Background
Polyomavirus‐associated nephropathy is associated with high risk of kidney allograft loss. Whether the cause of native end‐stage renal disease influences the risk of BK infection is ...unclear.
Methods
A retrospective, single‐center study of 2741 adult kidney transplant recipients between 1994 and 2014 was performed. Recipients had end‐stage renal disease due to polycystic kidney disease (PKD, n = 549), diabetes mellitus (DM, n = 947), hypertension (HTN, n = 442), or glomerulonephritis (GN, n = 803).
Results
A total of 327 recipients (12%) developed post‐transplant BK viremia over a median follow‐up time of 5 years. The incidence rate of BK viremia was lowest in patients with PKD (1.46 per 100 person‐years) compared to other causes of ESRD (DM = 2.06, HTN = 2.65, and GN = 2.01 per 100 person‐years). A diagnosis of PKD was associated with a lower risk of post‐transplant BK viremia (adjusted HR (95% CI) = 0.67 (0.48‐0.95), P = 0.02). BK nephropathy was significantly less common in patients with PKD (0.21 per 100 person‐years) compared to those with HTN (0.80 per 100 person‐years, P ≤ 0.001). Among patients with PKD, the risk of BK viremia was lower in patients with nephrectomy, compared to those without nephrectomy (adjusted HR (95% CI) = 0.42 (0.19‐0.92), P < 0.05).
Conclusion
ESRD due to PKD is associated with a lower risk of post‐transplant BK infection. The renal tubular epithelial cells in PKD are unique; they are in a proliferative but non‐differentiated state. Whether this characteristic of renal tubular epithelial cells alters the BK viral reservoir or replication in PKD patients warrants further study.
Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological ...and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi‐omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter‐individual variation on long‐term outcomes.
Through integrative approaches in ex vivo renal allograft biopsies, this study elucidates the role of differential DNA methylation in interstitial fibrosis and tubular atrophy by influencing the expression of genes and upstream regulators involved in pathways that exacerbate organ injury and inhibit repair processes.
From 5000 to 10 000 kidney patients die prematurely in the United States each year, and about 100 000 more suffer the debilitating effects of dialysis, because of a shortage of transplant kidneys. To ...reduce this shortage, many advocate having the government compensate kidney donors. This paper presents a comprehensive cost‐benefit analysis of such a change. It considers not only the substantial savings to society because kidney recipients would no longer need expensive dialysis treatments—$1.45 million per kidney recipient—but also estimates the monetary value of the longer and healthier lives that kidney recipients enjoy—about $1.3 million per recipient. These numbers dwarf the proposed $45 000‐per‐kidney compensation that might be needed to end the kidney shortage and eliminate the kidney transplant waiting list. From the viewpoint of society, the net benefit from saving thousands of lives each year and reducing the suffering of 100 000 more receiving dialysis would be about $46 billion per year, with the benefits exceeding the costs by a factor of 3. In addition, it would save taxpayers about $12 billion each year.
This analysis of a government program to compensate kidney donors indicates the monetary value of saving thousands of lives each year and reducing the suffering of a hundred thousand more on dialysis would be about $46 billion per year, and would save taxpayers about $12 billion a year.
Targeting STAT3 signaling in kidney disease Pace, Jesse; Paladugu, Praharshasai; Das, Bhaskar ...
American journal of physiology. Renal physiology,
06/2019, Letnik:
316, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. ...STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.
The kidney is a key organ in the human body that excretes toxins and sustains the water–electrolyte balance. During embryonic development and disease progression, the kidney undergoes enormous ...changes in macrostructure, accompanied by a variety of microstructural histological changes, such as glomerular formation and sclerosis, tubule elongation and atrophy, interstitial establishment, and fibrosis progression. All of these rely on the frequent occurrence of cell death and growth. Notably, to overcome disease, some cells regenerate through self-repair or progenitor cell differentiation. However, the signaling mechanisms underlying kidney development and regeneration have not been elucidated. Recently, Wnt signaling has been noted to play an important role. Although it is a well-known developmental signal, the role of Wnt signaling in kidney development and regeneration is not well recognized. In this review, we review the role of Wnt signaling in kidney embryonic development, tissue repair, cell division, and progenitor cell differentiation after injury. Moreover, we briefly highlight advances in our understanding of the pathogenic mechanisms of Wnt signaling in mediating cellular senescence in kidney parenchymal and stem cells, an irreversible arrest of cell proliferation blocking tissue repair and regeneration. We also highlight the therapeutic targets of Wnt signaling in kidney diseases and provide important clues for clinical strategies.
We present the case of a 49-year-old patient with polycystic kidney disease in which, in the pre-transplant CT-scan evaluation, a Bosniak III cyst was found in the left kidney. After contrast ...enhanced ultrasound (CEUS) examination the cyst wasinterpreted as a Bosniak IV malignant cyst and surgical resection of the kidney was realised. The pathology report showed papillary renal cell carcinoma. This case report emphasizes the role of CEUS in polycystic kidney disease examination.
