Robert J. Ellis

Indoxyl sulphate and kidney disease: causes, consequences and interventions

In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m2) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest‐growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein‐bound, tryptophan‐derived metabolite that is generated by intestinal micro‐organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS; (ii) report effects of IS accumulation in clinical studies; (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro; and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.

Optimising assessment of kidney function when managing localised renal masses

Increased early and incidental detection, improved surgical techniques and technological advancement mean that the management of renal mass lesions is constantly evolving. The treatment of choice for renal mass lesions has historically been radical nephrectomy. Partial nephrectomy is now recommended for localised renal masses, owing to favourable renal functional outcomes. Ablative renal surgery confers a significant risk of chronic kidney disease. There are few studies assessing long term outcomes of nephrectomy on renal outcomes, and virtually no studies assessing long term outcomes for less invasive therapies such as ablation. Unless a renal mass is clearly benign on imaging, management decisions will be made with an assumption of malignancy. The content of this review applies to both benign and malignant renal mass lesions. We advocate for improved strategies for kidney function assessment and risk stratification, early targeted referral, and regular screening for chronic kidney disease for all patients after surgery.

The Correlates of Kidney Dysfunction – Tumour Nephrectomy Database (CKD-TUNED) Study: Protocol for a Prospective Observational Study

Background: Tumour nephrectomy conveys a significant risk of adverse renal functional outcomes postoperatively, however there are limited strategies for predicting patients at increased risk of these outcomes. The Correlates of Kidney Dysfunction – Tumour Nephrectomy Database (CKD-TUNED) study is a prospective observational study evaluating the risk of chronic kidney disease and end-stage kidney disease in tumour nephrectomy patients. Methods: The CKD-TUNED study involves analysis of clinical data and collection of tissue, urine and blood samples for the purposes of forming a tissue repository resource for future investigation. Recruitment began in 2013 and is expected to continue until 2023, with a projected sample size between 700-1000 subjects. Results: All relevant ethics and site-specific approvals have been granted and all relevant infrastructure is in place. Study methods are undergoing validation and refinement. As of June 2017 there are 267 participants enrolled in the study. Conclusion: It is anticipated that this study will have the potential to identify risk factors for adverse renal functional outcomes following tumour nephrectomy, which can be used in the development of predictive models with clinical utility, and in turn improve patient outcomes.

Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells

Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with declining kidney function. Although generally thought of as a consequence of declining kidney function, emerging evidence demonstrates direct cytotoxic role of IS on endothelial cells and cardiomyocytes, largely through the expression of pro-inflammatory and pro-fibrotic factors. The direct toxicity of IS on human kidney proximal tubular epithelial cells (PTECs) remains a matter of debate. The current study explored the effect of IS on primary cultures of human PTECs and HK-2, an immortalized human PTEC line. Pathologically relevant concentrations of IS induced apoptosis and increased the expression of the proapoptotic molecule Bax in both cell types. IS impaired mitochondrial metabolic activity and induced cellular hypertrophy. Furthermore, statistically significant upregulation of pro-fibrotic (transforming growth factor-β, fibronectin) and pro-inflammatory molecules (interleukin-6, interleukin-8, and tumor necrosis factor-α) in response to IS was observed. Albumin had no influence on the toxicity of IS. The results of this study suggest that IS directly induced a pro-inflammatory and pro-fibrotic phenotype in proximal tubular cells. In light of the associated apoptosis, hypertrophy, and metabolic dysfunction, this study demonstrates that IS may play a role in the progression of chronic kidney disease.

Predictors of new-onset chronic kidney disease in patients managed surgically for T1a renal cell carcinoma: an Australian population-based analysis

New‐onset chronic kidney disease (CKD) following surgical management of kidney tumors is common. This study evaluated risk factors for new‐onset CKD after nephrectomy for T1a renal cell carcinoma (RCC) in an Australian population‐based cohort.

