Publications by authors named "Mark Jesky"

22 Publications

  • Page 1 of 1

Imbalanced turnover of collagen type III is associated with disease progression and mortality in high-risk chronic kidney disease patients.

Clin Kidney J 2021 Feb 14;14(2):593-601. Epub 2020 Jan 14.

College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: Tubulointerstitial fibrosis is a major pathological feature in chronic kidney disease (CKD) and collagen type III (COL3) is a major component of the renal fibrotic scar. We hypothesized that a dysregulated turnover of COL3 is an important determinant of CKD progression. We assessed the relationship between fragments reflecting active formation (PRO-C3) and degradation (C3M) of COL3 and CKD disease progression and mortality in a prospective cohort of CKD patients.

Methods: We measured PRO-C3 and C3M in urine (uPRO-C3 and uC3M) and serum (sPRO-C3 and sC3M) of 500 patients from the Renal Impairment in Secondary Care study. Disease progression was defined as a decline in estimated glomerular filtration rate >30% or the start of renal replacement therapy within 12 and 30 months.

Results: Levels of uC3M/creatinine decreased, whereas levels of uPRO-C3/creatinine and sPRO-C3 increased with increasing CKD stage. uC3M/creatinine was inversely and independently associated with disease progression by 12 months {odds ratio [OR] 0.39 [95% confidence interval (CI) 0.18-0.83]; P = 0.01 per doubling of uC3M/creatinine} with development of end-stage renal disease [hazard ratio (HR) 0.70 (95% CI 0.50-0.97); P = 0.03 per doubling of uC3M/creatinine]. sPRO-C3 at baseline was independently associated with increased mortality [HR 1.93 (95% CI 1.21-3.1); P = 0.006 per doubling of sPRO-C3] and disease progression by 30 months [OR 2.16 (95% CI 1.21-3.84); P = 0.009 per doubling of sPRO-C3].

Conclusions: Dynamic products of COL3 formation and degradation were independently associated with CKD progression and mortality and may represent an opportunity to link pathological processes with targeted treatments against fibrosis.
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http://dx.doi.org/10.1093/ckj/sfz174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886548PMC
February 2021

Collapsing Glomerulopathy Affecting Native and Transplant Kidneys in Individuals with COVID-19.

Nephron 2020 7;144(11):589-594. Epub 2020 Sep 7.

Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom,

Since the emergency of novel coronavirus COVID-19 (SARS-CoV-2) in December 2019, infections have spread rapidly across the world. The reported incidence of acute kidney injury (AKI) in the context of COVID-19 is variable, and its mechanism is not well understood. Data are emerging about possible mechanisms of AKI including virus-induced cytopathic effect and cytokine storm-induced injury. To date, there have been few reports of kidney biopsy findings in the context of AKI in COVID-19 infection. This article describes 2 cases of collapsing glomerulopathy, 1 in a native kidney and, for the first time, 1 in a kidney transplant. Both individuals were black, and both presented without significant respiratory compromise. Indeed, the 2 patients we describe remained systemically well for the majority of their inpatient stay, which would support the hypothesis that for these patients, AKI was caused by a cytopathic viral effect, rather than that of a cytokine storm or acute tubular necrosis caused by prolonged hypovolaemia or the effect of medication known to exacerbate AKI. Here, we report 2 cases of AKI with collapsing glomerulopathy in COVID-19, one of which is in a kidney transplant recipient, not previously described elsewhere.
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http://dx.doi.org/10.1159/000509938DOI Listing
November 2020

High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial.

Lancet Haematol 2019 Apr 11;6(4):e217-e228. Epub 2019 Mar 11.

Centre for Clinical Haematology, University of Birmingham, Birmingham, UK.

Background: In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD).

Methods: In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6-8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602.

Findings: Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74-1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group.

Interpretation: In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients.

Funding: Gambro, Janssen, and Binding Site.
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http://dx.doi.org/10.1016/S2352-3026(19)30014-6DOI Listing
April 2019

A novel biomarker of laminin turnover is associated with disease progression and mortality in chronic kidney disease.

PLoS One 2018 1;13(10):e0204239. Epub 2018 Oct 1.

