Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

Validation of housekeeping gene and impact on normalized gene expression in clear cell renal cell carcinoma: critical reassessment of YBX3/ZONAB/CSDA expression.

BACKGROUND: YBX3/ZONAB/CSDA is an epithelial-specific transcription factor acting in the density-based switch between proliferation and differentiation. Our laboratory reported overexpression of YBX3 in clear cell renal cell arcinoma (ccRCC), as part of a wide study of YBX3 regulation in vitro and in vivo. The preliminary data was limited to 5 cases, of which only 3 could be compared to paired normal tissue, and beta-Actin was used as sole reference to normalize gene expression. We thus decided to re-evaluate YBX3 expression by real-time-PCR in a larger panel of ccRCC samples, and their paired healthy tissue, with special attention on experimental biases such as inter-individual variations, primer specificity, and reference gene for normalization. RESULTS: Gene expression was measured by RT-qPCR in 16 ccRCC samples, each compared to corresponding healthy tissue to minimize inter-individual variations. Eight potential housekeeping genes were evaluated for expression level and stability among the 16-paired samples. Among tested housekeeping genes, PPIA and RPS13, especially in combination, proved best suitable to normalize gene expression in ccRCC tissues as compared to classical reference genes such as beta-Actin, GAPDH, 18S or B2M. Using this pair as reference, YBX3 expression level among a collection of 16 ccRCC tumors was not significantly increased as compared to normal adjacent tissues. However, stratification according to Fuhrman grade disclosed higher YBX3 expression levels in low-grade tumors and lower in high-grade tumors. Immunoperoxidase confirmed homogeneous nuclear staining for YBX3 in low-grade but revealed nuclear heterogeneity in high-grade tumors. CONCLUSIONS: This paper underlines that special attention to reference gene products in the design of real-time PCR analysis of tumoral tissue is crucial to avoid misleading conclusions. Furthermore, we found that global YBX3/ZONAB/CSDA mRNA expression level may be considered within a "signature" of RCC grading.

Gitelman syndrome and glomerular proteinuria: a link between loss of sodium-chloride cotransporter and podocyte dysfunction?

We report on a 27-year-old patient presenting with chronic hypokalaemia, inappropriate kaliuresis, hypomagnesaemia and alkalosis, associated with moderate proteinuria. Genetic analysis evidenced a homozygous mutation (p.Arg399Cys) in the SLC12A3 gene coding for the sodium-chloride cotransporter (NCC), confirming the diagnosis of Gitelman syndrome. Further genetic testing did not show any mutation in NPHS2. A renal biopsy was performed in view of the unusual association with proteinuria. Light microscopy showed hypertrophy of the juxtaglomerular apparatus and discrete mesangial thickening. In addition to possible focal segmental glomerular sclerosis lesions, electron microscopy showed extensive segments of variably thickened glomerular basement membrane (GBM), contrasting with segments of regular GBM of low range thickness, and effacement of podocyte foot processes. Of interest, alterations of the GBM were also observed in a Slc12a3 knock-out mouse model for Gitelman syndrome. These data suggest that the association between Gitelman syndrome and secondary changes of the GBM is probably not coincidental. Possible mechanisms include angiotensin II- or renin-induced podocyte lesions, as well as chronic hypokalaemia.

Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy.

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

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.

Control of AA amyloidosis complicating Crohn's disease: a clinico-pathological study.

