The 56th ERA-EDTA congress showcased an impressive range of sessions, abstract presentations, and other activities for the delegates, who attended the congress from across the world. The EMJ congress team was among them, and we are delighted to report the latest news and updates from the congress directly to our readers. Top news stories from the congress are herein brought to you by our editorial team, who have curated the most pressing and important stories for your reading pleasure. Find out about novel biomarker DKK3 and its potential for predicting acute kidney injury; learn about the impact of employment status on mortality rates following dialysis; and take things interdisciplinary with the news of how diabetes drug linagliptin improves albuminuria in diabetic patients.
The theme of the congress this year was ‘precision nephrology’, with the committee eager to use this concept to focus not only on what we know already, but on what we need to know in order to deliver the very best care to patients. In his welcome address, congress co-president György Reusz described the “exceptional scientific programme” and commented on the delegates’ opportunity to “see Budapest at its best,” adding that “the rich history of the city combined with a vivid cultural milieu is waiting for ERA-EDTA visitors.” Indeed, according to the Central Statistics Office, 12.5 million tourists visited Budapest in 2018, demonstrating its popularity as a destination. You can read our exclusive interview with Prof Reusz in our Interviews section, in which he details his role as President of the Hungarian Society of Nephrology, the role of national societies in shaping future generations of nephrologists, and his highlights from the ERA-EDTA congress.
More than 2,000 abstracts were submitted for consideration to ERA-EDTA this year, demonstrating the high level of research and the true reach of the congress to so many people around the world. Hot topics included hypertension, nephrolithiasis, chronic kidney disease – lab methods, pathophysiology, anaemia, nutrition, and rehabilitation; paediatric nephrology; and renal transplantation to name just a few. In our Abstract Review section, our editorial team have hand-picked some of the abstracts we were most impressed by and invited the presenters to write a summary of their research and the abstract presentation at the congress. Read about the Hungarian Vasculitis Registry and the results from the first 5 years of the trial, the impact of chronic kidney disease on the hepatic clearance of citalopram, and changes in intraocular pressure during haemodialysis. The potential of these exciting presentations to one day impact clinical practice and improve patient care for people across the globe cannot be underestimated, and it is our great privilege to work with the authors to disseminate their research to our readers.
In addition to the abstract summaries, plenary lectures, and symposia, ERA-EDTA recognised some of the most outstanding researchers with awards at this year’s congress. Dr Olivier Devuyst, University of Zürich, Zürich, Switzerland, was awarded the ERA-EDTA Award for Outstanding Basic Science Contributions to Nephrology for his work in demonstrating the role played by aquaporins in peritoneal dialysis (PD), as well as the development of preclinical strategies to streamline the process of dialysis and reduce structural damage in the peritoneal membrane. Prof Claudio Ronco, International Renal Research Institute, St Bortolo Hospital, Vicenza, Italy, was awarded the ERA-EDTA Award for Outstanding Clinical Contributions to Nephrology for his exceptional work in critical care, extracorporeal therapies, PD, and the development of novel devices such as CARPEDIEM for neonatal dialysis. In addition, Dr Rebecca Herzog, Medical University of Vienna, Vienna, Austria, was recognised with the ERA-EDTA Stanley Shaldon Award for Young Investigators after her work focussing on PD, including the development of a novel PD-fluid, discovery of the role of a specific post-translational protein modification in PD, and revealing the PD effluent proteome. Hearty congratulations to all the winners from all of us here at EMJ.
Chronic Kidney Disease and the Mission of ERA-EDTA
Globally, 850 million people are affected by kidney diseases, with chronic kidney disease (CKD) afflicting an estimated 10–11% of the European population. These startling realities were presented by Prof György Reusz, the Congress President of the 56th Congress of the ERA-EDTA and reported in a ERA-EDTA press release, in order to emphasise the need for spirited discussion between the population and policymakers, and to encourage the urgent formation of preventative measures.
The increasing prevalence of CKD cases can in part be attributed to demographic factors, such as the ageing general population, yet this does not fully explain the upward trend. CKD is subject to multifactorial regulatory input from a multitude of other conditions, including obesity, hypertension, and diabetes. This paints a complex picture in which the management of other conditions must consider additional implications for CKD progression.
