Nephrotic syndrome with Minimal Change Disease and Atopy in NorthAfrican adults.

INTRODUCTION: In adults, minimal change disease (MCD) accounts for 15 to 25% of nephrotic syndrome (NS). Numerous reports have suggested a link between NS and atopy. However, data on treatment and prognosis of NS associated with allergy are limited. AIM: To examine the presenting characteristics, treatments and outcomes of adults with allergic MCD in a North African center. METHODS: This was an observational study using retrospectively collected data. Patients were recruited from the Nephrology department of Sahloul Hospital (Sousse, Tunisia) from January 2006 to December 2020. Adults with a biopsy proved MCD, which was associated with atopy, were included. RESULTS: Fifteen patients (eight males, age mean±SD: 34±13 years) were included. High eosinophil and immunoglobulin E (IgE) levels were noted in three and twelve patients respectively. The IgE mean level at the initial presentation was 1431 IU/ml. Allergic skin tests were positive in nine patients. All patients were treated with corticosteroids, five had anti-histamine therapy and five had hyposensitization therapy, which was successful in two patients. Thirteen patients had relapsed during follow-up. Mean eosinophil level was significantly higher in patients with frequent relapses compared to those with infrequent relapses (5415/mm³ vs. 239.12/mm³, respectively, p=0.022). Two patients had progressed to chronic renal failure. CONCLUSION: It is important to search for atopic disorders in patients with MCD to better control this disease and use specific treatments. However, the efficacy of anti-allergic therapies has to be proven.

Sarcoid-Like Reaction in the Kidney Following Rituximab for Mantle Lymphoma in a 60-Year-Old Man.

The sarcoid-like reaction is a rare autoinflammatory disease that can affect lymph nodes or organs but does not meet the diagnostic criteria for systemic sarcoidosis. Several drug classes have been associated with the development of a systemic sarcoid-like reaction, which defines drug-induced sarcoidosis-like reactions and can affect a single organ. Anti-CD20 antibodies (rituximab) have rarely been reported as responsible for this reaction and this adverse effect has mainly been described during the treatment of Hodgkin's lymphoma. We report a unique case of a sarcoid-like reaction complicating rituximab following the treatment of a mantle cell lymphoma and interesting only the kidney. The 60-year-old patient presented with severe acute renal failure 6 months after the end of his r-CHOP protocol and the urgent renal biopsy revealed acute interstitial nephritis rich in granulomas without caseous necrosis. After ruling out other causes of granulomatous nephritis, a sarcoid-like reaction was retained since infiltration was limited to the kidney. The temporal relationship between rituximab administration and the sarcoid-like reaction onset in our patient supported the diagnosis of a rituximab-induced sarcoidosis-like reaction. Oral corticosteroid treatment led to rapid and lasting improvement in renal function. Clinicians should be warned of this adverse effect and regular and prolonged monitoring of renal function should be recommended during the follow-up of patients after the end of treatment with rituximab.

Thrombotic microangiopathy due to acquired complement factor I deficiency in a male receiving interferon-beta treatment for multiple sclerosis.

AIMS: Interferon-beta (IFNß), the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rare serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. The aim of this article was to report a new mechanism explaining Interferon beta related thrombotic microangiopathy. METHODS: We report thrombotic microangiopathy in a 28-year-old male receiving interferon-beta treatment for multiple sclerosis. RESULTS: After three years of starting interferon beta therapy, the patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring haemodialysis and haemolytic anaemia. Corticosteroid and plasma exchange sessions permitted haemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after 2 years. CONCLUSION: IFNß treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.

Severe Acute Interstitial Nephritis, Dermatitis, and Hemolytic Anemia due to Polyparasitic Infection in an Immunocompetent Male Patient.

