However, its use is still based largely on observational studies and expert opinion. Well-designed randomized controlled trials are urgently needed to define the role of this expensive therapy. Ruggenenti, P. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. Kattah, A. Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Ravani, P.
Short-term effects of rituximab in children with steroid- and calcineurin-dependent nephrotic syndrome: a randomized controlled trial. Magnasco, A. Rituximab in children with resistant idiopathic nephrotic syndrome. Glassock, R. The pathogenesis of membranous nephropathy: evolution and revolution. Cara-Fuentes, G. Rituximab in idiopathic nephrotic syndrome: does it make sense? Chan, A. Rituximab's new therapeutic target: the podocyte actin cytoskeleton. Gregersen, J. B-cell depletion in the treatment of lupus nephritis.
Specks, U. Efficacy of remission-induction regimens for ANCA-associated vasculitis. Tony, H. This will include making trials cost-neutral to participating sites, assisting research units to negotiate costs with hospital-based services such as pathology and pharmacy, and lobbying for adequate funding for trial-specific costs and infrastructural support for units participating in investigator-initiated clinical trials.
More emphasis will also be placed on the conduct of rigorous feasibility surveys and feasibility trials at units before commencing larger trials with hard-clinical end points and substantial recruitment targets. This will serve to save resources in the long term by only moving forward with feasible trials that can realistically expect to be completed in a suitable time frame and by using appropriate resources.
Several strategies to engage and energize the nephrology community in the region have been identified and adopted by the AKTN. It will be imperative to maintain these approaches, as the success of the AKTN relies on an engaged membership base and enthusiastic support of, and participation in, its research activities. The AKTN has a responsibility to the nephrology community to educate its stakeholders in clinical trial design, conduct, and good clinical practice. Formal educational opportunities, including scholarships for the higher research degrees of PhD and Masters in Public Health, will continue to be offered, as well as regular workshops targeting specific aspects of trial design and conduct.
Informal educational opportunities, such as involvement on Trial Management Committees and assistance through AKTN trial endorsement, will also be available to researchers. Patient-centered outcomes have always been a focus of AKTN trials. As the Network has progressed, representatives of the kidney patient community have been included on core AKTN committees to ensure that Network activities are representative of the community's needs.
Quality-of-life outcomes that are meaningful for kidney patients will continue to feature in AKTN trials. The largest threat to the future of clinical trial CRGs is ongoing funding for core operations. Unlike the Australian model where research funding is sourced via a time-consuming, annual competitive federal government grant process for individual investigators or ad hoc funding made available from participation in pharmaceutical company sponsored research, research units in the UK are encouraged to participate in research through the provision of infrastructural support directly from the department of health in the form of clinical research personnel to facilitate investigator-initiated trial design and conduct.
Although it is yet to be formally evaluated whether this resource allocation has been successful in increasing clinical trial quality and output, the UK Clinical Research Network has been identified as world-class infrastructure that has improved clinical trial uptake by participants through raising public awareness of the importance of clinical trials. The AKTN aims to join with other clinical trial networks to lobby government funding bodies to recognize clinical trials as part of routine clinical care to allow provision of world-class, evidence-based clinical care to Australian and New Zealand patients.
This campaigning is to be at both state and federal health department levels, via the National Health and Medical Research Council, in conjunction with a working group established at a Medical Journal of Australia symposium, and directly to the relevant ministers. To increase recruitment success, international collaboration will continue to be a priority for individual trials, as will partnering with other national academic research groups to improve research efficiencies and output. An important goal of the AKTN is membership of a global clinical trials consortium consisting of multiple clinical trial networks that connect in order to 1 identify international research and clinical priorities, 2 provide a larger pool of renal patients available for trials, and 3 avoid duplication of research trials and development of methodologies.
