Renal Histological Lesions Research Articles

JAK3-STAT pathway blocking benefits in experimental lupus nephritis.

BackgroundLupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens. Cytokines are known to be central players in LN pathogenesis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is one important pathway that mediates signal transduction of several cytokines. In this study, we examined the pathogenic role of this pathway and how CP-690,550 treatment influences LN outcome.MethodsSix-month-old NZB/NZWF1 mice were divided into two different treatment groups: (1) control animals given vehicle treatment, cyclophosphamide, and mycophenolate mofetil treatment as positive controls of the therapy and (2) mice treated with CP-690,550, a JAK3 inhibitor. Mice were treated for 12 weeks. We evaluated renal function, anti-double-stranded DNA (anti-dsDNA) antibody, renal histology changes, kidney complement and immunoglobulin G (IgG) deposits, T-cell and macrophage infiltration, kidney inflammatory gene expression, and circulating cytokine changes.ResultsCP-690,550 treatment significantly reduced proteinuria and improved renal function and histological lesions of the kidney. Compared with vehicle-treated animals, those undergoing CP-690,550 treatment showed significantly diminished anti-dsDNA antibody and complement component C3 and IgG deposition in glomeruli. We also observed a significant reduction of T-cell and macrophage infiltration. Kidney gene expression revealed a reduction in inflammatory cytokines and complement and related macrophage-attracting genes. Circulating inflammatory cytokines were also reduced with treatment.ConclusionsOn the basis of our results, we conclude that the JAK-STAT pathway is implicated in the progression of renal inflammation in NZB/WF1 mice and that targeting JAK3 with CP-690,550 is effective in slowing down the course of experimental LN. Thus, CP-690,550 could become a new therapeutic tool in LN and other autoimmune diseases.

First histopathological study in kidneys of rodents naturally infected with Leptospira pathogenic species from Yucatan, Mexico

To report the renal histological lesions in synanthropic rodents, Mus musculus and Rattus rattus, naturally infected with Leptospira spp., captured in a rural community in Yucatan, Mexico. Kidney samples of synanthropic rodents were collected from a rural community in Yucatan, Mexico. Polymerase chain reaction was used to detect Leptospira spp. infection. Tissue kidney was fixed in 10% buffered formalin, processed according to the usual techniques for paraffin inclusion, cut and stained with hematoxylin and eosin, and examined using a conventional electronic microscope. A total of 187 rodents were captured. Nine individuals (4.8%) were positive for Leptospira spp. in the molecular analysis. All renal lesions observed in the histopathological study had been reported previously for Leptospira spp. infection. The histopathological lesions are present in the kidneys, plus the results of the polymerase chain reaction confirm that these rodents are true carriers of Leptospira spp.

Podocyte injury in diabetic nephropathy: implications of angiotensin II-dependent activation of TRPC channels.

Injury to podocytes is considered a major contributor to diabetic kidney disease: their loss causes proteinuria and progressive glomerulosclerosis. Podocyte depletion may result from improper calcium handling due to abnormal activation of the calcium permeant TRPC (Transient Receptor Potential Canonical) channels. Angiotensin II (Ang II) levels are found to be elevated in diabetes; furthermore, it was reported that Ang II causes activation of TRPC6 in podocytes. We hypothesized here that Ang II-mediated calcium influx is aggravated in the podocytes under the conditions of type 1 diabetic nephropathy (DN). Diabetes was induced in the Dahl Salt-Sensitive rats by an injection of streptozotocin (STZ-SS). Eleven weeks post treatment was sufficient for the animals to develop hyperglycemia, excessive urination, weight loss, microalbuminuria, nephrinuria and display renal histological lesions typical for patients with DN. Patch-clamp electrophysiology performed on podocytes of the freshly isolated glomeruli showed enhanced basal TRPC channel activity in the STZ-SS rats, and increased response to Ang II; total calcium influx triggered by Ang II application was also augmented in podocytes of these rats. Our studies have a strong potential for advancing the understanding of TRPC-mediated effects on podocytopenia in DN initiation.

Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats.

Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies.Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (p<0.01) decreased creatinine levels in the animals, along with a decrease in serum urea and blood urea nitrogen. Treatment with Coriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components.

The protective effect of nesfatin-1 against renal ischemia–reperfusion injury in rats

Introduction: The pathogenetic mechanisms underlying ischemia-reperfusion (I/R) injury involve oxidative stress, inflammation and apoptosis. Nesfatin-1, a novel peptide, has been reported to possess antioxidant, anti-inflammatory and anti-apoptic properties. The study was to examine the potential protective effects of nesfatin-1 on renal I/R injury. Materials and methods: I/R model was induced by placing a clamp across left renal artery for 45 min followed by 24 h reperfusion, along with a contralateral nephrectom. Twenty-four rats divided into three groups: sham-operated group, vehicle-treated I/R and nesfatin-1-treated I/R. Nesfatin-1 was intraperitoneally injected 30 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. Marker of oxidative stress and cells in kidney were also evaluated. Results: The animals with nesfatin-1 significantly improved renal functional and histologic lesions induced by I/R injury. The malondialdehyde (MDA) level decreased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were significantly increased. Moreover, nesfatin-1-treated rats had a markedly decrease in apoptotic tubular cells, as well as a decrease in caspase-3 activity and an increase in the bcl-2/Bax ratio. Conclusions: This is the first evidence that nesfatin-1 treatment ameliorates acute renal I/R injury by suppressing oxidative stress and cell apoptosis. Therefore, it is promising as a potential therapeutic agent for renal IR injury.

Endothelial progenitor cell-derived extracellular vesicles protect from complement-mediated mesangial injury in experimental anti-Thy1.1 glomerulonephritis.

Endothelial progenitor cells (EPCs) are known to induce tissue repair by paracrine mechanisms including the release of growth factors and extracellular vesicles (EVs), nanoparticles able to carry proteins and genetic information to target cells. The aim of this study was to evaluate whether EVs derived from EPCs may protect from complement-mediated mesangial injury in experimental anti-Thy1.1 glomerulonephritis. EVs were isolated by serial ultracentrifugation from supernatants of cultured human EPCs and characterized for their protein and RNA content. In vivo, EVs were injected i.v. in the experimental rat model of mesangiolytic anti-Thy1.1 glomerulonephritis evaluating renal function, proteinuria, complement activity and histological lesions. In vitro, the biological effects of EPC-derived EVs were studied in cultured rat mesangial cells incubated with anti-Thy1.1 antibody and rat or human serum as complement source. After i.v. injection in Thy1.1-treated rats, EVs localized within injured glomeruli and inhibited mesangial cell activation, leucocyte infiltration and apoptosis, decreased proteinuria, increased serum complement haemolytic activity (CH50) and ameliorated renal function. EV treatment decreased intraglomerular deposition of the membrane attack complex (MAC or C5b-9) and expression of smooth muscle cell actin and preserved the endothelial antigen RECA-1 and the podocyte marker synaptopodin. The protective effect of EVs was significantly reduced by pre-treatment with a high dose of RNase (1 U/mL), suggesting a key role for EV-carried RNAs in these mechanisms. Indeed, EPC-derived EVs contained different mRNAs coding for several anti-apoptotic molecules and for the complement inhibitors Factor H, CD55 and CD59 and the related proteins. The in vitro experiments aimed to investigate the mechanisms of EV protection indicated that EVs transferred to mesangial cell mRNAs coding for Factor H, CD55 and CD59 and inhibited anti-Thy1.1 antibody/complement-induced apoptosis and C5b-9/C3 mesangial cell deposition. EVs derived from EPCs exert a protective effect in Thy1.1 glomerulonephritis by inhibition of antibody- and complement-mediated injury of mesangial cells.

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Effect of ceftriaxone on the outcome of murine pyelonephritis caused by extended-spectrum-β-lactamase-producing Escherichia coli.