Department of Renal Medicine, Queen Elizabeth Hospital, Birmingham, United Kingdom.

Background: Patients with chronic kidney disease (CKD) have increased risk of development of end-stage renal disease (ESRD) and early mortality. Fibrosis is the central pathogenic process in CKD and is caused by dysregulated extracellular matrix (ECM) remodeling. The laminin γ1 chain (LAMC1) is a core structural protein present in the basement membrane of several organs, including the kidneys. We hypothesized that dysregulation of LAMC1 remodeling could be associated with a higher risk of adverse clinical outcomes in patients with CKD.

Methods: A novel immunoassay targeting LG1M, a specific MMP-9-generated neo-epitope fragment of LAMC1, was developed and used to measure the levels of the fragment in urine and serum from 492 patients from the Renal Impairment in Secondary Care (RIISC) study, a prospective cohort of patients with high-risk CKD. Patients were monitored for a median follow-up time of 3.5 years. Associations between serum and urine LG1M levels and progression of CKD at 12 months were assessed by a multivariable logistic regression model. The association with ESRD or mortality was assessed by Kaplan-Meier survival curves and Cox proportional hazards regression.

Results: Forty-six (11%) of the 416 patients who reached 12-month follow-up had progression of CKD; during the study follow-up, 125 patients (25.4%) developed ESRD and 71 patients (14.4%) died. Serum and urine levels of LG1M correlated with baseline eGFR (r = -0.43, p<0.0001 and r = -0.17, p = 0.0002, respectively). Serum levels of LG1M were higher in patients with one-year progression of CKD compared to those who did not progress (p<0.01). Baseline serum levels of LG1M were associated with development of ESRD (HR 3.2, 95% CI 1.99-5.2 for patients in the highest LG1M tertile compared to patient in the lowest tertile). Baseline urinary levels of LG1M (uLG1M) were significantly associated with mortality (HR 5.0, 95% CI 2.8-8.9, p<0.0001 for patients in the highest LG1M tertile compared to patients in the lowest tertile). Urine LG1M was retained in the model for prediction of mortality (HR per standard deviation of uLG1M: 1.01, 95% CI 1.00-1.02, p = 0.001).

Conclusions: LG1M, a marker of basement membrane remodeling, is increased in serum and urine of patients with CKD and levels are associated with one-year disease progression, development of ESRD, and mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204239PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166934PMC
March 2019

Association of Elevated Urinary miR-126, miR-155, and miR-29b with Diabetic Kidney Disease.

Am J Pathol 2018 09 6;188(9):1982-1992. Epub 2018 Jul 6.

Wales Kidney Research Unit, Division of Infection and Immunity, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom; Cardiff Institute of Tissue Engineering and Repair, Cardiff University, Cardiff, United Kingdom. Electronic address:

Effective diabetic kidney disease (DKD) biomarkers remain elusive, and urinary miRNAs represent a potential source of novel noninvasive disease sentinels. We profiled 754 miRNAs in pooled urine samples from DKD patients (n = 20), detecting significantly increased miR-126, miR-155, and miR-29b compared with controls (n = 20). These results were confirmed in an independent cohort of 89 DKD patients, 62 diabetic patients without DKD, and 41 controls: miR-126 (2.8-fold increase; P < 0.0001), miR-155 (1.8-fold increase; P < 0.001), and miR-29b (4.6-fold increase; P = 0.024). Combined receiver operating characteristic curve analysis resulted in an area under the curve of 0.8. A relative quantification threshold equivalent to 80% sensitivity for each miRNA gave a positive signal for 48% of DKD patients compared with 3.6% of diabetic patients without DKD. Laser-capture microdissection of renal biopsy specimens, followed by quantitative RT-PCR, detected miR-155 in glomeruli and proximal and distal tubules, whereas miR-126 and miR-29b were most abundant in glomerular extracts. Subsequent experiments showed miR-126 and miR-29b enrichment in glomerular endothelial cells (GEnCs) compared with podocytes, proximal tubular epithelial cells, and fibroblasts. Significantly increased miR-126 and miR-29b were detected in GEnC conditioned medium in response to tumor necrosis factor-α and transforming growth factor-β1, respectively. Our data reveal an altered urinary miRNA profile associated with DKD and link these variations to miRNA release from GEnCs.
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http://dx.doi.org/10.1016/j.ajpath.2018.06.006DOI Listing
September 2018

Association between urinary free light chains and progression to end stage renal disease in chronic kidney disease.

