Background: Current clinical management of clear cell renal cell carcinoma (ccRCC) frequently requires surgical excision. Surgery for suspected ccRCC is routinely carried out before histopathological diagnosis, yet up to 20% of enhancing small renal masses are benign and could be managed conservatively. Differences in tissue chemistry, using magnetic resonance spectroscopy of human renal neoplasia biopsies, showed a clear distinction between ccRCC, non-ccRCC and healthy kidney tissue. We aimed to develop a preoperative in vivo diagnosis of renal lesions that could better inform the need for surgery or monitoring. Methods: Using a 3T Prisma magnetic resonance imaging (MRI) scanner we developed an in vivo protocol for measuring chemical changes occurring when a healthy kidney develops a ccRCC lesion. The protocol uses one dimensional respiratory triggered proton point resolved spectroscopy (PRESS), a minimum voxel size of 2 cm3, a shim value of less than 30 Hz and a minimum of 100 averages. Results: Healthy kidneys were compared with three ccRCC lesions, each with a different grade and size. The chemical differences included increases in the resonance intensity for lipid methylene and methyl, choline and creatine. Conclusions: These MRI data now need to be substantiated with a larger study to characterize the malignant potential and relationship to grade and loss of cellular differentiation in ccRCC lesions in vivo.

There was an error in the original publication [...]

AIM:Evaluate the area-level incidence of kidney failure due to diabetes among Australians aged ≤ 45 years. METHODS:Using Australian registry and census data (2000-2022), incidence rates and prevalence of kidney failure (defined as commencing kidney replacement therapy) due to diabetes among people aged ≤ 45 years were compared by geographical region. RESULTS:Incidence (per 100 000/year, 95% confidence interval) of kidney failure due to diabetes among people aged ≤ 45 years in Australia was 0.72 (0.68-0.77) in 2000-2011, and 1.13 (1.07-1.18) in 2012-2022 (incidence rate ratio [IRR] 1.56, 1.50-1.62). Between 2012 and 2022, there were 48 regions where the crude incidence of kidney failure due to diabetes was more than double the national average, the highest being 49.8 cases per 100 000 per year. Between 2012 and 2022, all jurisdictions had similar age-sex-adjusted point estimates for kidney failure incidence (range 0.78-1.48) except for the Northern Territory (15.8, 13.9-17.8). The most significant characteristics associated with the rate of incident kidney failure were residence in remote areas (IRR 13.9, 13.1-14.8, ref. major cities), socioeconomic disadvantage (IRR 2.96, 2.75-3.19, ref. advantaged areas), and Aboriginal and Torres Strait Islander ethnicity (IRR 24.2, 23.0-25.5). Between the eras, people born outside Australia had the largest increase in incident cases (IRR 2.47, 2.23-2.72) but had a lower overall incidence than those born in Australia (IRR 0.55, 0.52-0.59). CONCLUSION:In Australia, there was an increase in the incidence of kidney failure due to diabetes among people aged ≤ 45 years in the last two decades. There was a strong relationship between the risk of kidney failure and social determinants of health, including place of residence, socioeconomic status and Indigenous status.

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in diagnosis and management. Methods: A systematic review of immunohistochemical markers of RCC studies published between 1990 and 2019 was undertaken to select candidate biomarkers of RCC. Immunohistochemical staining of 73 clear cell RCC tumors and paired normal tissue was undertaken using selected markers. Semi-quantitative and quantitative analysis of staining intensity between paired samples was undertaken to evaluate utility as potential biomarkers, using Chi-square tests and paired t-tests for analysis. As an exploratory analysis, staining intensity was also compared on clinical/demographic variables using linear and logistic regression. Results: There were 123 candidate biomarkers identified in 91 studies. Four candidate markers were selected for further investigation: aminopeptidase A (APA)/cluster of differentiation (CD)249, aminopeptidase N (APN)/CD13, gamma-glutamyl transferase (GGT), and neuron-specific enolase (NSE). APA, GGT, and APN all demonstrated reduced staining intensity in the tumor compared with normal tissue (p < 0.001 for all). NSE demonstrated a statistically significant increase in expression in tumor compared with normal tissue (p < 0.001), and this was more pronounced in patients aged >60 years (p = 0.038). Conclusions: The utility of APA, APN, and GGT as diagnostic biomarkers in clear cell RCC is limited. NSE may have some role as a biomarker for clear cell RCC, particularly among older patients; however, further investigation is required.

