Severe Tubulointerstitial Damage Research Articles

Unusual course of glyphosate-induced acute kidney injury: a case report of tubulointerstitial nephritis treated with steroids.

Glyphosate is a widely used herbicide that is generally considered safe; however, acute kidney injury (AKI) caused by glyphosate ingestion can be severe and require hemodialysis. We present a unique case of a 68-year-old Japanese man who developed AKI after accidental ingestion of glyphosate and required hemodialysis. Based on the clinical presentation and findings, the patient was diagnosed with renal AKI with severe tubulointerstitial damage. However, the precise pathogenesis of the tubulointerstitial damage remained unclear. An elevated beta-2 microglobulin level discovered by the urinalysis during admission raised the suspicion of tubulointerstitial nephritis caused by glyphosate. Gallium scintigraphy revealed accumulation in both kidneys. A renal biopsy revealed acute tubulointerstitial nephritis rather than acute tubular necrosis, which is commonly observed with glyphosate-induced renal injury. After initiating steroid therapy, his kidney function gradually improved and he was weaned from hemodialysis. This report is the first to describe glyphosate-induced acute tubulointerstitial nephritis that was successfully treated with immunosuppressive therapy. Furthermore, this report highlights the importance of steroid therapy for cases of persistent kidney injury after the discontinuation of agents associated with acute tubulointerstitial nephritis.

Clinical characteristics and prognosis of 12 cases of lupus nephritis complicated with thrombotic microangiopathy

To investigate the clinical characteristics, pathological features, treatment regimen, and prognosis of children with lupus nephritis (LN) and thrombotic microangiopathy (TMA), as well as the treatment outcome of these children and the clinical and pathological differences between LN children with TMA and those without TMA. A retrospective analysis was conducted on 12 children with LN and TMA (TMA group) who were admitted to the Department of Nephrology, Children's Hospital of Nanjing Medical University, from December 2010 to December 2021. Twenty-four LN children without TMA who underwent renal biopsy during the same period were included as the non-TMA group. The two groups were compared in terms of clinical manifestations, laboratory examination results, and pathological results. Among the 12 children with TMA, 8 (67%) had hypertension and 3 (25%) progressed to stage 5 chronic kidney disease. Compared with the non-TMA group, the TMA group had more severe tubulointerstitial damage, a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score at onset, and higher cholesterol levels (P<0.05). There were no significant differences between the two groups in the percentage of crescent bodies and the levels of hemoglobin and platelets (P>0.05). There is a higher proportion of individuals with hypertension among the children with LN and TMA, as well as more severe tubulointerstitial damage. These children have a higher SLEDAI score and a higher cholesterol level.

Different Clinical Courses of Nephronophthisis in Dizygotic Twins.

Siblings with nephronophthisis occasionally show different clinical courses; however, the reasons for this remain unclear. We herein report cases of nephronophthisis in a pair of dizygotic twins with different clinical courses. The brother developed end-stage kidney disease at 17 years old; however, his sister did not show kidney insufficiency. Kidney biopsies revealed severe tubulointerstitial damage at 14 and 22 years old in the brother and sister, respectively. Both had a homozygous NPHP1 deletion with different heterozygous mutations related to hereditary cystic kidney disease. Since the dizygotic twins were exposed to similar environmental factors, genetic factors may have influenced their clinical course more strongly than environmental factors.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several invitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the invivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis invivo.

MO223: Contribution of Interstitial CD138 + Plasma Cells on the Renal Outcome in Patients with Anca-Associated Vasculitis