Numerous evidence corroborates roles of gap junctions/hemichannels in proper kidney development. We analyzed how Dab1 gene functional silencing influences expression and localization of Cx37, Cx40, ...Cx43, Cx45, Panx1 and renin in postnatal kidneys of
mice, by using immunohistochemistry and electron microscopy. Dab1 Δ102/221 might lead to the activation of c-Src tyrosine kinase, causing the upregulation of Cx43 in the medulla of
mice. The expression of renin was more prominent in
mice (
< 0.001). Renin granules were unusually present inside the vascular walls of glomeruli capillaries, in proximal and distal convoluted tubules and in the medulla. Disfunction of Cx40 is likely responsible for increased atypically positioned renin cells which release renin in an uncontrolled fashion, but this doesn't rule out simultaneous involvement of other Cxs, such as Cx45 which was significantly increased in the
cortex. The decreased Cx37 expression in
medulla might contribute to hypertension reduction provoked by high renin expression. These findings imply the relevance of Cxs/Panx1 as markers of impaired kidney function (high renin) in
mice and that they have a role in the preservation of intercellular signaling and implicate connexopathies as the cause of premature death of
mice.
Kidney diseases remain a worldwide public health problem resulting in millions of deaths each year; they are characterized by progressive destruction of renal function by sustained inflammation. ...Pyroptosis is a lytic type of programmed cell death involved in inflammation, as well as a key fibrotic mechanism that is critical in the development of kidney pathology. Pyroptosis is induced by the cleavage of Gasdermins by various caspases and is executed by the insertion of the N-terminal fragment of cleaved Gasdermins into the plasma membrane, creating oligomeric pores and allowing the release of diverse proinflammatory products into the extracellular space. Inflammasomes are multiprotein complexes leading to the activation of caspase-1, which will cleave Gasdermin D, releasing several proinflammatory cytokines; this results in the initiation and amplification of the inflammatory response.
The efficacy of Gasdermin D cleavage is reduced by a change in the redox balance. Recently, several studies have shown that the attenuation of reactive oxygen species (ROS) production induced by antioxidant pathways results in a reduction of renal pyroptosis. In this review, we discuss the role of pyroptosis in the pathogenesis of chronic kidney disease (CKD) and acute kidney disease; summarize the clinical outcomes and different molecular mechanisms leading to Gasdermin activation; and examine studies about the capacity of antioxidants, particularly Nrf2 activators, to ameliorate Gasdermin activity.
We illustrate the potential influence of the deregulation of redox balance on inflammasome activity and pyroptosis as a novel therapeutic approach for the treatment of kidney diseases.
. 35, 40-60.
Pax genes encode developmental regulators that are expressed in a variety of tissues and control critical events in morphogenesis. In the kidney, Pax2 and Pax8 are expressed in embryonic development ...and in specific renal diseases associated with aberrant epithelial cell proliferation. Prior genetic and cell biological studies suggest that reducing the activity of Pax proteins in renal cancer or in polycystic kidney disease can slow the progression of these conditions. The Pax proteins may be critical for providing tissue and locus specificity to recruit epigenetic modifiers that control gene expression and chromatin structure. Although they are nuclear, targeting Pax proteins to inhibit function may be feasible with small molecules. Such inhibition of Pax protein function may provide novel therapies for subsets of renal disorders that are tissue- and cell type–specific and avoid systemic effects on non-Pax–expressing cells and tissues. Given the paucity of effective treatments for renal cancer and cystic disease, the Pax family of proteins represents new pharmaceutical targets that merit exploration and further development.
Consensus recommendations have been published to help better define those patients who would benefit from simultaneous liver–kidney transplantation (SLK). We conducted a survey of transplant centers ...that perform SLK (n = 88, 65% response rate) to determine practice patterns in the United States. The majority of centers (73%) stated that they use dialysis duration whereas only 30% of centers use acute kidney injury duration as a criterion for determining need for SLK. Dialysis duration >4 weeks was used by 32% of centers, >6 weeks by 37% and >8 weeks by 32% of centers. Glomerular filtration rate (GFR) was estimated using the modified diet in renal disease (MDRD)‐4 equation in roughly half of centers whereas the MDRD‐6 equation was used by only 6%. In patients with chronic kidney disease, GFR < 40 mL/min was used by 24% of centers as a criterion for SLK transplants instead of the recommended threshold of < 30 mL/min. Regional differences in practices were also observed. This survey demonstrates significant variation in the criteria used for SLK among transplant centers, with few centers following the current published recommendations, and emphasizes the need for evidence‐based guidelines and uniformity in studying renal dysfunction in liver transplant candidates.
In this survey of US transplant centers, the authors demonstrate the significant variation in the criteria used for simultaneous liver–kidney transplantation among centers, with few centers following the current published recommendations. See editorial by Feng and Trotter on page 2869.
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