M.-K. Lai

Population-Based Case–Control Study of Chinese Herbal Products Containing Aristolochic Acid and Urinary Tract Cancer Risk

Background Consumption of Chinese herbs that contain aristolochic acid (eg, Mu Tong) has been associated with an increased risk of urinary tract cancer. Methods We conducted a population-based case–control study in Taiwan to examine the association between prescribed Chinese herbal products that contain aristolochic acid and urinary tract cancer. All patients newly diagnosed with urinary tract cancer (case subjects) from January 1, 2001, to December 31, 2002, and a random sample of the entire insured population from January 1, 1997, to December 31, 2002 (control subjects), were selected from the National Health Insurance reimbursement database. Subjects who were ever prescribed more than 500 pills of nonsteroidal anti-inflammatory drugs and/or acetaminophen were excluded, leaving 4594 case patients and 174 701 control subjects in the final analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multivariable logistic regression models for the association between prescribed Chinese herbs containing aristolochic acid and the occurrence of urinary tract cancer. Models were adjusted for age, sex, residence in a township where black foot disease was endemic (an indicator of chronic arsenic exposure from drinking water [a risk factor for urinary tract cancer]), and history of chronic urinary tract infection. Statistical tests were two-sided. Results Having been prescribed more than 60 g of Mu Tong and an estimated consumption of more than 150 mg of aristolochic acid were independently associated with an increased risk for urinary tract cancer in multivariable analyses (Mu Tong: at 61–100 g, OR = 1.6, 95% CI = 1.3 to 2.1, and at >200 g, OR = 2.1, 95% CI = 1.3 to 3.4; aristolochic acid: at 151–250 mg, OR = 1.4, 95% CI = 1.1 to 1.8, and at >500 mg, OR = 2.0, 95% CI = 1.4 to 2.9). A statistically significant linear dose–response relationship was observed between the prescribed dose of Mu Tong or the estimated cumulative dose of aristolochic acid and the risk of urinary tract cancer (P < .001 for both). Conclusions Consumption of aristolochic acid–containing Chinese herbal products is associated with an increased risk of cancer of the urinary tract in a dose-dependent manner that is independent of arsenic exposure.

Risks of Kidney Failure Associated With Consumption of Herbal Products Containing Mu Tong or Fangchi: A Population-Based Case-Control Study

BACKGROUND Taiwan has a remarkably high incidence of end-stage renal disease (ESRD). The objective of this study is to determine the association between prescribed herbal products containing aristolochic acid and ESRD. STUDY DESIGN Population-based case-control study. SETTING & PARTICIPANTS All new ESRD cases in Taiwan and a simple random sample (200,000 people) drawn from the national health insurance reimbursement database in 1997-2002. PREDICTOR Age; sex; hypertension; diabetes; cumulative doses of nonsteroidal anti-inflammatory drugs, acetaminophen, and adulterated herbal supplements potentially containing aristolochic acid before the development of chronic kidney disease; and indications for prescribing such herbs, including chronic hepatitis, chronic urinary tract infection, chronic neuralgia, or chronic musculoskeletal diseases. OUTCOMES & MEASUREMENTS Occurrence of ESRD through construction of multiple logistic regression models. RESULTS There were 36,620 new ESRD cases from 1998 through 2002. After exclusion of cases with chronic kidney disease diagnosed before July 1, 1997, there were 25,843 new cases of ESRD and 184,851 controls in the final analysis. Women, older age, hypertension, and diabetes were significantly associated with increased risks of the development of ESRD. After adjustment for known risk factors, cumulative doses >60 g of Mu Tong (OR, 1.47 [95% CI, 1.01-2.14] for 61-100 g; OR, 5.82 [95% CI, 3.89-8.71] for >200 g) or Fangchi (OR, 1.60 [95% CI, 1.20-2.14] for 61-100 g; OR, 1.94 [95% CI, 1.29-2.92] for >200 g) were associated with increased risk of the development of ESRD with a dose-response relationship. This relationship persisted when analyses were limited to participants who consumed <500 pills of nonsteroidal anti-inflammatory drugs and those without diabetes. LIMITATIONS No measurement of renal function, no contact with patients, over-the-counter sales were not recorded, and potential underestimation of exposure dose for cases and ORs. CONCLUSIONS Consumption of >60 g of Mu Tong or Fangchi from herbal supplements was associated with an increased risk of developing kidney failure.

Increased risks of chronic kidney disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid

Aim:  Nephropathy associated with aristolochic acid (AA) has been documented by human and animal studies. Ancient Chinese herbology claimed to reduce toxicity in their mixtures. It was the objective of this study to determine the risk of chronic kidney disease (CKD) associated with AA‐related Chinese herbal products (CHP) or mixtures of herbs in a national cohort.

Curcumin enhances the immunosuppressive activity of cyclosporine in rat cardiac allografts and in mixed lymphocyte reactions.

