Teresa Yuk-Hwa Wong

The natural history of immunoglobulin a nephropathy among patients with hematuria and minimal proteinuria

PURPOSE To determine the natural history of immunoglobulin (Ig) A nephropathy among patients who presented with hematuria and minimal proteinuria, and factors associated with the development of adverse clinical events, such as proteinuria. SUBJECTS AND METHODS In Hong Kong, all patients who present with isolated hematuria are referred for renal biopsy after urologic diseases are ruled out. We reviewed the clinical course of 72 consecutive patients with histologically confirmed IgA nephropathy who presented with hematuria and minimal proteinuria (0.4 g/day or less). All patients were normotensive and had normal renal function at presentation. Adverse events were defined as proteinuria greater than 1 g per day, hypertension, or impaired renal function (serum creatinine level 120 micromol/L or estimated creatinine clearance < 70 mL per minute). RESULTS The mean (+/- SD) age at presentation was 27 +/- 8 years; 56 (78%) were female. Nine patients (13%) had grade 2 histologic lesions. During a median follow-up of 7 years, 32 patients (44%) developed adverse events: 24 (33%) developed proteinuria of 1 g per day or more, 19 (26%) became hypertensive, and 5 (7%) developed impaired renal function. Another 30 patients (42%) had persistently abnormal urinalysis examinations. Only 10 patients (14%) had complete resolution of hematuria. The median time for progression from proteinuria (> l g/day) to renal impairment was 84 months (range 56 to 132). In a multivariate analysis, age at presentation (relative risk [RR] per 10 years of age = 2.0; 95% confidence interval [CI], 1.2 to 3.4) and histologic grade (grade 2 versus grade 1, RR = 4.5; 95% CI, 1.7 to 12) were independent predictors of developing an adverse event. CONCLUSIONS IgA nephropathy that presents with hematuria and minimal proteinuria is usually a progressive disease. Life-long follow-up with regular monitoring of blood pressure and proteinuria is recommended.

Oral Sodium Bicarbonate for the Treatment of Metabolic Acidosis in Peritoneal Dialysis Patients: A Randomized Placebo-Control Trial

Acidosis causes malnutrition in peritoneal dialysis (PD) patients. The effect of oral bicarbonate in PD patients with Kt/V <2.1 has not been studied. We randomly assigned 60 PD patients with acidosis and Kt/V <2.1 to oral sodium bicarbonate (0.9 g thrice daily) or placebo. Patients were followed for 12 mo. We compared their nutritional status, including subjective global assessment (SGA) score and normalized protein nitrogen appearance (NPNA), hospitalization and all-cause mortality. Treatment with oral bicarbonate resulted in a higher plasma bicarbonate level at 4 wk (27.8 +/- 2.6 versus 24.7 +/- 3.9 mmol/L, P = 0.002), and the difference persisted until 52 wk. Bicarbonate treatment had a significant effect on the change in overall SGA score (repeated measures ANOVA, P = 0.0003). The overall SGA score of the treatment group was higher than the placebo group at 24 wk (5.07 +/- 0.94 versus 4.40 +/- 1.00, P = 0.015), and the difference persisted thereafter. NPNA rose in the treatment group (1.17 +/- 0.32 to 1.28 +/- 0.26 g/kg per d, P = 0.034), but declined in placebo group (1.13 +/- 0.25 to 1.03 +/- 0.28 g/kg per d, P = 0.054). The treatment group had a shorter hospitalization than the placebo group (8.4 +/- 17.7 versus 16.8 +/- 21.7 d/yr; P = 0.02). Mortality was not significantly different. Although our trial has limited statistical power, we find that in PD patients with mild acidosis and Kt/V <2.1, oral sodium bicarbonate probably improve nutritional status and reduce the duration of hospitalization.

Conservative management of polymicrobial peritonitis complicating peritoneal dialysis--a series of 140 consecutive cases.

