Nephropathy induced by aristolochic acid (AA) containing herbs

INTRODUCTION — In 1991, clinicians in Belgium noted an increasing number of women who presented with acute, often near end-stage kidney disease (ESKD) following exposure to aristolochic acid (AA) at a weight reduction clinic [1,2]. An initial survey of seven nephrology centers in Brussels identified 14 women under the age of 50 years who had presented with advanced kidney failure due to biopsy-proven chronic tubulointerstitial nephritis over a three-year period; nine of these patients had been exposed to the same slimming regimen [1]. A total of more than 300 cases have been identified, a third of whom have already undergone kidney transplantation.

The epidemiology is unknown, as is the risk for development of severe kidney damage. However, the publication of case reports from several countries in Europe and Asia, particularly in China, indicate that the incidence of herbal medicine-induced nephrotoxicity is more common than previously thought [3-7].

PATHOLOGY — The major lesion, which is located principally in the cortex, is extensive interstitial fibrosis with atrophy and loss of the tubules. Cellular infiltration of the interstitium is scarce. Thickening of the walls of the interlobular and afferent arterioles results from endothelial cell swelling. The glomeruli are relatively spared, and immune deposits are not observed. These findings suggest that the primary lesions may be centered in the vessel walls, thereby leading to ischemia and interstitial fibrosis.

An extremely high incidence of cellular atypia and urothelial (transitional cell) carcinoma of the renal pelvis, ureter, and bladder has been associated with AA nephropathy [8-10].

PATHOGENESIS — AA nephropathy is caused by exposure to AA, a family of compounds found in the plant genus Aristolochiaceae, including the Aristolochia and Asarum species (also known as birthwort or Dutchman's pipe) [11]. AA also causes urothelial malignancy [12] and was classified a human (class I) carcinogen by the World Health Organization International Agency for Research on Cancer.

Support for AA as the major nephrotoxin is provided by findings in animal models (rabbit, rat, and mice) of disease [13-17]. In one study, for example, rabbits were given intraperitoneal injections of AA (0.1 mg AA/kg five days a week for 17 to 21 months) [13]. Histologic examination of the kidneys and genitourinary tract revealed kidney hypocellular interstitial fibrosis and atypical and malignant uroepithelial cells.

However, it is not clear if AA has been part of the herbal preparations used by all patients [1]. Furthermore, AA (0.15 mg/tablet) has been used as an immunomodulatory drug for 20 years in Germany by thousands of patients, sometimes in doses comparable with that found in AA-containing slimming regimens; despite this exposure, there is no report relating chronic tubulointerstitial nephritis to AA in Germany.

The necessity to stimulate the intrarenal renin-angiotensin system (salt deprivation) to obtain fibro-interstitial lesions is consistent with the combined exposure concept observed with several potential nephrotoxins [18]. Blockade of the renin-angiotensin system, however, does not prevent kidney interstitial fibrosis by AA [19]. How far transdifferentiation and apoptosis play an important role in this fast-developing type of chronic tubulointerstitial disease of the kidneys is still not clear [20]. One study suggests that AA induces tubular epithelial cell death via apoptosis by dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and posttranslational activation of p53, supporting the hypothesis that p53 promotes kidney injury in AA nephropathy [21].

Another uncertain factor is why only some patients exposed to the same herbal preparations develop kidney disease. Females appear to be at greater risk than males. Other possibly important factors include toxin dose, batch-to-batch variability in toxin content, individual differences in toxin metabolism, and a genetically determined predisposition toward nephrotoxicity and/or carcinogenesis [22].

In one of the two studies showing a link between AA and carcinogenesis, an increased dose of AA was associated with an enhanced risk of carcinoma [9]. Tissue samples revealed AA-related deoxyribonucleic acid (DNA) adducts, indicating a possible mechanism underlying the development of malignancy. The presence of these adducts was noted in another report of two patients with urothelial malignancy and AA nephropathy [23].

The demonstration of AA-derived DNA adducts in kidney cortical and urothelial tumor tissue of patients with documented Balkan endemic nephropathy (BEN) associated with the dominance of the A:T→T:A transversions in the p53 tumor suppressor gene mutational spectrum helped identify AA as an etiological agent of the upper tract malignancy spectra in urothelial cancers among BEN patients [24,25]. In addition, molecular epidemiological evidence associated urothelial-cell carcinoma of the upper urinary tract to dietary exposure to AA through the contamination of flour prepared from locally grown wheat grain in the endemic cohort [26]. In this study, aristolactam-DNA adducts were present in 70 percent of the endemic cohort (n = 67) and in 94 percent of subjects with A:T→T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor A:T→T:A mutations were detected in tumors of upper urinary tract carcinoma patients (n =10) residing in nonendemic regions (ie, regions not exposed to AA). The authors proposed a molecular epidemiological approach using deoxyadenosine-aristolactam adducts and TP53 mutational spectra as biomarkers of exposure to and carcinogenic effects of AA in the evaluation of the disease in countries where Aristolochia species have been used for medicinal purposes.

The etiology of herbal medicine-induced nephrotoxicity and BEN is exposure to AA, a toxic component of all Aristolochia species. The slower progression toward end-stage kidney disease (ESKD) of patients with BEN has to do with lower doses of AA ingested during the consumption of contaminated bread as compared with the high dose of AA found in the herbal mixtures used by patients in the "slimming" clinic. The higher prevalence of women in the herbal medicine-induced nephrotoxicity cohorts can be attributed to the fact that young women are more likely to attend such clinics. The exact mechanism, however, by which exposure to AA results in chronic kidney damage remains uncertain.