PLoS One 2018 9;13(5):e0197043. Epub 2018 May 9.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Background: Patients with chronic kidney disease (CKD) are at an increased risk of developing end-stage renal disease (ESRD). We assessed for the first time whether urinary free light chains (FLC) are independently associated with risk of ESRD in patients with CKD, and whether they offer incremental value in risk stratification.

Materials And Methods: We measured urinary FLCs in 556 patients with CKD from a prospective cohort study. The association between urinary kappa/creatinine (KCR) and lambda/creatinine (LCR) ratios and development of ESRD was assessed by competing-risks regression (to account for the competing risk of death). The change in C-statistic and integrated discrimination improvement were used to assess the incremental value of adding KCR or LCR to the Kidney Failure Risk Equation (KFRE).

Results: 136 participants developed ESRD during a median follow-up time of 51 months. Significant associations between KCR and LCR and risk of ESRD became non-significant after adjustment for estimated glomerular filtration rate (eGFR) and albumin/creatinine ratio (ACR), although having a KCR or LCR >75th centile remained independently associated with risk of ESRD. Neither KCR nor LCR as continuous or categorical variables provided incremental value when added to the KFRE for estimating risk of ESRD at two years.

Conclusions: Urinary FLCs have an association with progression to ESRD in patients with CKD which appears to be explained to a degree by their correlation with eGFR and ACR. Levels above the 75th centile do have an independent association with ESRD, but do not improve upon a current model for risk stratification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197043PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942781PMC
August 2018

Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease.

PLoS One 2018 16;13(4):e0195730. Epub 2018 Apr 16.

University of Birmingham, Birmingham, United Kingdom.

Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901993PMC
July 2018

Urinary endotrophin predicts disease progression in patients with chronic kidney disease.

Sci Rep 2017 12 11;7(1):17328. Epub 2017 Dec 11.

Department of Renal Medicine, Queen Elizabeth Hospital, Birmingham, UK.

Renal fibrosis is the central pathogenic process in progression of chronic kidney disease (CKD). Collagen type VI (COL VI) is upregulated in renal fibrosis. Endotrophin is released from COL VI and promotes pleiotropic pro-fibrotic effects. Kidney disease severity varies considerably and accurate information regarding CKD progression may improve clinical decisions. We tested the hypothesis that urinary endotrophin derived during COL VI deposition in fibrotic human kidneys is a marker for progression of CKD in the Renal Impairment in Secondary Care (RIISC) cohort, a prospective observational study of 499 CKD patients. Endotrophin localised to areas of increased COL VI deposition in fibrotic kidneys but was not present in histologically normal kidneys. The third and fourth quartiles of urinary endotrophin:creatinine ratio (ECR) were independently associated with one-year disease progression after adjustment for traditional risk factors (OR (95%CI) 3.68 (1.06-12.83) and 8.65 (2.46-30.49), respectively). Addition of ECR quartiles to the model for disease progression increased prediction as seen by an increase in category-free net reclassification improvement (0.45, 95% CI 0.16-0.74, p = 0.002) and integrated discrimination improvement (0.04, 95% CI 0.02-0.06, p < 0.001). ECR was associated with development of end-stage renal disease (ESRD). It is concluded that ECR predicts disease progression of CKD patients.
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http://dx.doi.org/10.1038/s41598-017-17470-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725589PMC
December 2017

Arterial stiffness alone does not explain arteriovenous fistula outcomes.

J Vasc Access 2018 Jan;19(1):63-68

1 Department of Vascular Access and Renal Transplantation, University Hospitals Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham - UK.

Introduction: Marked arterial adaptation is critical in permitting and sustaining the increased blood flow within an arteriovenous fistula (AVF). The aim of this investigation was to evaluate markers of arterial disease and their association with the early post-operative AVF outcomes.