BACKGROUND: Immunosuppressive drugs may prevent or partially reverse progression of renal AA-amyloidosis, a rare complication of Crohn's disease, often fatal due to renal failure. MATERIALS AND METHODS: The clinical, biological and pathological data of 16 patients treated since 1976 were reviewed. Serum amyloid A was determined in surviving patients. RESULTS: The median age of the 16 patients (13 men) was 23·5 years (range 16-69). At Crohn's disease onset, Montreal phenotypes were similar to reported data. Out of 15 patients with renal insufficiency, 8 developed a nephrotic syndrome and 7 a low grade proteinuria. The single patient without renal insufficiency had nephrotic syndrome. A significant correlation (P < 0·05) between the extension of renal amyloid A and sclerosis was found in 12 patients. One patient had a 10 year remission of nephrotic syndrome with immunosuppressive drugs. In 6 patients treated with anti-TNF-α (Tumor-Necrosis-Factor-α) agents, anaphylactic reaction (1/6), death from septic shock (1/6), 5-year remission (1/6) or reduction of nephrotic syndrome (1/6) and stabilization of renal insufficiency (2/6) were observed. Surgery was performed in 10 patients. Kidney transplantation was performed in 5 of the 8 patients dialysed for end-stage renal failure. Among 6/16 patients (37%) still alive, 3 belong to the 5 transplanted patients (survival: 3-20 years) and 3 to the anti-TNF-α drugs treated patients; all but one exhibited a low serum amyloid A level. CONCLUSIONS: Suppression of Crohn's disease inflammation potentially leads to the control of amyloid A production, assessed by a decrease of serum amyloid A. Kidney transplantation provides a long survival.

Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial.

BACKGROUND: In the MAINTAIN Nephritis Trial, azathioprine (AZA) and mycophenolate mofetil (MMF) were compared as maintenance immunosuppressive treatment of proliferative lupus nephritis (LN) after a short-course of intravenous cyclophosphamide. Here, we compare the pathological findings on repeat kidney biopsies between the two groups. METHODS: Per protocol, repeat renal biopsies were obtained in 30 patients (16 AZA and 14 MMF) at 2 years (±6 months). Baseline and follow-up biopsies were graded according to the International Society of Nephrology/Renal Pathological Society (ISN/RPS) classification. The activity and chronicity indices (AI, CI) were calculated using two different semiquantitative scoring systems (Morel-Maroger and National Institutes of Health). Statistics were performed by non-parametric tests. RESULTS: The clinical characteristics of the 30 re-biopsied patients only marginally differ from the entire MAINTAIN cohort (105 patients). Clinical baseline and follow-up characteristics of AZA- and MMF-treated re-biopsied patients did not differ. Time (SD) to repeat renal biopsy was 25.0 (2.0) and 26.5 (3.3) months in AZA and MMF patients, respectively. More patients had normal renal biopsies or Classes I/II/V LN at follow-up compared to baseline and conversely, less patients had Class IV LN at follow-up. In both groups, the AI statistically decreased at follow-up compared to baseline, while the CI slightly, but significantly, increased. No differences could be detected between the groups. CONCLUSION: Centralized pathological analyses, including ISN/RPS classification and comparisons of AI/CI, failed to find differences between MMF and AZA at 2 years, a result well in line with the absence of difference in long-term clinical outcome reported elsewhere.

Prognostic relevance of number and bilaterality of positive surgical margins after radical prostatectomy.

PURPOSE: Positive surgical margin (PSM) status following radical prostatectomy (RP) is a well-established prognostic factor. The aim of the present study is to evaluate whether number of PSMs or bilaterality of PSMs might have prognostic significance for biochemical recurrence (BCR) in the population with a PSM status following RP. METHODS: We evaluated 1,395 RP pathology reports from our center between 1980 and 2006. All patients who underwent (neo)-adjuvant therapy were excluded, leaving a cohort of 1,009 patients, with 249 (24.7%) subjects having a PSM at RP of whom 29.4% had multiple PSMs (≥ 2 sites), while 13.6% had bilateral PSMs. Median follow-up was 40 months (range 0-258 months). We used BCR-free survival as the primary study outcome. BCR was defined as any rise in PSA above or equal to 0.2 ng/ml. RESULTS: Of patients with a PSM status, 41% (95% CI: 33-49%) developed BCR within 5 years, compared to 12% (95% CI: 9-15%) in the population without a PSM. Multivariable analysis identified PSA at diagnosis and RP Gleason score as independent predictive factors for BCR. Increasing number and/or bilaterality of PSM did not lead to significant higher rates of BCR. CONCLUSION: In patients with a PSM, the number of positive sites or bilaterality of PSM status does not add prognostic information for risk of BCR. Survival curve slopes were different for patients with bilateral PSM, showing a significant tendency to progress to BCR earlier during follow-up than patients with unilateral PSM.

Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer?

BACKGROUND: The potential impact of intraoperative analgesics on oncological outcome after radical prostatectomy is debated. Some investigators have suggested that use of opioids favour relapse, whereas regional analgesia and NSAIDs improve oncological outcomes. OBJECTIVE: To evaluate the impact of intraoperative analgesia (epidural and intravenous) on the incidence of biochemical recurrence-free (BRF) survival. DESIGN, SETTING AND PARTICIPANTS: This retrospective study includes 1111 consecutive retropubic radical prostatectomies (RRPs) for localised prostate cancer, performed between 1993 and 2006. Median follow-up was 38 months (interquartile range 16-69). BRF survival probabilities were compared with log-rank tests and the Cox regression model. MAIN OUTCOME MEASURES AND RESULTS: Epidural analgesia was used in 52% of patients, intravenous ketorolac in 25%, sufentanil in 97%, clonidine in 25% and ketamine in 16%. Univariate and multivariate analyses showed that intravenous sufentanil significantly reduced BRF survival rate, hazard ratio 7.78 [95% confidence interval (CI) 5.79, 9.78), for extracapsular extension stage pT 2 or less, hazard ratio 0.44 (95% CI 0.12, 0.75), Gleason score at least 7, hazard ratio 1.96 (95% CI 1.65, 2.26), positive margin, hazard ratio 1.87 (95% CI 1.58, 2.02) and lymph node involvement, hazard ratio 1.77 (95% CI 1.27, 2.27, P > 0.05). In contrast, neither epidural analgesia nor other analgesics were associated with a statistically significant effect (P > 0.05). CONCLUSION: This retrospective analysis suggests that intraoperative sufentanil administration is associated with an increased risk of cancer relapse after RRP, whereas epidural analgesia, with local anaesthetic and opioid, was not associated with a significant effect.

A homozygous mutation in INVS causing juvenile nephronophthisis with abnormal reactivity of the Wnt/beta-catenin pathway.

Mutations in the INVS gene coding for inversin have been identified in patients with nephronophthisis type 2 (NPHP2), typically causing infantile onset of ESRD and potentially associated with situs inversus. We report a novel family with a homozygous INVS mutation (c.2695 C > T; p.Arg899X) deleting the C-terminus of inversin. Both affected patients had juvenile ESRD and were discordant for situs inversus. The end-stage kidneys showed chronic interstitial nephritis with cysts and abnormal expression of ß-catenin and Dishevelled-1 supporting up-regulated canonical Wnt pathway in tubular cells. This case shows that INVS mutation can cause juvenile nephronophthisis with abnormal reactivity of the Wnt/ß-catenin pathway.

Absence of gadolinium deposits in the peritoneal membrane of patients with encapsulating peritoneal sclerosis.

UNLABELLED: Background. Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) characterized by the development of an extensive fibrosis of the visceral peritoneum that may eventually lead to intestinal constriction. Its cause remains elusive. Nephrogenic systemic fibrosis (NSF), a disabling disease that can follow gadolinium-based contrast injection during magnetic resonance imaging, is characterized by systemic fibrosis of the skin, joints, liver, heart and vessels. Affected tissues are infiltrated by CD34+ and CD68+ fibroblasts. In the present study, we tested the hypothesis that EPS could have been triggered by a previous gadolinium injection. Methods. We performed histopathological analysis of the peritoneal membrane of two EPS and two control patients all exposed to long-term PD, including immunostaining with CD34 and CD68. The presence of gadolinium and other metals was also assessed by conventional and energy-filtered transmission electron microscopy. RESULTS: Numerous CD34+ and CD68+ cells were found in both the EPS and control patients within the vascular endothelium and in macrophages, respectively, but not in interstitial fibrocytes, as it could be expected in NSF. No trace of gadolinium deposits could be found in the four peritoneal samples; dispersed tiny iron inclusions were evidenced in the connective tissue of both EPS patients. CONCLUSIONS: These findings argue against the implication of gadolinium in the development of EPS in long-term PD patients.