Abstract BACKGROUND AND AIMS Plasma cells (PC) are the most differentiated antibody and cytokine-producing B lineage cells and are thought to contribute to the perpetuation of inflammation in patients with ANCA-associated vasculitis (AAV). Agents targeting PCs are of interest in AAV, however, little is known about the role of interstitial CD138 + PCs in these patients. In this study, we aim to demonstrate the impact of this cell population in the prediction of renal outcomes in patients with AAV. METHOD Forty AAV patients with glomerulonephritis, diagnosed between 2014 and 2018 at the Division of Nephrology of the Medical University of Graz were included and followed for 36 months. Histological assessments using the kidney allograft Banff classification were performed to describe the tubulointerstitial (TI) damages. Immunohistochemistry analysis was performed in 29 patients to assess the renal interstitial CD138 + cell expression. More than ten CD138 + cells per high power field were stated as high expression (excluding CD138 staining of renal tubular epithelial cells). Changes in kidney function, the incidence of renal relapses (RR), and end-stage renal disease (ESRD) were analyzed. RESULTS In the kidney biopsies, N = 21 (72%) patients had a high expression of CD138 + plasma cells. No significant difference was observed in PR3 and MPO serotypes in the group of patients with high CD138 + cell expression (43% versus 57%, P = .793). In addition, no significant difference was seen in the changes in kidney function and the incidence of RR or ESRD between the groups with high and low expression of CD138 + cells during the follow-up period. However, patients with more severe TI damage had more severe proteinuria {urinary albumin/creatinine ratio: 51 [interquartile range (IQR) 42–123] versus 360 (IQR 202–1112) mg/g Creatinine; P = .016} at 3-year follow-up, and tended to have a higher rate of RR and ESRD [i0/i1: N = 2/18 (11%) versus i2/i3: N = 6/22 (27%), P = .258 and i0/i1: N = 2/18 (11%) versus i2/i3: N = 6/22 (27%), P = .258, respectively]. CONCLUSION Our data indicate a significant proportion of CD138 + PCs in kidney specimens of patients with AAV. Despite the lack of association between this cell population and our cohort’s renal outcome, these results provide additional insights on the renal B-cell clusters in patients with AAV. In addition, our findings go along with already existing data on the association between extended TI damage and worse renal outcome.

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections.

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein–Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.

Angiotensin II type 1a receptor loss ameliorates chronic tubulointerstitial damage after renal ischemia reperfusion

We investigate whether suppressing the activation of the angiotensin II type 1a receptor (AT1a) can ameliorate severe chronic tubulointerstitial damage (TID) after renal ischemia reperfusion (IR) using AT1a knockout homozygous (AT1a−/−) male mice. To induce severe chronic TID after renal IR, unilateral renal ischemia was performed via clamping of the right renal pedicle in both AT1a−/− and wild-type (AT1a+/+) mice for 45 min. While marked renal atrophy and severe TID at 70 days postischemia was induced in the AT1a+/+ mice, such a development was not provoked in the AT1a−/− mice. Although the AT1a+/+ mice were administered hydralazine to maintain the same systolic blood pressure (SBP) levels as the AT1a−/− mice with lower SBP levels, hydralazine did not reproduce the renoprotective effects observed in the AT1a−/− mice. Acute tubular injury at 3 days postischemia was similar between the AT1a−/− mice and the AT1a+/+ mice. From our investigations using IR kidneys at 3, 14, and 28 days postischemia, the multiple molecular mechanisms may be related to prevention of severe chronic TID postischemia in the AT1a−/− mice. In conclusion, inactivation of the AT1 receptor may be useful in preventing the transition of acute kidney injury to chronic kidney disease.

A Rare Genetic Defect of MBL2 Increased the Risk for Progression of IgA Nephropathy.