The risk that CKD poses to public health is often underappreciated, often in spite of epidemiological and economic significance: dialysis, a common endpoint for patients living with CKD, incurs annual costs of approximately €60,000–80,000 per patient. This neglected attention may arise from the fact that prognostic signs for CKD remain sparse until an advanced stage has progressed, at which point preventative measures are ineffective. Couple this with the general misconceptions amongst the general population and medical community regarding CKD risk, and it easy to understand how an international health burden has grown, and indeed, continues to grow.
This recognition, however, does present ample opportunities for the dissemination of information and collaboration of efforts. “We see enormous potential in the field of early detection, especially, because it can stop the disease from advancing, or slow its progress at least,” explained Prof Reusz to the international ensemble of nephrologists. Through improving CKD prevention, and heightening the profile of the disease, ERA-EDTA declared their key objective for this year’s congress and set the stage for days of inspiring discussion.
Promise of New Treatments on the Horizon for Alport Syndrome
NEW therapies for Alport syndrome (AS) could be just around the corner, according to a study presented at ERA-EDTA 2019 and reported in a ERA-EDTA press release. In their analysis, the authors set out five reasons why the disease is an attractive area for drug development.
The first reason highlighted is that studies into AS may provide fresh insights into the causes of chronic kidney disease (CKD), and therefore contribute to efforts to find new therapies for this condition. This is because AS leads to progressive proteinuria, renal fibrosis, and kidney failure, so findings may be extrapolated to other more common causes of CKD.
The researchers also note that orphan designation will be given to any new drug approved for AS, which will encompass benefits for pharma companies such as a shortened approval timeline and a period of market exclusivity. There is also a large number of patients who would benefit from new treatments for AS, with it being the second most frequently inherited kidney disease after autosomal dominant polycystic kidney disease (ADPKD). Additionally, clinical trials for this condition should be easier to facilitate as AS patients are young and have very few comorbidities. The final factor is that there is currently no approved treatment for AS, meaning there is tremendous scope to help patients with the condition. Currently, the only recommended form of management is renin –angiotensin system blockade.
“A specific disease-modifying therapy for AS remains an unmet need, but I am sure this will change, because AS has become a very attractive target for pharmaceutical companies to target,” confirmed lead author Prof Rosa Torra, Fundacio Puigvert, Barcelona, Spain.
There have indeed been numerous insights in recent years into AS, revealing crucial information that could help facilitate drug development. The researchers believe that these could pave the way for more effective clinical trial endpoints in AS in the future, rather than decline in glomerular filtration rate levels.
“Similarly to other renal diseases, this is probably too late an endpoint to make a significant impact on the course of the disease,” explained Prof Torra. “Theoretically, treatment prior to the appearance of renal fibrosis offers more promising long-term renal outcomes. GBM aspect and degree of fibrosis on renal biopsy as well as proteinuria could be excellent endpoints for clinical trials.”
Studies Vital to Prove Efficacy of PCSK9 Inhibitors in Chronic Kidney Disease
PATIENTS with advanced chronic kidney disease (CKD) are routinely excluded from clinical trials that aim to reduce the progression of cardiovascular (CV) disease despite this patient population being at high risk of CV mortality. As such, there is little evidence to suggest that the current gold standard treatment of lipid-lowering therapy would benefit patients on maintenance haemodialysis, and in addition reduced kidney function could make patients more susceptible to statin-related adverse events including myopathy.
In a study reported in a ERA EDTA press release dated 13th June 2019, researchers have called for mandatory studies to investigate a novel therapy that could address this persistent problem in CKD patients. Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) is a protein that, when released, reduces the ability of the body to clear low-density lipoprotein (LDL) from circulation by blocking the expression of LDL-receptor on the surface of liver cells. Monoclonal antibodies evolocumab and alirocumab are currently approved PCSK9 inhibitors and are considered a novel therapy for lowering the levels of LDL in patients, a known contributor to CV disease in both the general population and CKD patients.
Both of these antibodies have lowered the risk of CV events in large clinical trials. Their capacity for lowering LDL was not linked to baseline kidney function, and had positive effects on patients diagnosed with moderate CKD. Although this is positive news for many patients with kidney disease, those patients with very advanced CKD and thus severely impaired kidney function were not included in these studies. Since this population is at the highest risk of CV disease, it will be important for future studies to assess the efficacy of the antibodies in these patients.
