Tubulointerstitial Compartment Research Articles

The role of renin–angiotensin system in the chronic allograft nephropathy: an immunohistochemical study

Background: Evidences suggest a role of renin–angiotensin system (RAS) in the development of chronic allograft injury. Methods: We correlated intrarenal angiotensin-converting enzyme, angiotensin II (Angio II) and transforming growth factor β1 (TGFβ1) expression in 58 biopsies-proven chronic allograft nephropathy (CAN) with tissue injury and allograft survival. Results: The biopsies with CAN were graded according to Banff classification as I (22 cases), II (17) and III (19); 27 biopsies also showed a mononuclear inflammatory infiltrate in scarred areas. There were increased expression of angiotensin converting-enzyme (ACE), Angio II and TGFβ1 mainly in tubulointerstitial compartment in the group with CAN; there was no association of Angio II and TGFβ1 expression with interstitial fibrosis. There were no significant differences of ACE, Angio II and TGFβ1 expression between the patients treated and untreated with RAS blockade, and with the graft outcome. Interstitial inflammatory infiltrate had positive correlation with interstitial fibrosis and significant impact on graft survival at 8 years. Conclusions: Our study showed in a group of cases with CAN a high percentage of inflammatory infiltrate that correlated with interstitial fibrosis and graft outcome. The chronic inflammatory changes in these cases did not show significant association with local RAS expression.

Thioredoxin-Interacting Protein: A Potential Therapeutic Target for Treatment of Progressive Fibrosis in Diabetic Nephropathy

Thioredoxin-interacting protein (TXNIP) is an endogenous inhibitor of the antioxidant thioredoxin, and a critical agent in the in vivo regulation of glucose. The well-described induction of TXNIP by high glucose may represent an important pathogenic trigger of complications arising in the diabetic environment, with sustained overexpression of TXNIP triggering the increased production of reactive oxygen species and collagen, both major contributors to the development of diabetic nephropathy (DN). To examine a possible therapeutic role for targeted TXNIP inhibition in DN, transgenic (mRen-2)27 rats were rendered diabetic with streptozotocin and then treated with 20 μ<smlcap>M</smlcap> TXNIP deoxyribozyme (DNAzyme) delivered continuously over 12 weeks by an implanted osmotic mini-pump. Renal injury was measured using biochemical parameters of kidney function along with histological markers of damage. Catalytic activity of TXNIP DNAzyme was determined by TXNIP gene and peptide expression in the rat kidneys. TXNIP DNAzyme localization was demonstrated with a fluorescent-labelled TXNIP DNAzyme. A panel of markers was used to assess the extent of oxidative stress and renal fibrosis including superoxide level, nitrotyrosine staining, TGF-β1, NLRP3 and collagen IV expression. Fluorescent-labelled TXNIP DNAzyme was localized to tubulo-epithelial cells, but was not identified in glomeruli or endothelial cells. Elevated renal cortical TXNIP gene and protein expression seen in kidneys of DN animals were significantly attenuated by TXNIP DNAzyme (p < 0.05). Downstream markers of TXNIP activity, particularly oxidative stress, inflammasome signalling, tubulo-interstitial fibrosis and collagen deposition, were also attenuated in the tubulo-interstitium of DN rats treated with TXNIP DNAzyme. Consistent with the identified site of action of the DNAzyme, the effects of the TXNIP inhibition were limited to the tubulo-interstitial compartment. This study supports the role of TXNIP as an important mediator of progressive tubulo-interstitial fibrosis in DN, and also supports the notion of TXNIP inhibition as a potential new therapeutic target for DN.

Spectrum of histopathological findings in patients with acute kidney injury following H1N1 influenza infection: A study of three cases

Acute kidney injury (AKI) and failure can be found in association with swine-associated influenza A (H1N1) virus contributing to increased morbidity and mortality. We present three cases of H1N1 infection with AKI, the first in the background of renal amyloidosis, the second in a kidney transplant recipient, and the third in a patient who presented with renal failure following upper respiratory tract infection. Renal biopsy in all of them revealed mesangial prominence with tubulointerstitial nephritis. All of them recovered following conservative management. H1N1 infection is known to be associated with dismal prognosis and kidney involvement is mainly in the tubulointerstitial compartment. Contrary to the reported literature mentioning poor prognosis, all three patients in our study recovered fully.