Urinary tract infections (UTIs) due to extended-spectrum-β-lactamase (ESBL)-producing Enterobacteriaceae in children are becoming more frequent, and they are commonly treated initially with a second- or third-generation cephalosporin. We developed a murine model of ascending UTI caused by ESBL-producing Escherichia coli. Using this model, we investigated the renal bacterial burden, interleukin-6 (IL-6) expression, and histopathological alterations caused by ESBL- and non-ESBL-producing bacteria after 1, 2, or 6 days with or without ceftriaxone therapy. The renal bacterial burden, IL-6 concentration, and histological inflammatory lesions were not significantly different between mice infected with ESBL- and non-ESBL-producing bacteria without treatment at any of the time points examined. Following ceftriaxone administration, the bacterial burden was eliminated in the kidneys of mice infected with ESBL- and non-ESBL-producing bacteria on the 6th postinfection day. The histological analysis demonstrated that among mice treated with ceftriaxone, those infected with ESBL-producing bacteria had more profound renal alterations than those infected with non-ESBL-producing bacteria on the 6th day (P < 0.001). In comparison, microbiological outcomes did not differ significantly between mice infected with ESBL- and non-ESBL-producing bacteria at any of the time points examined. The effectiveness of ceftriaxone in mice with UTIs due to ESBL-producing E. coli may have therapeutic implications; it is, however, hampered by limited activity on the histopathological lesions, a finding that needs further investigation.

The heme oxygenase system suppresses perirenal visceral adiposity, abates renal inflammation and ameliorates diabetic nephropathy in Zucker diabetic fatty rats.

The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity and diabetic nephropathy.

Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats

The present study compared the progression of renal injury in Sprague-Dawley (SD) and Dahl salt-sensitive (SS) treated with streptozotocin (STZ). The rats received an injection of STZ (50 mg/kg ip) and an insulin pellet (2 U/day sc) to maintain the blood glucose levels between 400 and 600 mg/dl. Twelve weeks later, arterial pressure (143 ± 6 vs. 107 ± 8 mmHg) and proteinuria (557 ± 85 vs. 81 ± 6 mg/day) were significantly elevated in STZ-SS rats compared with the values observed in STZ-SD rats, respectively. The kidneys from STZ-SS rats exhibited thickening of glomerular basement membrane, mesangial expansion, severe glomerulosclerosis, renal interstitial fibrosis, and occasional glomerular nodule formation. In additional studies, treatment with a therapeutic dose of insulin (4 U/day sc) attenuated the development of proteinuria (212 ± 32 mg/day) and renal injury independent of changes in arterial pressure in STZ-SS rats. Since STZ-SS rats developed severe renal injury, we characterized the time course of changes in renal hemodynamics during the progression of renal injury. Nine weeks after diabetes onset, there was a 42% increase in glomerular filtration rate in STZ-SS rats vs. time-control SS rats with reduced renal blood flow. These results indicate that SS rats treated with STZ develop hyperfiltration and progressive proteinuria and display renal histological lesions characteristic of those seen in patients with diabetic nephropathy. Overall, this model may be useful to study signaling pathways and mechanisms that play a role in the progression of diabetes-induced renal disease and the development of new therapies to slow the progression of diabetic nephropathy.

Pitfalls in recommending evidence-based guidelines for a protean disease like Henoch–Schönlein purpura nephritis