Commenting on the results, Thimoteus Speer, Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Centre, Homburg/Saar, Germany, said: “In particular, in patients with advanced CKD, the high annual costs of therapy with PCSK9 inhibitors have to be balanced against weak evidence for a benefit,” adding “Specific studies in CKD patients are mandatory to prove the efficacy and safety of PCSK9 inhibitors and to determine their ability to improve outcomes in these patients.”
Is a New Approach to Dialysis Clinical Trials Needed?
HISTORICALLY, the success of randomised clinical trials (RCT) for new treatments for end-stage renal disease (ESRD) has not been comparable to the results of other diseases. Whether the results were negative or inconclusive, the majority of ESRD RCT have not culminated in much hope for ERSD patients. Analyses from a systematic review reported in a ERA-EDTA press release suggest that new approaches to these RCT are needed, which will improve many aspects of the RCT themselves and, hopefully, the results that come from them.
Investigating trial design and outcome measures of RCT that involved a total of 10,713 ESRD patients, the review concluded that pragmatic clinical trials (PCT) and patient-centred outcomes (especially improved quality of life) may provide the best chance of clinical improvement for the patients and the testing of new therapeutic interventions. Not only will PCT improve external and internal validity, but also be more representative of the diverse and complex ERSD population by having broader inclusion criteria, of which the traditional framework of RCT does not allow.
Prof Csaba Kovesdy, author of the review entitled ‘Clinical trials in end-stage renal disease-priorities and challenges’ commented: “The recent emergence of various RCT designs could aid in making ESRD clinical trials more successful.” PCT involve clinically relevant comparators, evaluation of interventions within clinical practice, and the testing of practical, meaningful outcomes. Feasibility of PCT in the haemodialysis population can be achieved by clustering patients within dialysis units and testing of medical and technical interventions within the framework of routine clinical practice.
Prof Kovesdy concluded that: “The application of such novel RCT designs could result in benefits including reduced trial cost, the examination of a broader, more representative population, and the testing of a higher number and more clinically relevant interventions, which is really needed.”
Mortality Rate Following Dialysis could be Impacted by Employment Status
EMPLOYMENT during the 6 months preceding dialysis was associated with a higher survival rate in a retrospective study reported in a ERA-EDTA press release dated 14th June 2019. The study analysed patients who had undergone dialysis and found that those who had not been in employment for 6 months prior to the treatment had a higher rate of mortality.
The study analysed 496,989 patients in the USA who had initiated maintenance haemodialysis from 2006–2015. They looked at the employment status of these patients and found that 26% (n=129,622) had been working prior to starting dialysis, but this fell to 15% when dialysis began. While it is to be expected that the older patients were less likely to maintain a job throughout the treatment, there was also a social aspect to consider, such as female populations who became unemployed more frequently. Results showed that patients who lost their jobs presented with a significantly higher death rate than those who had been in employment for at least 6 months before the dialysis began (p<0.0001).
Quality of life is impacted by state of employment for most people; haemodialysis patients are no exception to this. Working can provide social support, a stable financial position, and self-esteem, which in turn all raise quality of life. Those who are unemployed can face difficulties in both the social and financial aspects of their lives and can experience psychological and physical ailments. They can experience depression and drug and alcohol abuse.
Remaining in employment throughout the 6 months prior to initiation of dialysis was associated with higher rates of transplantation and better protection against mortality, but it is important to remember that these data can be interpreted in several ways: were these patients unemployed because they had been extremely ill before dialysis and therefore less likely to survive, regardless of job status? The authors recognised the limitations due to the retrospective nature; therefore, they could only draw conclusions based on associations between the variables that were known.
Targeting Metabolic Acidosis Slows Renal Decline in Late-Stage Chronic Kidney Disease
Metabolic acidosis, a condition in which the kidneys are unable to maintain normal acidic balance in the body, is common in patients with late-stage chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR]: <30 mL/min/1.73 m2). As well as kidney function decline, it is associated with several dangerous comorbidities, including insulin resistance, muscle wasting, and bone disease. Results of the UBI trial, reported in a ERA-EDTA press release, attest to the benefits of correcting this condition with sodium bicarbonate to improve the overall clinical picture in these patients.
A cohort consisting of 740 patients with Stage 3b or 4 CKD were given either sodium bicarbonate (376 patients) or standard of care (364 patients). Following 3 years, the sodium bicarbonate arm of the study experienced significantly less doubling of creatine (6.6% compared to 17.0%), translating into a 64% relative risk reduction in kidney disease progression (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.22–0.58; p<0.001).