A formalized model of international collaboration would streamline this process for the future, saving time in setting up contractual and logistical arrangements. A proposed model of a global trials consortium would include a joint funding model, and is outlined in Figure 4. Proposed model for international collaboration in a global clinical trials consortium. The aim of the AKTN is to conduct investigator-driven, patient-focused clinical research directed to improving patient outcomes.
The Network has a role in educating renal physicians, nurses, and allied health professionals in trial design and conduct.
The objective of the AKTN is to increase nephrology research output from the region, reduce the dearth of clinical evidence in the specialty, and be an important link for international collaboration, with the ultimate aim of improving health outcomes for patients with kidney disease. National Center for Biotechnology Information , U. Kidney International. Kidney Int.
Informing Clinical Practice in Nephrology by Mohsen El Kossi, Arif Khwaja | Waterstones
Published online Oct 2. Author information Article notes Copyright and License information Disclaimer. E-mail: ua. This article has been cited by other articles in PMC. Abstract Chronic kidney disease is a major public health problem globally. Keywords: chronic kidney disease, clinical trials, collaborative research, health policy, investigator initiated, randomized controlled trial.
Open in a separate window. Figure 1. Figure 2. Figure 3. Augmented infrastructure to support research The Network has accrued a critical mass of trials expertise. Increased collaboration It has been proposed that a number of the barriers to successful completion of clinical trials can be overcome by multicenter collaboration. Table 3 AKTN clinical trials: coordinated, facilitated, and endorsed. Establishment of clinical research priorities Clinical research priorities for the AKTN have been determined via a combination of a evaluation of surveys of all AKTN clinician and health consumer members; b development of special interest groups in renal transplantation, hemodialysis, peritoneal dialysis, and chronic kidney disease; c recommendations of the Caring for Australasians with Renal Impairment CARI Guidelines Writing Groups; and d dialog with the Cochrane Renal Group to identify important gaps in evidence.
Expanded educational and career opportunities for renal clinician scientists As a medical specialty, nephrology is experiencing a workforce shortage in Australasia. Enhanced clinical trial quality Samuels and Molony 18 outlined the importance of maintaining high standards in several features of clinical trial design and conduct. Increased funding opportunities Lack of funding availability is the main reason research studies do not proceed to commencement.
Increased renal clinical trial output Since , 23 clinical trial proposals have been presented to the AKTN for consideration of coordination, facilitation, or endorsement, and have undergone review for scientific quality, clinical merit, and statistical rigor. Trials With seven coordinated or facilitated trials currently active, a primary priority of the Network is completing the first of these and publishing clinical trial results to inform clinical practice.
Refining operational processes The importance of simplified protocols that closely mirror standard practice of clinical care for renal patients has been identified through the AKTN experience. Energizing the renal research community Several strategies to engage and energize the nephrology community in the region have been identified and adopted by the AKTN. Sustainable funding The largest threat to the future of clinical trial CRGs is ongoing funding for core operations.
WHY WE (STILL) NEED TRIALS
National and International collaborations To increase recruitment success, international collaboration will continue to be a priority for individual trials, as will partnering with other national academic research groups to improve research efficiencies and output. Figure 4. Notes All the authors declared no competing interests. Chronic kidney disease as a global public health problem: approaches and initiatives—a position statement from Kidney Disease Improving Global Outcomes.
Am J Kidney Dis. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. J Am Soc Nephrol. Statement 6: Expenses and Net Capital Investment. Annual Data Report, Chapter United States Renal Data System, United States Renal Data System. Taiwan: Bureau of National Health Insurance, The contribution of chronic kidney disease to the global burden of major noncommunicable diseases.
The number, quality, and coverage of randomized controlled trials in nephrology. The causal role of smoking in engendering lung cancer is now universally accepted, even though it is based exclusively on observational data, and one could potentially construct alternative hypotheses how an association between smoking and lung cancer could be biased by confounders like for example inhalation of phosphorus from the fires of the matches used to light cigarettes. Nevertheless, the causal association between tobacco smoking and lung cancer has hardly been questioned despite a lack of RCTs.
