Progressive Interstitial Fibrosis Research Articles

Cellular communication network factor 2 (CCN2) promotes the progression of acute kidney injury to chronic kidney disease

Here we evaluated the efficacy of depleting cellular communication network factor 2 (CCN2) produced by renal tubular epithelial cells in preventing the progression of severe acute kidney injury (AKI) to chronic kidney disease (CKD). We used conditional Ccn2 knockout mice in which expression of Ccn2 was controlled by γ-glutamyl transpeptidase promoter–regulated Cre recombinase. AKI was induced by ischemia–reperfusion injury. An effect of inhibiting Ccn2 expression by tubular epithelial cells on acute damage, assessed according to the levels of kidney injury molecule-1, was not detected 3 days after injury. However, by day 14, interstitial fibrosis and the levels of the extracellular matrix and profibrotic cytokines were reduced in Ccn2 knockout mice compared with wild-type mice. The ectopic expression of the pan-caspase inhibitor p35 reduced the number of apoptotic cells in damaged tubular epithelial cells 3 days after ischemia–reperfusion injury. In contrast, interstitial fibrosis was exacerbated, accompanied by increased levels of transforming growth factor-β and plasminogen-activator inhibitor-1 14 days after insult. Depletion of CCN2 from tubular epithelial cells slowed the progression of interstitial fibrosis, which was promoted by ectopic expression of p35 in the same cells. These results indicate that tubular epithelial cells, which should be eliminated by apoptosis during physiological repair of AKI, produced CCN2 in the damaged kidney and that CCN2 expression in damaged tubular epithelial cells made a critical contribution to the transition from AKI to CKD. Moreover, inhibiting CCN2 expression may represent a therapeutic approach for preventing the progression of AKI to CKD, irrespective of the stage of kidney disease.

MON-023 HYPOKALEMIC NEPHROPATHY IN NEPHROTIC SYNDROME PATIENT

Hypokalemic nephropathy (HN) caused by prolonged K+ deficiency is associated with metabolic alkalosis, polydipsia, polyuria, growth retardation, hypertension, and progressive tubulointerstitial injury. Histopahologic report of HN in nephrotic syndrome (NS) patient is rare. A 27 year male suffered from weakness, especially lower leg, since two weeks prior to admission. The patients had a history of NS since childhood and cared by nephrologist. Recent condition was hemodynamically stable, laboratory examination showed potassium serum 1.85 mmol/L, albumin plasma 1.8 g/dL, serum creatinine 2.45 mg/dL, and marked dyslipidemia. The patient was clinically assesed with hypokalemia, relapse nephrotic syndrome and renal insufficiency. Intravenous potassium was given and renal biopsy was performed. Histopathologic findings showed global sclerosis. The specific findings may related to HN were mesangial proliferation and specific lesions on tubules including athrophy, vacuolization, intratubular deposition of amorphous and laminated hyaline materials and colloidisation of tubular epithelial, and interstitial nephritis. The patient was discharged at 10th day of hospitalization with potassium level 2.93 mmol/L, and serum creatinine 1.95 mg/dL. The patient was treated with oral methylprednisolone, mychophenolate mofetil, ACE-inhibitor, simvastatin and oral potassium Hypokalemic nephropathy may associate with chronic hypokalemia. Hypokalemia, especially if persistently occurs, can induce a variety of changes in renal tissue, impairing tubular transport and possibly inducing chronic tubulointerstitial disease and cyst formation. HN also associated with alterations in intrarenal vasoactive substances, leading to vasoconstriction, salt-sensitivity, and progression of interstitial fibrosis. Histopathological changes in HN, including severe tubular dilatation, intratubular deposition of amorphous and laminated hyaline materials, intratubular cellular casts, and tubular atrophy is found. More attention is paid to athrophy and vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. One function that is not impaired is the ability to appropriately conserve potassium, which can be important in distinguishing between extrarenal and renal sources of potassium losses when the cause of hypokalemia is not clear.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) A case with nephrotic syndrome associated with HN is reported. Chronic hypokalemia may involve in the development of hypokalemic nephropathy. Hallmark of histopathologic finding are tubular epithel athrophy, intratubular amorphous deposition and vacuolization of tubular cells, and interstitial nephritis to fibrosis.