PURPOSE Because polymicrobial peritonitis is believed to be caused by bowel perforation in peritoneal dialysis patients, surgical exploration is often recommended. However, there is recent evidence that antibiotic therapy may be a safe alternative. METHODS We studied 140 consecutive episodes of dialysis-related polymicrobial peritonitis from January 1995 to June 2001. All episodes were treated primarily with intraperitoneal antibiotics. When there was no response, the Tenckhoff catheter was removed, usually after about 10 days of treatment. Laparotomy was performed only when there was clinical suspicion of surgical pathology. RESULTS Ninety patient-episodes (64%) responded to antibiotics alone by day 10; 56 patients (40%) had complete cure with no relapse in 4 months. Nine patients (6%) died within 2 days. Laparotomy was performed in 8 patients who did not respond by day 10, but only 3 had underlying surgical disease (strangulated hernia, ischemic colitis, and colonic cancer). In a multivariate logistic regression analysis, age and the presence of fungus, anaerobes, or Pseudomonas species in the dialysis fluid were independent predictors of poor primary response; and presence of fungus was the only independent predictor of failure to cure in 4 months. CONCLUSION Most patients with dialysis-related polymicrobial peritonitis responded to antibiotic therapy, and surgical exploration was needed only in a few patients. A careful examination of isolated organisms may help in identifying patients who need Tenckhoff catheter removal or surgical intervention.

The clinical course of culture-negative peritonitis complicating peritoneal dialysis

BACKGROUND Culture-negative peritonitis is a serious complication in peritoneal dialysis patients. METHODS We studied all consecutive episodes of culture-negative peritonitis in our unit from 1995 to 2001. We identified 1,182 episodes of peritonitis recorded; 212 episodes in 149 patients had negative culture results. RESULTS The overall primary response rate was 67.5%, and the complete cure rate was 37.7%. In 95 episodes (44.8%), technical problems during the collection of dialysis effluent were suspected. There was a history of antibiotic therapy within 30 days before the onset in 56 episodes (26.4%). Recent antibiotic therapy was associated with a lower primary response rate (31 of 56 versus 113 of 156 episodes; P = 0.019) and lower complete cure rate (12 of 56 versus 68 of 156 episodes; P = 0.003). Furthermore, a history of peritonitis from 31 to 120 days before the onset also was associated with a lower complete cure rate (P = 0.001). Multivariate analysis showed that recent peritonitis was the only independent predictor of treatment failure (odds ratio, 2.87; 95% confidence interval, 1.56 to 5.29). CONCLUSION Most of the culture-negative peritonitis could be explained by recent antibiotic therapy or technical problems during dialysate culture. Recent peritonitis and antibiotic therapy are associated with a poor treatment response. Early Tenckhoff catheter removal is recommended in this group of patients.

Differential effects of transforming growth factor-beta on the synthesis of connective tissue growth factor and vascular endothelial growth factor by peritoneal mesothelial cell.

Background: Previous studies found that transforming growth factor-β (TGF-β) plays a conflicting role in peritoneal fibrosis. We hypothesise that TGF-β acts on peritoneal mesothelial cells (PMC) via VEGF and CTGF as downstream mediators. Methods: The effect of TGF-β in primary culture of rat PMC was studied. VEGF and CTGF mRNA expression was examined by real time quantitative polymerase chain reaction (RT-QPCR), and VEGF antigen level in cell supernatant by ELISA. Results: Incubation of rat PMC with TGF-β resulted in a time- (3–72 h) and concentration- (0–50 pg/ml) dependent increase in VEGF mRNA expression, and VEGF protein level in the cell supernatant. When stimulated with TGF-β 100 pg/ml, there was a 20-fold up-regulation of VEGF mRNA expression (p < 0.001). The CTGF mRNA expression and protein level of PMC was slightly increased at low concentration of TGF-β (50 pg/ml) but decreased at a higher concentration (100 pg/ml or above). The effect of TGF-β on PMC CTGF, but not VEGF, gene expression was inhibited by Smad decoy oligodeoxynucleotide. The effect of TGF-β on PMC VEGF gene expression and protein synthesis was inhibited by PD98059 (a specific MAP kinase inhibitor) and chelerythrine (a specific protein kinase C inhibitor), but not cholera toxin (activator of cyclic AMP) or herbimycin A (inhibitor of protein tyrosine kinase). The up-regulation of CTGF mRNA expression was inhibited by PD98059, but not chelerythrine, cholera toxin or herbimycin A. Furthermore, CTGF gene expression in TGF-β-stimulated PMC was inhibited by co-administration of recombinant VEGF. Conclusions: Our data demonstrate that TGF-β induces PMC production of VEGF and CTGF via different signalling pathways. At high concentration of TGF-β, VEGF production predominates and CTGF production was inhibited. Since CTGF and VEGF have different biologic effects, our results may explain the complex activity of TGF-β in peritoneal physiology.