Curcumin (CCM; diferuoylmethane) is a dietary pigment in curry with known antineoplastic and anti-inflammatory effects. The immunosuppressive effects of CCM were studied in (1) rat heterotopic cardiac transplant models, using Brown-Norway (BN, RT1(n)) hearts to WKY (RT1(u)) hosts or Buffalo (BUF, RT1(b)) hearts to Wistar-Furth (WF, RT1(u)) hosts, (2) reverse transcriptase-polymerase chain reaction analysis of cytokines from transplanted specimens, and (3) mixed lymphocyte reactions (MLR). In the BN-to-WKY model, CCM alone significantly increased the mean survival time (MST) to 20.5 to 24.5 days, as compared to 9.1 days among nontreated controls. The combination of CCM and subtherapeutic doses of CsA produced further prolongation of the MST to 28.5 to 35.6 days, better than that of CCM or CsA alone (P <.05). In a BUF-to-WF model, CCM alone did not increased the MST, unless it was combined with subtherapeutic doses of CsA, wherein two thirds of the grafts survived for more than 60 days (P <.05 as compared to either treatment group). Cytokine analysis revealed significantly reduced expression of interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and granzyme B in the day 3 specimens of the CCM and CCM CsA-treated allografts compared with the nontreated allograft controls. MLRs using the two MHC-incompatible rat strains (BNxWKY) showed an effect of increasing concentrations of CCM and/or CsA, which by combination index (CI) analysis showed a synergistic effect (CI = 0.22 to 0.81). This study for the first time demonstrates the effectiveness of CCM as a novel adjuvant immunosuppressant with cyclosporine both in vivo and in vitro.

Prolonged ischemia potentiates apoptosis formation during reperfusion by increase of caspase 3 activity and free radical generation

ISCHEMIC injury to the kidney or renal allograft before implantation is an important cause of renal dysfunction and delayed graft function. In the setting of prolonged ischemia, a major source of primary renal dysfunction comes from the generation of reactive oxygen species (ROS) during the reperfusion phase. The overproduction of ROS after reoxygenation of the kidney may initiate the cascade of renal tubular injury and necrosis/apoptosis and can lead to oxidative damage of DNA, proteins, and lipids. It has been implicated that the prolonged ischemic interval during renal surgery potentiates damage to the kidneys. However, it is uncertain whether the kidney damage elicited by the prolonged ischemic interval is directly related to the overproduction of ROS. Lucigenin luminescence can be used as the basis for assaying superoxide dismutase activity, but should not be used for measuring, or even detecting O2 . In this investigation, by using MCLA-amplified ultrasensitive chemiluminescence (CL), we studied the production of reactive oxygen species (ROS) in rat kidneys after ischemia-reperfusion (I/R) injury in vivo and the relationship of ROS production to the duration of the ischemic interval.

Sirolimus Does Not Absolutely Abolish the Occurrence/Recurrence of Urothelial Carcinoma in Renal Transplant Recipients

OBJECTIVE Sirolimus (SRL), an immunosuppressant shown to possess anti-proliferative properties, was hypothesized to mitigate the occurrence of posttransplantation malignancy. We examined its effect on posttransplantation urothelial carcinoma (UC). METHODS This retrospective case analysis included renal allograft recipients with UC treated with SRL in a single institute. RESULTS Among 90 renal recipients treated with SRL, 6 had previous/new-onset UC in the native kidney/ureter or bladder: at a mean period of 28 months (range, 7-49) of administering SRL for these recipients, UC occurred/recurred in 4 of the 6 patients. Individual cases are presented in detail. CONCLUSION SRL does not absolutely abolish the occurrence/recurrence of UC among renal transplant recipients. Its potency as an anti-cancerous immunosuppressant for transplant recipients with UC deserves to be further defined in larger studies, probably by controlling SRL blood levels at lower or much higher ranges than used herein.

Optimal C2 Concentration of Cyclosporin Corrected With Good Efficacy and Safety in Asian Kidney Transplant Recipients

INTRODUCTION Calcineurin inhibitors (CNI) are known for their renal toxicity. Lower CNI exposure is a reasonable option to mitigate potential CNI-induced renal toxicity. Herein we have presented our long-term results after lower cyclosporine (CsA) exposure in the first year. MATERIALS AND METHODS Between 1997 and 2004, 63 renal transplant recipients received CsA-based immunosuppression. CsA dosing was adjusted according to the 2-hour whole blood concentration (C2) level. We retrospectively reviewed acute rejection and graft survivals rates, as well as whole blood C2 levels. RESULTS Review of serial mean C2 concentrations at 1, 2, 3, 6, and 12 months after transplantation were 1341, 1241, 1191, 1059, and 927 ng/mL, respectively. These levels were slightly lower than those suggested by the Consensus for C2 levels by Levy et al in 2002, namely, 1600 to 2000 ng/mL (mean, 1700); 1400 to 1600 ng/mL (mean, 1500); 1200 to 1400 ng/mL (mean, 1300); 1000 to 1200 ng/mL (mean, 1100), and 800 to 1000 ng/mL (mean, 900), respectively. Acute rejection rate at 3 months and 1 year are 17.5% and 23.8%. Graft survival at 1 year was 97% and at 5 years, 89%. Two patient were lost to fulminant hepatitis and acute myocardial infarction during the first year, which were not associated with underimmunosuppression. CONCLUSION Appropriate CsA C2 levels may be lower among Taiwanese. Our C2 dosing strategy resulted in good outcomes with acceptable side effects in our single-center experience. Appropriate CsA C2 levels for Asians deserve more attention in trials of larger scale; most reference levels are presently concluded from studies of Caucasians.

