Late onset membranous nephropathy complicating donor lymphocyte infusion for leukaemia relapse after allogeneic stem cell transplantation.
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Adult↗
Biomedical subjects
K N Lai
Publications and source records attributed to K N Lai.
An animal study of the effects on p16 and PCNA expression of repeated treatment with high-energy laser and intense pulsed light exposure.
BACKGROUND AND OBJECTIVE: Non-ablative skin rejuvenation treatments that involve the use of laser/light sources together with cooling devices have gained much popularity in recent years due to the lack of down time that is associated with them. One important but neglected issue is long-term safety. Does the repeated use of non-ablative skin rejuvenation lead to photoaging? Are we creating another sun-bed phenomenon? Recently, we performed an in vitro study to examine the effect of sub-lethal QS 755 nm lasers on the expression of p16INK4a on melanoma cell lines, and found that sub-lethal laser damage could increase DNA damage, which led to an increase in p16 expression. Our objective was to assess the cutaneous effect of repeated exposure to high-energy lasers and intense pulsed light sources on male Institute of Cancer Research (ICR) mice. STUDY DESIGN/MATERIALS AND METHODS: Twenty-eight male ICR mice were divided into four groups. Other than the control group, all groups received either laser (585 nm pulsed dye laser or 1,320 nm Nd:YAG laser) or intense pulsed light (IPL) treatment. All four groups were anesthetized with a mixture of Hypnorm/Dormicum before treatment. The animals were irradiated twice a week for 6 months. Signs of toxicity such as mortality and weight loss were checked once a week. Skin tumor formation was evidenced by lesions of greater than 1 mm in diameter that persisted for 2 weeks. At the end of the 6 months, the expression of proliferating cell nuclear antigen (PCNA) and p16 in the mouse skin was determined by immunohistochemical staining and immunoblotting using specific monoclonal antibodies for mouse PCNA and p16. The results were expressed as mean +/- standard error of the mean (SEM). Statistical difference was assessed by multiple ANOVA. A P-value of <0.05 was considered to be significant. RESULTS: At the end of the 6 months, none of the animals had developed any signs of toxicity such as mortality or weight lost. There was no evidence of tumor formation. There were significant elevations of p16 and PCNA in all treated groups as compared to the control group (ANOVA P < 0.05). This particularly applied to the group that was treated with the 1,320 nm Nd:YAG laser. CONCLUSION: The repeated use of high-energy laser and intense pulsed light source did not cause any toxicity in mice. The changes in p16 and PCNA imply that further studies are necessary to consider the implications of repeated exposure to longer wavelength radiation in human skin.
Animals↗
Recurrent glomerulonephritis after kidney transplantation.
Thirty to fifty percent of kidney transplant recipients have glomerular diseases as the underlying causes of end-stage renal failure. While recurrence of glomerulonephritis is an important cause of late renal allograft failure, the risk factors for recurrence are largely unknown or imprecise and prediction remains difficult. Recurrent disease usually presents with similar manifestations as the native disease. With regard to treatment of recurrent glomerular disease in the renal allograft, plasma exchange may be effective in reducing proteinuria in patients with early recurrence of focal and segmental glomerulosclerosis, but immunosuppressive therapy is generally ineffective in the prevention or treatment of recurrent disease. General supportive measures including strict blood pressure control and inhibition or blockade of the rennin-angiotensin pathway are helpful in retarding the rate of deterioration in renal allograft function. Despite the risk of recurrence, kidney transplantation following primary glomerulonephritides enjoys graft and patient survival rates comparable to other causes of end-stage renal failure. With a few exceptions, living related renal transplantation is not contraindicated in view of the favorable outcome and the donor shortage. This review discusses commonly encountered recurrent glomerulonephritides, with special emphasis on the influence of post-transplant prophylactic immunosuppression and emerging treatments.
Diabetic Nephropathies↗
Pathogenic IgA in IgA nephropathy: still the blind men and the elephant?
IgA nephropathy (IgAN), the most common glomerulonephritis worldwide, remains an important cause of end-stage renal failure. The pathology is characterized by mesangial deposition of IgA. The disease is now recognized as arising from anomalies of the IgA molecule and the kidneys are innocent bystanders. The immunochemical nature of the IgA molecule and its mesangial uptake command a pivotal role in the pathogenesis of IgAN.
Acetylgalactosamine↗
Leptin induces TGF-beta synthesis through functional leptin receptor expressed by human peritoneal mesothelial cell.