Methods: We included all patients in whom an AVF had been performed after enrolment to the Renal Impairment In Secondary Care (RIISC) study. Primary AVF failure (PFL) was defined as thrombosis at six-week review. All patients underwent BP Tru and Vicorder pulse wave analysis assessments and also had assays of advanced glycation end-products prior to AVF formation. These were correlated with the short-term AVF outcomes.

Results: One hundred and eight AVFs were created in 86 patients. The primary patency (PPT) group were found to have significantly higher body mass index (BMI) (p = 0.01). Intraluminal vein diameter was significantly greater in the PPT group than the PFL group (p≤0.01). Mean augmentation index and augmentation index 75 was significantly higher in the PPT group than the PFL group (p = 0.03 and 0.03, respectively). Aortic pulse wave velocity was slower in the PPT group at 10.2 m/s than the PFL group at 10.8 m/s (p = 0.32). Advanced glycation end-product measurements did not vary significantly between the PPT and PFL groups (p = 0.4). Logistic regression analysis provided a predictive model, which demonstrated a predictive value of 78.1% for AVF patency at 6 weeks.

Conclusions: All patients in this end-stage renal disease cohort have significant aortic stiffness. The results for pulse wave velocity were slower in the PPT group suggesting a tendency towards stiffer vessels and PFL.
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http://dx.doi.org/10.5301/jva.5000791DOI Listing
January 2018

Early eculizumab use in atypical haemolytic uraemic syndrome in a Jehovah's Witness refusing blood products.

Oxf Med Case Reports 2017 Jun 15;2017(6):omx025. Epub 2017 Jun 15.

Department of Nephrology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Thrombotic microangiopathy (TMA) is characterized by microscopic angiopathic haemolytic anaemia, thrombocytopenia and organ injury. Supportive therapies include the use of blood products. Recently the terminal complement inhibitor eculizumab has been approved in atypical haemolytic uraemic syndrome (aHUS) in some countries. We report the case of a 23-year-old female Jehovah's Witness presenting with vaginal haemorrhage from thrombocytopaenia, severe anaemia (nadir Hb 28 g/L) and anuric acute kidney injury with TMA secondary to aHUS. Despite a life threatening illness, the patient declined the use of blood components and plasma exchange. Eculizumab was administered early with subsequent improvement and resolution of haemolysis, return to baseline renal function whilst avoiding use of blood products. This case demonstrates the effective use of eculizumab for life saving therapy in a patient refusing blood products. It highlights the importance of accessibility for high cost therapies, but the disparity in access between healthcare systems.
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http://dx.doi.org/10.1093/omcr/omx025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471596PMC
June 2017

Serum endotrophin, a type VI collagen cleavage product, is associated with increased mortality in chronic kidney disease.

PLoS One 2017 12;12(4):e0175200. Epub 2017 Apr 12.

Nordic Bioscience A/S, Herlev Hovedgade, Herlev, Denmark.

Background: Patients with chronic kidney disease (CKD) are at increased risk of end-stage renal disease (ESRD) and early mortality. The underlying pathophysiological processes are not entirely understood but may include dysregulation of extracellular matrix formation with accelerated systemic and renal fibrosis. We assessed the relationship between endotrophin (ETP), a marker of collagen type VI formation, and adverse outcomes in a cohort of patients with CKD.

Methods: We measured serum ETP levels in 500 patients from the Renal Impairment in Secondary Care (RIISC) study, a prospective observational study of patients with high-risk CKD. Patients were followed up until death or progression to ESRD. Cox regression analysis was used to assess the relationship between ETP and risk of adverse outcomes.

Results: During a median follow-up time of 37 months, 104 participants progressed to ESRD and 66 died. ETP level was significantly associated with progression to ESRD (HR 1.79 [95% CI 1.59-2.02] per 10 ng/mL increase; HR 11.05 [4.98-24.52] for highest vs lowest quartile; both P<0.0001). ETP level was also significantly associated with mortality (HR 1.60 [1.35-1.89] per 10 ng/mL increase; HR 12.14 [4.26-34.54] for highest vs lowest quartile; both P<0.0001). After adjustment for confounding variables, ETP was no longer significantly associated with progression to ESRD but remained independently associated with mortality (HR 1.51 [1.07-2.12] per 10 ng/mL increase, P = 0.019).