Aristolochic acid I aggravates renal injury by activating the C3a/C3aR complement system

Previous studies have reported that the complement system is unconventionally activated in many kinds of glomerulonephritis. Multiple complement components participate in the pathogenic process by triggering immune response or other intracellular signaling pathways. Here, we have investigated the role of C3a and its receptor C3aR in aristolochic acid nephropathy (AAN), which, is featured with progressive interstitial fibrosis. Over release of C3a and increased expression of C3aR parallels to the up-regulation of α-SMA and TGF-β1 in AAN, which appeared to promote epithelial-mesenchymal-transition (EMT). To identify the role of complement activation in AAN, we used an inhibitor of C3aR (C3aRA) to block the coupling of C3a to its receptor. Our results confirmed from decreased EMT, the protective effect of C3aRA in cell apoptosis and inflammatory response induced by aristolochic acid I. These results showed that C3a and its receptor C3aR played pathogenic roles in AAN, and renal tubular epithelial cells were potentially pivotal targets of complement activation that could cause pro-fibrotic effects.

Advances in Detection of Kidney Transplant Injury.

Early detection of graft injury after kidney transplantation is key to maintaining long-term good graft function. Graft injury could be due to a multitude of factors including ischaemia reperfusion injury, cell or antibody-mediated rejection, progressive interstitial fibrosis and tubular atrophy, infections and toxicity from the immunosuppressive drugs themselves. The current gold standard for assessing renal graft dysfunction is renal biopsy. However, biopsy is usually late when triggered by a change in serum creatinine and of limited utility in diagnosis of early injury when histological changes are equivocal. Therefore, there is a need for timely, objective and non-invasive diagnostic techniques with good early predictive value to determine graft injury and provide precision in titrating immunosuppression. We review potential novel plasma and urine biomarkers that offer sensitive new strategies for early detection and provide major insights into mechanisms of graft injury. This is a rapidly expanding field, but it is likely that a combination of biomarkers will be required to provide adequate sensitivity and specificity for detecting graft injury.

Increased Renal Expression of Adhesion Molecules and Inflammation in Diabetic Nephropathy

Diabetic nephropathy (DN) is the primary risk factor for end‐stage renal disease (ESRD). Previously, we reported that the T2DN rat develops hyperglycemia by 3 months of age, proteinuria by 6 months and progressive renal injury which closely mimics human diabetic nephropathy, including focal glomerular sclerosis, mesangial matrix expansion, thickening of basement membranes, and progressive renal interstitial fibrosis. However, the role of adhesion molecules and renal inflammation in the pathogenesis of DN in this model has not been studied. In the present study, we compared the expression of cytokine and adhesion molecules, as well as the infiltration of inflammatory cells in young (3‐month old), middle‐aged (12‐month old) and elderly (18‐month old) T2DN and SD rats. We found that the expression of the adhesion molecules, ICAM‐1 and E‐selectin, were elevated in elderly T2DN (1.3‐fold and 1.8‐fold, respectively), and E‐selectin level was already higher in young T2DN (2.1‐fold) than in age‐matched SD rats. The number of infiltrating CD45+ leucocytes, CD3+ T cells, CD3−/CD4+ monocytes and CD68+ macrophages per gram of kidney were increased by 2.81±0.45, 2.82±0.44, 3.06±1.05, and 7.86±3.75 times, respectively, in elderly T2DN versus SD control. The rise in infiltrating inflammatory cells was correlated with elevated proteinuria (1144±202 in T2DN vs. 293±47 mg/day in SD) and plasma creatinine level (1.01±0.1 mg/dl in elderly T2DN vs. 0.50±0.02 mg/dl in SD), a greater degree of glomerular sclerosis and a 2‐fold increase in renal fibrosis in elderly T2DN rats versus age‐matched SD rats. These results indicate that the increased expression of adhesion molecules promotes infiltration of inflammatory cells, which is associated with the progression of DN and suggests that immune modulatory drugs may slow the progression of this disease.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

SDF‑1/CXCR4 induces epithelial‑mesenchymal transition through activation of the Wnt/β‑catenin signaling pathway in rat chronic allograft nephropathy.

