, valsartan, and simvastatin, a single dose of rituximab (375 mg/m2) and a 3-day course of pulse methylprednisolone were prescribe for the acute rejection episode. The patient was maintained on the same immunosuppressive regimen: cyclosporine, azathioprine, and prednisolone. Five months after the therapy, proteinuria was reduced to 0.5 g/day with a normalized serum albumin level. At 4 years post transplantation, his renal function remains stable. His serum albumin is 4.5 g/dL and urine protein-to-creatinine ratio 0.2.

Role of Adaptor Proteins and Clathrin in the Trafficking of Human Kidney Anion Exchanger 1 (kAE1) to the Cell Surface

Kidney anion exchanger 1 (kAE1) plays an important role in acid–base homeostasis by mediating chloride/bicarbornate (Cl−/HCO3−) exchange at the basolateral membrane of α‐intercalated cells in the distal nephron. Impaired intracellular trafficking of kAE1 caused by mutations of SLC4A1 encoding kAE1 results in kidney disease – distal renal tubular acidosis (dRTA). However, it is not known how the intracellular sorting and trafficking of kAE1 from trans‐Golgi network (TGN) to the basolateral membrane occurs. Here, we studied the role of basolateral‐related sorting proteins, including the mu1 subunit of adaptor protein (AP) complexes, clathrin and protein kinase D, on kAE1 trafficking in polarized and non‐polarized kidney cells. By using RNA interference, co‐immunoprecipitation, yellow fluorescent protein‐based protein fragment complementation assays and immunofluorescence staining, we demonstrated that AP‐1 mu1A, AP‐3 mu1, AP‐4 mu1 and clathrin (but not AP‐1 mu1B, PKD1 or PKD2) play crucial roles in intracellular sorting and trafficking of kAE1. We also demonstrated colocalization of kAE1 and basolateral‐related sorting proteins in human kidney tissues by double immunofluorescence staining. These findings indicate that AP‐1 mu1A, AP‐3 mu1, AP‐4 mu1 and clathrin are required for kAE1 sorting and trafficking from TGN to the basolateral membrane of acid‐secreting α‐intercalated cells.

Human kidney anion exchanger 1 interacts with kinesin family member 3B (KIF3B)

Impaired trafficking of human kidney anion exchanger 1 (kAE1) to the basolateral membrane of α-intercalated cells of the kidney collecting duct leads to the defect of the Cl(-)/HCO(3)(-) exchange and the failure of proton (H(+)) secretion at the apical membrane of these cells, causing distal renal tubular acidosis (dRTA). In the sorting process, kAE1 interacts with AP-1 mu1A, a subunit of AP-1A adaptor complex. However, it is not known whether kAE1 interacts with motor proteins in its trafficking process to the plasma membrane or not. We report here that kAE1 interacts with kinesin family member 3B (KIF3B) in kidney cells and a dileucine motif at the carboxyl terminus of kAE1 contributes to this interaction. We have also demonstrated that kAE1 co-localizes with KIF3B in human kidney tissues and the suppression of endogenous KIF3B in HEK293T cells by small interfering RNA (siRNA) decreases membrane localization of kAE1 but increases its intracellular accumulation. All results suggest that KIF3B is involved in the trafficking of kAE1 to the plasma membrane of human kidney α-intercalated cells.

JNK1/2 inhibitor reduces dengue virus-induced liver injury

ABSTRACT High viral load with liver injury is exhibited in severe dengue virus (DENV) infection. Mitogen activated protein kinases (MAPKs) including ERK1/2 and p38 MAPK were previously found to be involved in the animal models of DENV‐induced liver injury. However, the role of JNK1/2 signaling in DENV‐induced liver injury has never been investigated. JNK1/2 inhibitor, SP600125, was used to investigate the role of JNK1/2 signaling in the BALB/c mouse model of DENV‐induced liver injury. SP600125‐treated DENV‐infected mice ameliorated leucopenia, thrombocytopenia, hemoconcentration, liver transaminases and liver histopathology. DENV‐induced liver injury exhibited induced phosphorylation of JNK1/2, whereas SP600125 reduced this phosphorylation. An apoptotic real‐time PCR array profiler was used to screen how SP600125 affects the expression of 84 cell death‐associated genes to minimize DENV‐induced liver injury. Modulation of caspase‐3, caspase‐8 and caspase‐9 expressions by SP600125 in DENV‐infected mice suggests its efficiency in restricting apoptosis via both extrinsic and intrinsic pathways. Reduced expressions of TNF‐&agr; and TRAIL are suggestive to modulate the extrinsic apoptotic signals, where reduced p53 phosphorylation and induced anti‐apoptotic Bcl‐2 expression indicate the involvement of the intrinsic apoptotic pathway. This study thus demonstrates the pivotal role of JNK1/2 signaling in DENV‐induced liver injury and how SP600125 modulates this pathogenesis. HighlightsSP600125 treatment improves leucopenia, thrombocytopenia, RBC counts and liver injury in DENV‐infected mice.SP600125 inhibits the phosphorylation of both JNK1/2 and p38 MAPK to reduce DENV‐induced liver injury.SP600125 treatment modulates both extrinsic and intrinsic pathways of apoptosis to improve DENV‐induced liver injury.

