Jean-Louis Vanherweghem

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

BACKGROUNDnChinese-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.nnnMETHODSnThe 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.nnnRESULTSnAmong 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.nnnCONCLUSIONSnThe prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

The Epidemiology, Diagnosis, and Management of Aristolochic Acid Nephropathy: A Narrative Review

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

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

BACKGROUNDnAristolochic 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.nnnSTUDY DESIGNnCase series.nnnSETTING & PARTICIPANTSnSingle-center cohort of 38 women given kidney transplants for end-stage aristolochic acid nephropathy.nnnOUTCOMES & MEASUREMENTSnThe 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.nnnRESULTSnUpper-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.nnnLIMITATIONSnSmall sample size of this case series.nnnCONCLUSIONSnUpper-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.

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

BACKGROUNDnInterstitial 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.nnnMETHODSnMale 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.nnnRESULTSnIn 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.nnnCONCLUSIONnAn 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.

Valvular heart disease and Chinese-herb nephropathy

Snt-Jean-Louis Vanhenveghem (Dec 20127, p 1858)‘ wonders whether Chinese-herb nephropathy might not be caused by the intake of fenfluramine. We do not believe that this hypothesis is supported by available evidence. We previously reported aortic insdliciency in five of 12 patients, one of whom required valvular surgery: a finding now corroborated by Vanhenveghem, and speculated that aortic insufficiency could be another extrarenal manifestation of Chineseherb intoxication. The observation that appetite suppressants lead to valvular disease raises the more likely hypothesis that the aortic insufficiency in our patients was due to the concomitant intake of fenfluramine and diethylpropion.’ It is, however, unlikely that appetite suppressants are implicated in Chineseherb nephropathy. Indeed, since 1975 fenfluramine and diethylpropion have been included in the Brussels slimming regimen. The rapidly progressive interstitial disease has been observed only after 199&ie, when the Chinese herbs Srephaniu retrundra and Mugnoliu oficinalis replaced pancreas powder, laminaria powder, and fucus extract? The discovery that Srephaniu tetrandru had been inadvertently replaced by the aristolochic-acid rich Aristolochiufung chi led to the suggestion that aristolochic acid, a known carcinogenic agent, was the cause of Chinese-herb nephropathy. Our subsequent finding of aristolochic acid DNA adducts in the renal tissue of six patients with Chinese-herb nephropathy: together with urothelial cellular atypias and in-situ carcinomas,2 strongly supported a causal effect of aristolochic acid. The uneven distribution of Chineseherb nephropathy among patients given the same herbal mixture means that the toxic effect of aristolochic acid might have been potentiated by another agent, perhaps the simultaneously ingested appetite suppressants.

Effects of dexfenfluramine on aristolochic acid nephrotoxicity in a rat model for Chinese-herb nephropathy

Chinese-herb nephropathy (CHN) is a progressive renal interstitial fibrosis initially reported after concomitant intake of an anorexigen, (dex)fenfluramine, and a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acid (AA). We thus tested the possible enhancing effect of the active enantiomer dexfenfluramine (DXF) on AA nephrotoxicity in a rat model for CHN. Groups of 12 salt-depleted male Wistar rats received daily subcutaneous injections of 7xa0mg/kg body weight DXF (DXF group), 7xa0mg/kg body weight AA (AA group), a combination of the same doses of AA and DXF (AA+DXF group), or vehicle (control group) for up to 35 days. Six animals per group were killed on day 10 and the remaining six on day 35. Renal function was evaluated by determining serum creatinine and urinary leucine aminopeptidase activity. Histological evaluation of kidney samples was performed and tubulointerstitial injuries were semiquantified. The DXF group did not differ from controls for any parameter. Similarly elevated serum creatinine levels, decreased leucine aminopeptidase enzymuria, and renal lesions were observed in the AA and the AA+DXF groups after both 10 and 35 days. The formation of specific AA–DNA adducts in liver and renal tissue samples was assessed by the 32P-postlabelling method. Specific AA–DNA adduct levels were significantly increased in kidney tissues from AA+DXF rats compared with AA rats. These functional and histological data suggest that DXF does not enhance AA nephrotoxicity in a rat model for CHN. Further investigations are needed to clarify the mechanism by which DXF may enhance AA–DNA adduct formation.

Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity?

Pozdzik A A, Berton A, Schmeiser H H, Missoum W, Decaestecker C, Salmon I J, Vanherweghem J‐L & Nortier J Lu2028(2010) Histopathology56, 449–463

Clinical significance of blood-device interaction in hemodialysis. A review.

