Genetic Deletion of the Lipid Raft Protein Caveolin-1 Leads to Worsening Renal Fibrosis (2018)

Type of publication:
Journal article

Author(s):
*Chand S , Hazeldine J, Smith S, Borrows R.

Citation:
Journal of Clinical Nephrology and Renal Care 2018 Jun;4(1):037

Abstract:
Background
Renal disease is a major global public health issue. Renal interstitial fibrosis is the characteristic histopathological finding in all progressive renal disease. Caveolin-1 is the essential structural protein for lipid rafts called caveolae that are ubiquitously distributed among fibroblasts, endothelial and epithelial cells. Caveolin-1 acts as an intracellular signalling pathway chaperone in fibrotic disease. Presently, caveolin-1 expression is associated with more severe renal disease in human and previous murine studies. In non-renal fibrosis, caveolin-1 protects against fibrosis. The purpose of this study was to investigate if caveolin-1 knockout led to an increased fibrotic phenotype using the unilateral ureteric obstruction model of renal fibrosis.
Methods
Using 2 time-points of the unilateral ureteric obstruction model, wild-type and caveolin-1 knockout mouse kidneys were analysed for caveolin-1 expression and markers of fibrosis using histology, Gomori staining, real-time quantified polymerase chain reaction, Western blotting and confocal microscopy.
Results
Confocal microscopy shows caveolin-1 staining mainly in glomerulus, lining of tubules as well as the vasculature. There was increased caveolin-1 expression the longer the unilateral obstruction occurred as well as in the contralateral compensating non-obstructed kidney. Caveolin-1 knockout had less fibrosis at day 3 histologically but more at day 14 as compared to wild-type. There were significantly more F4/80 positive staining cells at day 3 and day 14 in the wild-type injured kidney as compared to the caveolin-1 knockout mouse.
Conclusion
Caveolin-1 knockout leads to a worse fibrosis upon unilateral ureteric obstruction. Caveolin-1 expression manipulation timing remains to be elucidated in reducing renal fibrosis.

Link to full-text [no password required]

Strategies for investigating the genetics of chronic kidney disease (2018)

Type of publication:
Journal article

Author(s):
*Chand S.

Citation:
Scientific Journal of Genetics and Gene Therapy. 2018 July 4(1): 004-006.

Abstract:
This short review describes the strategies employed for investigating genetic variation in chronic kidney disease as well as highlighting potential shortfalls that should be overcome in future studies.

Link to full-text [no password required]

Caveolin-1 in renal disease (2018)

Type of publication:
Journal article

Author(s):
*Chand S.

Citation:
Scientific Journal of Genetics and Gene Therapy. 2018 July: 007-014.

Abstract:
Caveolin-1 is the essential structural formation for lipid raft formation. It has been ascribed to several
disease processes in humans due to its ubiquitous distribution. Patients with chronic kidney disease suffer
great morbidity and mortality where manipulation of caveolin-1 could lead to new potential therapeutic
targets in this patient group. This review highlights caveolin-1 structure, signalling and provides examples
of studies of caveolin-1 single nucleotide polymorphism in chronic kidney disease.

Link to full-text [no password required]

Risk Prediction for Acute Kidney Injury in Acute Medical Admissions in the UK (2019)

Type of publication:
Journal article

Author(s):
The RISK investigators [including *Chand, S ]

Citation:
QJM: An International Journal of Medicine, Volume 112, Issue 3, March 2019, Pages 197–205

Abstract:
Background
Acute Kidney Injury (AKI) is associated with adverse outcomes; therefore identifying patients who are at risk of developing AKI in hospital may lead to targeted prevention.

Aim
We undertook a UK-wide study in acute medical units (AMUs) to define those who develop hospital-acquired AKI (hAKI); to determine risk factors associated with hAKI and to assess the feasibility of developing a risk prediction score.

Design
Prospective multi-centre cohort study across 72 AMUs in the UK.

Methods
Data collected from all patients who presented over a 24-h period. Chronic dialysis, community-acquired AKI (cAKI) and those with fewer than two creatinine measurements were excluded. Primary outcome was the development of h-AKI.

Results
Two thousand four hundred and fourty-six individuals were admitted to the seventy-two participating centres. Three hundred and eighty-four patients (16%) sustained AKI of whom two hundred and eighty-seven (75%) were cAKI and ninety-seven (25%) were hAKI. After exclusions, chronic kidney disease [Odds Ratio (OR) 3.08, 95% Confidence Interval (CI) 1.96–4.83], diuretic prescription (OR 2.33, 95% CI 1.5–3.65), a lower haemoglobin concentration and elevated serum bilirubin were independently associated with development of hAKI. Multi-variable model discrimination was only moderate (c-statistic 0.75).

Conclusions
AKI in AMUs is common and associated with worse outcomes, with the majority of cases community acquired. Only a small proportion of patients develop hAKI. Prognostic risk factor modelling demonstrated only moderate discrimination implying that widespread adoption of such an AKI clinical risk score across all AMU admissions is not currently justified. More targeted risk assessment or automated methods of calculating individual risk may be more appropriate alternatives.

