Progressive Interstitial Nephritis Research Articles

Aristolochic Acid Induces Chronic Kidney Disease in ACE Knockout Mice.

Background:Aristolochic acid I (AAI) is an extract from Chinese herbs that causes progressive interstitial nephritis. The aim of this research is to know whether chymases play the crucial role in AAI-induced nephropathy.Methods:The mice were treated with AAI via intraperitoneal injection and the accumulated AAI dosages are 30 mg/kg of body weight for two, four, six, and eight weeks. The animals were sacrificed after another two or four weeks for nephropathy development. Collection of blood, urine, and kidney samples for the further biochemical analysis, hematoxylin–eosin (H and E) and Masson's trichrome stained to detected pathologic, and MMP2 and MMP9 activity assays.Results:After the treatment of AAI, of the mice, their body weights were decreased (P < 0.01), and concentration of creatinine and blood urea nitrogen (BUN) in serum (P < 0.01) and urine collection were increased (P < 0.01). In the renal tissue sections, high amount of inflammatory cells were found by H and E stain, and increased fibrosis in renal interstitial tissue were observed by Masson's trichrome stain. In mice kidney tissue, significantly increased chymase activity after treatment of AAI was found (P < 0.01), but ACE activity did not show significant changes. In ACE KO mice, increased MMP2 and decreased MMP9 activity were found in the AAI-treated mice compared with AAI-untreated control (P < 0.01).Conclusions:Moreover, it was also observed that the deficiency of ACE would accelerate the disease development of AAI-induced nephropathy. These results may help to know more information about the role of AAI-induced chronic kidney disease and can be applied in developing new drug targets for nephropathy.

Protective role of relaxin in a mouse model of aristolochic acid nephropathy

BackgroundAristolochic acid nephropathy (AAN) is a chronic, progressive interstitial nephritis. To date, treatment strategies remain limited. Mounting evidence shows that relaxin (RLX) possesses powerful anti-fibrotic and anti-apoptotic characteristics, therefore, the present study aimed to investigate the possible protective role of RLX in aristolochic acid (AA) induced nephrotoxicity. MethodsThe in vitro cell tests were performed: the embryonic kidney cells 293 were treated with AA-I (40 μg/mL) or with AA-I (40 μg/mL) plus RLX (100 ng/mL) and the cell groups were then tested and the normal 293 cells were set as blank control. In addition, the in vivo animal tests were performed: mice were randomly divided into three groups: a control group injected intraperitoneally with an equal volume of saline every other day for 6 weeks, an AA group injected intraperitoneally with AA-I (5 mg/kg) every other day for 6 weeks, and an AA + RLX group treated with the AA-I for 6 weeks and subsequently received RLX (0.25 mg/kg/day) using an implanted osmotic mini-pump for an additional 2 weeks. 8 weeks post-AA-I, mice were sacrificed for analysis. ResultsIn the in vivo animal tests, RLX administration prevented increased plasma creatinine and nitrogen levels caused by aristolochic acid as well as alleviated the severity of renal ultrastructural lesions induced by aristolochic acid. Both in the in vitro cell tests and in the in vivo animal tests, Western blotting of the AA-I group showed increased expression of the pro-apoptotic protein genes Bax and the cleaved form of caspase-3, both of which were reversed by RLX. In contrast, the expression of the anti-apoptotic gene Bcl-2 correlated inversely to Bax in RLX treated mice. RLX restored the decreased phosphorylated Akt induced by AA-I. The protein expression of eNOS was also reduced in AA-I treated group compared with control, which was reversed in the presence of RLX. Immunohistochemical staining of the animal tissue revealed that RLX markedly reduced the overexpression of type IV collagen, fibronectin, and alpha-smooth muscle actin in AA-I treated mice. Conclusions: Our results suggest that RLX alleviates AA-I induced kidney fibrosis by reducing apoptosis and up-regulation the expression of p-Akt.

Extracellular Matrix: Alport Syndrome.

Patients present with X-linked inheritance; Alport syndrome occurs in approximately 1 in 50,000 newborns. The systemic features include progressive interstitial nephritis, renal failure by the fifth decade, and neurosensory deafness.

Localization of aristolochic acid in mouse kidney tissues by immunohistochemistry using an anti-AA-I and AA-II monoclonal antibody.