BACKGROUND:Metastatic renal cell carcinoma (RCC) is often treated with a combination of immunotherapy and tyrosine kinase inhibitors (TKIs). Patient-derived RCC cells were cultured and inter-individual differences to treatment with a panel of TKIs were evaluated. METHODS:Tumor tissue was collected during nephrectomy. Cells were cultured and treated with a panel of clinically relevant TKIs (sunitinib, cabozantinib, pazopanib, axitinib) at concentrations of 5 µM for 48-72 hours. Cell viability was evaluated using MTT assays. One-sided T-tests were used to evaluate results. RESULTS:Patient-derived cancer cells were able to be grown beyond 10 passages from 12/38 samples collected (27%). Four patient-derived samples were tested against the TKI panel. No substantial difference between drugs was seen for two samples. In one sample, there was a clear superior response to sunitinib (48% mean viability, vs >75% for the other drugs). For the final sample, sunitinib, cabozantinib, and axitinib demonstrated a superior response compared with pazopanib (71%, 77%, 70%, and 85% mean viability, respectively). CONCLUSIONS:Inter-individual variability in the responses of patient-derived RCC cultures to TKIs was seen, which may have biological and clinical significance. Future directions could build on this work to develop personalized cancer susceptibility profiles, with potential for translation into a clinical trial.

This study aimed to investigate the metabolic changes in the kidneys in a murine adenine-diet model of chronic kidney disease (CKD). Kidney fibrosis is the common pathological manifestation across CKD aetiologies. Sustained inflammation and fibrosis cause changes in preferred energy metabolic pathways in the cells of the kidney. Kidney cortical tissue from mice receiving a control or adenine-supplemented diet for 8 weeks (late inflammation and fibrosis) and 12 weeks (8 weeks of treatment followed by 4 weeks recovery) were analysed by 2D-correlated nuclear magnetic resonance spectroscopy and compared with histopathology and biomarkers of kidney damage. Tissue metabolite and lipid levels were assessed using the MestreNova software. Expression of genes related to inflammation, fibrosis, and metabolism were measured using quantitative polymerase chain reaction. Animals showed indicators of severely impaired kidney function at 8 and 12 weeks. Significantly increased fibrosis was present at 8 weeks but not in the recovery group suggesting some reversal of fibrosis and amelioration of inflammation. At 8 weeks, metabolites associated with glycolysis were increased, while lipid signatures were decreased. Genes involved in fatty acid oxidation were decreased at 8 weeks but not 12 weeks while genes associated with glycolysis were significantly increased at 8 weeks but not at 12 weeks. In this murine model of CKD, kidney fibrosis was associated with the accumulation of triglyceride and free lactate. There was an up-regulation of glycolytic enzymes and down-regulation of lipolytic enzymes. These metabolic changes reflect the energy demands associated with progressive kidney disease where there is a switch from fatty acid oxidation to that of glycolysis.

Background: The incidence of chronic kidney disease (CKD) and end -stage kidney disease (ESKD) is increasing worldwide. Hemodialysis (HD) is the mainstay of renal replacement therapy for patients with ESKD. Risk factors associated with late arteriovenous fistula (AVF) failure in HD patients are poorly investigated. Therefore, the aim of this study was to identify factors associated with late AVF failure in HD patients. Methods: Patients with end -stage renal disease (ESRD) who underwent forearm or upper arm AVF angioplasty at Second Affiliated Hospital of Chongqing Medical University between September 2009 and August 2018 were included. Patients were followed up for 36 months. Baseline characteristics were collected using electronic medical records (EMRs). Variables associated with late AVF failure were identified using Cox proportional hazards models. Results: There were 137 patients (64% male, 36% female) included in this study, with 50 (36.5%) experiencing AVF failure. Univariable log -rank analysis showed that age, C -reactive protein (CRP), erythrocyte sedimentation rate (ESR), intact parathyroid hormone (iPTH), albumin (ALB), and AVF patency rate were significantly different between patients who did and did not experience AVF failure. Cox regression analysis showed that CRP [P=0.002, hazard ratio (HR) =2.719, 95% confidence interval (CI) for HR: 1.432-5.164], ESR (P=0.030, HR =2.431, 95% CI: 1.088-5.434), iPTH (P=0.013, HR =0.325, 95% CI: 0.133-0.793), and ALB (P=0.040, HR =0.539, 95% CI: 0.299-0.972) were independently associated with AVF failure. Kaplan -Meier survival analysis showed that the cumulative patency rates of AVF at 6, 12, 18, 24, 30, and 36 months were 84%, 74%, 69%, 64%, 64%, and 64%, respectively. Conclusions: CRP, ESR, iPTH, and ALB were associated with AVF failure and should be used as reference in clinical practice.