Acute interstitial nephritis (AIN) is a relevant cause of acute renal failure. Drugs are the predominant cause, followed by infections and idiopathic lesions. AIN, as a form of hypersensitivity reaction, is an uncommon manifestation in the setting of human parasitic infections. We report a case of a polyparasitic infection (Giardia lamblia, Entamoeba coli, and Endolimax nana) resulting in a severe biopsy-proven AIN in a 61-year-old male patient. Despite the antiparasitic treatment followed by corticosteroid therapy, and during the 6-month follow-up period, the patient remained dialysis-dependent, and he developed autoimmune hemolytic anemia. Extensive search for another infection or neoplasia was negative. Immunological tests were also negative. The resulting hypersensitivity reaction to the triple parasite infection would have led to fatal evolution for the kidneys affected by this unusual type of AIN.

The pharmacogenetics of mycophenolate mofetil in Tunisian renal transplant patients.

Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of 245 kidney transplant patients being treated with MMF were recruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p < 0.05). In the cyclosporine-treated group, leukopenia was associated with the SLCO1B1-521T allele (p < 0.05). Both groups had an increased risk of rejection (p < 0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was found between the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.

Membranous nephropathy succeeding autologous hematopoietic stem cell transplant: a case report.

BACKGROUND: Membranous nephropathy (MN), the leading cause of nephrotic syndrome in adults, is characterized by the deposition of subepithelial immune deposits. Most of the cases are primary, while only approximately 25% of the cases are secondary to some known diseases. Recently, MN has been considered to be a possible presentation of chronic graft-versus-host disease (GVHD) of the kidney in allogeneic hematopoietic stem cell transplantation (HSCT) patients. In autologous HSCT populations, there have been scarce reports of associated MN, as a result of immune dysregulation leading to systemic autoimmunity and miming chronic GVHD. CASE PRESENTATION: We report an exceptional case of MN associated to an acute renal failure occurring within days following an autologous HSCT indicated by multiple myeloma. There was no evidence of GVHD or myeloma relapse. A complete remission of nephrotic syndrome with normalization of renal function were rapidly obtained by corticosteroid therapy. CONCLUSION: This is the first published case of acute renal failure due to MN occurring in the acute phase of an autologous HSCT. These findings support the antibodymediated autoimmune glomerular disease.

Identification of a novel AGXT gene mutation in primary hyperoxaluria after kidney transplantation failure.

Primary hyperoxaluria is a genetic disorder in glyoxylate metabolism that leads to systemic overproduction of oxalate. Functional deficiency of alanine-glyoxylate aminotransferase in this disease leads to recurrent nephrolithiasis, nephrocalcinosis, systemic oxalosis, and kidney failure. The aim of this study was to determine the molecular etiology of kidney transplant loss in a young Tunisian individual. We present a young man with end-stage renal disease who received a kidney allograft and experienced early graft failure. There were no improvement in kidney function; he required hemodialysis and graft biopsy revealed calcium oxalate crystals, which raised suspicion of primary hyperoxaluria. Genetic study in the AGXT gene by PCR direct sequencing identified three missense changes in heterozygote state: the p. Gly190Arg mutation next to two other novels not previously described. The classification of the deleterious effect of the missense changes was developed using the summered results of four different mutation assessment algorithms, SIFT, PolyPhen, Mutation Taster, and Align-GVGD. This system classified the changes as polymorphism in one and as mutation in other. The patient was compound heterozygous mutations. Structural analysis showed that the novel mutation, p.Pro28Ser mutation, affects near the dimerization interface of AGT and positioned on binding site instead of the inhibitor, amino-oxyacetic acid (AOA). With the novel AGXT mutation, the mutational spectrum of this gene continues to broaden in our population. The diagnosis of PH1 was not recognized until after renal transplant with fatal consequences, which led us to confirm the importance of screening before planning for kidney transplantation in population with a relatively high frequency of AGXT mutation carriers.

Antioxidant and antigenotoxic role of recombinant human erythropoeitin against alkylating agents: cisplatin and mitomycin C in cultured Vero cells.