An example from the field of Nephrology where concerns for the wellbeing of participants made the completion of an RCT difficult was a recent clinical trial that compared early vs. In cases like these observational studies employing various techniques to minimize bias may be the only feasible way to gain better understanding of a disease process or an intervention vide infra.
Finally, the most mundane deficiencies of RCTs are their high cost and the long time required for their completion. Compared to observational studies RCTs carry a price tag that is several magnitudes higher and typically they take many more years to complete. A significant proportion of RCTs are sponsored by Pharmaceutical companies to whom the investment is justified by future returns due to a new indication for their marketed drug or to higher sales boosted by the benefits shown by their agent in the clinical trial. What are clinicians to do if there is no RCTs for most major problems faced in clinical practice of Nephrology?
It is thus worthwhile to explore alternative ways to try and make causal inferences using methods other than RCTs. The principle advantage of RCTs is their controlled nature which eliminates many of the biases that hamper the interpretation of observational studies. There are, however, techniques that can be applied to observational data in order to eliminate bias, which could theoretically allow causal inference.
The simplest and most widely applied one is adjustment, whereby analyses can account for the bias introduced by a known confounder.
A variant of adjustment is the use of propensity scores, where the likelihood of a certain intervention or treatment is quantified using known determinants of the intervention, and analyses are then either conditioned stratified on or adjusted for the propensity scores. Once, however, active vitamin D is started it will usually lower the PTH level thus PTH is also an intermediate , but the lower PTH level will then often result in the discontinuation or in a dose-adjustment for active vitamin D thus it is a time-dependent confounder and may also be in the causal pathway to mortality.
If, for example some patients are materially better off they could presumably afford better insurance which could allow them to receive a more expensive version of active vitamin D which has a more beneficial side effect profile. A study that compared mortality in patients who received a newer paricalcitol vs. Without the ability to quantify all the possible ancillary benefits that may accompany paricalcitol use one cannot with certainty make causal inferences about the link between paricalcitol and survival in this observational study. A technique that can potentially address unmeasured confounders in observational studies is the instrumental variable approach.
Association of an instrument with the outcome can be interpreted as unconfounded proof of a causal relationship between the actual intervention of interest and the outcome. The simplest example of a valid instrumental variable is the random treatment allocation in a clinical trial, since a randomization determines the exposure to the intervention, b if randomization is successful than mortality is only affected through the treatment intervention, since all other relevant characteristics of exposed and unexposed patients are identical and c randomization by definition has no common source with the outcome.
A similar framework can be applied to observational studies to allow for unbiased estimates of causation. Since persons who are born with a certain genotype that determines higher CRP levels would experience these higher levels prior to the development of heart disease which is presumably not present at birth , a lack of association between the genotype and ischemic heart disease contradicted the hypothesis that CRP is causally responsible for the development of this condition. It is possible for example to imagine an unidentified gene in the above study of CRP which is in linkage disequilibrium with the CRP gene but is involved in some other pathologic process linked to heart disease, and thus act as an unmeasured confounder.
Mendelian randomization studies need the presence of genetically determined characteristics; hence our ability to use this method is finite. Researchers have attempted to find instrumental variables that are not determined by nature or by randomized interventions for use in observational studies in order to bypass the need for randomized controlled trials. An example is a recent study of active vitamin D, where the percentage of active vitamin D use in a given hemodialysis center was proposed as the instrumental variable. The criticism of the instrumental variable approach using instruments that are not created by randomization is that there is no telling if the chosen instrument is indeed conforming to the basic requirements that make it a valid tool; in the case of the above study[ 30 ] one could imagine that dialysis units with higher rates of active vitamin D use may provide different care in other unmeasured ways too, which in turn could also affect outcomes independently and thus act as a common source an unmeasured confounder.