Abstract Background and Aims Tubulointerstitial fibrosis is the common pathological manifestation in chronic kidney disease (CKD) and can indicate whether a patient will progress to kidney failure. The metabolic consequences of developing fibrosis are not well understood. This project aimed to investigate metabolic changes in the kidney cortex using an adenine-diet murine model of progressive CKD. Method C57Bl/6J mice were treated with an adenine-supplemented diet (0.2% adenine) or control diet for eight weeks. At the end of treatment, kidney function was assessed (serum creatinine, proteinuria), animals were euthanised, and the kidneys removed. A transverse section of the kidney was prepared for histology. Whole kidney cortical tissue was analysed using two-dimensional correlated spectroscopy (2D-COSY), a form of proton nuclear magnetic resonance (NMR) spectroscopy. Biochemical species, including metabolites and lipids, within the tissue were identified and compared with respective histological tubulointerstitial fibrosis level and traditional serum markers of kidney function, plasma creatinine and blood urea nitrogen. A 2D-COSY spectrum can be found in Figure 1A. Results The adenine-supplemented diet induced tubulointerstitial fibrosis, mirrored by increases in serum creatinine and blood urea nitrogen, indicating decreased kidney function. The 2D-COSY analysis demonstrated numerous changes in metabolites with parallel increasing levels of fibrosis that were detected. Increases in metabolites belonging to the glycolysis (D-glucose, glucose-6-phosphate and lactate) and pentose-phosphate (myo-inositol, D-ribose-5-phosphate, glucuronic acid) pathways were observed, as well as a decrease in lipid. Additionally, increases in creatinine, creatine and a number of amino acids were also observed. These changes are displayed in Table 1 and Figure 1B. Conclusion The primary cell type of the kidney cortex is the proximal tubular epithelial cell. Due to its unique function in water and solute transport, this cell has a very high metabolic demand and utilizes fatty acid oxidation as its primary source of energy. However, when these cells are under pathological stress that contributes to tubulointerstitial fibrosis, such as those present within this animal model of chronic kidney disease, metabolic dysfunction occurs. We observed significant decreases in various lipid signals belonging to fatty acids within the cell. These fatty acids are not being utilised and are instead esterified to triglycerides that accumulate in the kidney, causing lipotoxicity. Increased levels of glucose-6-phosphate, lactate and D-glucose, as well as increased myo-inositol, glucuronic acid D-ribose-5-phosphate are indicative of increased utilisation of the glycolysis and pentose phosphate pathway respectively as primary methods of energy metabolism. Here, we provide evidence that in tubulointerstitial fibrosis within the kidneys leads to a shift in the primary energy pathway used by proximal tubular epithelial cells. The study provides new insights into the changes in biochemical pathways that occur in the kidney during the development of CKD and its progression.

The relationship between the kidney cortex and medulla is not well understood in healthy populations. This study characterised the relationship between cortical/medullary thickness and measured glomerular filtration rate (GFR) in 390 living kidney donors. A positive relationship was observed between medullary, but not cortical, thickness and GFR. We propose that this reflects a correlation between juxtamedullary nephron number and GFR.