The aim of this study was to investigate the association between lectin pathway-related genetic variations and progression in IgA nephropathy. Biopsy-proven IgAN patients with eGFR ≥15 ml/min/1.73 m2 at baseline and a minimum follow-up of 12-months were enrolled. A total of 1,007 patients and 121 healthy controls were enrolled from two Chinese renal centers. The discovery cohort consisted of 606 patients, and the validation cohort consisted of 401 patients. First, promoters, all exons and their boundary regions of MBL2 and FCN2 were sequenced in 50 patients, and then 37 variations were identified. Of these variations, 7 expression-associated variations were selected and genotyped in the whole discovery cohort. We found that rs1800450 in MBL2 and rs7851696 in FCN2 were associated with an increased risk for ESRD as well as serum MBL or L-ficolin levels. However, only rs1800450 was successively validated for its association with ESRD (HR, 15.91; 3.27–77.34; P = 0.001) in the fully adjusted model in the validation cohort. In addition, 2.7% of patients, and 2.5% of healthy controls carried rs1800450-AA. IgAN patients with rs1800450-AA lacked expression of MBL in both serum and renal tissue and had more severe tubulointerstitial damage. Furthermore, a combined effect of rs1800450-AA with a previously reported clinical risk score was observed in which patients with both a high clinical risk score (≥1%) and rs1800450-AA had a strikingly increased 10-years ESRD risk by 37.1-fold (7.17 to 192.13-fold). In summary, IgAN patients carrying MBL2 rs1800450-AA have a high risk for renal function deterioration, probably due to inactivation of the complement MBL pathway.

Correlation of electrophoretic urine protein banding patterns with severity of renal damage in dogs with proteinuric chronic kidney disease.

Urine protein loss is common in dogs with chronic kidney disease (CKD). Currently available noninvasive means of evaluating CKD in dogs cannot accurately predict the severity of glomerular and tubulointerstitial damage. Electrophoretic analysis of urine proteins can indicate the compromised renal compartment (glomerular vs tubular), but extensive evaluation of protein banding pattern associations with histologic damage severity has not been performed in dogs. We aimed to evaluate electrophoretic banding patterns as indicators of the presence and severity of glomerular and tubulointerstitial damage in dogs with naturally occurring, predominantly proteinuric CKD. We performed a retrospective study using urine and renal tissue from 207 dogs with CKD. Urine protein banding patterns were correlated with histologic severity of renal damage. Sensitivity and specificity of banding patterns for the detection of glomerular and tubulointerstitial damage were determined. Banding patterns were 97% sensitive and 100% specific for the detection of glomerular damage and 90% sensitive and 100% specific for the detection of tubulointerstitial damage. Correlations between composite banding patterns and the severity of renal damage were strong, while glomerular banding patterns correlated moderately with glomerular damage severity, and tubular gel scores correlated weakly to moderately with the severity of tubulointerstitial damage. Urine protein banding patterns are useful for the detection of glomerular and tubulointerstitial damage in dogs with proteinuric CKD.

Urinary Level of Liver-Type Fatty Acid Binding Protein Reflects the Degree of Tubulointerstitial Damage in Polycystic Kidney Disease

Background/Aims: Polycystic kidney disease (PKD) is a common, progressive, and heritable type of kidney disease. Although certain imaging modalities are useful for the diagnosis and staging of PKD, they cannot adequately monitor the severity of interstitial inflammation and fibrosis. Therefore, the present study evaluated the urinary level of liver-type fatty acid binding protein (L-FABP) as a marker of interstitial inflammation and fibrosis in PKD. Methods: Male PCK/CrljCrl-Pkhd1pck/Crl (PCK) rats (n = 34) were used as an animal model of the PKD. Age-and sex-matched Sprague–Dawley rats (SD) (n = 34) were used as controls. Urine samples were obtained from the rats at 8, 12, 16, 20, and 24 weeks of age, and the sera and kidney tissues were obtained at 8, 16, 20, and 24 weeks of age. Results: All PCK rats developed cysts, and the degrees of tubular epithelial cell proliferation and interstitial inflammation increased linearly with age in these model rats relative to the controls. Interstitial fibrosis tended to increase in the PCK rats from 8 to 20 weeks of age, and revealed a peak level at 20 weeks. The urinary L-FABP levels increased linearly with age in the PCK rats, and the levels at 12, 16, 20, and 24 weeks were significantly higher than those in the controls. The urinary levels of L-FABP in the PCK rats correlated significantly with the severity of tubulointerstitial damage; specifically, we observed a significant correlation of the urinary levels at 16 weeks of age with the total kidney volume at 20 weeks. In contrast, both PCK and SD rats exhibited similar serum levels of L-FABP. Conclusion: Urinary L-FABP reflects the progression of tubulointerstitial damage, and therefore, may be a useful marker for monitoring the progression of PKD.