Histopathologic findings associated with APOL1 risk variants in chronic kidney disease

The effects of nephropathy risk variants in the apolipoprotein L1 gene (APOL1) on renal histopathology in African Americans with arterionephrosclerosis or putative ‘hypertension-associated' nephropathy are unknown. APOL1 genotype–phenotype correlations were performed in a blinded manner from renal biopsies in 196 self-reported African Americans with arterionephrosclerosis on kidney biopsy at a large national nephropathology practice. Subjects had chronic kidney disease without nephrotic syndrome. A discovery analysis compared histopathologic changes in the glomerular and tubulointerstitial compartments in 58 subjects with 2 versus 56 subjects with 0 APOL1 risk variants. Validation was performed in biopsies from 82 additional subjects with 0, 1, and 2 risk variants. Two risk variant versus zero risk variant group genotype associations and subphenotypes were assessed by χ2 analyses. ANOVA compared means of continuous variables. In discovery analyses, significantly less obsolescent glomerulosclerosis, more (solidified and disappearing) glomerulosclerosis, more thyroidization-type tubular atrophy, and more microcystic tubular dilatation were seen in patients with two versus zero APOL1 risk alleles. Greater degrees of arteriosclerosis were present in those with zero risk alleles. Segmental glomerulosclerosis did not differ significantly between groups. Presence of two of the following discriminatory histopathologic findings from discovery, that is, <50% obsolescent glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilatation, was specific for the presence of two APOL1 risk alleles in the validation phase. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants. These findings support involvement of multiple cell types in subnephrotic forms of APOL1-associated nephropathy, particularly renal tubule cells with resultant tubulointerstitial disease.

Platelet-derived growth factors (PDGFs) in glomerular and tubulointerstitial fibrosis

Renal fibrosis is the hallmark of chronic kidney disease progression and is characterized by an exaggerated wound-healing process with the production of renal scar tissue. It comprises both the glomerular and the tubulointerstitial compartments. Among the factors that contribute to kidney fibrosis, the members of the platelet-derived growth factor (PDGF) family are among the best characterized ones. They appear to be the key factors in driving renal fibrosis, independent of the underlying kidney disease. The PDGF family consists of four isoforms (PDGF-A, -B, -C, and -D) and two receptor chains (PDGFR-α and -β), which are constitutively or inducibly expressed in most renal cells. These components have an irreplaceable role in kidney development by recruitment of mesenchymal cells to the glomerular and tubulointerstitial compartments. They further regulate multiple pathophysiologic processes including cell proliferation, cell migration, expression and accumulation of extracellular matrix, production and secretion of pro- and anti-inflammatory mediators, vascular permeability, and hemodynamics. This review provides a brief update on the role of different PDGF isoforms in the development of glomerulosclerosis and tubulointerstitial fibrosis, newly identified endogeneous PDGF antagonists, and resulting potential therapies.

Qualitative and quantitative analysis of fibrosis in the kidney.

Renal fibrosis results from an excess accumulation of connective tissue, primarily collagen, in response to tissue injury-associated aberrant wound healing, which is over-expressed in the renal vascular, glomerular and tubulointerstitial compartments. Despite being the final common pathway of end stage kidney disease, there is a lack of consensus on standardized approaches to measure fibrosis. In this article we therefore describe how a combination of immunohistochemical staining and biochemical measurement of hydroxyproline can be used to qualitatively and quantitatively examine the different forms of fibrosis. These techniques provide measures of both the composition of fibrosis, and a means of evaluating interventions in this significant process.