Tumor heterogeneity and lack of pre-operative diagnostic biomarkers are key topics in the field of renal cell carcinoma (RCC) identification. Clear cell RCC (ccRCC) is an aggressive cancer subtype which accounts for most RCC related deaths. The capacity to monitor changes at a molecular or biochemical level using two-dimensional (2D) correlated magnetic resonance spectroscopy of human kidney cancer biopsies, offers an insight into how ccRCC differs from other kidney cancer subtypes (termed here, non-ccRCC). Using this technology, two new spectral assignments, isovalerylglycine and α-ketobutyrate, were elevated in the potentially aggressive ccRCC cancer subtype. The crosspeak at F2: 0.95 ppm, F1: 2.05 ppm was assigned to isovalerylglycine and the diagonal resonance at 2.77 ppm to α-ketobutyrate. Isovalerylglycine, an amino acid leucine catabolite, was 55% higher (p = 0.004) and α-ketobutyrate 108% higher (p < 0.001) in ccRCC compared with non-ccRCC tissue biopsies. They were also elevated compared with non-cancer kidney. The increase in α-ketobutyrate in ccRCC compared with non-ccRCC also provides further insight into the role of homocysteine metabolism in kidney cancer. These biomarkers provide metabolic insight that could have future diagnostic or clinical value. They may help develop a spectral signature that, preoperatively, improves distinction between life-threatening ccRCC, non-ccRCC and non-cancer kidney.

Perioperative immune checkpoint inhibitor (ICI) trials for intermediate high-risk clear cell renal cell carcinoma (ccRCC) have failed to consistently demonstrate improved patient outcomes. These unsuccessful ICI trials suggest that the tumour infiltrating immunophenotypes, termed here as the immune cell types, states and their spatial location within the tumour microenvironment (TME), were unfavourable for ICI treatment. Defining the tumour infiltrating immune cells may assist with the identification of predictive immunophenotypes within the TME that are favourable for ICI treatment. To define the immunophenotypes within the ccRCC TME, fresh para-tumour (pTME, n = 2), low-grade (LG, n = 4, G1-G2) and high-grade (HG, n = 4, G3-G4) tissue samples from six patients with ccRCC presenting at a tertiary referral hospital underwent spatial transcriptomics sequencing (ST-seq). Within the generated ST-seq datasets, immune cell types and states, termed here as exhausted/pro-tumour state or non-exhausted/anti-tumour state, were identified using multiple publicly available single-cell RNA and T-cell receptor sequencing datasets as references. HG TMEs revealed abundant exhausted/pro-tumour immune cells with no consistent increase in expression of PD-1, PD-L1 and CTLA4 checkpoints and angiogenic genes. Additional HG TME immunophenotype characteristics included: pro-tumour tissue-resident monocytes with consistently increased expression of HAVCR2 and LAG3 checkpoints; an exhausted CD8+ T cells sub-population with stem-like progenitor gene expression; and pro-tumour tumour-associated macrophages and monocytes within the recurrent TME with the expression of TREM2. Whilst limited by a modest sample size, this study represents the largest ST-seq dataset on human ccRCC. Our study reveals that high-risk ccRCC TMEs are infiltrated by exhausted/pro-tumour immunophenotypes lacking specific checkpoint gene expression confirming that HG ccRCC TME are immunogenic but not ICI favourable.