Cisplatin (CDDP) and mitomycin C (MMC), two alkylating agents used against various solid tumours, are a common source of acute kidney injury. Thus, strategies for minimizing CDDP and MMC toxicity are of a clinical interest. In this study, we aimed to investigate the protective role of recombinant human erythropoietin (rhEPO) against oxidative stress and genotoxicity induced by CDDP and MMC in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to CDDP/MMC (pre-treatment), (ii) cells were treated with rhEPO and CDDP/MMC simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to CDDP/MMC (post-treatment). Our results showed that rhEPO decreased the reactive oxygen species levels, the malondialdehyde levels and ameliorated glutathione (reduced and oxidized glutathione) modulation induced by CDDP and MMC in cultured Vero cells. Furthermore, rhEPO administration prevented alkylating agents-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, against CDDP- and MMC-induced oxidative stress and genotoxicity, especially in pre-treatment condition.

Protective effect of recombinant human erythropoeitin against cisplatin cytotoxicity and genotoxicity in cultured Vero cells.

Cisplatin is an effective agent against various solid tumors. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Therefore, strategies for minimising the toxicity of cisplatin are of a clinical interest. The aim of this study was to investigate the protective effect of recombinant human erythropoietin (rhEPO) against the cytotoxicity and apoptosis induced by cisplatin in cultured Vero cells. Three types of treatments were performed: (i) cells were treated with rhEPO 24 h before exposure to cisplatin (pre-treatment), (ii) cells were treated with rhEPO and cisplatin simultaneously (co-treatment), (iii) cells were treated with rhEPO 24 h after exposure to cisplatin (post-treatment). Our results showed that rhEPO reduced cisplatin-induced cell mortality. Besides, rhEPO administration prevented cisplatin-induced DNA damage. Furthermore, rhEPO decreased the caspase-3 activity and pro-apoptotic factors levels (p53 and Bax) induced by cisplatin. It increased also the expression of the anti-apoptotic factor Bcl2 in Vero cells. Altogether, our results suggest a protective action of rhEPO against cisplatin cytotoxicity and genotoxicity via an anti-apoptotic process. The most protective effect was observed with rhEPO when it was administrated 24 h before cisplatin treatment.

Cytotoxicity effects of amiodarone on cultured cells.

Amiodarone is a potent anti-arrhythmic drug used for the treatment of cardiac arrhythmias. Although, the effects of amiodarone are well characterized on post-ischemic heart and cardiomyocytes, its toxicity on extra-cardiac tissues is still poorly understood. To this aim, we have monitored the cytotoxicity effects of this drug on three cultured cell lines including hepatocytes (HepG2), epithelial cells (EAhy 926) and renal cells (Vero). We have investigated the effects of amiodarone on (i) cell viabilities, (ii) heat shock protein expressions (Hsp 70) as a parameter of protective and adaptive response and (iii) oxidative damage.Our results clearly showed that amiodarone inhibits cell proliferation, induces an over-expression of Hsp 70 and generates significant amount of reactive oxygen species as measured by lipid peroxidation occurrence. However, toxicity of amiodarone was significantly higher in renal and epithelial cells than in hepatocytes. Vitamin E supplement restores the major part of cell mortalities induced by amiodarone showing that oxidative damage is the predominant toxic effect of the drug.Except its toxicity for the cardiac system, our findings demonstrated that amiodarone can target other tissues. Therefore, kidneys present a high sensibility to this drug which may limit its use with subjects suffering from renal disorders.

Atypical hemolytic uremic syndrome in the Tunisian population.