Association of ENOS polymorphism with basal peritoneal membrane function in uremic patients

BACKGROUND Basal peritoneal permeability has a major impact on the outcome of peritoneal dialysis (PD) patients, but the determinant of this is unknown. Early evidence suggests that peritoneal permeability is affected by nitric oxide (NO) activity. Recently, a gene polymorphism of the endothelial NO synthase (ENOS) gene was identified that is associated with circulating nitrate levels. METHODS We performed a cross-sectional study to examine the relationship between ENOS4(a/b) gene polymorphism and basal peritoneal function in 86 Chinese incident PD patients. ENOS genotypes for variable number tandem repeats in intron 4 (a/b) were identified by polymerase chain reaction. Patients were classified into 2 groups according to results of a basal peritoneal equilibration test (PET) performed within 2 months of dialysis therapy: group A consisted of patients with low (L)/L average (LA) PET results, and group B consisted of those with H and HA PET results. RESULTS Group A (L/LA) had a significantly greater prevalence of ENOS aa/ab genotype than group B (H/HA; 30% versus 12%; P < 0.05). Frequencies of the ENOS a allele also were greater in group A (L/LA) than group B (H/HA) (16% versus 6%; P = 0.03). ENOS genotype remained an independent predictor for peritoneal transport after adjustment for sex, body weight, and prevalence of diabetes by multivariate analysis (adjusted odds ratio, 3.3; confidence interval, 1.1 to 3.7; P = 0.03). Subjects with the aa/ab genotype had significantly lower mass transfer area coefficients (7.35 +/- 3.4 versus 9.48 +/- 5.21 mL/min; P = 0.023) and dialysate-plasma creatinine ratios at 4 hours (0.55 +/- 0.13 versus 0.62 +/- 0.14; P = 0.048) than those with the bb genotype. CONCLUSION ENOS4(a/b) gene polymorphism is associated with basal peritoneal permeability in uremic Chinese patients.

Effective treatment of high-grade lymphoproliferative disorder after renal transplantation using autologous lymphocyte activated killer cell therapy.

Posttransplantation lymphoproliferative disorders (PTLD) is not uncommon and can occur in 2% to 5% of solid organ recipients on immunosuppression. Epstein-Barr virus (EBV) infection or reactivation and intensive anti-T lymphocyte treatment are important pathogenetic factors for a large proportion of these disorders. Nonclonal lesions with polymorphous histology have a potential for regressing when the immunosuppressants are reduced or stopped. Clonal tumors with a monomorphous histology carry a poor prognosis, and the mortality rate for monoclonal lymphoma has been reported as high as 80%. We report a renal transplant recipient who developed high-grade monoclonal lymphoma only 4 months after a live-donor transplantation. The tumor was EBV positive. Reduction of immunosuppressants resulted in minimal regression of the tumor. The patient was treated with adoptive immunotherapy using ex vivo generation of autologous lymphocyte activated killer (LAK) cells. She had leukapheresis, and autologous peripheral blood mononuclear cells were obtained and cultured in interleukin-2 (IL-2)-rich medium for 9 to 10 days. The IL-2-activated LAK cells were reinfused into the patient without any systemic administration of IL-2. The patient experienced no side effects during the infusion. There was no rejection episode, and the renal function of the patient remained stable after treatment. Computed tomography scan performed 2 months after the infusion showed marked regression of the lesions in the liver and spleen. Five months later, magnetic resonance imaging showed complete resolution of the tumor lesions. Ultrasonography 13 months after the LAK cell infusion showed no lesion. The allograft function was not affected after treatment. Adoptive immunotherapy using IL-2-activated autologous LAK cells was effective in treating this renal transplant patient with EBV-positive high-grade lymphoma. The patients kidney allograft functioned well without any rejection.

Cuffed-tunneled femoral catheter for long-term hemodialysis.

Background Hemodialysis access is a challenging problem in patients with exhausted dialysis access sites of their upper extremities. Femoral arterio-venous polytetrafluoroethylene (PTFE) graft is often necessary. The safety and efficacy of cuffed tunneled catheters at the femoral site for long-term hemodialysis has not been extensively studied. Methods We inserted 14 cuffed-tunneled femoral catheters in 11 hemodialysis patients with exhausted dialysis access sites of their upper extremities. Access survival and risk of infection were compared with the 11 femoral PTFE grafts in 10 patients of our center during the same period. The choice of dialysis access was determined by the individual nephrologist. Access survival was defined as the achievement of a blood flow rate of at least 180 ml/min. Results The median survival of tunneled femoral catheter and PTFE graft were 166 days and 560 days respectively (log-rank test, p = 0.33). Seven of the 14 tunneled femoral catheter remained in use 3 months after insertion. The incidence of catheter- or graft-related infection was 0.38 and 0.23 episodes per 100 catheter / graft days for tunneled femoral catheters and PTFE graft respectively (p = 0.6). Five tunneled catheters and one PTFE graft had to be removed because of infection. Blood flow rates achieved were comparable between tunneled femoral catheter and PTFE graft. Conclusions Our preliminary data suggest that the cuffed tunneled femoral catheter has reasonable access survival and an acceptable risk of infection. It may provide a safe and effective access for long-term hemodialysis patients with exhausted access in their upper extremities, especially high risk patients who are not suitable for femoral PTFE graft creation.