Genotype and Outcome After Kidney Transplantation in Alport Syndrome.

INTRODUCTION: Alport syndrome (AS) is caused by mutations in α3/α4/α5 (IV) collagen genes, the severity of which determine the progression of AS. Posttransplantation outcome is good, although anti-glomerular basement membrane (anti-GBM) glomerulonephritis occurs in 3% to 5% of recipients, clustering in patients with a severe mutation. We assessed whether the severity of the underlying AS mutation affects graft and patients outcome after transplantation, including the occurrence of anti-GBM nephritis. METHODS: We included 73 AS patients with an identified mutation (COL4A5, 57 patients; COL4A3, 9 patients; COL4A4, 6 patients; heterozygous composite COL4A3 and A4, 1 patient) who underwent transplantation between 1971 and 2014 and who had received a total of 93 kidney grafts. RESULTS: In all, 41 patients had a severe mutation (COL4A5, 30 patients; COL4A3, 6 patients; COL4A4, 5 patients), and 32 had a nonsevere mutation (COL4A5, 27 patients; COL4A3, 4 patients; COL4A4, 1 patient). Patient survival was similar in patients with severe and nonsevere mutations (89% vs. 84% at 5 years, 83% vs. 75% at 10, 15, and 20 years; P = 0.46). Graft survival was not affected by the severity of mutation (77% vs. 63% at 5 years, 60% vs. 55% at 10 years, 55% vs. 55% at 15 years, and 55% vs. 50% at 20 years; P = 0.65). Clinically significant anti-GBM glomerulonephritis occurred in 1 male patient with severe COL4A5 mutation 6 years after transplantation recurred in a subsequent graft, leading twice to graft loss. CONCLUSION: Although severe mutations affect the severity of AS, they do not have an impact on patient and graft survival after transplantation. De novo anti-GBM nephritis after transplantation was less frequent than previously reported, occurring in only 1.4% of AS patients, and in 2% of males with COL4A5 mutation.

TP53 mutations in p53-negative dysplastic urothelial cells from Belgian AAN patients: New evidence for aristolochic acid-induced molecular pathogenesis and carcinogenesis.

The Aristolochic Acid (AA)-specific mutational pattern was recently characterized in urothelial carcinoma (UC) from Belgian AA Nephropathy (AAN) patients (n=5). Besides the A>T transversion hallmark, a specific AA-mutational pattern was found in the TP53 hotspot region in p53-positive immunohistochemistry (IHC) areas and consisted of poly- or multiclonal TP53 alterations and an unusual high prevalence of G>T transversion. In the current study, these data were complemented using the same validated methodology for assessing the complete coding sequence of the TP53 gene in tumor areas stratified according to the percentage of p53-stained cells (i.e., [+], ≥60%; [+/-], 1-59%, [-], no staining). Results were compared to existing data (i.e., other series of AA-associated UC and IARC TP53 database). Aside of the TP53 hotspot region (exons 5-8), multiple mutations were also found in exons 4 and 10. A unique TP53 mutational pattern was characterized by a large spectrum of mutations among which A>T and C>T have the highest prevalence. Most A>T mutations were characterized by the 5'Py-A-Pu sequence. Interestingly, the majority of p53-negative areas were dysplastic (low grade intra-urothelial neoplasia) and disclosed TP53 mutations among which a majority of A>T transversions. Beside nonsense p53-negative mutations, several missense mutations are also known to affect p53 DNA- or zinc-binding domains, hence probably impairing the antigen binding site and/or masking the antigenic epitope. These uncommon histologic, immunopathologic and genetic features in Belgian AAN patients probably result from the unique pattern of duration and extent of AA exposure which led to a cumulative toxic dose ingested over a short period of time. Consequenlty, current results bring additional and valuable evidence unravelling the molecular pathogenesis of AA-induced carcinogenesis and the origin of related high-grade UCs.