The long-term prognosis of Henoch–Schonlein purpura nephritis (HSPN) depends on the severity of initial clinical symptoms and histological features [1, 2]. The risk of evolution into a chronic kidney disease (CKD) may be as high as 50, 40 and 15 % for the combination of onset with nephrotic and nephritic syndrome, nephrotic syndrome, nephritic syndrome and/or heavy non-nephrotic proteinuria, respectively [1]. The International Study of Kidney Disease in Children (ISKDC) classified the risk of progression on the basis of the histology severity mainly according to the extent of crescent formations. Combining three studies with a follow-up of about 6 years [3–5], Haas [2] demonstrated that 25 % of children biopsied for HSPN had severe outcomes (persistently active renal disease and/or worsened stages of CKD, including endstage renal failure), in correlation with the ISKDC grades of renal pathology damage. These data indicate that children with HSPN have to be carefully followed, since some cases can have a catastrophic evolution. However, the therapeutic choice can be challenging because—apart from mild renal clinical symptoms and histological lesions that almost always are associated with good long-term outcome, and the association of nephrotic and nephritic syndrome with high histological grade [1–6] that most frequently leads to CKD—the long-term prognosis cannot predicted with certainty at disease onset. More importantly, there is a paucity of evidence-based (EB) data to guide treatment decisions for HSPN. Doctors are therefore confronted with the dilemma of undertreatment and increased risk of CKD or over-treatment and the risk of unnecessary side effects. Recently, the Kidney Disease Improving Global Outcome (KDIGO) initiative published guidelines on the treatment of HSPN [7]. In view of the lack of EB data for HSPN treatment and similarities between HSPN and primary immunoglobulin A nephropathy (IgAN), the KDIGO guidelines resorted to data regarding the treatment of the two diseases in similar clinical conditions. The aims of the present paper are:

Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy

Diabetic nephropathy, as a severe microvascular complication of diabetic mellitus, has become the leading cause of end-stage renal diseases. However, no effective therapeutic strategy has been developed to prevent renal damage progression to end stage renal disease. Hence, the present study evaluated the protective effects of grape seed procyanidin B2 (GSPB2) and explored its molecular targets underlying diabetic nephropathy by a comprehensive quantitative proteomic analysis in db/db mice. Here, we found that oral administration of GSPB2 significantly attenuated the renal dysfunction and pathological changes in db/db mice. Proteome analysis by isobaric tags for relative and absolute quantification (iTRAQ) identified 53 down-regulated and 60 up-regulated proteins after treatment with GSPB2 in db/db mice. Western blot analysis confirmed that milk fat globule EGF-8 (MFG-E8) was significantly up-regulated in diabetic kidney. MFG-E8 silencing by transfection of MFG-E8 shRNA improved renal histological lesions by inhibiting phosphorylation of extracellular signal-regulated kinase1/2 (ERK1⁄2), Akt and glycogen synthase kinase-3beta (GSK-3β) in kidneys of db/db mice. In contrast, over-expression of MFG-E8 by injection of recombinant MFG-E8 resulted in the opposite effects. GSPB2 treatment significantly decreased protein levels of MFG-E8, phospho-ERK1/2, phospho-Akt, and phospho-GSK-3β in the kidneys of db/db mice. These findings yield insights into the pathogenesis of diabetic nephropathy, revealing MFG-E8 as a new therapeutic target and indicating GSPB2 as a prospective therapy by down-regulation of MFG-E8, along with ERK1/2, Akt and GSK-3β signaling pathway.

Increased Circulating miR-21 Levels Are Associated with Kidney Fibrosis

MicroRNAs (miRNAs) are a class of noncoding RNA acting at a post-transcriptional level to control the expression of large sets of target mRNAs. While there is evidence that miRNAs deregulation plays a causative role in various complex disorders, their role in fibrotic kidney diseases is largely unexplored. Here, we found a strong up-regulation of miR-21 in the kidneys of mice with unilateral ureteral obstruction and also in the kidneys of patients with severe kidney fibrosis. In addition, mouse primary fibroblasts derived from fibrotic kidneys exhibited higher miR-21 expression level compared to those derived from normal kidneys. Expression of miR-21 in normal primary kidney fibroblasts was induced upon TGFβ exposure, a key growth factor involved in fibrogenesis. Finally, ectopic expression of miR-21 in primary kidney fibroblasts was sufficient to promote myofibroblast differentiation. As circulating miRNAs have been suggested as promising non-invasive biomarkers, we further assess whether circulating miR-21 levels are associated with renal fibrosis using sera from 42 renal transplant recipients, categorized according to their renal fibrosis severity, evaluated on allograft biopsies (Interstitial Fibrosis/Tubular Atrophy (IF/TA). Circulating miR-21 levels are significantly increased in patients with severe IF/TA grade (IF/TA grade 3: 3.0±1.0 vs lower grade of fibrosis: 1.5±1.2; p = 0.001). By contrast, circulating miR-21 levels were not correlated with other renal histological lesions. In a multivariate linear regression model including IF/TA grade and estimated GFR, independent associations were found between circulating miR-21 levels and IF/TA score (ß = 0.307, p = 0.03), and between miR-21 levels and aMDRD (ß = −0.398, p = 0.006). Altogether, these data suggest miR-21 has a key pathogenic role in kidney fibrosis and may represent a novel, predictive and reliable blood marker of kidney fibrosis.