BACKGROUND: Hemolytic uremic syndrome consists of a triad of acquired hemolytic anemia, thrombocytopenia and renal failure. AIM: Our objectives were to determine epidemiology, clinical and laboratory characteristics of patients with atypical hemolytic uremic syndrome (aHUS) to determine the relationship between the complement protein deficit and aHUS in the Tunisian population. METHODS: We studied retrospectively four cases of atypical HUS in adults admitted in the Nephrology Department of Fattouma Bourguiba Universitary Hospital in Monastir between 2000 and 2008. RESULTS: Three patients had renal failure that required dialysis. One of them received kidney transplantation with no further recurrence of aHUS. Three patients had normal C3, C4, CFH, and FB levels, and in all patients anti-FH autoantibodies were absent. The kidney biopsy of one patient showed in addition to lupus glomerulonephritis histological findings consistent with TMA. A decrease in C3, C4 and CFH levels in this patient was found both before and after the cure. CONCLUSION: Nephrologists should be aware of autoimmune conditions and genetic abnormalities of the complement regulatory genes as possible pathogenic mechanisms in atypical HUS patients.

Ochratoxin A in human blood in Abidjan, Côte d'Ivoire.

Ochratoxin A (OTA) produced by Aspergillus and Penicillium genera contaminates a diversity of foods including cereals; cereals-derived foods; dry fruits; beans; cocoa; coffee; beer; wine; and foodstuffs of animal origin mainly poultry, eggs, pork and milk, including human breast milk. OTA is nephrotoxic to all animal species studied so far and most likely to humans, who show the longest half-life for elimination of this toxin among all species examined. Among other toxic effects, OTA is teratogenic, immunotoxic, genotoxic, mutagenic and carcinogenic, all of which lead to life-threatening pathologies through several molecular pathways. In Côte d'Ivoire, preliminary surveys conducted by us have proven from 1998 to 2004 the reality of ochratoxin A-contamination of foodstuffs. To assess OTA in human blood, the immunoaffinity columns were used along with HPLC for separation and fluorimetric quantification of blood samples collected in Abidjan from two categories of people: apparently healthy donors (n=63) and nephropathy patients undergoing dialysis (n=39). Among healthy donors, 34.9% show OTA concentrations ranging from 0.01 - 5.81 microg/l with a mean value of 0.83 microg/l, whereas, among nephropathy patients undergoing dialysis 20.5% are OTA positive in a range of 0.167-2.42 microg/l and a mean value of 1.05. Although the sex ratio is 0.82 (46 females for 56 males) ochratoxin A contamination is equally distributed in both sexes. Nephropathy patients undergoing dialysis appear, however, less frequently contaminated than healthy donors (20.5 versus 34.9%) and show higher OTA concentrations (higher mean value, p=0.01). Ochratoxin A concentrations found in human blood reflect concentrations previously detected in cereals and peanuts according to the eating habits and diets of people in Côte d'Ivoire. But, the prevalence of ochratoxin A in blood of nephropathy people undergoing dialysis appears lower than expected from the frequency of OTA contamination in cereals and peanuts. Pearson chi(2)-test indicates that among OTA-positive individuals renal dialysis and age are important modalities for consideration.

Karyomegaly of tubular kidney cells in human chronic interstitial nephropathy in Tunisia: respective role of Ochratoxin A and possible genetic predisposition.

Karyomegalic nephropathy associated to bizarre enlargement of nuclei in renal tubular epithelial cells was first described by Mihatch in 1979. We present herein additional cases occurring in three siblings suffering from chronic interstitial nephropathy (CIN) of unknown aetiology where the renal biopsies showed numerous enlarged and hyperchromatic nuclei. CIN of unknown aetiology has been previously characterized and showed striking similarities with Balkan Endemic Nephropathy (BEN). Ochratoxin A (OTA) is a nephrotoxic mycotoxin suspected to be the causal agent of the BEN as well as the Tunisian CIN of unknown aetiology. OTA is incriminated in the onset of these disclosed cases of karyomegalic nephropathy since high OTA concentrations were found in blood (505.83 ng/ml, 102.63 ng/ml and 1023 ng/ml) and in urine (94.40 ng/ml and 10.18 ng/ml) of two of them. Moreover, we have investigated OTA in blood and urine as well as in food samples of the entire household (21 people). Our findings suggest (i) a link between OTA and the outcome of this karyomegalic nephropathy, and (ii) the possible involvement of a genetic factor since the three cases have the same haplotype B27/35.