OBJECTIVE:To identify characteristics associated with the hospitalisation and death of people with COVID-19 living in residential aged care facilities (RACFs).DESIGN:Retrospective cohort study.SETTING, PARTICIPANTS:All confirmed (polymerase chain reaction testing) or probable SARS-CoV-2 infections (rapid antigen tests) in residents of the 86 RACFs in the Metro South Hospital and Health Service area (southeast Queensland), 13 December 2021 - 24 January 2022.MAIN OUTCOME MEASURES:Hospitalisation within 14 days or death within 28 days of COVID-19 diagnosis.RESULTS:Of 1071 RACF residents with COVID-19, 151 were hospitalised within 14 days and 126 died within 28 days of diagnosis. Likelihood of death increased with age (per five years: adjusted odds ratio [aOR], 1.38; 95% confidence interval [CI], 1.21-1.57), but not that of hospitalisation. Men were more likely to be hospitalised (aOR, 1.7; 95% CI, 1.2-2.4) or die (aOR, 2.5; 95% CI, 1.7-3.6) than women. The likelihood of hospitalisation was greater for those with dementia (aOR, 1.9; 95% CI, 1.2-3.0), heart failure (aOR, 1.7; 95% CI, 1.1-2.7), chronic kidney disease (aOR, 1.7; 95% CI, 1.1-2.5), or asthma (aOR, 2.2; 95% CI, 1.2-3.8). The likelihood of death was greater for residents with dementia (aOR, 2.2; 95% CI, 1.3-3.7), diabetes mellitus (aOR, 1.9; 95% CI, 1.3-3.0), heart failure (aOR, 2.0; 95% CI, 1.1-3.3), or chronic lung disease (aOR, 1.7; 95% CI, 1.1-2.7). The likelihood of hospitalisation and death were each higher for residents who had received two or fewer vaccine doses than for those who had received three doses.CONCLUSIONS:Most characteristics that influenced the likelihood of hospitalisation or death of RACF residents with COVID-19 were non-modifiable factors linked with frailty and general health status. Having received three COVID-19 vaccine doses was associated with much lower likelihood of hospitalisation or death.

Background: Routinely used clinical scanners, such as computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US), are unable to distinguish between aggressive and indolent tumor subtypes in masses localized to the kidney, often leading to surgical overtreatment. The results of the current investigation demonstrate that chemical differences, detected in human kidney biopsies using two-dimensional COrrelated SpectroscopY (2D L-COSY) and evaluated using multivariate statistical analysis, can distinguish these subtypes. Methods: One hundred and twenty-six biopsy samples from patients with a confirmed enhancing kidney mass on abdominal imaging were analyzed as part of the training set. A further forty-three samples were used for model validation. In patients undergoing radical nephrectomy, biopsies of non-cancer kidney cortical tissue were also collected as a non-cancer control group. Spectroscopy data were analyzed using multivariate statistical analysis, including principal component analysis (PCA) and orthogonal projection to latent structures with discriminant analysis (OPLS-DA), to identify biomarkers in kidney cancer tissue that was also classified using the gold-standard of histopathology. Results: The data analysis methodology showed good separation between clear cell renal cell carcinoma (ccRCC) versus non-dear cell RCC (non-ccRCC) and non-cancer cortical tissue from the kidneys of tumorbearing patients. Variable Importance for the Projection (VIP) values, and OPLS-DA loadings plots were used to identify chemical species that correlated significantly with the histopathological classification. Model validation resulted in the correct classification of 37/43 biopsy samples, which included the correct classification of 15/17 ccRCC biopsies, achieving an overall predictive accuracy of 86%, Those chemical markers with a VIP value >1.2 were further analyzed using univariate statistical analysis. A subgroup analysis of 47 tumor tissues arising from T1 tumors revealed distinct separation between ccRCC and non-ccRCC tissues. Conclusions: This study provides metabolic insights that could have future diagnostic and/or clinical value. The results of this work demonstrate a dear separation between clear cell and non-ccRCC and non-cancer kidney tissue from tumor-bearing patients. The clinical translation of these results will now require the development of a one-dimensional (ID) magnetic resonance spectroscopy (MRS) protocol, for the kidney, using an in vivo clinical MRI scanner.

This study tested the hypothesis that progression of chronic kidney disease (CKD) is less aggressive in patients whose primary cause of CKD was nephrectomy, compared with non-surgical causes. A sample of 5983 patients from five specialist nephrology practices was ascertained from the Queensland CKD Registry. Rates of kidney failure/death were compared on primary aetiology of CKD using multivariable Cox proportional hazards models. CKD progression was compared using multivariable linear and logistic regression analyses. Of 235 patients with an acquired single kidney as their primary cause of CKD, 24 (10%) and 38 (17%) developed kidney failure or died at median [IQR] follow-up times of 12.9 [2.5–31.0] and 33.6 [18.0–57.9] months after recruitment. Among patients with an eGFR < 45 mL/min per 1.73m2 at recruitment, patients with diabetic nephropathy and PCKD had the highest rates (per 1000 person-years) of kidney failure (107.8, 95% CI 71.0–163.8; 75.5, 95% CI 65.6–87.1); whereas, patients with glomerulonephritis and an acquired single kidney had lower rates (52.9, 95% CI 38.8–72.1; 34.6, 95% CI 20.5–58.4, respectively). Among patients with an eGFR ≥ 45 mL/min per 1.73m2, those with diabetic nephropathy had the highest rates of kidney failure (16.6, 95% CI 92.5–117.3); whereas, those with glomerulonephritis, PCKD and acquired single kidney had a lower risk (11.3, 95% CI 7.1–17.9; 11.7, 95% CI 3.8–36.2; 10.7, 95% CI 4.0–28.4, respectively). Patients who developed CKD after nephrectomy had similar rates of adverse events to most other causes of CKD, except for diabetic nephropathy which was consistently associated with worse outcomes. While CKD after nephrectomy is not the most aggressive cause of kidney disease, it is by no means benign, and is associated with a tangible risk of kidney failure and death, which is comparable to other major causes of CKD.