The expression of Toll-like receptors 2, 4 and 9 in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Increasing evidence suggested that Toll-like receptors (TLRs) were critically involved in immune responses of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate the expression of TLR-2, TLR-4 and TLR-9 in kidneys of patients with ANCA-associated vasculitis. Renal biopsy specimens were collected from 24 patients with AAV. The expression of TLR-2, TLR-4 and TLR-9 in kidneys was detected by immunohistochemistry. Double immunofluorescence staining was performed to detect the expression of TLRs on various kinds of cells. In renal specimens, immunohistochemical examination revealed that expression of TLR-2 and TLR-4 could be detected in the glomeruli of AAV patients, while TLR-2 and TLR-4 were scarcely detected in the glomeruli of normal controls. Double immunofluorescence staining of TLR-2, TLR-4 and CD31 indicated that TLR-4 and TLR-2 were expressed on endothelial cells in the glomeruli. In the tubulointerstitial compartment, expression of TLR-2, TLR-4 and TLR-9 could be detected in both AAV patients and normal controls. The mean optical density of TLR-2 and TLR-4 in the tubulointerstitial compartment in AAV patients were significantly higher than that in normal controls. Among AAV patients, correlation analysis showed that the mean optical density of TLR-4 in the glomeruli correlated inversely with the initial serum creatinine, the proportion of total crescents and the proportion of cellular crescents in renal specimens (r = -0·419, P = 0·041; r = -0·506, P = 0·012; r = -0·505, P = 0·012, respectively). The expression of TLR-2 and TLR-4 was dysregulated in kidneys of AAV patients. The expression of TLR-4 in glomeruli was associated with the severity of renal injury.

Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes.

Diabetic nephropathy is the major cause of end-stage renal failure throughout the world in both developed and developing countries. Diabetes affects all cell types of the kidney, including endothelial cells, tubulointerstitial cells, podocytes and mesangial cells. During the past decade, the importance of podocyte injury in the formation and progression of diabetic nephropathy has been established and emphasized. However, recent findings provide additional perspectives on pathogenesis of diabetic nephropathy. Glomerular endothelial damage is already present in the normoalbuminuric stage of the disease when podocyte injury starts. Genetic targeting of mice that cause endothelial injury leads to accelerated diabetic nephropathy. Tubulointerstitial damage, previously considered to be a secondary effect of glomerular protein leakage, was shown to have a primary significance in the progression of diabetic nephropathy. Emerging evidence suggests that the glomerular filtration barrier and tubulointerstitial compartment is a composite, dynamic entity where any injury of one cell type spreads to other cell types, and leads to the dysfunction of the whole apparatus. Accumulation of novel knowledge would provide a better understanding of the pathogenesis of diabetic nephropathy, and might lead to a development of a new therapeutic strategy for the disease.

Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria

Toll-like receptor 4 (TLR4), a component of the innate immune system, is recognized to promote tubulointerstitial inflammation in overt diabetic nephropathy (DN). However, there is no information on immune activation in resident renal cells at an early stage of human DN. In order to investigate this, we studied TLR4 gene and protein expression and TLR4 downward signaling in kidney biopsies of 12 patients with type 2 diabetes and microalbuminuria, and compared them with 11 patients with overt DN, 10 with minimal change disease (MCD), and control kidneys from 13 patients undergoing surgery for a small renal mass. Both in microalbuminuria and in overt DN, TLR4 mRNA and protein were overexpressed 4- to 10-fold in glomeruli and tubules compared with the control kidney and in MCD. In addition, NF-κB signaling was about fourfold higher in the glomeruli. TNF-α, IL6, CCR2, CCL5, and CCR5 mRNAs were markedly (about three- to fivefold) upregulated in microdissected glomeruli. While IL6, CCL2 and CCR5-mRNA, and CD68 were overexpressed in the tubulointerstitial compartment in clinical DN, they were not expressed in microalbuminuria. In a 6-year follow-up of microalbuminuric patients, glomerular TLR4 gene expression was associated with the subsequent loss of kidney function. Thus, innate immunity is activated in the glomeruli of patients with diabetic microalbuminuria. Enhanced TLR4 signaling may contribute to the progression occurring after the incipient, microalbuminuric form of nephropathy evolves to overt disease.

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.

Modulating kidney transplant interstitial fibrosis and tubular atrophy: is the RAAS an important target?

In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant.