Factors associated with acutely elevated serum creatinine following radical tumour nephrectomy: the Correlates of Kidney Dysfunction–Tumour Nephrectomy Database study

Background To identify factors associated with acutely elevated serum creatinine (SCr) within 7 days of radical tumour nephrectomy. Methods The study population consisted of 130 consecutive patients managed for renal tumours. The primary outcome was acute kidney injury (AKI) (defined as SCr increase ≥50% above baseline), assessed using multivariable logistic regression analysis. The secondary outcome was SCr percentage increase, assessed using multivariable linear regression analysis. Results Following nephrectomy, the mean percentage increase in SCr in the first week was 55%±29%, and 77 (59%) patients experienced AKI. Independent predictors of AKI post-nephrectomy were male gender [adjusted odds ratio (OR): 2.67; 95% confidence interval (95% CI): 1.01, 6.93], urine albumin-creatinine ratio (OR: 0.66; 95% CI: 0.47, 0.91), preoperative estimated glomerular filtration rate (eGFR) (OR: 1.03; 95% CI: 1.00, 1.05), laparoscopic nephrectomy (OR: 3.02; 95% CI: 1.00, 9.12), and non-clear cell renal cell carcinoma (RCC) (OR: 2.93; 95% CI: 1.04, 8.29). Independent predictors of a SCr increase were male gender (β: 12.0; 95% CI: 2.69, 21.3), urine albumin-creatinine ratio (β: –3.36; 95% CI: –6.55, –0.16), preoperative eGFR (β: 0.38; 95% CI: 0.10, 0.66), laparoscopic nephrectomy (β: 12.7; 95% CI: 1.05, 24.3) and obesity (β: 9.94, 95% CI: 0.61, 19.3). Conclusions Male gender, albuminuria, eGFR and laparoscopic nephrectomy independently associated with acutely elevated serum creatinine following radical tumour nephrectomy.

Multifocal Primary Neoplasms in Kidney Allografts: Evaluation of Two Cases

Renal cell carcinoma (RCC) is the fifth most common malignancy in kidney transplant recipients, with increased risk arising due to immunosuppression. De novo RCC occurrence in kidney allografts is much less common when compared with the native kidneys. Multifocal RCC in allograft kidneys is rarely described. In this report, we discuss two cases of de novo multifocal renal neoplasms in allograft kidneys. Case 1 had three distinct neoplastic lesions of >5 mm, and case 2 had four. Using the World Health Organization 2016 classification of adult renal tumours, case 1 had one clear-cell (cc) RCC (grade 3) and two papillary adenomas; all confined to the kidney. Case 2 had a nodular lesion classified as ccRCC (grade 4) with focal rhabdoid differentiation and some infiltration of renal sinus fat; a cc tubulopapillary RCC; a multilocular cystic renal neoplasm of low malignant potential; and a mucinous tubular and spindle cell carcinoma; the last three all confined to the kidney. This is the first report of mucinous tubular and spindle cell carcinoma in a kidney allograft. When considering multifocal RCC with discordant histology, it is likely that these represent independent tumourigenic events.

Outcome Measures Used to Report Kidney Function in Studies Investigating Surgical Management of Kidney Tumours: A Systematic Review

CONTEXT Most practice decisions relevant to preserving kidney function in patients managed surgically for kidney tumours are driven by observational studies. A wide range of outcome measures are used in these studies, which reduces comparability and increases the risk of reporting bias. OBJECTIVE To comprehensively and succinctly describe the outcomes used to evaluate kidney function in studies evaluating surgical management of kidney tumours. EVIDENCE ACQUISITION Electronic search of the PubMed database was conducted to identify studies with at least one measure of kidney function in patients managed surgically for kidney tumours, published between January 2000 and September 2017. Abstracts were initially screened for eligibility. Full texts of articles were then evaluated in more detail for inclusion. A narrative synthesis of the evidence was conducted. EVIDENCE SYNTHESIS A total of 312 studies, involving 127905 participants, were included in this review. Most were retrospective (n=274) studies and conducted in a single centre (n=264). Overall, 78 unique outcome measures were identified, which were grouped into six outcome categories. Absolute postoperative kidney function (n=187), relative kidney function (n=181), and postoperative chronic kidney disease (n=131) were most frequently reported. Kidney function was predominantly quantified using estimated glomerular filtration rate or creatinine clearance (n=255), most using the modification of diet in renal disease equation (n=182). Only 70 studies provided rationale for specific outcome measures used. CONCLUSIONS There is significant variability in the reporting and quantification of kidney function in studies evaluating patients managed surgically for kidney tumours. A standardised approach to measuring and reporting kidney function will increase the effectiveness of outcomes reported and improve relevance of research findings within a clinical context. PATIENT SUMMARY Although we know that the removal of a kidney can reduce kidney function, clinical significance of various approaches is a matter of debate. This article demonstrates significant variability in the way kidney function was reported across all studies of patients with kidney cancer undergoing surgery, indicating a need for standardisation.

