[Show abstract][Hide abstract] ABSTRACT: Kidney anion exchanger 1 (kAE1) plays an important role in acid-base homeostasis by mediating chloride/bicarbornate (Cl−/HCO3−) exchange at basolateral membrane of α-intercalated cells in 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 occur. Here, we studied the role of basolateral-related sorting proteins, including 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 assay, 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 co-localization 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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/m2 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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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/m2. 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.
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.
[Show abstract][Hide abstract] ABSTRACT: Patients with diffuse proliferative lupus nephritis (class IV) who responded to treatment within 6 months had better renal outcome than those who did not. Glomerular macrophage is known to be associated with poor renal outcome in glomerular diseases.
To evaluate association between glomerular macrophage number and early treatment response in lupus nephritis class IV patients.
Renal biopsies (n = 90, 86 females) diagnosed with lupus nephritis class IV were included in the study. The patients were divided into 2 groups (n = 45 each) according to response to treatment within 6 months. The treatment response group was defined as having decreased serum creatinine at least 25% from baseline and 24 hr urine protein or UPCR (urine protein creatinine ratio) < 1. The non-response group was defined as stable or increased serum creatinine and 24 hr urine protein or UPCR > or = 1. Immunohistochemistry for macrophage marker (CD68) was performed and the glomerular macrophages were counted on each biopsy. The relevant clinicopathologic data were collected.
The glomerular macrophage number in response and non-response group was 4.5 +/- 2.5 and 6.2 +/- 4.5 respectively (p = 0.029). The glomerular macrophage number was conversely and inversely correlated with activity (r = 0.281, p = 0.007) and chronicity (r = -0.358, p < 0.001) index, respectively
Lupus nephritis class IV patients who responded to treatment within 6 months had lower glomerular macrophages than those who did not. The glomerular macrophage number may be used to determine treatment response in lupus nephritis class IV patients.
Journal of the Medical Association of Thailand = Chotmaihet thangphaet 02/2013; 96 Suppl 2:S246-51.
[Show abstract][Hide abstract] ABSTRACT: Lupus nephritis (LN) is uncommon after the age of 50 years and studies of elderly patients with LN are rare. The authors conducted the current study to determine the clinical manifestations, pathological features and prognosis of 30 Thai patients with late onset LN in Siriraj hospital in Bangkok from 1989 to 2006.
Thirty LN patients with a disease onset beyond the age of 50 years from 1989 to 2006 were enrolled in this retrospective study. All of them received renal biopsy. The histological classifications were categorized according to 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification.
Clinical and pathologic records were collected from 30 patients (23 female and 7 men) who were followed-up for a mean period of 25.8 months (range, 6 to 96 months). The mean age was 56.6 +/- 4 years. Hypertension was diagnosed in 66.7% of patients and 41.3% had serum creatinine greater than 1.5 mg/dL. Nephrotic-range proteinuria was found in 63.3% of patients and creatinine clearance less than 50 ml/min was found in 70%. Of the 30 patients, the most common renal histologic finding was diffuse proliferative glomerulonephritis (63.30%). The overall probability of patient survival was 94.1% at 12 months, 68.6% at 36 months and 34.3% at 60 months. During the follow-up period (25.8 months; range, 6 to 96 months), 4 patients died. Infection was the leading cause of death (75%).
Lupus nephritis in the elderly patients is not uncommon. Prompt diagnosis should be made for appropriate management and optimal outcome.
Journal of the Medical Association of Thailand = Chotmaihet thangphaet 02/2012; 95 Suppl 2:S213-7.
[Show abstract][Hide abstract] ABSTRACT: 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.
Biochemical and Biophysical Research Communications 08/2011; 413(1):69-74. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibody-mediated rejection (AMR) has been recognized recently as an important cause of graft failure. Detection of C4d in renal allograft biopsies is a proven ancillary technique in the diagnosis of AMR. The prevalence of C4d staining in Western countries varies from 17% to 60% among indication biopsies. There are only a few C4d prevalence studies in an Asian population. The objective of this study was to identify prevalence of C4d among Thai renal transplant patients. Consecutive renal allograft biopsies from 99 patients from 1999 to 2007 were stained for C4d by an immunoperoxidase technique. The biopsy slides were evaluated for the diagnosis according to the Banff'07 classification and histological scores. The relevant clinical data were obtained from clinical records. The prevalence of C4d in renal allografts was reported as a percentage using a descriptive analysis. Chi-square and unpaired Student t tests were used to evaluate the association between clinicopathologic findings and C4d positivity. P values less than .05 were considered significant. The prevalence of positive C4d staining was 16.4%. Fourteen biopsies (10.4%) showed diffuse staining while 8 (5.9%) revealed focal staining. Transplant glomerulopathy, glomerulitis, and peritubular capillaritis were associated with C4d positivity. Most inflammatory cells in peritubular capillaritis were mononuclear cells. Banff score elements, including tubulitis, intimal arteritis, interstitial infiltrate, interstitial fibrosis, tubular atrophy, mesangial matrix increase, vascular fibrous thickening, and arteriolar hyaline thickening, were not associated with C4d positivity. Many factors contribute to the varied prevalence of C4d positivity, including immunologic risks for AMR, type of allograft biopsy, and technique of C4d staining. Our study showed no difference in C4d prevalence among Thai renal allograft patients compared to the Western population. The suggestion to use C4d staining on all allograft biopsies should applied to Thai patients as well.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
A retrospective analysis was undertaken in systemic lupus erythematosus patients (n = 150, 44 <15 years old, 106 0e;15 years old) who underwent renal biopsy. The specimens were evaluated for histological features of APSN and other significant clinical parameters. The result of antiphospholipid antibodies, clinical course, and renal function from chart review were analysed.
