Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed?
The authors have expertise in human physiology and are clearly familiar with the literature and reports that provide detailed information about the occurrence of cardiac arrhythmias in astronauts and cosmonauts. However, the author expertise could be improved by including cardiovascular clinician-scientists who have greater familiarity with the current literature and operational expertise in cardiovascular risk stratification and in recognizing and treating cardiovascular disease.
The authors should include experts in cardiology. As cardiovascular medicine evolves, the evidence book should portray a contemporary view of cardiovascular risk (not just arrhythmia risk) as reflected in current practice. This perspective would maximize the utility of the report for NASA flight surgeons who assess health risk prior to, during, and after long-term spaceflight.
Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report?
Some recommendations made in 2008, such as the need for better telemetry and improved preflight screening methods, have been incorporated into the current report. However, the general recommendation to refocus the report so that it addresses cardiac health holistically, rather than focusing solely or primarily on arrhythmias, has not been addressed in the current report.
RISK OF RENAL STONE FORMATION
The evidence report on the risk of renal stone formation suggests that astronauts may be at an increased risk for forming kidney stones due to changes in bone metabolism, dehydration, nutrition, and the supersaturation of urine salts. Should a stone become symptomatic in flight, the consequences to the mission and the health of the astronaut could range from performance reduction to acute, life-threatening illness. The single documented report of a renal stone during flight occurred in a Russian cosmonaut, and 32 stones have been reported post-flight in U.S. astronauts (as of mid-2016). Countermeasures to reduce the risk of renal stone for-
mation in flight include the administration of potassium citrate, increased hydration, diets low in oxalates and animal proteins, and the maintenance of bone minerals (thus avoiding increased calcium excretion by the kidneys) through bisphosphonates and resistive exercise. Models have been developed to predict the risk of stone formation in flight for specific mission scenarios, and diagnostic ultrasound is available in flight for routine monitoring. Nevertheless, gaps remain in the knowledge base concerning the magnitude of the risk and the effectiveness of proposed countermeasures in reducing the risk of symptomatic renal stones in flight.
Does the Evidence Report Provide Sufficient Evidence, as Well as Sufficient Risk Context, That the Risk Is of Concern for Long-Term Space Missions?
The authors provide clear evidence that astronauts experience increased supersaturation of salts in their urine during flights due to altered bone metabolism and dehydration, which may increase the risk of renal stone formation. It is currently unclear whether flight increases the risk of forming renal stones, because the reported incidence of renal stones post-flight is similar to the prevalence of kidney stones in the U.S. general population (Scales et al., 2012). The report presents the renal stone formation risk in the historical context and discusses strategies and countermeasures currently used to reduce the risk of renal stone formation. Furthermore, the report details the computer models designed to predict the likelihood of a renal stone event for various expedition mission scenarios. The report concludes with an identification of knowledge and implementation gaps.
While it seems logical that bone demineralization might contribute to an increased risk of renal stone formation through hypercalciuria (the increased urinary excretion of calcium), the committee believes that the contribution of bone demineralization to the renal stone risk may be overstated. The authors state, “the risk for renal stone formation is intimately linked to hypercalciuria induced by the unbalanced bone resorption during the uncoupled bone remodeling in space,” which suggests that eliminating bone loss will eliminate the risk of renal stone formation. However, ground-based studies suggest that renal stone formation is more complicated. The supersaturation of salts and crystallization is known to occur in normal urine. In most people, these crystals pass harmlessly from the body, but in others, these crystals are retained in the kidney and form stones. When hypercalciuria and salt supersaturation are
induced in laboratory “kidneys,” crystal organization and aggregation do not match what is found in human kidney stones. Ground-based studies indicate that genetics, diet, and hydration all contribute to the risk of stone formation; however, the relative contributions of the individual factors are not understood, and there are likely additional factors that have not yet been identified. Therefore, while urine supersaturation is necessary for stone formation, the process is complex, and this uncertainty as to what causes stones to form should be reflected in the report.