The Histopathologic Spectrum of Kidney Biopsies in Patients with Inflammatory Bowel Disease

Kidney disease as a complication of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), has been the subject of case reports. However, no cases series examining IBD and kidney disease has been published to date. This study aimed to evaluate a large series of kidney biopsy specimens from patients with IBD to better define the spectrum and relative frequencies of IBD-associated kidney pathology. A retrospective review of native kidney biopsy specimens obtained from March 2001 to June 2012 identified 83 patients with IBD. Standard processing of all biopsy specimens included light microscopy, immunofluorescence, and electron microscopy. There were 45 cases of CD and 38 cases of UC represented. The most common indication for kidney biopsy was acute or chronic kidney failure (63% [52 of 83]) and nephrotic-range proteinuria (16% [13 of 83]). IgA nephropathy was the most common diagnosis (24% [20 of 83]), followed by interstitial nephritis (19% [16 of 83]), arterionephrosclerosis (12% [10 of 83]), acute tubular injury (8% [7 of 83]), proliferative GN (7% [6 of 83]), and minimal-change disease (5% [4 of 83]). When compared, the frequency of IgA nephropathy in IBD was significantly higher than in all other native renal biopsy specimens from the same time period (24% [20 of 83] versus 8% [2734 of 33,630]; P<0.001). Of the 16 cases of interstitial nephritis, 9 (56%) had current or recent past exposure to aminosalicylates, including all cases of granulomatous interstitial nephritis. IBD is associated with a spectrum of kidney diseases most commonly affecting the glomerular and tubulointerstitial compartments. IgA nephropathy is the most frequent kidney biopsy diagnosis in IBD and has a significantly higher diagnostic prevalence compared with all non-IBD kidney biopsy specimens. This may reflect a common pathogenic mechanism. Although many cases of tubulointerstitial nephritis are related to aminosalicylate exposure, the possibility of a direct relationship with IBD cannot be ruled out.

Quiz Page November 2013: An Unusual Cause of Nephrotic Syndrome

Quiz Page November 2013: An Unusual Cause of Nephrotic Syndrome

Clinical and Pathological Characterization of Mesoamerican Nephropathy: A New Kidney Disease in Central America

An endemic of chronic kidney disease (CKD) of unknown cause among rural inhabitants in Central America has been identified. Young and otherwise healthy men working in plantations are frequently affected. The name Mesoamerican nephropathy (MeN) has been suggested. Clinically, MeN presents with low-grade proteinuria and progressive kidney failure. The renal pathology of this disease has not yet been described. Case series. 8 male patients with CKD of unknown cause and clinically suspected MeN were recruited from a nephrology unit in El Salvador. All recruited patients had been working on plantations. Kidney biopsies, blood, and urine samples were collected. Renal morphology examined with light microscopy, immunofluorescence, and electron microscopy; clinical and biochemical characteristics. A similar pattern was seen in all 8 biopsy specimens, with extensive glomerulosclerosis (29%-78%) and signs of chronic glomerular ischemia in combination with tubular atrophy and interstitial fibrosis, but only mild vascular lesions. Electron microscopy indicates podocytic injury. Biochemical workup showed reduced estimated glomerular filtration rate (27-79 mL/min/1.73 m(2) with the CKD Epidemiology Collaboration [CKD-EPI] creatinine equation), low-grade albuminuria, and increased levels of tubular injury biomarkers. Hypokalemia was found in 6 of 8 patients. Small number of patients from one country. This study is the first report of the biochemical and morphologic findings in patients with MeN. Our findings indicate that MeN constitutes a previously unrecognized kidney disease with damage to both glomerular and tubulointerstitial compartments.