In a study in mice, chronic administration of AA resulted in progressive kidney damage. AA activated Smad signaling, mediating epithelial–mesenchymal transition and kidney fibrosis via both transforming growth factor-beta-dependent and c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK)-dependent mechanisms. The blockade of JNK and specific knock-down of Smad3, but not Smad2, were able to attenuate AA-stimulated collagen matrix expression and epithelial–mesenchymal transition [17]. AA was shown to be involved in the early proximal tubular dysfunction, manifested by low-molecular-weight proteinuria, as is found in herbal medicine-induced nephrotoxicity [27]. In another report of cell line and mouse model data, several key enzymes in mitochondrial respiration were identified as direct binding targets of AA [28].

In acute AA nephropathy in mice, AA adducts formed with DNA were associated with tubular epithelial cell apoptosis via p53-mediated signaling. AA induced dephosphorylation of STAT3 with subsequent activation of p53 and tubular epithelial cell apoptosis.

In contrast, overexpression of STAT3, p53 inhibition, or p53 knock-down with small interfering ribonucleic acid (RNA) attenuated AA-induced tubular epithelial cell apoptosis. This supports the hypothesis that p53 promotes kidney injury in acute AA nephropathy. These results have to be interpreted with caution with regard to humans in view of the slowly progressive character of the disease in patients. On the other hand, experiments conducted on tissue from patients with BEN indicate that p53 is also activated [29].

Activation of the MAPK pathway, with involvement of p38 and extracellular signal-regulated kinase subpaths, may be involved in the progression of AA-associated urothelial carcinoma [30].

PRESENTATION AND PROGNOSIS — Affected patients typically present with chronic kidney function impairment. The blood pressure is either normal or only mildly elevated, protein excretion is only moderately increased (less than 1.5 g/day), and the urine sediment reveals only a few red and white cells. The elevation in protein excretion consists of both albumin and low-molecular-weight proteins that are normally filtered and reabsorbed by proximal tubular cells [31]. Thus, tubular dysfunction contributes to the proteinuria.

The plasma creatinine concentration at presentation has ranged from 1.4 to 12.7 mg/dL (123 to 1122 micromol/L) [2]. Kidney function tends to decline more rapidly than in other forms of interstitial nephritis [32]. As an example, in one study, among patients with AA nephropathy, compared with a control group of patients of similar age range and baseline serum creatinine, the creatinine doubling time was shorter (13 versus 52 months, respectively), and the two-year kidney survival time was worse (17 versus 74 percent, respectively) [33]. However, most patients who present with an initial plasma creatinine concentration below 2 mg/dL (176 micromol/L) appear to have relatively stable kidney function [33]. Progressive kidney failure resulting in eventual dialysis or transplantation may ensue in patients with more severe disease, even if further exposure to AA is prevented. The risk for progressive disease increases with the duration of exposure.

A similar clinical and pathologic process has been reported in a group of patients from Taiwan who had ingested herbal drugs from various sources and for different purposes. Their kidney biopsy samples showed histologic findings indicative of AA nephropathy, with extensive hypocellular interstitial fibrosis and atrophy and loss of tubules in all cases; these findings suggest that many different herbal drugs may contain AA [3].

TREATMENT — There is no proven, effective therapy for this disorder, which typically presents with marked interstitial fibrosis, but not prominent inflammation. Patients with AA nephropathy should avoid further exposure to AA and receive the same general care directed at slowing chronic kidney disease (CKD) progression as patients with CKD from other causes (see "Overview of the management of chronic kidney disease in adults"). An uncontrolled study suggested that corticosteroids may slow the rate of loss of kidney function [34].

The high incidence of cellular atypia of the genitourinary tract suggests that, at a minimum, these patients should undergo regular surveillance for abnormal urinary cytology. Whether more aggressive management strategies, such as bilateral native nephroureterectomies (particularly in those undergoing kidney transplantation), are required is unclear. Findings from one report support the more aggressive option [8].

Kidney transplantation is an effective modality for those who progress to end-stage kidney disease (ESKD). One report noted no recurrence in five such patients [33].

PREVENTION — Prevention of AA nephropathy and AA-associated cancers requires effective regulatory agency oversight of herbal preparations, food, and dietary supplements that may contain AA [35].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Overview – Aristolochic acid (AA) nephropathy is an interstitial nephritis related to AA that was first described in 1991. A high incidence of cellular atypia and urothelial (transitional cell) carcinoma of the renal pelvis, ureter, and bladder has been associated with this disease. (See 'Introduction' above and 'Pathology' above.)

●Pathology – The major histologic lesion in the kidney is interstitial fibrosis with atrophy and loss of the tubules in the kidney cortex. Thickening of the walls of the interlobular and afferent arterioles may be observed. Cellular infiltration of the interstitium is scarce, and glomeruli are spared. Immune deposits are not present. (See 'Pathology' above.)

●Risk factors – Risk factors for development of AA nephropathy include female sex, toxin (AA) dose, and a genetically determined predisposition toward nephrotoxicity and/or carcinogenesis. (See 'Pathogenesis' above.)

●Clinical presentation – Affected patients typically present with chronic kidney function impairment and normal or only mildly elevated blood pressure. Protein excretion is only moderately increased (less than 1.5 g/day), and the urine sediment reveals only a few red and white cells. The elevation in protein excretion consists of both albumin and low-molecular-weight proteins. (See 'Presentation and prognosis' above.)

●Treatment – There is no specific therapy for AA nephropathy. Patients with AA nephropathy should avoid further exposure to AA and receive the same general care directed at slowing chronic kidney disease (CKD) progression as patients with CKD from other causes. Kidney transplantation is an effective modality for those who progress to end-stage kidney disease (ESKD). Given the high incidence of cellular atypia of the genitourinary tract, patients should undergo regular surveillance for abnormal urinary cytology. (See 'Treatment' above.)