Genetic polymorphism of vascular endothelial growth factor : Impact on progression of IgA nephropathy

Background. Vascular endothelial growth factor (VEGF) plays a pivotal role in the capillary endothelial cell growth and proliferation and has known effects on glomerular microvascular permeability. Because certain VEGF polymorphisms are correlated with alterations in VEGF expression, we hypothesized that VEGF genetic polymorphisms may affect the renal survival and progression of primary IgA nephropathy. Methods. The study population consisted of 195 biopsy-proven IgA nephropathy patients at our center between 1984 and 2004. VEGF genotype polymorphism at −2578 positions was determined from peripheral blood leukocytes DNA using polymerase chain reaction methodologies. The primary end point was kidney survival as measured by the time interval from renal biopsy to end-stage renal disease or the requirement of renal replacement therapy. Results. In total, we studied 119 women (61%) and 76 men (39%), with a mean age of 35 ± 10 yr at the time of renal biopsy. Observed genotype frequency was 55.6%, 38.8%, and 5.1% for CC, CA, and AA genotypes respectively. Baseline characteristics did not differ significantly between three genotype groups for patient age, sex, prevalence of hypertension, degree of proteinuria, initial serum creatinine concentration, and the histological grading. After a median follow-up period of 11 yr, doubling of the baseline serum creatinine occurred in 107 of them; 99 patients reached end-stage renal disease requiring renal replacement therapy with a median renal survival of 88 months. The kidney survival in the CC genotype subgroup was similar to that of the CA/AA genotype subgroup during the first 2 yr but became worse than the latter thereafter (log-rank test P = 0.023). The kidney survival rates at the end of 6 yr were 76.8% in the CA genotype, 67.0% in the CC, and 50.0% in the AA genotype groups. Unadjusted hazard ratio of developing end-stage renal disease was 2.65 (95% CI, 1.16 to 6.06) for the CC group as compared to the CA/AA group. The influence of VEGF genotype upon renal survival, however, was not significant after multivariate Cox regression analysis. Conclusion. Our preliminary results raise the concern that the CC genotype of the VEGF promoter at −2578 position might be associated with increased risk of renal progression in patients with IgA nephropathy.

Measured-to-predicted creatinine generation ratio increases with time and decline in residual renal function in continuous ambulatory peritoneal dialysis

The expression of measured-to-predicted creatinine generation ratio (M/P) has been proposed as an index of compliance in continuous ambulatory peritoneal dialysis (CAPD) patients. Although M/P may not be sensitive enough for cross-sectional study, serial monitoring has been suggested to identify noncompliance. We attempted to evaluate serial changes of M/P from a nonselected group of CAPD patients. Sixty-three patients, all followed up for 2 years, were reviewed retrospectively. Their M/P ratios at years 0 and 2 were computed and compared. Baseline M/P had a normal distribution with a mean of 0.96 +/- 0.26. There was significant correlation between baseline M/P and residual glomerular filtration rate (GFR; r = -0.81; P < 0.0001). There were weak correlations between M/P and duration of dialysis (r = 0.52; P < 0.0001), body weight (r = -0.52; P < 0.0001), Kt/V (r = 0.31; P < 0.02), weekly creatinine clearance normalized to body surface area (r = 0.53; P < 0.0001), and serum albumin level (r = -0. 28; P < 0.05). After 2 years, M/P increased in 56 of 63 patients (88. 9%). Average M/P increased from 0.96 +/- 0.26 to 1.31 +/- 0.27 (P < 0.0001). Multivariant analysis showed M/P at year 0, which was largely determined by residual GFR, was the only independent factor affecting increase in M/P from year 0 to year 2. The general trend of increasing M/P was still present when only anuric patients were analyzed, although that was not statistically significant (1.21 +/- 0.14 to 1.32 +/- 0.24; P = 0.12). The finding of increasing M/P with time in CAPD patients, particularly those with significant residual renal function, suggests M/P may not be a reliable indicator of noncompliance, even for serial follow-up of the same patient. Better methods for assessment of compliance in CAPD patients are required.