Conclusions: Serum ETP level is independently associated with mortality in CKD. This study provides the basis for further exploratory work to establish whether collagen type VI formation is mechanistically involved in the increased mortality risk associated with CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175200PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389629PMC
April 2017

Health-Related Quality of Life Impacts Mortality but Not Progression to End-Stage Renal Disease in Pre-Dialysis Chronic Kidney Disease: A Prospective Observational Study.

PLoS One 2016 10;11(11):e0165675. Epub 2016 Nov 10.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Background: Chronic kidney disease (CKD) is associated with reduced health-related quality of life (HRQL). However, the relationship between pre-dialysis CKD, HRQL and clinical outcomes, including mortality and progression to end-stage renal disease (ESRD) is unclear.

Methods: All 745 participants recruited into the Renal Impairment In Secondary Care study to end March 2014 were included. Demographic, clinical and laboratory data were collected at baseline including an assessment of HRQL using the Euroqol EQ-5D-3L. Health states were converted into an EQ-5Dindex score using a set of weighted preferences specific to the UK population. Multivariable Cox proportional hazards regression and competing risk analyses were undertaken to evaluate the association of HRQL with progression to ESRD or all-cause mortality. Regression analyses were then performed to identify variables associated with the significant HRQL components.

Results: Median eGFR was 25.8 ml/min/1.73 m2 (IQR 19.6-33.7ml/min) and median ACR was 33 mg/mmol (IQR 6.6-130.3 mg/mmol). Five hundred and fifty five participants (75.7%) reported problems with one or more EQ-5D domains. When adjusted for age, gender, comorbidity, eGFR and ACR, both reported problems with self-care [hazard ratio 2.542, 95% confidence interval 1.222-5.286, p = 0.013] and reduced EQ-5Dindex score [hazard ratio 0.283, 95% confidence interval 0.099-0.810, p = 0.019] were significantly associated with an increase in all-cause mortality. Similar findings were observed for competing risk analyses. Reduced HRQL was not a risk factor for progression to ESRD in multivariable analyses.

Conclusions: Impaired HRQL is common in the pre-dialysis CKD population. Reduced HRQL, as demonstrated by problems with self-care or a lower EQ-5Dindex score, is associated with a higher risk for death but not ESRD. Multiple factors influence these aspects of HRQL but renal function, as measured by eGFR and ACR, are not among them.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104414PMC
June 2017

Serum tryptase concentration and progression to end-stage renal disease.

Eur J Clin Invest 2016 May 15;46(5):460-74. Epub 2016 Apr 15.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Background: Mast cell activation can lead to nonclassical activation of the Renin-Angiotensin-Aldosterone System. However, the relevance of this to human chronic kidney disease is unknown. We assessed the association between serum tryptase, a product of mast cell activation, and progression to end-stage renal disease or mortality in patients with advanced chronic kidney disease. We stratified patients by use of angiotensin-converting enzyme inhibitors/angiotensin receptor II blockers (ACEi/ARB).

Materials And Methods: This was a prospective cohort study of 446 participants recruited into the Renal Impairment in Secondary Care study. Serum tryptase was measured at recruitment by sandwich immunoassay. Cox regression analysis was undertaken to determine variables associated with progression to end-stage renal disease or death.

Results: Serum tryptase concentration was independently associated with progression to end-stage renal disease but not with death. In patients treated with ACEi or ARB, there was a strong independent association between higher tryptase concentrations and progression to end-stage renal disease; when compared to the lowest tertile, tryptase concentrations in the middle and highest tertiles had hazard ratios [HR] of 5·78 (95% confidence interval [CI] 1·19-28·03, P = 0·029) and 6·19 (95% CI 1·49-25·69, P = 0·012), respectively. The other independent risk factors for progression to end-stage renal disease were lower age, male gender, lower estimated glomerular filtration rate and higher urinary albumin creatinine ratio.