Expression and characterization of anionic components in the tubulointerstitial compartment of rat kidney during polymicrobial sepsis

The aim of the study was to evaluate sialic acids and hyaluronan expression, anionic components important for the structure and function of the renal tubulointerstitial compartment, in the early stages of sepsis. Two groups of rats were used: (1) sham-operated controls; (2) cecal ligation and puncture (CLP) (polymicrobial sepsis model). A search for microbial growth was made in the peritoneal fluid to document infection. Tubular function was evaluated by means of urinary protein loss, urinary Na+ and urea excretion. Kidney samples were processed to analyze histology, sialic acids (lectin histochemistry) and hyaluronan (immunohistochemistry) expression. Results showed increased urinary protein loss and fractional excretion of Na+ and urea reduction in the CLP group. Histological changes, particularly in the cortex and in proximal tubules of the CLP group, were observed. In septic rats, compared to controls, sialic acids decreased in amount and their acetylation increased in the tubules, although to a lesser extent in the proximal portion. Hyaluronan was expressed in the medullary interstitium and in a few areas of cortex in controls. In septic rats it increased in the cortical interstitium and appeared in proximal tubules. These results suggest correlation between expression changes of anionic components and tubulointerstitium morphofunctional alterations during sepsis. A role of these molecules in protection/defense and repair processes may be suggested.

Analysis of TNF-mediated recruitment and activation of glomerular dendritic cells in mouse kidneys by compartment-specific flow cytometry

Renal dendritic cells (DCs) form an interstitial network contributing to inflammatory and adaptive immune responses in the kidney. The presence and functional role of DC-like glomerular CD11c(+) mononuclear phagocytes is a matter of debate. Using compartment-specific flow cytometry we found that healthy mouse kidneys contained 1.3 CD11c(+) cells per 100 glomeruli and these increased by 4.6-fold and 13-fold after TNF stimulation and immune complex deposition, respectively. Compartment-specific mRNA expression revealed a predominantly glomerular expression of TNF receptors, chemokines, and adhesion molecules; all upregulated after TNF exposure. Intraperitoneal TNF injection induced influx of neutrophils and mononuclear phagocytes including DC-like CD11c(+) cells into both the glomerular and tubulointerstitial compartments, but reduced in TNF receptor (Tnfr) 1-deficient mice. Additionally, Tnfr2 deficiency impaired glomerular infiltration of CD11c(+) cells, but not neutrophils. Interstitial CD11c(+) cells infiltrated in the presence of Tnfr1 or Tnfr2. TNF exposure also induced similar maturation of glomerular and interstitial CD11c(+) cells as demonstrated by increased surface expression of MHC II, CD54, and costimulatory molecules CD40, CD80, and CD86. Thus, by compartment-specific flow cytometry we could demonstrate the constitutive presence of DC-like CD11c(+) mononuclear phagocytes in normal mouse glomeruli and their TNF-induced accumulation and activation.

Thalidomide suppresses inflammation in adenine-induced CKD with uraemia in mice

Persistent systemic inflammation has been widely recognized in patients with chronic kidney disease (CKD), and is associated with increased risk of morbidity and mortality. Intervention therapies aiming for the blockade of inflammatory cytokines are considered attractive approaches for CKD patients with signs of chronic inflammation. In this context, thalidomide, due to its potent anti-inflammatory and immunomodulatory properties, may represent an alternative strategy of treatment. In the present study, we developed an experimental model of CKD with uraemia in mice, induced by a diet rich in adenine, which causes progressive renal dysfunction, resembling the human uraemic features. Inflammatory parameters were analysed in this model of CKD and the potential beneficial effects of thalidomide as an anti-inflammatory drug was also investigated. C57/BL-6 mice were fed with an adenine-containing diet during a period of 6 weeks. Thirty mice were divided into three groups: Control group (animals receiving normal diet), ADE group (mice receiving adenine-containing diet) and ADE + TLD group (CKD mice receiving thalidomide, 30 mg/kg/day, by gavage). Besides biochemical and histopathological changes, local and systemic inflammatory parameters were also analysed, including expression of cytokines interleukin (IL)-1β, tumour necrosis factor-α, IL-6, IL-4 and IL-10 in kidney samples by real-time RT-PCR and quantification of serum levels of cytokines. Finally, the electrophoretic mobility shift assay (EMSA) for NF-κB was also examined. Adenine-fed mice developed advanced CKD characterized by a marked increase in serum urea, creatinine, phosphorus and intact parathyroid hormone (iPTH) levels. In addition, histological changes of tubulointerstitial injury, characterized by deposition of crystals in the kidney, accompanied by tubular dilatation, degeneration of proximal tubular epithelium with loss of the brush border, inflammatory cellular infiltration, foreign-body granuloma formation and interstitial fibrosis were also evident. By immunohistochemistry, Mac-2- and α-SMA-positive cells were identified in the tubulointerstitial compartment. Treatment with thalidomide significantly reduced serum urea, creatinine, phosphorus and iPTH levels and protected against tubulointerstitial injury. Local and systemic inflammation in the mice model of adenine-induced CKD was confirmed by the findings of significantly high expression of cytokine mRNA levels and NF-κB activation in the kidney tissue as well as marked increased serum levels of inflammatory cytokines. Thalidomide treatment significantly reduced gene expression of these cytokines and the activation of the NF-κB in the renal tissue and the circulating levels of cytokines. Dietary adenine caused advanced CKD with uraemia in mice providing a useful experimental model to study molecular and morphological changes associated with this disease. The negative impact of inflammation in this CKD model was overcome by the marked anti-inflammatory effects of thalidomide, promoting renal protection.