Epithelial-mesenchymal transition (EMT) has been demonstrated to serve a crucial role in the progression of interstitial fibrosis, which is one of the principal pathological features of chronic allograft nephropathy (CAN). However, to the best of our knowledge, the mechanisms of EMT in CAN have not been investigated. In the present study, the effect of stromal cell-derived factor 1 (SDF-1) and the Wnt signaling pathway on the progression of EMT following kidney transplantation was investigated. The CAN model was established using Fisher 344 and Lewis rats, treated with low-dose cyclosporine with or without AMD3100. CAN was confirmed by the pathological alterations and chronic allograft damage index scoring, and EMT was confirmed by western blotting and reverse transcription-quantitative polymerase chain reaction. In the AMD3100 group, there were lower expression levels of α-SMA and higher expression levels of E-cadherin, which indicated that CAN and EMT were ameliorated by AMD3100. The kidney tissue was analyzed using an mRNA + long noncoding (lnc)RNA microarray. A total of 506 mRNAs and 404 lncRNAs were demonstrated to be significantly differentially expressed between the two groups, which revealed the involvement of SDF-1/CXC chemokine receptor 4 (CXCR4) and the Wnt pathway. SDF-1 was demonstrated to induce EMT in vitro through the upregulation of α-SMA, downregulation of E-cadherin and the wound healing assay, and in the rat renal tubular epithelial cells via the nuclear accumulation of β-catenin, which were all inhibited by either AMD3100 or DKK-1. CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt pathway, was downregulated following treatment with SDF-1, which was inhibited by AMD3100 but not by DKK-1. Thus, CXXC5 may be a regulator downstream of SDF-1/CXCR4 in EMT. In conclusion, SDF-1/CXCR4 induces EMT of renal tubular epithelial cells with the involvement of the Wnt pathway, which may be a novel mechanism and therapeutic target in kidney allograft fibrosis of rats.

Astaxanthin ameliorates renal interstitial fibrosis and peritubular capillary rarefaction in unilateral ureteral obstruction

Loss of peritubular capillaries is a notable feature of progressive renal interstitial fibrosis. Astaxanthin (ASX) is a natural carotenoid with various biological activities. The present study aimed to evaluate the effect of ASX on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. For that purpose, mice were randomly divided into five treatment groups: Sham, ASX 100 mg/kg, UUO, UUO + ASX 50 mg/kg and UUO + ASX 100 mg/kg. ASX was administered to the mice for 7 or 14 days following UUO. The results demonstrated that UUO-induced histopathological changes in the kidney tissue were prevented by ASX. Renal function was improved by ASX treatment, as evidenced by decreased blood urea nitrogen and serum creatinine levels. Furthermore, the extent of renal fibrosis and collagen deposition induced by UUO was suppressed by ASX. The levels of collagen I, fibronectin and α-smooth muscle actin were increased by UUO in mice or by transforming growth factor (TGF)-β1 treatment in NRK-52E cells, and were reduced by ASX administration. In addition, ASX inhibited the UUO-induced decrease in peritubular capillary density by upregulating vascular endothelial growth factor and downregulating thrombospondin 1 levels. Inactivation of the TGF-β1/Smad signaling pathway was involved in the anti-fibrotic mechanism of ASX in UUO mice and TGF-β1-treated NRK-52E cells. In conclusion, ASX attenuated renal interstitial fibrosis and peritubular capillary rarefaction via inactivation of the TGF-β1/Smad signaling pathway.

Visceral Adipose Tissue Drives Cardiac Aging Through Modulation of Fibroblast Senescence by Osteopontin Production.

Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor β levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN's role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

Monoclonal immunoglobulin G deposits on tubular basement membrane in renal allograft: is this significant for chronic allograft injury?

BackgroundTubular basement membrane immune deposits (TBMID) has rarely been observed in renal allografts. It is usually found in BK virus nephropathy and immune complex glomerulonephritis; however, its significance is not well understood. We conducted a retrospective clinicopathological study on monoclonal immunoglobulin G (IgG) TBMID.MethodsWe studied 7177 renal allograft biopsy specimens obtained from Tokyo Women’s Medical University from 2007 to 2015 and performed light microscopic, electron microscopic and immunofluorescence studies.ResultsTubular basement membrane (TBM) deposits of IgG were found in 73 biopsies from 61 patients and the IgG subclass was obtained in 31 biopsies. There were no cases of monoclonal IgA or IgM TBMID. In total, 13 biopsies from 10 patients showed monoclonal IgG TBMID. Of these, seven showed monoclonal IgG1κ TBMID and one each showed monoclonal IgG2κ, IgG2λ and IgG3κ TBMID. Conversely, eight patients showed polyclonal IgG TBMID. In electron microscopy, large granular electron-dense deposits (EDDs) in the TBM were detected in all patients with monoclonal IgG1κ TBMID. EDDs were absent in TBM in patients with monoclonal IgG2κ, IgG2λ or IgG3κ TBMID. Progression of interstitial fibrosis and tubular atrophy (IFTA) was significantly higher in patients with monoclonal IgG1κ TBMID than in those with polyclonal IgG TBMID (P < 0.05). There were no significant differences in the other clinical parameters between monoclonal IgG1κ and polyclonal IgG TBMID.ConclusionsThis is the first study of patients with monoclonal IgG TBMID in renal allografts. We found that monoclonal IgG1κ TBMID was associated with EDD formation in TBM and IFTA progression.

Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: potential role of klotho expression.

Chronic kidney disease (CKD) is a global healthcare problem; however until now, there is no effective treatment that can stop its progression. In this study, we aimed to investigate the effect of empagliflozin, a sodium-glucose linked transporter-2 inhibitor (SGLT2I) in a model of unilateral ureteric obstruction (UUO) in rats, as a model of progressive renal interstitial fibrosis in vivo and the possibility of inclusion of klotho protein. Rats were randomly divided into five groups: group 1: control group, group 2: UUO untreated group, group 3: prophylactic SGLT2I treatment before UUO, group 4: immediate SGLT2I treatment after UUO, and group 5: delayed SGLT2I treatment (this group received distilled water 1week after UUO then empagliflozin for 2weeks). At the end of the experiment period, animals were sacrificed, and kidney fibrotic and inflammatory parameters were measured. Also kidney sections were examined histopathologically for CTGF expression. UUO resulted in renal dysfunction and fibrosis through upregulating inflammatory cascade (NF-κB-TLR4) as well as many fibrotic pathways (as TGF-β1, αSMA, Wnt, CTGF, and fibronectin) with significant reduction in the klotho protein expression. We hypothesized that both prophylactic and immediate treatment with empagliflozin after UUO in rats exert more renoprotective effect in comparison with delayed treatment via enhancement of renal klotho expression and activity, for further investigations.

Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice.

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

Renoprotective effects of ET(A) receptor antagonists therapy in experimental non-diabetic chronic kidney disease: Is there still hope for the future?

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.

Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

A Case of Tropical Eosinophilia in a Foreign Worker in Singapore

Tropical pulmonary eosinophilia (TPE) is a rare, but well recognized syndrome characterized by pulmonary interstitial infiltrates and marked peripheral eosinophilia. Early recognition and treatment with the antifilarial drug, diethylcarbamazine, is important, as delay before treatment may lead to progressive interstitial fibrosis and irreversible impairment. Here, we present a case of patient who presented with respiratory tract symptoms and marked eosinophilia. He was diagnosed with TPE from filariasis and was treated with antifilarial medications, leading to a full recovery. J Med Cases. 2018;9(1):1-4 doi: https://doi.org/10.14740/jmc2954w

A Case of Tropical Eosinophilia in a Foreign Worker in Singapore

Tropical pulmonary eosinophilia (TPE) is a rare, but well recognized syndrome characterized by pulmonary interstitial infiltrates and marked peripheral eosinophilia. Early recognition and treatment with the antifilarial drug, diethylcarbamazine, is important, as delay before treatment may lead to progressive interstitial fibrosis and irreversible impairment. Here, we present a case of patient who presented with respiratory tract symptoms and marked eosinophilia. He was diagnosed with TPE from filariasis and was treated with antifilarial medications, leading to a full recovery. J Med Cases. 2018;9(1):1-4 doi: https://doi.org/10.14740/jmc2954w

Amiloride modifies the progression of lithium-induced renal interstitial fibrosis.

Long-term administration of lithium has been associated with the development of a chronic interstitial fibrosis in addition to nephrogenic diabetes insipidus (NDI). Earlier studies have demonstrated that amiloride, by blocking the epithelial sodium channel ENaC and thus preventing lithium uptake into the principal cells of the collecting ducts, can partially reverse lithium-induced NDI. However, there are no long-term studies examining whether or not amiloride also modifies the progressive chronic interstitial fibrosis and tubular atrophy often evident with long-term lithium exposure. Using an established animal model of lithium-induced chronic interstitial fibrosis, rats were treated with amiloride and lithium for 5months following 1month of exposure to lithium alone and compared with control animals and those given only lithium. In this study, the 5months of amiloride therapy partially mitigated the lithium-induced NDI and limited the further progression of lithium-induced kidney fibrosis. This improvement was associated with decreased expression of the pro-fibrotic connective tissue growth factor (CTGF), along with reduced myofibroblast infiltration and decreased collagen deposition around the distended cortical collecting ducts. This may, in part, be mediated by modifying lithium-induced alterations in β-catenin activity through its effects on GSK-3β.