Loss-of-function mutations of SCN10A encoding Na V 1.8 α subunit of voltage-gated sodium channel in patients with human kidney stone disease

Human kidney stone disease (KSD) causes significant morbidity and public health burden worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defects to complex interaction between genetic and environmental factors. However, the genetic defects causing KSD in the majority of affected families are still unknown. Here, we report the discovery of mutations of SCN10A, encoding NaV1.8 α subunit of voltage-gated sodium channel, in families with KSD. The region on chromosome 3 where SCN10A locates was initially identified in a large family with KSD by genome-wide linkage analysis and exome sequencing. Two mutations (p.N909K and p.K1809R) in the same allele of SCN10A co-segregated with KSD in the affected family. Additional mutation (p.V1149M) of SCN10A was identified in another affected family, strongly supporting the causal role of SCN10A for KSD. The amino acids at these three positions, N909, K1809, and V1149, are highly conserved in vertebrate evolution, indicating their structural and functional significances. NaV1.8 α subunit mRNA and protein were found to express in human kidney tissues. The mutant proteins expressed in cultured cells were unstable and causing reduced current density as analyzed by whole-cell patch-clamp technique. Thus, loss-of-function mutations of SCN10A were associated with KSD in the families studied.

Clinicopathologic Features and Treatment Response of Early Acute Antibody-Mediated Rejection in Thai Kidney Transplant Recipients: A Single-Center Experience

BACKGROUND Acute antibody-mediated rejection (AMR) is a major cause of early kidney allograft dysfunction. This study was conducted to examine the clinicopathologic features and long-term outcomes of early AMR in our center. METHODS We retrospectively reviewed all patients who underwent kidney transplantation between January 2005 and December 2012. Patients who had histopathologic features of AMR within 3 months after transplantation were enrolled. RESULTS Of 444 patients, early acute AMR was diagnosed in 25 patients (5.36%). Seventeen patients (68%) were highly sensitized. Histological analysis revealed acute vascular rejection and thrombotic microangiopathy in 21 (84%) and 6 (24%) patients, respectively. Staining of C4d in peritubular capillaries was detected in 6/20 patients (12%). All patients received plasma exchange (PE) 1.5 blood volume for 1-5 sessions followed by intravenous immunoglobulin (IVIG) 2 g/kg. Sixteen patients (64%) received 1-2 doses of rituximab 375 mg/m(2). We repeated treatment with PE and IVIG in refractory cases. Allografts could be rescued in 20 patients (80%) whereas 5 patients (20%) lost their grafts. Kaplan-Meier survival analysis revealed lower cumulative graft survival in the early AMR group compared with patients without early AMR (1 year survival rate of 80% vs 96% and 3 survival of 64% vs 80%; P < .001). After median follow-up time of 25 months, 7/20 patients (33%) developed late AMR. CONCLUSION ABMR is a serious early complication after KT. Early detection and intensive treatment is mandatory for salvaging the graft. After surpassing from early AMR, long-term close monitoring is also necessary.

Clinicopathologic Characteristics and Outcomes of Late Acute Antibody-Mediated Rejection in Thai Kidney Transplant Recipients: A Single-Center Experience

BACKGROUND Late antibody-mediated rejection (ABMR) has worse prognosis than early ABMR. The objective of this study was to examine the clinical and pathological features of late acute ABMR in our experience. METHOD We retrospectively reviewed all patients who underwent kidney transplantation (KT) between January 2001 and December 2012. Patients who had glomerulitis and/or peritubular capillaritis on kidney biopsy performed 6 months after KT were enrolled. RESULTS Of 592 patients, late acute ABMR was diagnosed in 34 cases (5.74%) with a mean onset of 49.2 ± 30.2 months post-KT. Six patients (17.6%) had nonadherence. Allograft histopathology demonstrated concomitant transplant glomerulopathy in 23 patients (67.6%) and positive peritubular C4d staining in 25 patients (73.5%). Donor-specific antibody (DSA) was detected in 25 patients (73.5%). Anti-HLA class II antibody was more prevalent than class I (67.6% vs 20.6%; P = .003) and most of them were anti-HLA DQ. We prescribed intravenous immunoglobulin (IVIG) 1-2 g/kg for 30 patients (88.2%), plasma exchange (PE) for 27 patients (79.4%), and rituximab 375 mg/m(2) for 18 patients (52.9%). We repeated treatment with PE and IVIG in 12 refractory cases. For clinical outcome, 21 patients (61.7%) had deterioration of graft function; 9 of them (26.5%) eventually lost their graft. Thirteen patients (38.2%) had stable graft function. CONCLUSION Late acute ABMR has unsatisfactory prognosis in spite of aggressive standard antihumoral treatment. Surveillance of late ABMR using DSA monitoring may be helpful in early detection and management.