The clinical and histological response of HIV-associated kidney disease to antiretroviral therapy in South Africans

Little is known about the progression of kidney disease in HIV-infected patients in developing countries in the era of antiretroviral therapy (ART). HIV-infected patients were screened for kidney disease. Kidney biopsies were performed before and after initiation of ART to assess the clinical and histological response to treatment. Data were collected from all participants in accordance with the study protocol. The mean follow-up was 2.4 patient years on ART. There was a rapid immunological and renal response to ART. The renal response was reflected by a significant rise in the estimated glomerular filtration rate (eGFR) and rapid regression of proteinuria. The histological patterns were highly variable, ranging from non-specific lesions such as mesangial hyperplasia and interstitial nephritis to HIV-immune complex disease (HIV-ICD) with or without features of HIV-associated nephropathy (HIVAN). In the follow-up biopsies, the histological response to treatment was variable with a combination of no change, progression or regression of lesions. This study demonstrated a spectrum of renal histological lesions in HIV-associated kidney disease. Initiation of ART produced a rapid and sustained clinical renal response in all participants, irrespective of the histology. Follow-up biopsies showed an inconsistent histological response of lesions to treatment. In lesions that regressed, there appeared to be a discrete lag in histological response when compared with the rapid clinical response.

Aldosterone synthase gene polymorphism and renal histopathologic changes in kidney transplant patients receiving a calcineurin inhibitor

Aldosterone participates in the pathogenesis of calcineurin inhibitor nephrotoxicity (CIN), producing renal vasoconstriction and transforming growth factor beta (TGFß) expression. The objective of this study was to assess aldosterone polymorphisms and relationships to plasma aldosterone levels and the development of renal histological lesions in kidney transplant patients. Patients with kidney graft biopsy were divided according to the presence or absence of CIN. We determined aldosterone synthase (AS) -344 T/C and int 2 W/C gene polymorphisms and plasma aldosterone levels. Histological, biochemical and clinical variables were measured. Calcineurin inhibitor (CI) levels were significantly higher in patients with the int 2 WW genotype than in patients with WC or CC genotypes. There was a greater degree of interstitial fibrosis in patients with int 2 CC genotype. No relationship was found between the different polymorphisms and a higher degree and/or frequency of CIN. There was also no relationship with plasma aldosterone levels. The frequency of the different polymorphisms studied was not related to plasma aldosterone levels or the development of CIN; however, the int 2 CC genotype was related to a greater degree of interstitial fibrosis, whereas the WW genotype was related to higher CI serum levels.

Prognosis and outcome of pregnancies exposed to renin–angiotensin system blockers

To study pregnancy outcomes and fetal renal prognosis markers in cases of exposure to renin-angiotensin system blockers. We conducted a retrospective study of a series of 21 patients exposed to blockers of the renin-angiotensin system during pregnancy. Two markers were prenatally studied, fetal serum β2-microglobulin and amniotic fluid volume. Poor renal prognosis evaluation was based on postnatal glomerular filtration rate or on the presence of renal histologic lesions. Of the 21 fetuses, only one had a normal postnatal renal function at birth (oligohydramnios regression and normal β2-microglobulin). All fetuses with persistent oligohydramnios or β2-microglobulin ≥ 5 mg/L presented an adverse renal outcome. Exposure to renin-angiotensin system blockers complicated by oligohydramnios is associated with a very poor outcome. We propose a prenatal management based on amniotic fluid volume monitoring and fetal serum β2-microglobulin. However, our preliminary results have to be confirmed by a larger study.