Conclusion: Elevated serum tryptase concentration is an independent prognostic factor for progression to end-stage renal disease in patients with chronic kidney disease who are receiving treatment with an ACEi or ARB.
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http://dx.doi.org/10.1111/eci.12622DOI Listing
May 2016

Caveolin-1 single-nucleotide polymorphism and arterial stiffness in non-dialysis chronic kidney disease.

Nephrol Dial Transplant 2016 07 3;31(7):1140-4. Epub 2015 Oct 3.

Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, UK Centre for Translational Inflammation Research, University of Birmingham, Birmingham, UK.

Background: Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD.

Methods: Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology.

Results: The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders.

Conclusions: This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations.
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http://dx.doi.org/10.1093/ndt/gfv350DOI Listing
July 2016

Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury.

Eur J Haematol 2016 Jun 16;96(6):610-7. Epub 2015 Sep 16.

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

Objectives: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function.

Methods: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined.

Results: Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8-93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months.

Conclusion: In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to myeloma cast nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function.
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http://dx.doi.org/10.1111/ejh.12644DOI Listing
June 2016

Do Obese Individuals With Hypertension Have More Difficult-to-Control Blood Pressure and End Organ Damage Than Their Nonobese Counterparts?

J Clin Hypertens (Greenwich) 2015 Jun 23;17(6):466-72. Epub 2015 Mar 23.

Renal Unit, Birmingham Heartlands Hospital, Birmingham, UK.

The authors assessed whether individuals with elevated body mass index (BMI) and hypertension had more difficult-to-control blood pressure (BP) and more evidence of end organ damage using data collected prospectively over 11 years from a secondary care hypertension clinic. A total of 1114 individuals were divided by BMI criteria into normal (n=207), overweight (n=440), and obese (n=467). Mean daytime, nighttime, and 24-hour systolic BP and diastolic BP were similar in all groups. There was less nocturnal dip in obese compared with overweight groups (P=.025). Individuals with a normal BMI were taking fewer antihypertensive medications than those in the obese group (P=.01). Individuals classified as obese had a higher left ventricular mass index than those with a normal BMI (female, P=.028; male, P<.001); this relationship remained after multivariate linear regression. Obese individuals with hypertension required more medication to achieve similar mean ambulatory BP values, had less nocturnal dip in BP, and had a higher prevalence of left ventricular hypertrophy. As such, obese patients are at potentially increased risk of cardiovascular events.
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http://dx.doi.org/10.1111/jch.12532DOI Listing
June 2015

Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease.

Mayo Clin Proc 2014 May;89(5):615-22

Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, United Kingdom; Division of Immunity and Infection, University of Birmingham, Medical School, Birmingham, United Kingdom. Electronic address:

Objective: To determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD).

Patients And Methods: From January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels. The cohort was prospectively followed up for a median of 63 months (interquartile range, 0-93 months). Cox regression analysis was performed to determine variables predictive of mortality.

Results: High cFLC levels were an independent risk factor for death (hazard ratio [HR], 2.71; 95% CI, 1.98-3.70; P<.001). Other independent risk factors were age (HR, 1.79; 95% CI, 1.52-2.10; P<.001), South Asian ethnicity (HR, 0.33; 95% CI, 0.14-0.64; P=.02), preexisting cardiovascular disease (HR, 1.59; 95% CI, 1.09-2.31; P=.02), and high-sensitivity C-reactive protein (HR, 1.13; 95% CI, 1.00-1.28; P=.04). Neither estimated glomerular filtration rate nor albuminuria was an independent risk factor for death.

Conclusion: High cFLC levels independently predict mortality in people with CKD.
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http://dx.doi.org/10.1016/j.mayocp.2014.01.028DOI Listing
May 2014

The periodontal health component of the Renal Impairment In Secondary Care (RIISC) cohort study: a description of the rationale, methodology and initial baseline results.

J Clin Periodontol 2014 Jul 14;41(7):653-61. Epub 2014 May 14.

Periodontal Research Group, School of Dentistry, University of Birmingham, Birmingham, UK.