Aristolochic acids (AAs) are found in herbal medicines of Aristolochiaceae plants, including Aristolochia and Asarum species. AAs are associated with a rapidly progressive interstitial nephritis, which is called aristolochic acid nephropathy (AAN). However, the in-situ localization of AAs in the target organ, the kidney, has not been investigated yet. In the present study, the accumulation of aristolochic acid I (AA-I) in mouse kidney was revealed by immunoperoxidase light microscopy as well as colloidal gold immunoelectron microscopy (IEM) based on an anti-AA-I and AA-II monoclonal antibody (mAb). Male BALB/c mice were treated with 1.25 or 2.50 mg kg(-1) of AA-I per day for 5 days. Paraffin sections and ultra-thin sections of kidney tissue were respectively prepared. Under light microscopy, the apical surface of proximal tubules was strongly stained for AA-I, whereas no obvious immunostaining was found in the distal tubules and glomerulus, which remained relatively intact. Under electron microscopy, epithelial cells of the proximal tubules, distal tubules and collecting tubules were broken to various degrees. Gold labeling in the proximal and distal tubules was stronger than that in the collecting tubules. In renal tubules, immunogold signals of AA-I tended to accumulate in the mitochondria and peroxisomes, though the signals could be observed all over the cell. Gold signals were also found in the erythrocytes of glomeruli. The MAb against AA-I and AA-II provides a clue for the identification of proteins or factors which might interact with AA-I and thus induce targeted damage of kidney.

Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology

BackgroundBalkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood.MethodsWe performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions.ResultsUsing specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders.ConclusionOur data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.

Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice

Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three-day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2-positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8-week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy. We characterized a novel in vivo model for cholemic nephropathy, which offers new perspectives to study the complex pathophysiology of this condition. Our findings suggest that urinary-excreted toxic BAs represent a pivotal trigger for renal tubular epithelial injury leading to cholemic nephropathy in CBDL mice.

Chronic renal failure from lead: myth or evidence-based fact?

In this mini review, we would like to challenge the well-established 'fact' that lead exposure causes chronic renal failure (CRF). Even though only scarce evidence exists of the relationship between lead and renal failure, a World Health Organization Environmental Health Criteria document summarizes that 'Lead has been a very common cause of acute or chronic renal failure'. It is also written and cited in textbooks and numerous publications that chronic lead nephropathy causes a slowly progressive interstitial nephritis manifested by a reduced glomerular filtration rate, and that there is a growing consensus that lead contributes to hypertension in the general population. We will argue that, when published reports are carefully scrutinized, such statements on lead and CRF are not evidence based but are rather founded on a few narrative reports on lead-exposed individuals and statistical associations between lead and serum creatinine (or urea) in a few population studies. We will, however, not argue that lead is not toxic and that lead does not cause other types of severe health effects where the evidence is unquestionable, but we do not believe that the kidneys are an early victim after lead exposure.

Acute interstitial nephritis associated with ulcerative colitis

Although drugs used in inflammatory bowel diseases (IBD) cause renal injury, glomerulopathies may also accompany IBD. We report a case with the rare association of ulcerative colitis (UC) and acute progressive interstitial nephritis. Although the kidney is acknowledged as a target organ for injury as a result of drug nephrotoxicity, our findings lend support to the novel recognition that the deranged autoimmune system emerging in UC causes interstitial nephritis as an extraintestinal manifestation. Overt renal failure due to interstitial nephritis has rarely been reported in UC patients. The case presented here therefore provides novel information on UC-associated nephropathy.

Herbal medicines and chronic kidney disease

Alternative and indigenous systems of medicine are popular amongst the poorer sections of society in the developing world. Their use in the developed world has also increased in recent times. The source and composition of these medicines vary in different parts of the world, but herbs and other botanicals are central to these systems. Largely outside the ambit of regulatory control, herbal remedies are prepared by quasi-trained herbalists and not tested for safety. Toxicity can occur when a herb with unknown toxicity is consumed, incorrect identification leads to substitution of an innocuous herb with a toxic one, preparations are contaminated with toxic non-herbal compounds or when a herb potentiates the nephrotoxic effect of a conventional therapy. Renal injury has been reported in association with several herbs. The best-known herb-induced chronic kidney disease (CKD) is aristolochic acid nephropathy. The condition is characterized by progressive interstitial nephritis, with a proportion of patients developing urothelial malignancies. The toxic compound is aristolochic acid (AA); AA-DNA adducts have been identified in the renal and urothelial tissues. Recent evidence suggests that AA also contributes to the development of Balkan endemic nephropathy. The role of herbs has been postulated in the development of CKD in other parts of the developing world, especially amongst the rural population. Public awareness and regulation of use of herbal medicines are required to eradicate this entity from the community.