The syndrome of dialysis-associated leukopenia and complement activation by cellulosic membranes, including the so-called first use syndrome, is reviewed and the pathophysiology of these phenomena is discussed. Subsequently the clinical side effects of hemodialysis, including dialysis-associated hypoxemia, are discussed. The hypoxemia, according to the authors, is mainly related to the loss of carbon dioxide through the dialyser. A minor role may be played by complement activation causing temporary sequestration of leukocytes in the pulmonary capillaries with (asymptomatic) peripheral leukopenia on the one hand and plugging of the pulmonary capillary bed with transient pulmonary hypertension and hypoxemia on the other. The question of dialysis-associated eosinophilia and ethylene oxide hypersensitivity is addressed as also contributing to the first use syndrome. The effects of interleukin release from monocytes and of contamination of the dialysis fluid are briefly discussed. The rare syndrome of silicone rubber spallation with hepato-and splenomegaly is also mentioned and finally the pathogenesis and symptomatology of the beta 2 microglobulin amyloidosis syndrome in long-term dialysis patients is presented.

Analgesic nephropathy: an underestimated cause of end-stage renal disease

Addiction and abuse of antipyretic analgesics has been recognized early after the turn of this century. The incidence markedly increased and the syndrome spread over many countries in the first half of the 20th century. The syndrome and its pathology, consisting of renal papillary necrosis and tubulo-interstitial nephritis, was first described in the medical literature in the early 1950s in Switzerland by Spühler and Zollinger, who rightly suspected chronic analgesic (Saridon) intoxication as being the cause in their cases. Clinically the disease is characterized by slowly progressive renal failure with renal colics from passage of necrotic papillae. Death from uremia is common unless dialyzed. The disease has been particularly prevalent in certain areas of Australia, Belgium, Western Germany, in Switzerland and some other countries. The nephrotoxic agents are mixtures of salicylates (aspirin) with phenacetin or acetaminophen. The principal nephrotoxic compound is probably aspirin--the aminophenol derivatives increasing its nephrotoxicity. However, all these components alone may cause--exceptionally--the syndrome. Rarely some newer, nonsteroid analgesics (NSAIDs) can also be nephrotoxic. Phenacetin has--in particular in compound mixtures--mood-altering (euphoric) properties, giving rise to craving, addiction and chronic abuse. Addiction has been greatly facilitated by the over-the-counter availability of these cheap analgesic mixtures. Mass addiction--and abuse--may occur in all kinds of communities, in factories or families because of the euphoric effect, taking away fatigue and weariness and increasing productivity. There is a relation between the per capita consumption of antipyretic analgesics and analgesic nephropathy in several countries and in certain districts. The pattern of sales and mass consumption (and the incidence of nephropathy) is substantially promoted by the local presence of production facilities, usually accompanied by vigorous sales and advertising policies. Individual addiction usually occurs in psychoneurotic females often with social and marital problems and mental instability, often with long histories of headaches, backpains, and other, often psychogenic disorders. Analgesic nephropathy is often complicated by anemia, peptic ulcer, premature aging and atherosclerosis and in 8-10% by uro-epithelial carcinoma (the so called analgesic syndrome). The diagnosis depends largely on the history of chronic abuse of analgesics, which is often doggedly denied, hampering the diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Néphropathie aux acides aristolochiques (« néphropathie aux herbes chinoises »)

Aristolochic acid nephropathy is a renal disease of toxic origin characterized by a progressive interstitial fibrosis and frequently associated with urinary tract cancer. It was initially reported in Belgium after the intake of slimming pills containing root extracts of a Chinese herb, Aristolochia fangchi. In the following decades, numerous cases have been reported worldwide, particularly in Asian countries. Several experimental models of aristolochic acid nephropathy (AAN) have been designed. They confirm the causal link between AA exposure and the onset of acute and chronic renal toxicity, as well as urinary tract cancer. These experimental models offer the opportunity to study the mechanisms of renal interstitial fibrosis and carcinogenesis. In terms of public health, the history of this nephropathy demonstrates that it is mandatory to submit all natural medicinal products to the same controls of efficacy, toxicity and conformity applied to the classical drugs derived from the pharmaceutical producers. Any unusual observation of renal failure and/or cancer of the urinary tract should lead to a questioning about any prior exposure to AA. The confirmation of the ingestion of AA containing compounds by phytochemical analysis is not always feasible. However, the renal biopsy remains a crucial diagnostic point through the demonstration of a hypocellular interstitial fibrosis with a decreasing corticomedullary gradient, mostly in advanced cases of kidney disease. Moreover, the detection of AA-related DNA adducts within a renal or urothelial tissue sample could confirm the prior AA exposure. The persistence of these specific DNA adducts in renal tissue is very long (up to 20xa0years). Finally, considering the highly carcinogenic properties of AA, a systematic endo-urological screening is absolutely necessary.