Introduction: Chronic kidney disease (CKD) is associated with significant morbidity and mortality. There is a need to identify novel and modifiable risk factors in such patients. The periodontal component of the Renal Impairment In Secondary Care (RIISC) study aims to evaluate the association between chronic periodontitis and CKD progression.

Methods: The RIISC study is a prospective, observational cohort study of patients with CKD from a renal clinic at a hospital in the West Midlands region of the UK. Patients undergo a periodontal examination and plaque and saliva sampling. To benchmark the oral health status of the RIISC cohort, we compared it to the Adult Dental Health Survey 2009 (ADHS), a representative survey of the oral health of community dwelling adults in the UK.

Results: Of the first 500 patients recruited into the RIISC study, 469 patients underwent a dental examination and 80 (17%) were edentulous. Among dentate subjects, patients within RIISC were significantly more likely to have any (OR 4.0 95% CI 2.7-5.9) or severe (OR 3.8 95% CI 2.5-5.6) periodontitis compared to the ADHS sample.

Conclusion: The prevalence and severity of chronic periodontitis in this cohort of CKD patients is markedly higher than a geographically matched control population.
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http://dx.doi.org/10.1111/jcpe.12263DOI Listing
July 2014

Allopurinol is an independent determinant of improved arterial stiffness in chronic kidney disease: a cross-sectional study.

PLoS One 2014 14;9(3):e91961. Epub 2014 Mar 14.

Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom; School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom.

Background: Arterial stiffness is increased in patients with CKD and is a powerful predictor of cardiovascular morbidity and mortality. Use of the xanthine oxidase inhibitor allopurinol has been shown to improve endothelial function, reduce left ventricular hypertrophy and possibly improve cardiovascular outcome. We explored the relationship between use of allopurinol and arterial stiffness in patients with chronic kidney disease (CKD).

Methods: Cross-sectional observational study of 422 patients with CKD with evidence of, or at high risk of, renal disease progression. Arterial stiffness was determined by carotid-femoral pulse wave velocity (PWV).

Results: The mean age was 63 ± 16 years, median estimated glomerular filtration rate was 25 (interquartile range: 19-31) ml/min/1.73 m(2) and mean PWV was 10.2 ± 2.4 m/s. Seventy-seven patients (18%) were receiving regular allopurinol, 61% at a dose of 100 mg/day (range: 50-400 mg/day). Patients receiving allopurinol had significantly lower peripheral pulse pressure, central pulse pressure, central systolic blood pressure, serum uric acid level tissue advanced glycation end product levels but comparable high-sensitivity C-reactive protein levels. Use of allopurinol was associated with lower PWV. After adjusting for age, gender, ethnicity, tissue advanced glycation end product level, peripheral pulse pressure, smoking pack years, presence of diabetes mellitus and use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, the use of allopurinol remained a significant independent determinant of PWV (mean difference: -0.63 m/s; 95% CI, -0.09 to -1.17 m/s, p = 0.02).

Conclusion: In patients with CKD, use of allopurinol is independently associated with lower arterial stiffness. This study provides further justification for a large definitive randomised controlled trial examining the therapeutic potential of allopurinol to reduce cardiovascular risk in people with CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954864PMC
November 2014

The impact of chronic kidney disease and cardiovascular comorbidity on mortality in a multiethnic population: a retrospective cohort study.

BMJ Open 2013 Dec 3;3(12):e003458. Epub 2013 Dec 3.

Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

Objective: To assess the impact of chronic kidney disease (CKD) and cardiovascular comorbidity on mortality in a multiethnic primary care population.

Design: Retrospective cohort study.

Setting: Inner-city primary care trust in West Midlands, UK.

Participants: Individuals aged 40 years and older, of South Asian, black or white ethnicity, registered with a general practice and with their kidney function checked within the last 12 months (n=31 254).

Outcome Measure: All-cause mortality.

Results: Reduced estimated glomerular filtration rate, higher albuminuria, older age, white ethnicity (vs South Asian or black ethnicity) and increasing cardiovascular comorbidities were independent determinants of a higher mortality risk. In the multivariate model including comorbidities and kidney function, the HR for mortality for South Asians was 0.697 (95% CI 0.56 to 0.868, p=0.001) and for blacks it was 0.533 (95% CI 0.403 to 0.704, p<0.001) compared to whites.