Marked increase in leptin concentration in spent peritoneal dialysate has been reported following continuous ambulatory peritoneal dialysis treatment. The present study was designed to determine whether functional leptin receptor is expressed by human peritoneal mesothelial cells and if so, the possible implication in dialysis. Expression of leptin receptors in cultured mesothelial cells and omental tissue was examined. The effect of leptin on the production of transforming growth factor-beta (TGF-beta) by mesothelial cells in the presence or absence of high glucose was determined using in vitro culture model of human peritoneal mesothelial cells and adipocytes. The signaling mechanism involved in leptin-induced TGF-beta synthesis by mesothelial cells was studied. Both mRNA and protein of the full-length leptin receptor are constitutively expressed in mesothelial cells. The leptin receptor expression in mesothelial cells was upregulated by glucose but not leptin. In adipocytes, glucose increased the mRNA expression and synthesis of leptin. The Janus kinase-signal transducers and activation (JAK-STAT) signal transduction pathway in mesothelial cells was activated by either exogenous or adipocytes-derived leptin. Exogenous leptin induced the release of TGF-beta by mesothelial cells. The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression. Our novel findings reveal that functional leptin receptor is present on human peritoneal mesothelial cells. The leptin-induced TGF-beta synthesis in mesothelial cells is associated with the expression of leptin receptor and the activation of the JAK-STAT signal transduction pathway.
Cells, Cultured↗
Hepatitis B-related membranous nephropathy should be treated with a specific anti-viral agent.
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Antiviral Agents↗
Proliferating cell nuclear antigen (PCNA) as a proliferative marker during embryonic and adult zebrafish hematopoiesis.
We investigated the expression of proliferative cell nuclear antigen (PCNA) in zebrafish to delineate the proliferative hematopoietic component during adult and embryonic hematopoiesis. Immunostaining for PCNA and enhanced green fluorescence protein (eGFP) was performed in wild-type and fli1-eGFP (endothelial marker) and gata1-eGFP (erythroid cell marker) transgenic fish. Expression of PCNA mRNA was examined in wild-type and chordin morphant embryos. In adult zebrafish kidney, the renal tubules are surrounded by endothelial cells and it is separated into hematopoietic and excretory compartments. PCNA was expressed in hematopoietic progenitor cells but not in mature neutrophils, eosinophils or erythroid cells. Some PCNA+ cells are scattered in the hematopoietic compartment of the kidney while others are closely associated with renal tubular cells. PCNA was also expressed in spermatogonial stem cells and intestine crypts, consistent with its role in cell proliferation and DNA synthesis. In embryos, PCNA is expressed in the brain, spinal cord and intermediate cell mass (ICM) at 24 h-post fertilization. In chordin morphants, PCNA is significantly upregulated in the expanded ICM. Therefore, PCNA can be used to mark cell proliferation in zebrafish hematopoietic tissues and to identify a population of progenitor cells whose significance would have to be further investigated.
Animals↗
Long-term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine.
The short-term outcome of patients with diffuse proliferative lupus nephritis (DPLN) has improved with advances in immunosuppressive treatment. However, the impact of different immunosuppressive regimens on long-term renal function remains to be defined. This prospective cohort study examined the long-term renal function and disease relapse in adults with biopsy-proven DPLN, significant proteinuria, and hypoalbuminemia, who had been treated with sequential immunosuppression comprising prednisolone and oral cyclophosphamide as induction followed by low-dose prednisolone and azathioprine as maintenance. Sixty-six patients with 68 episodes of DPLN were included, with follow-up of 91.7 +/- 36.7 months. 82.4% achieved complete remission and 39.1% relapsed during follow-up. Patients in partial remission were at higher risk of relapse compared with those in complete remission (hazard ratio 6.2, P < 0.001). Serum creatinine remained stable over time (P = 0.931), while creatinine clearance showed a significant increase with time after treatment (P = 0.032). Three (4.4%) patients had doubling of baseline creatinine, but none reached end-stage renal failure or died. Univariate and mixed model analyses showed that the evolution of long-term renal function was significantly influenced by the chronicity score and creatinine clearance at baseline, and by the renal function at one year after treatment. These data demonstrate the efficacy of sequential immunosuppression in preserving renal function in most Chinese subjects with DPLN. The results also indicate that irreversible renal scarring (as reflected by baseline chronicity score), renal reserve (as reflected by renal function at baseline and one year), and an induction regimen that is effective in preserving the nephron mass are critical determinants of long-term renal outcome.
Administration, Oral↗
Modulation of intra-pulmonary TGF-beta expression by mycophenolate mofetil in lupus prone MRL/lpr mice.