Urinary protein markers predict the severity of renal histological lesions in children with mesangial proliferative glomerulonephritis

BackgroundSeveral renal histopathological features, including mesangial hypercellularity, glomerulosclerosis, tubular atrophy and interstitial fibrosis, are considered to be independent predictors of end-stage renal failure in patients with glomerular diseases. Mesangial proliferative glomerulonephritis (MesPGN) is characterized by proliferations of mesangial cells with increase in mesangial matrix and/or deposits in mesangial region. The purpose of this study is to determine the association between urinary protein markers measured at the same time as renal biopsy and the severity of renal histological lesions in children with MesPGN, and to evaluate whether these markers could serve as predictors of severe renal histological lesions in this population.MethodsNinety-eight children with MesPGN (40 with IgA nephropathy, 37 with IgM nephropathy, and 21 with MesPGN without IgA/IgM deposition) were enrolled. Urinary level of IgG, albumin, transferrin, α1-microglobulin, β2-microglobulin and N-acetyl-β-glucosaminidase from a morning sample before biopsy was measured.The scores of mesangial hypercellularity, glomerulosclerosis, and tubule-interstitial damage were used to semi-quantitatively evaluate renal histological lesions.ResultsThe urine proteins, as independent factors associated with severe mesangial cellularity (> 5 mesangial cells/ mesangial area) were transferrin, albumin, α1-microglobulin, IgG and 24-hour total protein, with severe glomerulosclerosis (≥ 10 % glomeruli showing segmental adhesions or sclerosis) were transferrin and 24-hour total protein, and with severe tubule-interstitial damage (focal or diffuse tubular and interstitial lesions) were transferrin and N-acetyl-β-glucosaminidase. Urinary transferrin achieved the area under-the-receiver-operating-characteristic curve (AUC) of 0.86 and 0.82, respectively, for predicting severe mesangial cellularity and glomerulosclerosis. Urinary N-acetyl-β-glucosaminidase achieved the highest AUC of 0.82 for predicting severe tubule-interstitial damage. The combination of urinary protein markers, however, did not improve the predictability for renal histological lesions.ConclusionsUrinary protein markers are useful to predict the severity of renal histological lesions in children with MesPGN, which suggests that urinary proteins might be useful to predict the development and progression of renal histological lesions, and assist in evaluating the outcome and prognosis in children with MesPGN as non-invasive and easily repeatable indicators on the follow-up examination.

Prospective assessment of renal histopathological lesions in patients with end-stage liver disease: Effects on long-term renal function after liver transplantation

The incidence of organic renal lesions in patients with end-stage liver disease is unknown. The goal of this study was to make a prospective evaluation of renal histological lesions in a group of unselected patients awaiting liver transplantation. Sixty cirrhotic patients underwent a renal biopsy via the transjugular route. The potential effect of renal lesions on renal function was evaluated five years after transplantation. The yield of biopsies enabling satisfactory analysis was 77%, and no major complications occurred. Proteinuria>0.5 g/day was observed in only 8.7% of these patients, microscopic haematuria in 4.3%, creatinine levels>133 mmol/L (1.5mg/dl) in 10.9%, and Modification of the Diet in Renal Disease (MDRD) clearance<60 ml/min in 13.0%. Twenty-five patients (55.3%) had a morphological diagnosis of renal disease, 15 displayed IgA nephropathy and immunofluorescence testing showed that 12 had specific diabetic linear staining for IgG and albumin, of whom seven had associated histological lesions of diabetic nephropathy. Five years after liver transplantation, renal function had significantly deteriorated more in patients with initial diabetic lesions than in those with normal histology or IgA nephropathy alone. In patients with end-stage liver disease, IgA nephropathy and diabetic lesions were frequently found despite the absence of renal impairment and/or urinalysis anomalies. Our results strongly suggest that severe renal failure develops preferentially in liver transplant recipients with diabetes or carbohydrate intolerance, and that pre-existing arterial lesions may favour the nephrotoxicity of calcineurin inhibitors. Diabetes prior to transplantation needs to be strictly managed and requires a renal sparing immunosuppressive regimen after transplantation.