The pathogenesis of diabetic nephropathy: focus on microRNAs and proteomics

The prevalence of type 2 diabetes mellitus is growing exponentially in Western countries, and the incidence of this condition is today increasing worldwide. Other than for cardiovascular complications, diabetes is particularly challenging for the kidney's health and proper function. Prolonged exposure of the kidneys to hyperglycemia in fact often results in a clinical complication called diabetic glomerulosclerosis, also known as diabetic nephropathy. Diabetic nephropathy represents today the leading cause of end-stage renal disease in Western countries. When left untreated or undiagnosed, diabetic nephropathy is ultimately responsible for the need for dialysis and, in the worst cases, kidney transplantation of the affected individuals. The pathogenesis of diabetic nephropathy has been studied extensively. A great number of metabolites, cytokines, proteins and transcription factors play a role in the accumulation of extracellular matrix and mesangial proliferation in the glomerulus; importantly, these phenotypic alterations are considered the 2 histological hallmarks of diabetic nephropathy. Additional effort is however required to understand the wide network of biochemical pathways that link diabetes to the renal damage in the long run. The integrative analysis of the proteomic and transcriptomic features of body fluids and/or bioptic samples among different categories of patients affected by diabetic nephropathy, if based on the accurate classification of the histopathological changes in the glomerular and tubulointerstitial compartment, could lead to the identification of new early biomarkers. This approach could represent an effective, noninvasive, alternative tool for early diagnosis and intervention.

Mediators of Inflammation and Their Effect on Resident Renal Cells: Implications in Lupus Nephritis

Lupus nephritis affects up to 70% of patients with systemic lupus erythematosus and is a major cause of morbidity and mortality. It is characterized by a breakdown of immune tolerance, production of autoantibodies, and deposition of immune complexes within the kidney parenchyma, resulting in local inflammation and subsequent organ damage. To date, numerous mediators of inflammation have been implicated in the development and progression of lupus nephritis, and these include cytokines, chemokines, and glycosaminoglycans. Of these, type I interferons (IFNs) can increase both gene and protein expression of cytokines and chemokines associated with lupus susceptibility, and interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and hyaluronan have been shown to elicit both pro- and anti-inflammatory effects on infiltrating and resident renal cells depending on the status of their microenvironment. Expression of IL-6, TNF-α, type I IFNs, and hyaluronan are increased in the kidneys of patients and mice with active lupus nephritis and have been shown to contribute to disease pathogenesis. There is also evidence that despite clinical remission, ongoing inflammatory processes may occur within the glomerular and tubulointerstitial compartments of the kidney, which further promote kidney injury. In this review, we provide an overview of the synthesis and putative roles of IL-6, TNF-α, IFN-α, and hyaluronan in the pathogenesis of lupus nephritis focusing on their effects on human mesangial cells and proximal renal tubular epithelial cells.

Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy

The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades. Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD). In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy. The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions. It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions. In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review.