Renal Disease Involvement Research Articles

Arsenite Exposure to Human RPCs (HRTPT) Produces a Reversible Epithelial Mesenchymal Transition (EMT): In-Vitro and In-Silico Study.

The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media.

Atherosclerosis and renal disease involvement in patients with systemic lupus erythematosus: a cross-sectional cohort study.

To investigate the association between LN, renal function and atherosclerosis measured by coronary artery calcium (CAC) and carotid plaque in a cross-sectional study of patients with SLE. Presence of CAC and carotid plaque was measured in 147 SLE patients with and without LN. The patients were divided into four groups according to LN and renal function [by first quartile of estimated glomerular filtration rate (eGFR): 70 ml/min/1.73 m2]. Impaired renal function was defined by an eGFR <70 ml/min/1.73 m2. We used multivariate logistic regression models to explore the association between LN, renal function, CAC and carotid plaque. Of the 147 SLE patients, 74 had LN. Median age of the study cohort was 46 years, 89% were women and median eGFR was 89 ml/min/1.73 m2. CAC score >0 was present in 57 (39%) and carotid plaque in 29 (20%) of the SLE patients. The presence of CAC and/or carotid plaque was highest in SLE patients with impaired renal function. Regression analyses showed that compared with SLE patients without LN and eGFR ⩾70 ml/min/1.73 m2 (reference group), only the combination of LN and impaired renal function was associated with the presence of CAC (odds ratio: 6.82, 95% CI: 1.59, 29; P = 0.01) and carotid plaque (odds ratio: 5.60, 95% CI: 1.19, 26; P = 0.03). Our findings indicate that LN in combination with impaired renal function defined by an eGFR <70 ml/min/1.73 m2 is strongly associated with the presence of atherosclerosis in SLE.

HNF1B-associated clinical phenotypes: the kidney and beyond.

Mutations in HNF1B, the gene encoding hepatocyte nuclear factor 1β are the most commonly identified genetic cause of renal malformations. HNF1B was first identified as a disease gene for diabetes (MODY5) in 1997, and its involvement in renal disease was subsequently noted through clinical observations in pedigrees affected by MODY5. Since then, a whole spectrum of associated phenotypes have been reported, including genital malformations, autism, epilepsy, gout, hypomagnesaemia, primary hyperparathyroidism, liver and intestinal abnormalities and a rare form of kidney cancer. The most commonly identified mutation, in approximately 50% of patients, is an entire gene deletion occurring in the context of a 17q12 chromosomal microdeletion that also includes several other genes. Some of the associated phenotypes, especially the neurologic ones, appear to occur only in the context of this microdeletion and thus may not be directly linked to HNF1B. Here we review the spectrum of associated phenotypes and discuss potential implications for clinical management.

The cost of care of systemic lupus erythematosus (SLE) in the UK: annual direct costs for adult SLE patients with active autoantibody-positive disease

The aim of the Systemic LUpus Erythematosus Cost of Care In Europe (LUCIE) study was to evaluate the annual direct medical costs of managing adults with active autoantibody-positive disease on medication for SLE in secondary care. This paper presents the UK analyses only. A cost-of-illness study was conducted from the perspective of the National Health Service. Health resource utilization data were retrieved over a two-year period from four centres in England and unit cost data were taken from published sources. At baseline, 86 patients were included, 38 (44.2%) had severe SLE and 48 (55.8%) had non-severe SLE. The mean (SD) SELENA-SLEDAI score was 7.7 (5.7). The mean (SD) annual direct medical cost of was estimated at £3231 (£2333) per patient and was 2.2 times higher in patients with severe SLE compared with patients with non-severe SLE (p < 0.001). Multivariate model analyses showed that renal disease involvement (p = 0.0016) and severe flares (p = 0.0001) were associated with higher annual direct costs. Improvement of the overall stability of SLE and early intervention to minimize the impact of renal disease may be two approaches to mitigate the long-term direct cost of managing SLE patients in the UK.