The likelihood of starting renal replacement therapy (RRT) was also diminished in the sodium bicarbonate-treated group (6.9% versus 12.3%), a risk reduction amounting to 50% (p=0.004; HR: 0.5; 95% CI: 0.31–0.81; p=0.005). A 57% relative risk reduction was also seen in the sodium bicarbonate-treated group, and importantly, the treatment was well-tolerated and exhibited no significantly adverse effects on total body weight or hospitalisations.
Lead investigator Dr Antonio Bellasi, Department of Nephrology and Dialysis, S. Anna Hospital, Como, Italy, concluded that “[Our] study shows that that this very cost-effective treatment is safe and improves kidney and patient survival.” This study serves as a brilliant example of finding novel uses for drugs that have pre-established safety profiles and are widely administered.
Increased Cholecalciferol Dosage Reduces Risk of Fracture Following Kidney Transplant
KIDNEY transplant remains the gold standard of treatment for patients with kidney failure, increasing survival rates and quality of life. However, this treatment option is not without its drawbacks, one of which being an increased risk of fractures. Now, building on previous research, the VITALE study has shown that an increase in supplementary vitamin D, greater than previous recommendations, may safely lower the risk of fractures. The results from this study were revealed in a ERA-EDTA press release on 14th June, 2019.
Chronic kidney disease–mineral bone disease occurs as a result of the failing kidneys being unable to maintain normal levels of parathyroid hormone, vitamin D, and blood levels of calcium and phosphate, all of which play vital roles in maintaining bone health. To counteract this, Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend correcting the vitamin D deficiency via a supplementation of vitamin D3 (cholecalciferol); dosage is based on the requirements of the general population, but there is no high-level evidence to support this measurement. Thus, the prospective, multicentre, double-blind, controlled trial, VITALE aimed to assess skeletal and non-skeletal effects of high versus low doses of cholecalciferol after kidney transplantation.
The trial enrolled 536 kidney transplant recipients (mean age: 50.8 years, 335 males), randomising them to either 100,000 IU (high dose) or 12,000 IU (low dose) cholecalciferol every 2 weeks for 2 months, before switching to monthly dosage for 22 months. ‘Low dose’ corresponded to a minimum recommended intake of 400 UI/day. The high dose group had significantly higher vitamin D levels than the low dose group at 24 months (43.1 [12.8] ng/mL versus 25.1 [7.4] ng/mL compared with 20.2 [8.1] versus 19.2 [7.0] ng/mL at study inclusion; p<0.0001). Similarly, the incidence of fracture was also significantly lower in the high dose group (1% versus 4% in the low dose group; p=0.02). The high dose treatment was well-tolerated, with no increased risk of vascular calcification, hypercalcaemia, or hyperphoshataemia.
Commenting on the results of the trial, lead investigator Dr Marie Courbebaisse of Assistance publique – Hôpitaux de Paris, Paris, France, commented: “Our study shows that currently recommended doses of vitamin D are not sufficient to protect patients from the risk of fracture after kidney transplantation.”
Novel Biomarker Could Predict Acute Kidney Injury
DESPITE acute kidney injury (AKI) being a common complication of cardiac surgery with an incidence of 7–40%, it is poorly predicted and has a big impact on intensive care unit stays and mortality. Severity of AKI can fluctuate from subclinical to severe, requiring renal replacement therapy with dialysis. To prevent the late diagnosis and development of severe AKI, sensitive biomarkers need to be identified. The results from an observational cohort study testing DKK3, a novel renal biomarker, were reported in a ERA-EDTA press release.
Two patient cohorts formed the study group (N=949): the derivation cohort (n=733) were patients who had undergone elective cardiac surgery at the Saarland University Medical Centre, Homburg, Germany, and the validation cohort (n=216) contained patients who were about to receive elective cardiac surgery and enrolled in the prospective RenalRIP multicentre trial.
By using urinary concentrations of DKK3: creatinine, significant improvements in AKI prediction was observed in the derivation cohort (p<0.0001). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations were used to predict outcomes of AKI post-surgery. Patients with urinary concentrations of DKK3:creatinine >471 pg/mg were at a higher risk of developing AKI (p=0.026), persistent renal dysfunction (p=0.0072), and dialysis dependency (p=0.020).