Anti‐neutrophil cytoplasmic antibody (ANCA)–associated vasculitides are uncommon causes of kidney failure. In kidney transplant recipients who developed kidney failure secondary to ANCA‐associated vasculitis, disease recurrence is unlikely due to ongoing immunosuppression, and patients generally have good immunological outcomes. This study compared transplant outcomes between ANCA‐associated vasculitis and other etiologies of kidney disease. All 18 901 adult kidney transplant recipients (1990‐2018) were ascertained from the ANZDATA Registry. Cox proportional hazards models were used to compare allograft failure between etiologies of kidney disease. Of 254 participants whose primary disease was ANCA‐associated vasculitis, 95 (37%) developed allograft failure; of those who developed graft failure, 62 (65%) died with a functioning allograft. Compared with patients with IgA nephropathy, those with ANCA‐associated vasculitis had higher rates of all‐cause allograft failure (HR: 1.4, 95% CI: 1.2‐1.7); however, rates of death‐censored allograft failure were similar (HR: 1.0, 95% CI: 0.7‐1.4). The most frequent causes of death in the ANCA‐vasculitis group who died with a functioning graft were infection (23%) and malignancy (36%). Kidney transplant recipients who developed kidney failure secondary to ANCA‐associated vasculitis may have had a higher risk of dying due to complications of immunosuppression compared with most other causes of kidney failure; however, they also had lower risks of disease recurrence and rejection.

Thrombotic microangiopathy (TMA) is characterised by abnormalities in the walls of arterioles and capillaries, precipitated by hereditary or acquired characteristics, and culminating in microvascular thrombosis because of dysregulated complement activity. A number of drugs can precipitate TMA, including vascular endothelial growth factor (VEGF) inhibitors, because of their effects on endothelial repair. Pazopanib is a VEGF inhibitor used for the treatment of renal cell carcinoma (RCC); it is uncommonly associated with TMA. A 52-year-old male, 5 years post his second kidney transplant secondary to immunoglobulin (Ig) A nephropathy, presented with hypertension, fluid overload, and worsening graft function (peak creatinine 275 µmol/L, baseline 130–160 µmol/L) and nephrotic range proteinuria 2 months after commencing pazopanib for metastatic RCC. His maintenance immunosuppression included ciclosporin, mycophenolate, and prednisolone. Haematological parameters were unremarkable. Allograft biopsy demonstrated glomerular and arteriolar changes consistent with chronic active TMA, with overlying fea-tures of borderline cellular rejection. He was treated with intravenous methylprednisolone 250 mg for 3 days and commenced on irbesartan 75 mg daily. Drug-induced TMA from pazopanib was suspected, particularly given the documented association with other tyrosine kinase inhibitors (TKIs). In consultation with his medical oncologist, pazopanib was ceased, and an alternate TKI cabozantinib was commenced. Serum creatinine remained <200 µmol/L 3 months after admission. This is the first reported biopsy-proven case of TMA attributed to pazopanib in a kidney transplant recipient. With increasing clinical indications for and availability of TKIs, clinicians need to be aware of their association with TMA events in kidney transplant recipients, who are already susceptible to TMA due to abnormal vasculature, infectious triggers, ischaemia-reperfusion injury, and use of calcineurin inhibitor.