Mycophenolate mofetil-induced hyperbilirubinemia in renal transplant recipients

PATIENTS AND METHODSCase 1A 27-year-old man with end-stage renal disease secondary tocryptic etiology received his first renal allograft from his sister inMay 1998. Initially, he was treated with standard cyclosporine(CyA) and steroid dual immunosuppression. He had a rathersmooth recovery from the transplantation with rapid decrease ofhis serum creatinine levels. During serial follow-up of his CyApharmacokinetic studies, the average concentration of blood CyA(CsA-Cav) reached a maximum of 812 ng/mL on postoperative day9. His serum total bilirubin level (T-Bili) increased from 1.0 mg/dLpreoperatively to 1.7 mg/dL at that time. In order to avoid thehepatotoxicity and nephrotoxicity of CyA, the dose was reduced.Meanwhile, MMF was added to ensure sufficient immunosuppression.The patient was found to be icteric 1 week later and his T-Bili rose to3.7 mg/dL. Further investigation showed that his CyA-Cav decreasedto around 650 ng/mL. In order to further reduce the dose of CyA, thedose of MMF was increased to 1.5 g/d. But, unexpectedly, his T-Biliclimbed to 5.7 mg/dL in 1 day. MMF-induced hyperbilirubinemia wasstrongly suspected, and MMF was discontinued (Fig 1A).Case 2A 49-year-old man with end-stage renal disease secondary topolycystic kidney disease received his first kidney transplantationfrom a cadaveric donor in February 1999. He was initially treatedwith standard CyA/steroid dual immunosuppression. He developedposttransplant diabetes mellitus and had a Banff type IB biopsy-proven acute rejection episode on postoperative day 10. Therejection episode was successfully rescued by 4 days of rabbitantithymocyte immunoglobulin therapy. MMF (1.0 to 1.5 g/d) wasadded to rescue acute rejection. In addition, he continued toreceive CyA and steroids. Three days after he started to take MMF,his T-Bili increased to 2.7 mg/dL (Fig 1B).Abdominal sonography did not reveal any dilatation of intrahe-patic or common bile duct in either of them. Except for CyA, noother proicteric drugs were used in these two patients by retrospec-tive chart review. There were no significant changes of other liverfunction parameters, including serum alanine aminotransferase,aspartate aminotransferase, lactate dehydrogenase, alkaline phos-phatase, and hepatitis markers in both of them.RESULTS

Urachal Adenocarcinoma Following Kidney Transplantation: The First Case Report

A 53-year-old man who underwent successful kidney transplantation for stage 5 chronic kidney disease presented to our clinic with intermittent painless gross hematuria. Urachal adenocarcinoma, stage III A by Sheldon system, was diagnosed after serial histopathologic and radiological studies. The patient was treated with extended partial cystectomy, en bloc resection of urachus and umbilicus, pelvic lymphadenectomy, and ileocystoplasty. There were no complications seen in this patient. Neither urachal adenocarcinoma recurrence, metastasis, nor de novo uroileal cancer developed during 48-month follow-up. His reconstructed bladder functioned efficiently, without compromising the transplanted kidney function. Our case demonstrated that conservative surgery and augmentation ileocystoplasty could be offered to kidney transplant recipients with localized urachal carcinoma.

An audit of nephroureterectomy for upper tract urothelial carcinoma

BACKGROUND The boundary of nephroureterctomy has been revisited and lymph node dissection has been recommended recently. We investigated the role of synchronous ipsilateral adrenalectomy in treating patients with upper tract urothelial carcinoma. METHODS 110 patients with clinically localized upper tract urothelial carcinoma treated by nephroureterectomy and bladder cuff resection were retrospectively evaluated. 70 patients underwent nephroureterectomy without concomitant ipsilateral adrenalectomy, whereas nephroureterectomy and ipsilateral adrenalectomy was performed in other 40 patients. Cancer specific, metastasis and local recurrence free survival during a follow-up of median 46 months were analyzed. RESULTS No patient had adrenal metastasis among the 40 adrenalectomized patients. A total of 4 patients developed local recurrences; including 1 of the 70 adrenalectomy-sparing and 3 of the 40 adrenalectomized patients (p = 0.102, chi-square test). Five patients with adrenalectomy and four without adrenalectomy had distant metastases (p = 0.212, chi-square test). The five-year local recurrence free survival (p = 0.09, log-rank test), metastasis-free survival (p = 0.292, log-rank test), and cancer-specific survival (p = 0.117, log-rank test) did not have significant difference between both groups. CONCLUSIONS This is the only study in recent 2 decades to evaluate the necessity of synchronous adrenalectomy in treating localized upper tract urothelial carcinoma. Adrenal-sparing nephroureterectomy seems justified for clinically localized upper tract urothelial carcinoma.