We investigated the expression profile of inflammatory cytokines in the lung of lupus-prone MRL/lpr mice and evaluated the therapeutic potential of mycophenolate mofetil (MMF) in reducing pulmonary cytokines in active lupus. Eight-week old female MRL/lpr mice (n = 20) were treated with MMF in vehicle by oral gavage. Disease control MRL/lpr mice (n = 30) or normal control MRL mice (n = 20) received vehicle alone. The mice were sacrificed after eight or 12 weeks of treatment. Gene expression and protein synthesis of IL-1beta, MCP-1 and TGF-beta1 in lung tissues were determined. We found an increase in the gene expression of IL-1beta, MCP-1 and TGF-beta1 in lung tissues of untreated MRL/lpr mice compared with MRL mice at either 16 weeks or 20 weeks of age. MMF treatment significantly prolonged the survival of MRL/lpr mice, down-regulated the gene expression of IL-1beta, MCP-1 and TGF-beta1 in lung tissues at the end of eight or 12 weeks of treatment. Protein synthesis of TGF-beta1 was decreased following eight weeks of MMF treatment. We conclude that MMF treatment can reduce the TGF-beta1 gene expression and protein synthesis in lung tissues of lupus-prone mice. Our findings provide experimental data suggesting a beneficial potential of MMF therapy in pulmonary involvement of lupus.
Animals↗
Angiotensin inhibition or blockade for the treatment of patients with quiescent lupus nephritis and persistent proteinuria.
Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 +/- 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 +/- 3.6 g/L, 102.54 +/- 34.48 micromol/L, 137.6 +/- 10.9 and 81.9 +/- 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 +/- 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.
Adult↗
Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids.
Severe acute respiratory syndrome (SARS) is a new disease which has spread rapidly and widely. We wished to know whether evaluation of in vitro cytokine production could contribute to improved understanding of disease pathogenesis and to better patient management. Numbers of unstimulated and mitogen-stimulated cytokine-secreting peripheral blood mononuclear cells were measured repeatedly during and after hospitalization in 13 patients with SARS using enzyme-linked immunospot technology. Numbers of interferon-gamma, interleukin (IL)-2, IL-4, IL-10 and IL-12 secreting cells induced by T cell activators were below normal in many or most patients before and during treatment with corticosteroids and ribavirin but returned essentially to normal after completion of treatment. Staphylococcus aureus Cowan 1 (SAC)-stimulated IL-10 secreting cells were increased in early SARS but fell during treatment. SAC-induced IL-12 secreting cells were deficient before, during and long after treatment. Numbers of cells induced to produce IL-6 and tumour necrosis factor-alpha by T cell or monocyte activators were higher than normal in many early SARS patients and were still increased in some during and after treatment. We conclude that prolonged dysregulated cytokine production occurs in SARS and that future studies should be directed at improving anti-inflammatory and antiviral therapies in order to limit cytokine impairment.
Adrenal Cortex Hormones↗
Regulation of complement C3 and C4 synthesis in human peritoneal mesothelial cells by peritoneal dialysis fluid.
Although complement is activated in the peritoneal cavity during chronic peritoneal dialysis (PD), little is known about its role in peritoneal defence and injury related to long-term PD. We examined the impact of glucose and commercial peritoneal dialysis solutions on complement expression in HPMCs obtained by primary culture from omental tissues of consented patients undergoing elective abdominal surgery. Constitutive expression of C3 and C4 mRNA in HPMCs was up-regulated upon exposure to 75 mm glucose in a time-dependent manner. C3 and C4 protein was secreted in both apical and basolateral directions. Glucose doses beyond 100 mm markedly down-regulated C3 and C4 expression, and stimulated LDH release dose-dependently. Such cytotoxic effects were attenuated using equivalent doses of mannitol instead of glucose. Treatment with conventional lactate-buffered dialysis solution gave rise to down-regulation of C3 and C4 expression, and heightened LDH release in HPMCs. These effects correlated with the glucose strength of the solution, persisted despite replacement with a bicarbonate-buffered solution, aggravated by glycated albumin, and were partially abrogated by supplementation with 10% fetal bovine serum in the culture system. Our findings suggest that the artificial conditions imposed by PD lead to alterations in local complement synthesis that have implications for the role of the peritoneal mesothelium in both inflammation and defence.
Cell Membrane Permeability↗
Differential expression of receptors for advanced glycation end-products in peritoneal mesothelial cells exposed to glucose degradation products.