BK virus nephropathy in renal transplant recipients.

BK virus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients and can result in graft loss. The reactivation of BK virus in renal transplant recipients is largely asymptomatic, and routine surveillance especially in the first 12-24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and anti-viral treatment in the early stages may be effective in stopping BK virus replication. Urinary decoy cells, although highly specific, lack sensitivity to diagnose BKVN. Transplant biopsy remains the gold standard to diagnose BKVN, good surrogate markers for surveillance using quantitative urinary decoy cells, urinary SV40 T immunochemical staining or polyoma virus-Haufen bodies are offered by recent studies. Advanced BKVN results in severe tubulo-interstitial damage and graft failure. Retransplantation after BKVN is associated with good outcomes. Newer treatment modalities are emerging.

Epithelial mesenchymal transition in the progression of renal disease in dogs.

Chronic kidney disease (CKD) in dogs is the final common pathway resulting from persistent renal injury and is characterized by progressive tubulointerstitial damage (TID). Pathogenesis of CKD is divided into an initial inflammatory phase with a predominantly mononuclear infiltrate followed by a fibrotic phase with increased numbers of fibroblasts and extracellular matrix deposition that causes a progressive reduction of functional parenchyma. Proteinuria is a common manifestation of renal diseases in dogs, and its role in the pathogenesis of CKD is still uncertain. Nevertheless, the degree of proteinuria in dogs correlates with TID progression. Increased protein filtration may have direct effects on tubular epithelial cells (TECs) that induce them to express the major histocompatibility complex type II, and thereby contribute to lymphocyte recruitment. Thus, an active pro-inflammatory role is proposed for TECs in TID progression. Moreover TECs are believed to actively participate in the mechanisms of renal fibrosis. Epithelial-Mesenchymal-Transition (EMT) of TECs in canine TID has been studied in the last decade. Down-regulation of adhesion molecules and loss of epithelial markers in TECs directly correlate with the severity of TID and with de novo expression of mesenchymal markers. Tubular basement membrane (TBM) disruption is an early EMT event. Increased activity of Matrix Metalloproteinase-2 and its co-localization with TBM splitting suggests an active role for the enzyme in inducing EMT. Processes occurring in canine CKD share many similarities with its human counterpart, making the dog a good model in which to examine the mechanisms of TID progression.

PROTECTIVE EFFECTS OF ISOLATED SOY PROTEINFEEDING ON RENAL TUBULES IN THE EARLY STAGEOF DIABETIC NEPHROPATHY.

Progression of diabetic nephropathy (DN) is strongly related to the severity of tubulointerstitial damage. Isolated soy protein (ISP) feeding has shown beneficial effects in animal DN models. However, the mechanisms underlying the renal effects of ISP feeding in early disease stages have not been clarified. In this study, 6-week-old obese Zucker (fa/fa) rats and lean control rats were fed 20% casein or 20% ISP diet for either 2 or 24 weeks. In casein-fed fa/fa rats, the levels of urinary markers of tubular injury started to increase 2 weeks after the commencement of experimental feeding, and the increase continued over time. The levels of these markers were significantly lower in ISP-fed fa/fa rats than in casein-fed fa/fa rats. Renal MCP-1, IL-1β, and TNF- α mRNA levels and urinary MCP-1 levels were also lower in ISP-fed fa/fa rats than in casein-fed fa/fa rats after 2 weeks. IL- 1β-induced upregulation of MCP-1 expression in cultured tubular NRK-52E cells was suppressed by ISP peptides produced by digestion with pepsin and trypsin, but not by casein peptides. In conclusion, casein feeding induces tubular damage at the early stage of DN, whereas ISP feeding alleviates it. The renoprotective effects of ISP may be associated with the downregulation of renal inflammatory cytokines.

