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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

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

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.

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

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.

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

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.