Autoclaving peritoneal dialysate fluid (PDF) degrades glucose into glucose degradation products (GDPs) that impair peritoneal mesothelial cell functions. While glycation processes leading to formation of advanced glycation end-products (AGE) were viewed commonly as being mediated by glucose present in the PDF, recent evidence indicates that certain GDPs are even more powerful inducers of AGE formation than glucose per se. In the present study, we examined the expression and modulation of AGE receptors on human peritoneal mesothelial cells (HPMC) cultured with GDPs, conventional PDF or PDF with low GDP content. HPMC cultured with GDPs differentially modulated AGE receptors (including RAGE, AGE-R1, AGE-R2 and AGE-R3) expression in a dose-dependent manner. At subtoxic concentrations, GDPs increased RAGE mRNA expression in HPMC. 2-furaldehyde (FurA), methylglyoxal (M-Glx) and 3,4-dideoxy-glucosone-3-Ene (3,4-DGE) increased the expression of AGE-R1 and RAGE, the receptors that are associated with toxic effects. These three GDPs up-regulated the AGE synthesis by cultured HPMC. In parallel, these GDPs also increased the expression of vascular endothelial growth factor (VEGF) in HPMC. PDF with lower GDP content exerted less cytotoxic effect than traditional heat-sterilized PDF. Both PDF preparations up-regulated the protein expression of RAGE and VEGF. However, the up-regulation of VEGF in HPMC following 24-h culture with conventional PDF was higher than values from HPMC cultured with PDF containing low GDP. We have demonstrated, for the first time, that in addition to RAGE, other AGE receptors including AGE-R1, AGE-R2 and AGE-R3 are expressed on HPMC. Different GDPs exert differential regulation on the expression of these receptors on HPMC. The interactions between GDPs and AGE receptors may bear biological relevance to the intraperitoneal homeostasis and membrane integrity.
Animals↗
IgA nephropathy complicating graft-versus-host disease, another nephropathy causing nephrotic syndrome after bone marrow transplantation.
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Bone Marrow Transplantation↗
Long-term outcome of isoniazid prophylaxis against tuberculosis in Chinese renal transplant recipients.
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Adult↗
The pathogenetic role of immunoglobulin G from patients with systemic lupus erythematosus in the development of lupus pleuritis.
OBJECTIVE: To investigate the pathophysiological effect of immunoglobulin G (IgG) from systemic lupus erythematosus (SLE) patients on pleural mesothelial cells and related mechanisms. METHODS: Serum IgG from 28 lupus patients and 13 healthy controls was purified by protein-G affinity chromatography. The concentrations of anti-dsDNA-, anti-histone- and/or anti-nucleohistone-containing IgGs were determined by enzyme-linked immunosorbent assay (ELISA). Lupus patients were divided into an active (n = 12) and an inactive group (n = 16) on the basis of the SLE Disease Activity Index (SLEDAI). The binding of IgG to a human pleural mesothelial cell line (MeT-5A) under different conditions, including pretreatment with DNase and preincubation with exogenous histone, DNA or nucleohistone, was examined using flow cytometry and cellular ELISA. The effect of IgG on MeT-5A cell proliferation was studied using an MTT assay. Gene expression and protein synthesis for interleukin 1beta (IL-1beta), monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor beta1 (TGF-beta1) in MeT-5A cells were determined using reverse transcription-polymerase chain reaction and ELISA. RESULTS: The binding of IgG to MeT-5A cells was higher in the active lupus group than the inactive lupus group (P = 0.047) and controls (P = 0.003). The binding decreased in both lupus groups following pretreatment of MeT-5A cells with DNase. The binding of IgG to MeT-5A cells was greater by 112% in the active lupus group after preincubation with histone (P < 0.001), but not with DNA or nucleohistone. Exposure of MeT-5A cells to IgG from either lupus group induced cell proliferation when compared with IgG from healthy controls (P = 0.04). Gene expression and protein synthesis of MCP-1, TGF-beta1 and IL-1beta in MeT-5A cells were significantly increased after incubation with IgG from patients with active lupus when compared with IgG from the inactive lupus and control groups (P < 0.01). The concentration of anti-dsDNA antibodies correlated with the binding of IgG to MeT-5A cells and the synthesis of cytokines by MeT-5A cells. The serum level of anti-histone antibodies in the active lupus group was higher than that in the inactive group (P = 0.015) and the serum concentration correlated with cell binding and MCP-1 production. CONCLUSIONS: IgG from lupus patients can bind to MeT-5A cells and the binding is modulated by DNA or histone. Binding of anti-dsDNA-containing IgG to MeT-5A cells induces the synthesis of proinflammatory cytokines. Our findings suggest that the binding of anti-dsDNA antibodies, particularly the IgG isotype, to pleural mesothelium plays a direct pathogenetic role in inducing inflammatory injury in the serositis of SLE.
Acute Disease↗
IL2-receptor antagonist (basiliximab) induction therapy is associated with lower morbidity and mortality in renal transplant recipients.
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Adult↗
Burkholderia urinary tract infection after renal transplantation.
Urinary tract infection is a common complication after renal transplantation. The etiologies are diverse and the bacterial agents may sometimes be acquired during the hospital stay. We report a patient who developed Burkholderia cepacia urinary tract infection after renal transplantation. The bacteria showed in vivo resistance to all of the available antibiotics. A graft nephrectomy was eventually required to clear the infection. The consequence of some fastidious infection may be catastrophic and early recognition and treatment is necessary to optimize the treatment.
Burkholderia Infections↗