Imbalance of regulatory T cells to Th17 cells in IgA nephropathy

Background. Dysregulation of CD4 + T cell subsets participates in the pathogenesis of IgA nephropathy (IgAN). FoxP3 + regulatory T cells (Treg) and Th17 cells are two novel subsets of CD4 + T cells. This study aims to investigate Treg/Th17 balance in IgAN patients. Methods. Peripheral frequencies of Th17 and Treg functional subsets – CD45RA + FoxP3low resting Treg (rTreg) and CD45RA-FoxP3high activated Treg (aTreg) were assessed in 63 adult IgAN patients. Expression of transcription factors (FoxP3 and RORγt) and related cytokines of Treg and Th17 were analysed. Renal expression of FoxP3 and IL-17A were detected by immunohistochemistry. Results. Compared with normal controls, IgAN patients had decreased frequency of CD45RA-FoxP3high aTreg subset (p < 0.05), increased frequency of Th17 (p < 0.05) and decreased ratio of Treg/Th17 (p < 0.05). Frequency of aTreg subset correlated with SBP(r = − 0.57, p < 0.05), DBP (r = − 0.50, p < 0.05), eGFR (r = 0.68, p < 0.05) and 24 h proteinuria (r = − 0.58, p < 0.05). RORγtmRNA/FoxP3mRNA ratio increased in IgAN (p < 0.05). Serum IL-17A, IL-21, IL-23, IL-1β and IL-6 elevated while IL-10 decreased in IgAN (p < 0.05), and serum IL-17A correlated with 24 h proteinuria (r = 0.35, p < 0.05). Serum TGF-β1 wasn't different between the two groups. Renal interstitial infiltration of FoxP3 + mononuclear cells were observed in IgAN patients, particularly prominent in those with > 25% tubular atrophy/interstitial fibrosis. Tubular IL-17A expression was found in 34 out of 63 IgAN patients. Compared with 29 patients without IL-17A expression, these patients had lower renal function, greater proteinuria, and more severe tubulointerstitial damage. Conclusions. Imbalance of Treg/Th17 found in IgAN may play a role in disease pathogenesis and progression.

Pauci-immune crescentic glomerulonephritis complicating Sjögren's syndrome in a 12-year-old girl

Dear Sirs,We read with great interest the article by Jung SK et al. onmesangial proliferative glomerulonephritis and IgA depos-its in a child with Sjogren's syndrome (SS) recentlypublished in Pediatric Nephrology[1]. The most commonform of renal involvement in SS is tubulointerstitialnephritis, generally causing mild renal dysfunction [2].Glomerulonephritis (GN) is rare with membranoprolifer-ative and membranous nephropathy being the mostcommonly described glomerular lesions, whereas cres-centic GN has been only occasionally reported in adults[3, 4]. Wefolloweda12-year-oldgirlwithprimarySS,whopresented with acute renal failure due to pauci-immunecrescentic GN with severe tubulointerstitial damage. Thepatient had a 7-year history of sicca syndrome withenlargement of both lacrimal glands and an abnormalSchirmer's test, pointing to the diagnosis of SS. At theage of 12 years, she presented with general malaise andthe biochemical signs of acute renal failure (creatinine9.5 mg/dl, BUN 103 mg/dl), oliguria (0.4 ml/kg/h),moderate proteinuria (1.23 g/l) and microscopic hematu-ria. Antistreptolysin O, anti-cardiolipin and lupus antico-agulant antibodies were absent. Viral serology (hepatitis Band C, HIV) was negative as well. Rheumatoid factor andC3, C4 complement levels were normal. Anti-DNAantibody titer measured by ELISA was 1:200. ANCA,ANA, and Anti-Ro/SS-A could be measured by immuno-fluorescence on the 90th day only. C-ANCA and p-ANCAwere negative, ANA titer (Hep-2) was 1:160 and Anti-Ro/SS-A were present (+).Renal biopsy contained 54 glomeruli, from which twowere completely sclerotic, four demonstrated fibrocellu-lar crescents, and all remaining glomeruli showed largecellular crescents (Fig. 1a). Tubulointerstitial inflamma-tion with patchy cellular infiltrates containing lympho-cytes, plasma cells, and monocytes was present (Fig.1b).Immunofluorescence with antibodies against IgG, IgA,IgM, C1q, C3, fibrinogen, κ and 1 light chains wasnegative.The patient received three pulses of methylprednisolone1,000 mg daily, followed by oral prednisolone 60 mg/day.Alternate-day plasmapheresis with substitution of 1 plasmavolume (x 4 times) and intravenous cyclophosphamidetreatment (750 mg/m