The prevalence of APSN in systemic lupus erythematosus patients who underwent renal biopsies was 34% (16% in <15-year-old group, 41.5% in > or =15-year-old group). APSN was associated with more severe hypertension (P = 0.002 for systolic and P = 0.004 for diastolic blood pressure), acute renal failure (P = 0.003), persistent heavy proteinuria (P < 0.001 for 4+ proteinuria), severe lupus nephritis (class III and IV, P = 0.014, high activity and chronicity indices, P < 0.001) and a tendency to progress to end-stage renal disease.
Systemic lupus erythematosus patients who underwent renal biopsies in our institute showed a prevalence of APSN comparable to those in western countries. The presence of APSN was significantly higher in the adult than in the paediatric population. Its association with poor prognostic indicators suggests poor renal outcome. Clinicians should be aware of this condition in order to give proper care to systemic lupus erythematosus patients.
[Show abstract][Hide abstract] ABSTRACT: Focal segmental glomerulosclerosis (FSGS) is the leading cause of nephrotic syndrome in an adult worldwide. The prevalence of FSGS is estimated as being 20-30% in adults over the age of 15 years and slightly higher (30-35%) in the elderly (age > 60 years). The diagnosis solely relies on pathologic findings, which sclerosis involves some, but not all glomeruli (focal), and sclerosis affects a portion, but not the entire, glomerular tuft (segmental). The pathogenesis remains inconclusive but podocyte injury has been postulated. Even though steroid is the mainstay treatment, only 20-40% of patients are complete respond.
Journal of the Medical Association of Thailand = Chotmaihet thangphaet 09/2006; 89 Suppl 2:S262-79.
[Show abstract][Hide abstract] ABSTRACT: The fibroblast growth factor (FGF) family has functions in development, cell proliferation, migration, and differentiation. While FGF-2 induces fibrosis, the role of FGF-1 in inflammation and fibrosis is less defined. We examined the expression of FGF-1 and FGF receptor (FGFR-1) to determine if renal diseases with varying etiologies of inflammation, including lupus nephritis (LN), acute interstitial nephritis (AIN) and acute rejection superimposed on chronic allograft nephropathy (CAN), showed varying patterns of expression. We also examined the expression of fibroblast-specific protein-1 (FSP-1), which has been linked to epithelial-mesenchymal transition (EMT) and fibrosis, to determine whether it was linked to potential profibrotic and inflammatory FGF-1 mechanisms.
Proliferative LN (PLN) (N= 12), nonproliferative lupus nephritis (NPLN) (N= 5), AIN (N= 6), CAN (N= 4), and normal kidneys (N= 3) were studied. FGF, FGFR-1, and FSP-1 were localized by immunohistochemistry, and intensity scored on a 0 to 3+ scale. Double staining with CD68 and separate immunohistochemical staining for CD4 and CD8 with serial sections analysis were done to identify if T lymphocytes or macrophages showed staining for FGF-1 and FGFR-1 or FSP-1.
In normal kidneys, FGF-1 was expressed in mesangial cells (0.67 +/- 0.58), glomerular endothelial (0.67 +/- 0.58), visceral, and parietal epithelial cells (1.67 +/- 0.58). FGFR-1 showed a similar pattern of staining but also was expressed in tubular epithelium, and arterial endothelium and smooth muscle. Expression of FGF-1 was increased over normal in glomerular parenchymal cells only in CAN in podocytes (2.30 +/- 0.58 vs. 3.00 +/- 0.00) (P < 0.05) and parietal epithelial cells (1.67 +/- 0.58 vs. 2.25 +/- 0.50) (P < 0.05). Infiltrating glomerular and interstitial inflammatory cells in diseased glomeruli also expressed FGF-1 and FGFR-1. Tubular cells expressed slightly increased FGFR-1 in renal diseases vs. normal, whereas tubules remained negative for FGF-1 in diseased kidneys. FSP-1 expression was prominent in the interstitium in all kidneys with interstitial inflammation, and most prominent in CAN. Interstitial FSP-1+ cells were consistent with a myofibroblast-type morphology, and did not stain with CD-68. FSP-1 expression was closely associated with inflammatory cells expressing FGF-1 and FGFR-1. FSP-1 also showed positivity within crescents and occasional podocytes in PLN.
The expression of FGF-1 and FGFR-1 in infiltrating lymphocytes and macrophages, and of FGFR-1 in tubules, is supportive, but does not prove causality, of the possibility that FGF-1 might have both autocrine and paracrine functions in renal inflammation. However, the initial stimulus for renal inflammation, whether immune complex, hypersensitivity or rejection, did not alter expression patterns of FGF-1 or its receptor. The colocalization of inflammatory infiltrates with interstitial fibrosis supports the possibility of a contribution of FGF-1 for chemotaxis and associated fibrosis, further supported by interstitial FSP-1 expression closely associated with these inflammatory cells expressing FGF-1 and FGFR-1.
Kidney International 12/2005; 68(6):2621-8. · 8.52 Impact Factor