Renal histological lesions and outcome in liver transplant recipients

Chronic kidney disease in liver transplant (OLT) recipients is often attributed to calcineurin inhibitors (CNI) toxicity, but little is known about the spectrum of their renal histological lesions. Between 1988 and 2008, 1698 OLTs were performed in our center. We retrospectively analyzed clinical and histological data on 23 recipients (1.4%) referred for kidney biopsy (KB). Median age at OLT was 50.2 yr, 65.2% were men, 30.4% had hepatitis C, and 95.7% were given CNI. KB was performed 6.9 yr (median) post-OLT. Median creatinine was 1 mg/dL pre-OLT and 2.2 mg/dL at KB. Main pathological diagnoses were focal segmental and global glomerulosclerosis (n = 8, 34.8%), glomerular diseases (7, 30.4%), CNI toxicity (2, 8.7%), and diabetic nephropathy (2, 8.7%). Moderate/severe interstitial fibrosis, tubular atrophy, arteriosclerosis, and hyalinosis were present in 47.8%, 43.5%, 60.9%, and 56.5%, respectively. Twelve patients (52.5%) reached end-stage renal disease (ESRD) and 17 (73.9%) died. Death was more common among those reaching ESRD, but the difference was not significant (83.3% vs. 63.6%, p = 0.37). Renal histology is variable and not limited to CNI toxicity in OLT recipients referred for KB. Whether management based on KB findings can directly improve outcomes remains unclear.

Evaluation of Kidney Injury in Dogs with Pyometra Based on Proteinuria, Renal Histomorphology, and Urinary Biomarkers

Proteinuria is a feature of pyometra-associated renal dysfunction, but its prevalence and clinical relevance are not well characterized. To define which subset of dogs with pyometra has clinically relevant kidney injury by quantification of proteinuria; light, immunofluorescence, and electron microscopic examination of kidney biopsy specimens; and measurement of urinary biomarkers. Forty-seven dogs with pyometra. Ten clinically healthy intact bitches of comparable age. Prospective study. Routine clinicopathological variables including urinary protein to creatinine ratio (UPC) were analyzed. Validated assays were used to quantify urinary biomarkers for glomerular (urinary albumin, urinary immunoglobulin G, urinary C-reactive protein, urinary thromboxane B(2)) and tubular function (urinary retinol-binding protein, urinary N-acetyl-β-d-glucosaminidase). Kidney biopsy specimens from 10 dogs with pyometra and dipstick urine protein concentrations of 2+ or 3+ were collected during ovariohysterectomy. Urinalysis was repeated within 3 weeks after surgery in 9 of the 10 dogs. UPC (median, range) was significantly higher in dogs with pyometra (0.48, 0.05-8.69) compared with healthy bitches (0.08, 0.02-0.16) (P < .01). Twenty-two of 47 dogs with pyometra had UPC>0.5, 12 had UPC>1.0, and 7 had UPC>2.0. Glomerulosclerosis and tubulointerstitial nephritis were common kidney biopsy findings in proteinuric dogs with pyometra. Dogs with glomerulosclerosis (5/10), either global or focal and segmental, had UPC>1.0 at ovariohysterectomy and afterward. Dogs with structural glomerular and tubular changes mostly had urinary biomarker to creatinine ratios above the 75th percentile. Dogs with pyometra and UPC>1.0 or high ratios of urinary biomarkers appear likely to have clinically relevant renal histologic lesions and require monitoring after ovariohysterectomy. Future studies should evaluate the role of pyometra-associated pathogenic mechanisms in causing or exacerbating focal and segmental glomerulosclerosis in dogs.