A Rare Case of Solitary Kidney Metastasis following Primary Laryngeal Squamous Cell Carcinoma

Laryngeal cancer is the 14th most common malignancy worldwide, and its common subtype squamous cell carcinoma (SCC) is highly associated with tobacco use and long-term alcohol consumption. The incidence of distant metastasis from a primary laryngeal cancer has been reported to be very low, between 6.5% and 8.5%, according to published tumour registry data. Distant metastases of laryngeal SCC most commonly involve the lung, liver, bone and mediastinum, seldom involving the kidney. Renal metastasis has been well established in many other cancers such as lymphoma, lung, breast and gastric carcinoma. This report discusses the rare case of a solitary renal metastasis following a primary laryngeal SCC.

Expression of S100 Calcium Binding Protein A1 (S100A1) Aids in the Differentiation of Renal Cell Carcinoma Versus Normal Kidney Tissue

Aim: To investigatenongenomic effects of aldosteroneon renal protein expressions of sodium hydrogen exchanger 1 and 3 (NHE1and3), andproteinkinaseCbeta 1 and2 (PKCβ 1 and2) Introduction: Wehave previously demonstrated that aldosterone rapidly elevates epidermal growth factor receptor (EGFR) phosphorylation and increases extracellular signal-related kinase1and2(ERK1⁄2)inratkidney.ERK1⁄2inducedbyaldosterone activates NHE (1 and 3) in renal tubular cells. In vitro studies showed that aldosterone nongenomically stimulates PKCβ. PKCβ1alsomediatedstimulationofNHEactivity.Therearenoreports ofproteinexpressionsofNHE(1and3)andPKCβ (1and2) simultaneously in ratkidney regarding these circumstances. Methods: Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (150mg/kg BW). After 30minutes, abundances and localizations of NHE (1 and 3) and PKCβ (1 and 2) proteins were determined by Western blot analysis and immunohistochemistry, respectively. Results: ByWestern blot analysis, aldosterone increased renal protein abundances of NHE1 andNHE3 to be 152%and 134%, respectively (P< 0.05). Aldosterone significantly enhanced protein abundances of PKCβ1 by 30%, whereas PKCβ2 protein trended to decline. Aldosterone increasedmore protein expressions of NHE1 and NHE3 in the medulla than cortex. Protein expression PKCβ1 was enhanced in the glomeruli, renal vasculatures and thin limb of Henles loop by aldosterone. However, PKCβ2 was declined in the medulla. Conclusion: This in vivo study is the first to demonstrate simultaneously that aldosterone rapidly elevates PKCβ1 and NHE (1 and 3) protein abundances in rat kidney. The stimulation of NHE protein expressions by aldosterone, per se, may occur through PKCβ1 activation. 002 KEY ROLE OFAPOPTOSIS INHIBITOR OF MACROPHAGE IN PHLOGOGENIC ACTION OF GLOMERULAR NEPHRITOGENIC IGA IN IGA NEPHROPATHY TAKAHATA A, KITADA K, NOGI C, ARAI S, MAKITA Y, SUZUKI H, NAKATA J, HORIKOSHI S, MIYAZAKI T, SUZUKI Y Division of Nephrology, Department of Internal Medicine Juntendo University School of Medicine, Bunkyo-ku, Japan, Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Bunkyo-ku, Japan