Complement in Human Disease

As part of innate immunity, the complement system embodies the “first line of defense” to various initial insults, including trauma, infection, hemorrhage, ischemia, and autoimmunity. While of beneficial intention, excessive complement activation can inadvertently damage healthy host tissues and thereby exacerbate the initial pathological events by causing an “innocent bystander effect.” “Complementology” represents a rapidly evolving field. Recent scientific efforts have identified novel complement activation pathways and select complement-inhibiting compounds, which have been shown to ameliorate myriad autoimmune or inflammatory conditions. These findings have renewed the enthusiasm for novel pharmacological strategies targeting numerous inflammatory conditions, which currently elude successful transfer “from bench to bedside,” such as acute lung injury, sepsis, burn, ischemia-reperfusion injury, traumatic brain injury, and kidney disease. The abundant involvement of the complement system in human health and disease is reflected by the wide range of topics covered in this special issue of Clinical and Developmental Immunology. B. Nilsson and N. Ekdahl provide a summarizing article on current indications, techniques, sampling, and interpretations for clinical complement analyses. In addition, an easy-to-follow algorithm is provided for routine laboratory operations. G. Cazander et al. illustrate the success of targeted complement inhibition of complement in wound healing and demonstrate how revesal of complement hyperactivity using several complement inhibitors has resulted in novel and innovative wound care strategies, which may soon be subject of clinical trials. K. J. Welsh et al. challenge recent evidence that complement plays a critical role in the host defense against Mycobacterium tuberculosis. Following aerosol challenge with Mycobacterium tuberculosis, the authors demonstrate that “C7-knockout” mice had markedly reduced liver colony forming units and lung occlusion in conjunction with significantly increased total lymphocytes, decreased macrophages, and increased numbers of CD4+ cells. In line, expression of lung IFN-γ and TNF-α was increased in these animals, underscoring a crucial role of C7 in the disease manifestation of Mycobacterium tuberculosis. S. R. Stowell et al.'s manuscript reviews the role of complement in transfusion-related mortality. This is of particular interest, as excessive complement activation during transfusion represents one of the most common features associated with fatality. The treating physician is furthermore provided with several strategies aiming to immunomodulate the complement system during incompatible red blood cell transfusions. In two reviews, F. Bu et al. and S. F. Heeringa and colleagues review complement involvement in renal disease. Bu reviews the pathogenetic role of genetic variations in complement genes and complement dysregulation at the cell surface results in different forms of atypical hemolytic uremic syndrome, and how this understanding may result in novel complement-modulating treatment approaches. In S. F. Heeringa's paper, the pathogenesis of complement associated glomerulopathies is reviewed. Heeringa describes how defective complement control via the alternative pathway results in glomerular C3 deposition and how this understanding has generated a complement pan-blockade or plasma substitution as potential treatment strategies, which have been proven successful. H. Nishiura et al. shed further light on the importance of the C5a receptor (C5aR) during erythropoiesis. Strikingly, expression and regulation of RP S19 oligomer, which binds to C5aR, may regulate C5aR function as a connector for the erythroblast-macrophage island or for erythroblast differentiation in the bone marrow. D. Rittirsch et al. and J. Charchaflieh et al. review the highly elaborate immune response following trauma and sepsis, which is—at least in part—driven by excessive complement activation and may result in a deadly downward spiral of SIRS, sepsis, septic shock, and multiorgan failure. Recent clinical concepts, such as “damage control surgery,” transition such findings into the clinical setting in an attempt to improve outcome of a highly vulnerable patient population. These manuscripts represent an exciting and insightful snapshot of current complement research. State-of-the-art, existing challenges, and emerging future topics are highlighted in this special issue, which may inspire the reader and help advance the present complement research. We would like to thank all authors, reviewers, and the Editor-in-Chief for making this special issue in Clinical and Developmental Immunology possible. Michael A. Flierl Daniel Rittirsch Markus S. Huber-Lang Philip F. Stahel

PAX2 in human kidney malformations and disease

Human PAX2 mutations have been associated with abnormalities in the developing and adult kidney ranging from congenital abnormalities of the kidney and urinary tract (CAKUT) to oncogenic processes. Defining the relationship of PAX2 to human renal disease requires an appreciation of its fundamental role in renal development. Given the highly conserved nature of the PAX2 gene in vertebrates, it is not surprising that much of our understanding of PAX2 involvement in renal disease has been derived from animal models. The following review will outline the current evidence supporting involvement of PAX2 in the pathologic processes involving the kidney.

Heme Oxygenase 1: Does It Have a Role in Renal Cytoprotection?