“Urinary DKK3 can significantly improve the prediction of AKI beyond the established clinical models and available biomarkers. Measurement of urinary DKK3 might therefore represent a personalised medicine approach in patients having cardiac surgery. It gives us the chance to detect patients at risk for AKI and subsequent kidney function loss and to take care of them intensively,” explained study investigator Prof Danilo Fliser, Homburg/Saar, Germany. “A DKK3-ELISA test provides relatively simple identification of at-risk patients. We think it is time to implement it in clinical practice.”
Call Made to Increase Nephrological Research Activities
STRENGTHENING nephrological research activity was a key message from this year’s ERA-EDTA Congress, and this was demonstrated by the formation of the Nephrology and Public Policy Committee (NPPC), which presented a 5-year plan to stimulate research collaboration in Europe during the event.
The NPPC was established following concerns that there are insufficient levels of nephrology research occurring. For instance, a 2013 study showed that just 2.6% of trials overall were classified as nephrology. Additionally, very few of these were diagnostic, screening, or health services research studies, with the vast majority relating to treatment (75.4%) or prevention (15.7%), reported an ERA-EDTA press release.
“Epidemiological and clinical research and public policy in Europe are generally considered to be comprehensive and successful, but there is potential for improvement and scope for new opportunities,” said Prof Ziad A. Massy, Chair, NPPC. “Especially in nephrology we have to further intensify our research activities. With 850 million people suffering from kidney diseases of any kind worldwide, nephrology has to be one of the main areas of medical research.”
To make the growth in research activities a reality, the NPPC, supported by the ERA-EDTA, have created a 5-year research plan. Eight action points underpin the initiative, with the aim of boosting research collaboration and grant applications under the umbrella of the ERA-EDTA.
The action points include a focus on collaborative research with the purpose of improving classification and prognosis of kidney diseases; promote active collaboration between paediatric and adult nephrologists to plan a successful transition process from paediatric to adult care of CKD; supporting the development of world-leading big data research via various methods; and the creation of a European network of kidney units to increase insights into AKI progression and complications.
One of the major aims of the plan is to use new insights gathered to highlight the urgency of tackling kidney disease throughout and to ultimately encourage a more concerted effort in this area. Prof Massy added: “Although many trials in nephrology have been initiated within the last 5–8 years, we still have to catch up. In my view it is especially important to generate epidemiologic and healthcare data in order to sensitise the public as well as policy makers to kidney diseases. It is high time to put the global spread of kidney diseases into focus.”
Diabetes Medication Could Improve Albuminuria
LINGALIPTIN, the diabetes medication, was found to improve albuminuria in diabetic patients, but did not impact glomerular filtration rate (GFR) and cardiovascular (CV) risk. This was found in a late-breaking clinical trial, CAMELINA, that was presented at ERA-EDTA on the 14th June 2019. The study follows a recent development that found another class of diabetes drug, SGLT2 inhibitors, had the ability to slow the development of chronic kidney disease (CKD).
The multicentre, double-blind, randomised CARMELINA trial set out to assess 5 mg of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LINA) in its ability to minimise CKD and CV problems in patients with diabetes, compared with placebo. DPP-4 inhibitors are often prescribed as second or third-line options for Type 2 diabetes mellitus patients who are not displaying a sufficient response to the more commonly used medication such as metformin. They work by blocking the DPP-4 enzyme responsible for destroying incretins, which stimulate insulin production; therefore, the drugs facilitate a drop in blood sugar levels.
Results showed that 646 of the 6,979 patients had renal disease due to nephrotic-range proteinuria; these patients had a 3-fold greater drop in GFR. This group were high-risk for CV events and showed poor kidney outcomes. The groups did not display a difference in loss of GFR (-6.51 per year versus placebo -7.07 per year). The drug did not impact the risk for major adverse CV events (HR:1.02; 95% confidence interval [CI]: 0.89, 1.17). A greater proportion of patients in the LINA group reverted to normoalbuminuria or demonstrated a lower urine albumin:creatinine ratio of ≥50%.
Lead investiagor Prof Wanner, Divison of Nephrology, University Hospital Würzburg, Würzburg, Germany, concluded the study: “The study clearly showed that there is a group of patients with diabetes who clearly are in need of outcome-enhancing therapies, because their prognosis is rather poor. Nephrotic-range proteinuria might be a good marker to stratify these patients. I would advise to treat these patients with SGLT2 inhibitors instead, or a combination of SGLT2 inhibitor and DPP-4 inhibitor.”
