Joëlle Nortier

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia Fangchi)

BACKGROUND Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Aristolochic acid nephropathy: A worldwide problem

Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain aristolochic acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administrations warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.

Late Onset of Bladder Urothelial Carcinoma After Kidney Transplantation for End-Stage Aristolochic Acid Nephropathy: A Case Series With 15-Year Follow-up

BACKGROUND Aristolochic acids are nephrotoxins and predispose to upper-tract urothelial carcinoma. The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tract urothelial carcinoma is not well defined. STUDY DESIGN Case series. SETTING & PARTICIPANTS Single-center cohort of 38 women given kidney transplants for end-stage aristolochic acid nephropathy. OUTCOMES & MEASUREMENTS The prevalence of upper urinary tract urothelial carcinoma was determined by collecting pathological results of specimens obtained by means of bilateral ureteronephrectomy. We also established the cumulative incidence of bladder urothelial carcinoma in biopsies performed during prospective screening cystoscopies during a 15-year follow-up. RESULTS Upper-tract urothelial carcinoma was found in 17 patients with aristolochic acid nephropathy (44.7%). During follow-up, bladder urothelial carcinoma was diagnosed in 15 patients 68 to 169 months after cessation of aristolochic acid exposure (39.5%): 8 urothelial carcinoma in situ, 4 noninvasive low-grade papillary urothelial carcinoma, and 3 infiltrating urothelial carcinoma. 12 of 17 patients (71%) with a history of upper-tract urothelial carcinoma developed bladder urothelial carcinoma during follow-up, whereas this occurred in only 3 of 21 patients (14%) without upper-tract urothelial carcinoma (P < 0.01). Despite local and/or systemic chemotherapy, 3 patients died and 2 radical cystectomies were performed. LIMITATIONS Small sample size of this case series. CONCLUSIONS Upper-tract and bladder urothelial carcinoma are dramatic complications in kidney transplant recipients with aristolochic acid nephropathy, confirming the carcinogenic properties of aristolochic acids. We identified upper-tract urothelial carcinoma as a potent risk factor for the subsequent development of bladder urothelial carcinoma after kidney transplantation for aristolochic acid nephropathy. Because this complication may occur years after aristolochic acid discontinuation, we suggest regular cystoscopies in addition to the bilateral ureteronephrectomy in kidney transplant recipients with aristolochic acid nephropathy.

Intraperitoneal Secretion of Interleukin-6 during Continuous Ambulatory Peritoneal Dialysis.

Interleukin-6 (IL-6) was determined in serum and peritoneal dialysis effluent (PDE) of patients on chronic ambulatory peritoneal dialysis (CAPD) by a biological assay measuring the proliferation of the IL-6-dependent 7TD1 cell line. Six patients free of peritonitis displayed low but significant levels of IL-6 (mean +/- 42 pg/ml) in PDE, while IL-6 was undetectable in serum. In 6 patients with staphylococcal peritonitis, a tremendous increase in PDE levels of IL-6 was noted (range: 5,832-37,491 pg/ml), while serum IL-6 remained either undetectable or on a low level except in one case. After 5 days of antibiotic treatment, IL-6 levels in PDE returned to basal values. We conclude that CAPD results in an intraperitoneal secretion of IL-6 which is markedly but transiently increased during peritonitis episodes.

Cancer and renal insufficiency results of the BIRMA study

Background:Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed.Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006.Results:A total of 1218 patients were included. The prevalence of elevated SCR (⩾1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR<90 ml min−1 per 1.73 m2. In all, 78.6% of treated patients (n=1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment.Conclusions:The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing.

Regulation of lipid accumulation by AMK-activated kinase in high fat diet–induced kidney injury

AMP-activated protein kinase (AMPK) is an important energy sensor that may be critical in regulating renal lipid accumulation. To evaluate the role of AMPK in mediating renal lipid accumulation, C57BL/6J mice were randomized to a standard diet, a high-fat diet, or a high-fat diet plus AICAR (an AMPK activator) for 14 weeks. Renal functional and structural studies along with electron microscopy were performed. Mice given the high-fat diet had proximal tubule injury with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrent with an increase of tissue lipid and overloading of the lysosomal system. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome accumulation. Characterization of vesicles by special stains (Oil Red O, Nile Red, Luxol Fast Blue) and by electron microscopy showed they contained onion skin-like accumulations consistent with phospholipids. Moreover, cholesteryl esters and phosphatidylcholine-containing phospholipids were significantly increased in the kidneys of mice on a high-fat diet. AMPK activation with chronic AICAR treatment prevented the clinical and structural effects of high-fat diet. Thus, high-fat diet contributes to a dysfunction of the lysosomal system and altered lipid metabolism characterized by cholesterol and phospholipid accumulation in the kidney. AMPK activation normalizes the changes in renal lipid content despite chronic exposure to lipid challenge.

Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy

BACKGROUND Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis. METHODS Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway. RESULTS In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments. CONCLUSION An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway.

Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy

Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7‐(deoxyadenosin‐N6‐yl)‐aristolactam I (dA‐AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA‐AAI adduct induces AT to TA transversions in the tumor‐suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin‐layer chromatography 32P‐postlabeling and mass spectrometric analysis we report the detection of dA‐AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA‐AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA‐AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA‐associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long‐term persistence of dA‐AAI provides a useful long‐term biomarker of exposure and attests to the role of AA in human urothelial malignancy.

Neonatal disease in neutral endopeptidase alloimmunization: lessons for immunological monitoring

Neutral endopeptidase (NEP) alloimmunization has recently been determined to cause severe forms of neonatal disease as a result of the transplacental passage of anti-NEP antibodies. However there is a wide spectrum of neonatal disease variability. We present the medical histories of a large family, specifically of two alloimmunized sisters in their second pregnancy in whom we established the basis of immunological surveillance and therapeutic intervention during pregnancy and after delivery. One mother developed dramatically high titers of IgG1 and IgG4, and was treated with IvIg and one plasma exchange, both of which substantially reduced the anti-NEP Ab titer. However, the neonatal syndrome observed in her infant was severe, partly due to treatment delay. Anti-NEP Ab were also found in the mother’s milk and the infant’s urine. In contrast, the other mother had a normal second pregnancy and delivered a healthy neonate, which was related to the fact that she only produced the non-complement activating IgG4 subclass of anti-NEP antibodies. Thus, anti-NEP Ab (titer and subclass) seem to be highly sensitive biomarkers of neonatal risk. Interventional strategy aimed at reducing anti-NEP titer, should be started early during pregnancy and, possibly, even before pregnancy in those mothers producing anti-NEP IgG1. Careful monitoring of anti-NEP Ab titer and subclass is mandatory in NEP-deficient mothers during their pregnancies.

Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature

I. Simon, K.M. Wissing, V. Del Marmol, S. Antinori, M. Remmelink, E. Nilufer Broeders, J.L. Nortier, M. Corbellino, D. Abramowicz, A. Cascio. Recurrent leishmaniasis in kidney transplant recipients: report of 2 cases and systematic review of the literature.
Transpl Infect Dis 2011: 13: 397–406. All rights reserved