Assessment of the transcriptional activity of p53 improves the prediction of recurrence in superficial transitional cell carcinoma of the bladder.

PURPOSE: To investigate the value of p53 functional analysis of separated alleles in yeast (FASAY) as a witness of p53/p21 pathway alteration and as a predictor of recurrence in superficial transitional cell carcinomas. EXPERIMENTAL DESIGN: p53 transcriptional activity was prospectively analyzed in 52 newly diagnosed transitional cell carcinoma using FASAY competent for the transactivation of p21 and bax promoters. TP53 and p21 gene expression was quantified by real-time PCR, and expression of corresponding proteins was assessed by immunohistochemistry. In addition to tumor stage and grade, the predictive value of FASAY, real-time PCR, and immunohistochemistry for tumor recurrence was assessed by Cox survival analysis. RESULTS: A total (p21 and bax) or partial (bax only) loss of transcriptional activity was observed in 15 of 52 (29%) and 4 of 52 (7.7%) cases, respectively, a partial loss being consistently associated with R283H mutation. p53 nuclear overexpression grossly overestimated (approximately 40%) or underestimated (approximately 10%) the true incidence of p53 transcriptional abnormalities, especially in Ta-T1 grade 1 to 2 tumors. Loss of p21 transactivation significantly correlated with decreased p21 gene expression and lack of expression of p21 (P = 0.001). FASAY had a better predictive value for recurrence than p53 immunohistochemistry (Cox hazard ratio, 6.57 versus 3.95; P = 0.0002 versus 0.019, respectively), whereas neither p21 immunohistochemistry (hazard ratio, 1.9; P = 0.29) nor TP53 or p21 gene expression were significant predictors of recurrence. The prognostic difference between FASAY and p53 immunohistochemistry was maintained in the subgroup of Ta-T1 grade 3 tumors. CONCLUSIONS: FASAY is a valuable surrogate marker for assessing p53/p21 pathway alteration and predicts transitional cell carcinoma recurrence better than p53 immunohistochemistry.

Long-term Outcome of Kidney Recipients Transplanted for Aristolochic Acid Nephropathy.

BACKGROUND: Aristolochic acids (AA) are nephrotoxic and carcinogenic. The aim of this study was to assess the long-term outcome of patients with AA nephropathy (AAN) after kidney transplantation. METHODS: Observational study. Patients' characteristics, long-term surveillance and follow-up data, patient and graft survival, as well as outcomes with respect to rejection, cardiovascular complications, infections, and cancers with a focus on urothelial carcinomas, are reported. RESULTS: Twenty patients transplanted for AAN were included. All were submitted to prophylactic bilateral ureteronephrectomy and annual surveillance of the bladder. Median duration of posttransplant follow-up was 12.5 (3-19) years. Time from diagnosis of AAN to renal replacement therapy was relatively short (1 [0-15] years). Immunosuppression consisted of a triple therapy in the majority of patients. Nineteen patients had upper urinary tract multifocal atypia. Eleven patients presented with urothelial carcinomas of the upper tract; 2 of them with additional bladder urothelial carcinomas. Of these 2 patients, one required radical cystectomy. One patient developed a hepatocarcinoma. Patient survival was 100% in AAN patients at 5, 10, and 15 years after transplantation. Graft survival at 5, 10, and 15 years was 95%, 83%, and 75%. CONCLUSIONS: Despite a high prevalence of urothelial carcinoma and the risk of bladder carcinoma, the long-term patient and kidney graft survival is excellent in patients with AAN, provided that prophylactic bilateral ureteronephrectomy and lifelong surveillance of the bladder are performed.

[Malacoplakia in children]. / Malacoplalakie chez l'enfant.