Matrix metalloproteinases and their role in the renal epithelial mesenchymal transition.

Tubular cell epithelial-mesenchymal transition (EMT) is a fundamental contributor to renal fibrosis. The aim of this study was to investigate the activity of different matrix metalloproteinases by immunohistochemistry and gel-zymography in a model of chronic canine kidney disease. Immunohistochemistry for antibodies against MMP-9, MMP-2, MMP-13, MMP-14 and TIMP-2 was performed on 28 renal biopsy specimens. Selected cases were chosen for gelatin zymography. In moderate and severe tubulo-interstitial damage, increased expression of MMP-2 was noted. A peculiar staining pattern for MMP-2 in variable-sized vesicles, corresponding to the area of basement membrane splitting, was observed. The immunoexpression of MMP-9 and TIMP-2 was reduced in the same cases, compared to control dogs. The splitting of the membrane suggests an active role of this gelatinase in the disruption of type-IV collagen, the main basement membrane component, confirmed by MMP2 gelatinolytic activity by gel-zymography. These data could provide the basis for clinical trials examining the potential benefits of selective MMP-2 inhibitors in dogs with chronic kidney disease.

The relationship between the TGF-β1 gene −509C/T polymorphism and tubulointerstitial damage resulting from primary nephrotic syndrome

Background: The aim of this study was to investigate the correlation between the transforming growth factor (TGF)-β1 gene −509C/T polymorphism and the susceptibility to primary nephrotic syndrome (PNS), and in particular to the severe degree of tubulointerstitial damage (TID) seen in Chinese. Methods: Ninety-eight PNS patients and 128 normal controls were studied. The extent of tubulointerstitial changes was evaluated and patients were divided into two groups according to the severe or mild degree of TID. The TGF-β1gene −509C/T polymorphism was detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, and the serum level of TGF-β1 was determined by enzyme-linked immunosorbent assay (ELISA). Results: No statistical differences in genotype or allele frequency of the TGF-β1 gene −509C/T were found between PNS and normal subjects. However, T allele and CT + T T genotype frequency were higher in the PNS with severe TID than the mild TID and controls. Additionally, the serum concentration of TGF-β1 was significantly higher in the PNS with severe TID group than the other two groups and in the T T genotype individuals than the CC and CT genotype individuals. A logistic regression analysis demonstrated that TGF-β1 gene −509C/T genotype was the risk factor of TID in PNS patients [OR (odd ratio) 2.34, confidence interval (CI) 0.98–3.46, p = 0.012]. Conclusion. TGF-β1 gene −509C/T polymorphism was associated with severe TID. The higher value in serum concentration of TGF-β1 was also associated with severe TID and the T T genotype/T allele. T allele gene might be the important risk factor for susceptibility.