A novel heterozygous missensemutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy

BackgroundFamilial Juvenile Hyperuricemic Nephropathy is an autosomal dominant nephropathy, characterized by decreased urate excretion and progressive interstitial nephritis. Mutations in the uromodulin coding UMOD gene have been found responsible for the disease in some families.Case presentationWe here describe a novel heterozygous p.K307T mutation in an affected female with hyperuricemia, renal cysts and renal failure. The proband's only son is also affected and the mutation was found to segregate with the disease.ConclusionsThis mutation is the fourth reported in exon 5. Initial studies identified a mutation clustering in exon 4 and it has been recommended that sequencing this exon alone should be the first diagnostic test in patients with chronic interstitial nephritis with gout or hyperuricemia. However, regarding the increasing number of mutations being reported in exon 5, we now suggest that sequencing exon 5 should also be performed.

Importance of sodium dodecyl sulfate pore-graduated polyacrylamide gel electrophoresis in the differential diagnostic of Balkan nephropathy.

Balkan nephropathy (BN) is an endemic disease, which leads to end-stage renal failure and artificial renal replacement therapy. Pathologically it is characterized by progressive interstitial nephritis in a large population of villages situated in the proximity of a bend of the Danube up to a distance of 100 km from the river in several parts of Bulgaria, Romania, and the former Yugoslavia. The urinary proteins of 19 patients with BN from the region of Vratza, Bulgaria were examined using ultrathin layer sodium dodecyl sulfate (SDS) pore-graduated polyacrylamide gel electrophoresis (PAGE) and silver staining. The documentation of urinary proteins pattern was performed using laser densitometry and consecutive electronic processing for the purpose of characterizing and quantifying protein excretion. Our results show that the proteinuria of BN is predominantly tubular, consisting of low molecular weight species (10-65 kilodaltons). The amount of tubular protein changes with the progression of the disease. SDS-polyacrylamide gel electrophoresis (PAGE) is a diagnostic method for early diagnosis of tubular failure in BN. Using our method of SDS-PAGE, tubular failure can be detected even at a total protein concentration below 0.1 g/L and when the serum creatinine concentration is normal. Additionally, our method of SDS-PAGE supports the differentiation of BN from glomerular disease.

Glomerular filtration rate and calcium metabolism in long-term lithium treatment.

Does long-term lithium treatment induce an irreversible renal damage, and does polyuria or changes in the calcium metabolism indicate this? To elucidate these questions GFR, diuresis, S-Ca, S-Mg, S-PTH and bone mineral content (photonabsorptiometry) were determined in 29 consecutive patients on long-term lithium therapy for 2.5--12 years and in 4 patients, who had been admitted to the Renal Clinic with lithium-induced polyuria. Only 1 of the patients had had a known lithium intoxication (S-Li > 2 mmol/l). None had a history of renal disease or significant analgesic consumption. In the consecutive series the GFR was not significantly reduced and no correlations were found between this parameter and the duration of lithium therapy, average S-Li, highest S-Li noted, diuresis or any of the calcium parameters. The morning diuresis was significantly increased in comparison with a control group with normal kidney function. 2 of the 4 polyuric patients had a decreased GFR, but in 1 case it was normalized on desmopressin supplementation. Renal biopsy in the patient with one S-Li of 2.35 and a low GFR in the consecutive series, and in 3 of the polyuric patients, revealed focal interstitial fibrosis and nephron atrophy. The mean S-Ca, S-Mg, S-PTH and bone mineral content were increased, but no significant intercorrelations between these parameters were found. Neither were any intercorrelations found between the calcium parameters and time on lithium therapy, average S-Li, highest S-Li noted or morning diuresis. In conclusion a relatively well-managed lithium therapy for up to 12.5 years does not seem to influence the GFR, even if renal biopsy in 4 of our patients revealed interstitial nephritis and data in the literature indicate a progressive interstitial nephritis. The present study did not support the proposition that polyuria is an alarming sign of pronounced renal lesion. Calcium metabolism is influenced by lithium therapy but from the clinical point of view no negative effects could be found. S-Ca should probably be checked regularly in patients on long-term lithium therapy.

Natural antibodies to EBV-VCA antigens in common marmosets (Callithrix jacchus) and response after EBV inoculation.

Healthy common marmosets from two separate colonies, one in England and one in France, were found to have antibodies cross-reacting with Epstein-Barr virus structural antigens (EBV-VCA). All seropositive animals were at least 2 years old. Experimental EBV infection of marmosets of different ages led to seroconversion of inoculated weanlings. Adult animals either developed antibody for the first time or showed an increase in their existing titers. Both control and infected animals developed a progressive interstitial nephritis. The lymphocytic infiltration was more extensive, diffuse and immature in appearance in inoculated animals, but no definite evidence of lymphoproliferative disease or lymphoma was found.