Heme oxygenase (HO) was first identified as the rate-limiting enzyme in the degradative pathway of heme, but is now recognized to be involved in diverse biological processes. Different isoforms of HO exist; HO-1 (HMOX1) is ubiquitously present in mammalian tissue with low constitutive expression under physiological conditions, but is upregulated in response to a variety of potentially noxious stimuli. HO-1, an integral component of an important cytoprotective mechanism, mediates its action through removal of heme, the generation of heme breakdown reaction products (biliverdin, free iron, and carbon monoxide), and modulation of key cellular molecules. Data from experimental models in which HO-1 was induced or inhibited, together with observations in genetically modified animals, showed a beneficial effect of HO-1 in several pathways leading to kidney injury. The discovery of a functional guanosine thymine tandem repeat polymorphism in the promoter region of the human HO-1 gene has stimulated clinical investigations in a variety of diseases. However, despite theoretical and experimental support for an important pathophysiological role for HO-1, the relevance of this polymorphism in native kidney or renal transplant function is equivocal. This article reviews the molecular genetics of HO-1, its myriad cytoprotective effects allied to how these are mediated, and relates these findings to experimental and clinical evidence of HO-1 involvement in renal disease.

Cutaneous manifestations in renal failure patients: A case series

Cutaneous involvement in renal disease is due to a host of factors ranging from metabolic disturbances to immunosuppressive drugs. Herein we report a series of six cases of renal failure with varied cutaneous manifestations ranging from infections to neoplasms due to prolonged immunosuppression. Our first case had cutaneous cryptococcosis where skin lesions gave a clue to the diagnosis of altered sensorium and underlying meningitis. The second case initially presented with florid warts and was treated successfully but later presented with an explosive recurrence of skin lesions due to malignant transformation. Our third case had basal cell carcinoma over the presternal region that was successfully treated with liquid nitrogen cryotherapy. Our fourth case had diabetic nephropathy that presented with septicemia and purpura fulminans. The last case had cutaneous manifestations of drug therapy because of heparin infusion. To conclude, cutaneous manifestations in patients with renal failure are varied and a high degree of suspicion is needed for early diagnosis and aggressive treatment to effectively combat mortality and morbidity.

The association of −627 interleukin-10 promoter polymorphism in Chinese patients with systemic lupus erythematosus

The objective of the study is to examine whether interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 119 Chinese patients with SLE. One hundred unrelated healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of a polymerase chain reaction (PCR)-based restriction analysis. The PCR product length was determined to be 412 bp (CC) whereas two fragments of 236 and 176 bp were determined to be excisable lengths (AA). The relationship between the IL-10 gene polymorphism and clinical manifestations of SLE was evaluated. For the genotype and allelic frequency, there were statistically significant differences between the SLE patients and the normal control subjects (p=0.007 and 0.003, respectively). But we did not detect any association of carriage rate of the IL-10 polymorphism and the normal control subjects (p=0.077). Furthermore, we did not detect any association of IL-10 genotype with antinuclear antibody, malar rash, photosensitivity, discoid lupus, mucosal ulcer, arthritis, serositis, hematology, immunology, involvement of central nervous system, and renal disease involvement in the SLE patients. The significant relation of -627 IL-10 genotype and allelic frequency with SLE implies that the IL-10 gene polymorphism can serve as a candidate gene marker for further study in patients with SLE in Taiwan.

Glomerulonephritis associated with hepatitis c virus infection

We report 4 patients with glomerulonephritis (GN) associated with hepatitis C virus (HCV) infection seen between August 1993 and July 1996. Two of them were male and median age was 41 years. Anti-HCV was detected by enzyme-immunoassay and HCV-RNA by PCR. Serum cryoglobulins, 24-hour proteinuria, and erythrocyte dismorphism were also determined. Viremia, cryoglobulinemia, hematuria and proteinuria were observed in all patients. Liver biopsies revealed inflammatory activity in 3 cases, and renal biopsies revealed membranoproliferative glomerulonephritis in 3 patients and mesangial proliferative glomerulonephritis in 1 patient. Two patients are on specific therapy for HCV infection (IFN in combination with ribavirin) and have presented clinical and laboratory improvement. The occurrence of active liver disease and viremia concurrent with urinary alterations suggests viral involvement in renal disease, a conclusion supported by the by improvement of urinary alterations observed after treatment for HCV. We conclude that the search for viral markers in patients with GN is important since their detection could change the therapeutic approach.

Pulmonary Involvement in Renal Disease

Pulmonary Involvement in Renal Disease