Conclusions: The HR for death is lower for South Asian and black individuals compared to white individuals. This is, in part, independent of age, gender, socioeconomic status, kidney function and comorbidities. Risk of death is higher in individuals with CKD and with a higher cumulative cardiovascular comorbidity.
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http://dx.doi.org/10.1136/bmjopen-2013-003458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855607PMC
December 2013

The natural history of, and risk factors for, progressive chronic kidney disease (CKD): the Renal Impairment in Secondary care (RIISC) study; rationale and protocol.

BMC Nephrol 2013 Apr 25;14:95. Epub 2013 Apr 25.

Department of Nephrology, University Hospital Birmingham, Birmingham B15 2WB, UK.

Background: Chronic kidney disease (CKD) affects up to 16% of the adult population and is associated with significant morbidity and mortality. People at highest risk from progressive CKD are defined by a sustained decline in estimated glomerular filtration rate (eGFR) and/or the presence of significant albuminuria/proteinuria and/or more advanced CKD. Accurate mapping of the bio-clinical determinants of this group will enable improved risk stratification and direct the development of better targeted management for people with CKD.

Methods/design: The Renal Impairment In Secondary Care study is a prospective, observational cohort study, patients with CKD 4 and 5 or CKD 3 and either accelerated progression and/or proteinuria who are managed in secondary care are eligible to participate. Participants undergo a detailed bio-clinical assessment that includes measures of vascular health, periodontal health, quality of life and socio-economic status, clinical assessment and collection of samples for biomarker analysis. The assessments take place at baseline, and at six, 18, 36, 60 and 120 months; the outcomes of interest include cardiovascular events, progression to end stage kidney disease and death.

Discussion: The determinants of progression of chronic kidney disease are not fully understood though there are a number of proposed risk factors for progression (both traditional and novel). This study will provide a detailed bio-clinical phenotype of patients with high-risk chronic kidney disease (high risk of both progression and cardiovascular events) and will repeatedly assess them over a prolonged follow up period. Recruitment commenced in Autumn 2010 and will provide many outputs that will add to the evidence base for progressive chronic kidney disease.
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http://dx.doi.org/10.1186/1471-2369-14-95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664075PMC
April 2013

Chronic kidney disease after nonrenal solid organ transplantation: a histological assessment and utility of chronic allograft damage index scoring.

Transplantation 2012 Feb;93(4):406-11

Department of Nephrology and Renal Transplantation, Renal Institute of Birmingham, University Hospital Birmingham, Birmingham, United Kingdom.

Background: It is proposed that chronic calcineurin inhibitor (CNI) nephrotoxicity has a central role in chronic kidney disease after nonrenal solid organ transplantation (NRSOT), although there are little data on renal histology in this setting. The aim of this study was to assess the histological features and renal outcomes of a cohort of patients with chronic kidney disease after NRSOT.

Methods: Renal biopsies of 62 NRSOT recipients were evaluated for histological diagnoses. Biopsies were graded for chronic allograft damage index parameters and for arteriolar hyalinosis. The sum of all chronic allograft damage index parameters and arteriolar hyalinosis scores was called chronic damage index.

Results: The biopsies were performed at a median of 4 (range: 0.3-15.9) years after NRSOT and at serum creatinine of 318±17.7 μmol/L (mean±standard deviation). Twenty-two (35.5%) biopsies showed predominant features of chronic CNI nephrotoxicity, 27 (43.5%) predominant features of hypertensive nephropathy, and 12 (19.3%) an alternative primary renal pathology. Twenty-four (38.7%) patients had progression to end-stage renal disease, at a median of 1.5 (0-10.1) years after biopsy and 6.9 (0.3-19.2) years after NRSOT. The risk of renal progression was associated with in situ damage measured by chronic damage index.

Conclusions: Although CNI nephrotoxicity is an important cause of renal failure after NRSOT, many patients do not have overt histological evidence of CNI toxicity. Quantitative parameters of chronic damage can stratify renal prognosis.
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http://dx.doi.org/10.1097/TP.0b013e318240e984DOI Listing
February 2012