Urinary Excretion of Liver Type Fatty Acid Binding Protein Accurately Reflects the Degree of Tubulointerstitial Damage

To investigate the relationship between liver-type fatty acid-binding protein (L-FABP), a biomarker of chronic kidney disease, in the kidney and the degree of tubulointerstitial damage, folic acid (FA)-induced nephropathy was studied in a mouse model system. As renal L-FABP is not expressed in wild-type mice, human L-FABP (hL-FABP) transgenic mice were used in this study. hL-FABP is expressed in the renal proximal tubules of the transgenic mice that were injected intraperitoneally with FA in NaHCO3 (the FA group) or only NaHCO3 (the control group) and oral saline solution daily during the experimental period. The FA group developed severe tubulointerstitial damage with the infiltration of macrophages and the deposition of type I collagen on days 3 and 7 and recovered to the control level on day 14. The gene and protein expression levels of hL-FABP in the kidney were significantly enhanced on days 3 and 7. Urinary hL-FABP in the FA group was elevated on days 3 and 7 and decreased to the control level on day 14. The protein expression levels of hL-FABP in both the kidney and urine significantly correlated with the degree of tubulointerstitial damage, the infiltration of macrophages, and the deposition of type I collagen. In conclusion, renal expression and urinary excretion of hL-FABP significantly reflected the severity of tubulointerstitial damage in FA-induced nephropathy.

Urinary Fatty Acids and Liver-Type Fatty Acid Binding Protein in Diabetic Nephropathy

Background: The aims of this clinical study were to investigate the associations of urinary free fatty acid (FFA) levels with tubulointerstitial damage, and to determine the clinical significance of urinary liver-type fatty acid binding protein (L-FABP) in diabetic nephropathy. Methods: Fifteen patients with nephrotic syndrome due to diabetic nephropathy and 12 patients with minimal-change nephrotic syndrome (MCNS) were studied. Urinary and serum FFA concentrations (palmitic, oleic, linoleic, and arachidonic acids) were measured by gas chromatography, and urinary L-FABP levels were quantified using an ELISA technique. Tubulointerstitial damage was assessed using renal biopsy specimens. Results: The levels of urinary linoleic and arachidonic acids were significantly elevated in diabetic nephropathy compared to MCNS patients, though serum FFA levels were lower in diabetic nephropathy than MCNS patients. The degree of tubulointerstitial damage was significantly severer in the patients with diabetic nephropathy than MCNS. Urinary L-FABP and 8-OHdG (8-hydroxydeoxyguanosine) concentrations were significantly higher in the diabetic nephropathy subjects. Conclusion: Elevated urinary excretion of FFA may be a reflection of FFA overload in the proximal tubules, and FFA may be an important promoter of tubulointerstitial damage in diabetic nephropathy patients. Urinary L-FABP levels may reflect the stress induced by FFA to the proximal tubules, leading to severe tubulointerstitial damage.

Evidence for Abundant Presence of Chymase-Positive Mast Cells in the Kidneys of Patients with Immunoglobulin A Nephropathy: Effect of Combination Therapy with Prednisolone and Angiotensin II Receptor Blocker Valsartan

Several investigators have reported chymase-positive mast cells in tubulointerstitial damage. However, the significance of the presence of chymase in the pathophysiology of renal diseases is unclear. We investigated relationships among chymase, renal damage, and intra-renal circulation. The participant pool consisted of 52 patients with immunoglobulin A (IgA) nephropathy who underwent renal biopsy. Of these, 18 were examined before and 2 months after the initiation of treatment with prednisolone alone (n=9) or combined with the angiotensin II receptor blocker valsartan (n=9). Biopsied renal specimens were evaluated, and the degree of renal circulation (resistive index; RI) was calculated by measuring flow velocity using Doppler sonography. The number of chymase-positive mast cells as visualized by immunohistochemical staining correlated significantly with both tubulointerstitial damage (rho=0.69, p<0.001) and RI (r=0.52, p<0.001). Treatment with prednisolone combined with valsartan effectively decreased both chymase-positive mast cells and RI, displaying a significant correlation between these biomarkers (rho=0.85, p=0.016). However, no such effect was observed with prednisolone alone. The severity of tubulointerstitial damage and the degree of proteinuria were similar in both treatment groups throughout the study term. We concluded that the presence of chymase-positive mast cells and the associated decrease in renal circulation corresponded to disease progression in IgA nephropathy. Combination therapy using prednisolone and valsartan may lead to improvements in intra-renal circulation and to interference in the recruitment of chymase-positive mast cells.