Semaphorin-3A and Netrin-1 predict the development of kidney injury in children with congenital hydronephrosis

Congenital obstructive nephropathy is amongst the main causes of chronic renal failure in children. Early diagnosis and initiation of the treatment will delay progressive renal tubular atrophy and interstitial fibrosis with the loss of nephrons. The aim of this study was to evaluate whether urinary (u) semaphorin-3A (SEMA-3A) and Netrin-1 may be potential biomarkers in children with congenital hydronephrosis due to ureteropelvic junction obstruction (UPJO). The study consisted of 42 children with severe hydronephrosis who needed surgery and two control groups (Control One: 42 children with mild, non-obstructive hydronephrosis; Control Two: 44 healthy children). All children had normal renal function. Urinary semaphorin-3A and Netrin-1 levels were measured in different groups using immunoenzymatic ELISA commercial kits. Compared with Control One and Control Two groups, the preoperative median uSEMA-3A/creatinine (cr.) and uNetrin-1/cr. levels increased significantly in the children with severe hydronephrosis (p < .01). One month after surgery, uSEMA-3A/cr. and uNetrin-1/cr. levels had decreased significantly in the children with severe hydronephrosis (p < .01), but were still higher than those in both control groups (p < .05). Receiver operator characteristic (ROC) analyses revealed a good diagnostic profile for uSEMA-3A and uNetrin-1 in terms of identifying children with a differential renal function of <40% [area under the curve (AUC) 0.825 and 0.745, respectively]. Our results indicate that increased concentrations of uSEMA-3A and uNetrin-1 are found in urine from children with severe hydronephrosis and that their concentrations are related to the degree of obstruction.

Interstitial complement C3 activation and macrophage infiltration in patients with hypertensive nephropathy .

The interplay between interstitial complement C3 activation and macrophage infiltration might play an important role in the pathogenesis of hypertensive nephropathy (HN), but human data are limited. We sought to investigate interstitial complement C3 expression and macrophage infiltration in HN as well as the relationships between C3 activation and macrophage infiltration, their association with clinicopathologic data, and changes in renal function. Using immunohistochemistry, we analyzed 20 renal tissue specimens from HN patients and 40 control specimens for complement C3, angiotensin (AGT), angiotensin II, and macrophage marker CD68 levels. Serum creatinine levels, estimated glomerular filtration rate (eGFR), annual rates of change in eGFR, and the interstitial fibrosis, glomerulosclerosis, and arteriolar lesion scores were recorded. Patients with HN showed elevated levels of interstitial C3 expression, AGT, angiotensin II, and interstitium-infiltrating macrophages compared to controls. The enhanced interstitial expression of C3 was correlated significantly with interstitial macrophage density, serum creatinine level as well as interstitial fibrosis, glomerulosclerosis, and arteriolar lesion scores, but was inversely correlated with eGFR and annual rates of change in eGFR. In human HN, inflammation involving complement C3 activation and macrophage infiltration as well as interactions between them, may play important roles in the pathogenesis and progression of interstitial fibrosis and kidney damage. .

Deconstructing interstitial fibrosis and tubular atrophy: a step toward precision medicine in renal transplantation

The prerequisite for successful treatment is an accurate diagnosis, a concept coined precision medicine. Progression of interstitial fibrosis and tubular atrophy is widely considered the natural course for all transplanted kidneys. In this issue, Gosset etal. describe discrete disease entities in individual patients and their contribution to interstitial fibrosis and tubular atrophy and its progression. This represents a major step forward in stratifying patients for targeted treatment trials (i.e., a step toward precision medicine in renal transplantation).

Insights into cellular and molecular basis for urinary tract infection in autosomal-dominant polycystic kidney disease

Urinary tract infection (UTI) is a broad term referring to an infection of the kidneys, ureters, bladder, and/or urethra. Because of its prevalence, frequent recurrence, and rising resistance to antibiotics, UTI has become a challenge in clinical practice. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder of the kidney and is characterized by the growth of fluid-filled cysts in both kidneys. Progressive cystic enlargement, inflammation, and interstitial fibrosis result in nephron loss with subsequent decline in kidney function. ADPKD patients frequently develop UTI; however, the cellular and molecular mechanisms responsible for the high UTI incidence in ADPKD patients remain virtually unaddressed. Emerging evidence suggests that α-intercalated cells (α-ICs) of the collecting ducts function in the innate immune defense against UTI. α-ICs inhibit bacterial growth by acidifying urine and secreting neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron. It is necessary to determine, therefore, if ADPKD patients with recurrent UTI have a reduced number and/or impaired function of α-ICs. Identification of the underlying cellular and molecular mechanisms may lead to the development of novel strategies to reduce UTI in ADPKD.