Altmetrics

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study) (2019)

Type of publication:
Journal article

Author(s):

Schmidinger M.; Bamias A.; Procopio G.; Hawkins R.; Sanchez A.R.; Vazquez S.; *Srihari N.; Kalofonos H.; Bono P.; Pisal C.B.; Hirschberg Y.; Dezzani L.; Ahmad Q.; Jonasch E.; Gimeno R.A.; Herranz U.A.; Ardavanis A.; Ashraf S.A.; Barone C.; Bella S.R.; Belz H.; Companario E.B.; Bolling C.; Bothe K.; Carteni G.; Espinosa J.C.; Clausse M.; Confente C.; Coskun H.; Herrero G.C.; Demey W.; D’hondt R.; Santasusana M.D.; Doshi G.; Elkiran E.; Facchini G.; Fein L.; Calvo O.F.; Flaherty A.; Fountzilas G.; Fruehauf J.; Diaz E.G.; Garcia R.; Dominguez R.G.; Ghosn M.; Glorieux P.; Goebell P.J.; Gutierrez L.G.-A.; Gonzalez M.; Green N.B.; Arnau M.G.; Harich H.-D.; Hegele A.; Perez C.H.; Herrmann E.; Horniniger W.J.; Hutson T.E.; Janetschek G.; Kalantari H.; Klausmann M.; Kolin M.; Krause S.; Kroening H.; Sorrosal J.J.L.; Lazaro M.; Lema M.; Lema M.L.; Lin J.; Lueck A.; Lybaert W.; Magi A.; Marina V.A.; Rey J.P.M.; Matus G.; Melear J.; Gonzalez B.M.; Milella M.; Montalar J.; Ferrandis J.M.; Nathan P.; Nechushtan H.; Nusch A.; Ojamaa K.; Oksuzoglu B.; Ozkan M.; Papazisis K.; Passalacqua R.; Pe’er A.; Gracia J.L.P.; Pichler A.; Pokker H.; Porta C.; Rauchenwald M.; Richardet M.E.; Richey S.L.; Garcia J.M.R.; Rudolph R.; Sabbatini R.; Salmon J.-P.; Lobera C.S.; Sarid D.L.; Saylors G.B.; Schrijvers D.; Schulze M.; Sevilay A.; Shumaker G.G.; Siemer S.; de Prado y Otero D.S.; Stoiber F.; Rodriguez C.S.; Varela M.S.; Vasanthan S.; Estevez S.V.; Vehling-Kaiser U.; Vogelzang N.; Weiss H.; Whenham N.; Wyendaele W.; Yildiz R.; Yucel I.; Zarba J.J.; Zarkar A.; Zhong W.; Ziem P.

Citation:
The Oncologist; Apr 2019; vol. 24 (no.4); p. 491-497

Abstract:
BACKGROUND Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC).SUBJECTS, MATERIALS, AND METHODS Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups.RESULTS Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. CONCLUSION PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. IMPLICATIONS FOR PRACTICE PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months.

Full-text available [NHS OpenAthens account required]

Altmetrics

Biomarkers and Pharmacogenomics in Kidney Transplantation (2018)

Type of publication:
Journal article

Author(s):
Crowley, L E; *Mekki, M; *Chand, S

Citation:
Molecular Diagnosis and Therapy; Oct 2018; vol. 22 (no. 5); p. 537-550

Abstract:
This review is focused on present and future biomarkers, along with pharmacogenomics used in clinical practice for kidney transplantation. It aims to highlight biomarkers that could potentially be used to improve kidney transplant early and long-term graft survival, but also potentially patient co-morbidity. Future directions for improving outcomes are discussed, which include immune tolerance and personalising immunosuppression regimens.

How accurate is glycated haemoglobin in patients with liver cirrhosis? A case series (2018)

Type of publication:
Conference abstract

Author(s):
*Basavaraju N.; *Rangan S.; *Singh P.; *Moulik P

Citation:
Diabetic Medicine; Mar 2018; vol. 35 ; S1

Abstract:
Introduction: Glycated haemoglobin (HbA1c) is the gold standard for monitoring glycaemic control in patients with diabetes. We present three cases of chronic liver disease where HbA1c may be misleading. Case 1: A 71-year-old Caucasian woman with liver cirrhosis due to hepatitis C, Type 2 diabetes, previous bladder tuberculosis and chronic kidney disease stage 3 was evaluated in clinic. Her capillary glucose (CG) was 6 to 9 mmol/l, no hypoglycaemia. She was anaemic; HbA1c was low at 34mmol/mol. Fructosamine was elevated at 296umol/l (205 to 285). Case 2: A 38-year-old Caucasian man with alcoholic liver cirrhosis, portal hypertension, and Type 2 diabetes was admitted with haematemesis. His CG was 10 to 14 mmol/l and HbA1c 26mmol/mol. He had iron deficiency anaemia, deranged liver enzymes and renal function. Fructosamine was normal at 246umol/l. Case 3: A 65-year-old Caucasian woman with non-alcoholic steatohepatosis/cirrhosis, portal hypertension, Type 2 diabetes, iron deficiency anaemia was admitted with melena. Her CG was 12 to 14mmol/l and HbA1c 44mmol/mol. Results showed acute kidney injury, deranged liver enzymes, normal albumin but low haemoglobin. Fructosamine is awaited. All patients required insulin for management of their diabetes. Discussion: The degree of glycation (glucose binding to N-terminal valine of HbA) is dependent on glycation rate, glucose availability and lifespan of red blood cells. Reference range of HbA1c is based on normal lifespan of RBC. There are very limited studies in evaluating the accuracy of HbA1c in chronic liver disease (CLD). Multiple factors can shorten RBC survival in CLD, including anaemia, portal hypertension, hypersplenism, variceal bleeding, resulting in falsely low HbA1c. Fructosamine, glycated albumin can also be inaccurate. Capillary glucose monitoring should guide glycaemic management.

Link to full-text [NHS OpenAthens account required]