Malakoplakia is a rare inflammatory disease, related to Enterobacteria infection in the context of a disorder of cell-mediated immunity. This disease does not have any specific clinical or laboratory signs and the diagnosis is exclusively based on histology. Malakoplakia is exceptional in children and usually involves the gastrointestinal tract. The authors report a rare case of malakoplakia of the urinary bladder in a 4-year-old child, in whom the initial diagnosis was an anomaly of the urachus.

International variation in histologic grading is large, and persistent feedback does not improve reproducibility.

Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.

Telithromycin-induced acute interstitial nephritis: a first case report.

Telithromycin, a ketolide antibiotic used for the treatment of community-acquired respiratory infections, is widely prescribed in primary care practice. Treatment-related adverse events are mainly of gastrointestinal origin and generally mild in intensity. The authors report the first case of telithromycin-induced severe acute interstitial nephritis. Practitioners should be aware of the possibility that telithromycin therapy could result in this form of drug-induced acute renal failure.

Enteric hyperoxaluria: a hidden cause of early renal graft failure in two successive transplants: spontaneous late graft recovery.

A 37-year-old patient underwent two successive renal transplantations 7 months apart. He remained dialysis dependent. Early biopsy of both grafts revealed widespread calcium oxalate deposition suggestive of acute oxalate nephropathy. Several causes of oxalate nephropathy, including primary oxalosis and an increased intake of oxalic acid precursors, were excluded. Two years later, the identification of steatorrhea with radiologic signs of chronic pancreatitis led to the hypothesis of enteric hyperoxaluria. Surprisingly, 11 months after the second transplantation, graft function improved progressively allowing interruption of dialysis. Three years later, renal function is stable. The causes and prevention of acute oxalate-induced graft failure are highlighted. Subclinical evidence of enteric hyperoxaluria should be looked for and appropriate therapy instituted as early as possible. The possibility of a late recovery of renal function warrants attentive patience from attending physicians.

Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to date.

Chinese herbs nephropathy (CHN) is a rapidly progressive interstitial nephropathy reported after the introduction of Chinese herbs in a slimming regimen followed by young Belgian women. It is characterised by early, severe anaemia, mild tubular proteinuria and initially normal arterial blood pressure in half of the patients. Renal histology shows unusual extensive, virtually hypocellular cortical interstitial fibrosis associated with tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex. Urothelial malignancy of the upper urinary tract develops subsequently in almost half of the patients. Suspicion that the disease was due to the recent introduction of Chinese herbs in the slimming regimen was reinforced by identification in the slimming pills of the nephrotoxic and carcinogenic aristolochic acid (AA) extracted from species of Aristolochia. This hypothesis was substantiated by the identification of premutagenic AA-DNA adducts in the kidney and ureteric tissues of CHN patients. Finally, induction of the clinical features (interstitial fibrosis and upper urothelial malignancy) typical of CHN in rodents given AA alone removed any doubt on the causal role of this phytotoxin in CHN, now better called aristolochic acid nephropathy (AAN). AAN is not restricted to the Belgian cases. Similar cases have been observed throughout the world, but AA is sometimes incriminated on the basis of the known content of AA in the herbs. The possibility remains that in some individuals in whom AA has not been demonstrated, other phytotoxins might be implicated. Biological and morphological features of AAN are strikingly similar to those reported in another fibrosing interstitial nephropathy of still unknown aetiology, Balkan endemic nephropathy (BEN). Interestingly, AA was incriminated as the cause of BEN many years ago, a hypothesis yet to be fully explored. The intake of AA and the presence of tissular AA-DNA adducts in patients with an unequivocal diagnosis of BEN remains to be demonstrated. The tragic phenomenon of CHN, recognised only 10 years ago, has been at the root of significant research and progress both in nephrology and oncology. It has provided a fascinating opportunity to understand the link between a fibrosing interstitial nephropathy and urothelial carcinoma. It allows the categorisation of interstitial nephritis on the basis of histological findings, of initiating toxic substances and of associated clinical features. Finally, it has led to the withdrawal in several countries of a previously unsuspected carcinogenic and nephrotoxic substance.