What is thus the optimal method to allow for causal inferences? As discussed above, properly designed and conducted RCTs do provide a higher degree of certainty as they eliminate many of the biases that can be present in observational studies, but they are by no means infallible. A commonly cited example that is meant to prove that RCTs refute the results of observational studies is the one of studies examining the link between blood hemoglobin level and mortality in patients with CKD and ESRD.
Not surprisingly, due to this uncertainty the aforementioned studies have lead to a number of hypotheses which have or will be tested first in observational studies, [ 36 ] which may lead to yet more hypotheses. Furthermore, the notion that these RCTs were in discordance with all prior observational studies neglects the fact that some observational studies have in fact provided earlier evidence that hemoglobin levels above a certain threshold may be deleterious; [ 37 ] these were ignored either because of infatuation with prevailing scientific paradigms at the time, or because of the a priori conviction that observational studies are always inferior.
In retrospect the hemoglobin-ESF story in CKD provides a prime example for how we should not rank the various types of investigations based on prior convictions about their advantages or disadvantages, but rather consider all of them as pieces of the same puzzle Figure 2 , with all of them being able to provide useful information and increase our knowledge about a subject, but without any of them being infallible. We need to realize that absolute certainty cannot ever be attained in Medicine. Our goal should be to continuously broaden our knowledge to achieve increasing certainty about biological processes and disease therapies, while constantly keeping an open mind.
Recent Activity. The field of nephrology, like many other disciplines, has been suffering from a lack of RCTs. The view that without RCTs, there is no reliable evidence has hampered our ability to ascertain the best course of action for our patients. However, many clinically important questions in medicine and public health, such as the association of smoking and lung cancer, are not amenable to RCTs owing to ethical or other considerations.
We provide a description of the various pros and cons of RCTs and of observational studies using examples from the nephrology literature, and argue that it is simplistic to rank them solely based on preconceived notions about the superiority of one over the other. Such approaches are especially important in a field like nephrology where there are myriads of potential interventions based on complex pathophysiologic states, but where properly designed and conducted RCTs for all of these will probably never materialize.
The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Adv Chronic Kidney Dis. Author manuscript; available in PMC Jan 1. PMID: Copyright notice.
The publisher's final edited version of this article is available at Adv Chronic Kidney Dis. See other articles in PMC that cite the published article. Abstract A common frustration for practicing Nephrologists is the adage that the lack of randomized controlled trials RCTs does not allow us to establish causality, but merely associations.
Keywords: observational studies, randomized controlled trials, causal inference. Introduction A frequent lament in Nephrology is the lack of randomized controlled trials RCTs , and thus the inability to conclusively establish a cause-and-effect relationship between an exposure and an outcome. Open in a separate window. Figure 1. Association vs. Criterion Definition Counterargument 1. Temporal relationship Exposure precedes the disease. None 2.
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Strength of association The stronger the association, the more likely it is that the relation is causal. Weak associations do not rule out causality. Furthermore, the presence of a strong unmeasured confounder could result in strong associations without true causation. Strength of association should not be mistaken for statistical significance. Dose response Increasing amount of exposure increases the risk proportionally.
Causality can also be present with mechanisms that have threshold effects in which case increasing exposure would not lead to further increase in effect. It is also possible that the presence of an unmeasured confounder could change the shape of the dose-effect curve in spite of a true cause-effect relationship.
Consistency The association is consistent when results are replicated in studies in different settings using different methods. Certain biologic processes may be different under different circumstances, hence the lack of an association in one population does not rule out a cause-effect relationship in another. Biologic plausibility The association agrees with currently accepted understanding of biologic processes. It is always possible that new mechanisms of disease are discovered; hence studies that disagree with established understanding of biological processes may force a reevaluation of accepted beliefs.
An association that is seemingly biologically implausible may be merely highlighting a yet unknown mechanism. Experimentation The condition can be altered prevented or ameliorated by an appropriate experimental intervention.
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