Ochratoxin A and beta2-microglobulinuria in healthy individuals and in chronic interstitial nephropathy patients in the centre of Tunisia: a hot spot of Ochratoxin A exposure.

Ochratoxin A (OTA) is a nephrotoxic mycotoxin considered to be the causal agent of the Balkan endemic nephropathy (BEN). In Tunisia, a chronic interstitial nephropathy (CIN) of unknown aetiology, resembling BEN, has been characterised wherein OTA seems to be implicated too. However, despite the considerable number of investigations conducted so far, the role of OTA in the outcome of this human nephropathy is still uncertain. In this study, an attempt is being made to consolidate the link between OTA and the Tunisian CIN of unknown aetiology. Blood OTA and beta(2)-microglobulinuria levels were measured in several groups of healthy individuals and patients having different renal diseases of known and unknown aetiologies (100 nephropathy patients and 40 healthy subjects). The high blood OTA and beta(2)-microglobulinuria levels seem to be strongly associated to the CIN of unknown aetiology. Our results support the involvement of this nephrotoxic agent in the outcome of this particular human nephropathy and underline furthermore the importance of beta(2)-microglobulinuria in the characterization of this disease.

Secondary Amyloidosis, a Fatal Complication of Behcet's Disease: Three Case Reports.

Renal amyloidosis (RA) is known to be one of the many complications of Behcet's disease (BD) but its frequency has been often underestimated. In this paper, we report on three cases of RA in a series of 105 patients with BD. RA was clinically suspected in our patients by the presence of edema and/or hypotension. The nephrotic syndrome was present in all of them and one patient had associated renal failure. Renal biopsy showed amyloid deposits type AA in all cases.Our patients received Colchicine at doses of 1 mg per day but with disappointing results. Their prognosis was significantely impaired with our three patients dying at ten years, six months and four weeks after diagnosis of RA. We will try, through this clinical experience and based on the relevant literature to better understand this kind of morbid association.

Ochratoxin A and human chronic nephropathy in Tunisia: is the situation endemic?

Ochratoxin A (OTA) is a nephrotoxic mycotoxin that is being increasingly considered as the main causal agent of Balkan endemic nephropathy (BEN), a fatal kidney disease associated with the end stage of urothelial tumours. However, despite the considerable amount of data, it is still controversial whether OTA plays a causative or only a subordinate role in the induction of this human nephropathy. Tunisia for years had to confront a very similar human nephropathy, which is tentatively called chronic interstitial nephropathy of unknown cause. This study tends firstly to consolidate the suspected link between this Tunisian chronic interstitial nephropathy (CIN) of unknown cause and the presence of OTA in the blood and food of such patients, and second to enlighten the endemic character of this particular nephropathy. Therefore, in four consecutive inquiries, performed within the period 1991-2000, blood and food OTA contaminations were assayed and compared for 954 nephropathy patients and 205 healthy subjects from the Tunisian general population. This survey was also designed to show that, although the whole population is likely to be exposed to OTA, specific people living in conditions showing similarities with the Balkans do have a kidney disease apparently linked to ochratoxin in food. The results showed that the highest incidences were found in patients with CIN of unknown cause. Indeed, the percentages of OTA-positive samples ranged from 93% to 100%, whereas it was only from 62% to 82% in healthy subjects. Mean OTA concentrations were also higher in patients with CIN of unknown cause than in controls (44.4 +/- 19 microg/L to 55.6 +/- 19 microg/L as opposed to 1.22 +/- 1.2 microg/L to 3.35 +/- 2.32 microg/L, respectively). This study emphasizes further the implication of OTA on this particular human nephropathy and underlines the probable causative role of OTA in the onset of this disease. It is important to note that the highest levels of food OTA contamination were found in the group presenting with CIN of unknown cause, indicating that, similar to the case in the Balkans, people are exposed to OTA essentially by their food.