Due to the emphasis on the hypercalciuria risk of renal stones, the report focuses on mitigation strategies for calcium oxalate stones. Potassium citrate, the only approved operational countermeasure for flight, addresses the risk of calcium oxalate stones as well as the risk of uric acid stones by raising urine pH. However, the changes in urine chemistry from the administration of potassium citrate may increase the risk of forming calcium phosphate or brushite stones (Krieger et al., 2015). This possibility should be addressed in the report. Furthermore, the report devotes an entire paragraph to the use of bisphosphonates to “inhibit bone loss” and theoretically “mitigate renal stone formation” (p. 17). Word choice should be critically evaluated in this paragraph to ensure that the relationship between bone loss and renal stone formation is not overstated.
Finally, while the report focuses on describing, quantifying, and preventing renal stone formation in flight, it is unlikely that the risk will ever be completely eliminated. This is reflected in the NASA evidence report Risk of Adverse Health Outcomes and Decrements in Performance Due to In-Flight Medical Conditions (Antonsen et al., 2017), in which the development of renal stones was listed as one of three particular risks specifically cited as a potential issue requiring management during long-duration missions beyond low Earth orbit. New technologies have been developed to treat renal stones, and some may be suitable for use during a mission (e.g., Simon et al., 2016). These technologies should be discussed in this report.
Does the Evidence Report Provide Evidence That the Named Gaps Are the Most Critical Presented?
The seven gaps identified by the evidence report are well supported as being critical to determining the risk of renal stone formation in space. However, the committee recommends some changes in the presentation of the gaps. For example, Gap B6 (What are the contributing factors other than loss of bone mineral density?) could be reworded to “What are
the contributing factors?” so that the loss of bone mineral density is not overemphasized. Perhaps ongoing research will suggest that dehydration is a larger contributing factor than the loss of bone mineral density. Additionally, Gap B8 (Do pharmaceuticals work effectively in spaceflight to prevent renal stones?) and Gap B16 (Can inhibitors of stone formation be sufficiently provided through dietary sources?) could be reworded to reflect that it is unlikely that the renal stone risk will ever be zero. For example, the question could be framed as, At what point are the pharmaceutical countermeasures or delivery of inhibitors through dietary sources considered good enough at reducing the risk of renal stones? Furthermore, Gap B9 (What is the frequency of post-flight stone formation; the incidence and types of stones; and the time course of stone formation? How does stone formation correlate with food intake and hydration status?) could be separated into two gaps, with one focused on food and hydration. The first part of Gap B9 could be extended to include microstructure in addition to incidence and composition (rather than type) as stones are heterogeneous composites of crystals, and micro-structural differences compared to Earth may help elucidate the mechanisms of stone formation in spaceflight.
Are There Any Additional Gaps or Aspects to Existing Gaps That Are Not Addressed for This Specific Risk?
The gaps included in the evidence report include many of the gaps that are the most important to address. An additional gap that should be listed is “How does the increased urine retention of spaceflight (and thus the retention of the crystals of supersaturated salts) influence the risk of renal stone formation?” Urinary retention has occurred in spaceflight and required bladder catheterization; this would likely increase the risk of renal stone formation as well as other urological conditions. Another gap to consider including in the evidence report is “Do supplements or other pharmaceuticals under investigation for spaceflight contribute to renal stone formation?” Furthermore, the lack of understanding of the factors that contribute to the risk of renal stone formation suggests that a gap should still exist that addresses the numerical modeling of kidney stone formation in microgravity. The report includes a literature summary of modeling kidney stone formation in microgravity, but these models will likely be improved by further research into the factors that contribute to stone formation, which can then be incorporated into the model.
The fidelity of the reporting of symptomatic kidney stones in the U.S. astronaut corps, particularly for retired astronauts, should be addressed and is perhaps within the scope of Gap B5.
Does the Evidence Report Address Relevant Interactions Among Risks?
The evidence report focuses on the contribution of altered bone metabolism to kidney stone formation. The associated risks that are not directly discussed include those discussed in separate evidence reports: Risk of Inadequate Nutrition (Smith et al., 2015); Risk of Adverse Health Outcomes and Decrements in Performance Due to In-Flight Medical Conditions (Antonsen et al., 2017); Risk of Therapeutic Failure Due to Ineffectiveness of Medication (Wotring, 2011); and Risk of Adverse Health Effects Due to Host-Microorganism Interactions (Ott et al., 2016) (in the case of struvite stones that arise from bacterial infection). These associated risks should be considered, particularly for countermeasures such as dietary stone inhibitors, technologies to treat stones, and pharmacological agents intended to reduce stone formation, such as potassium citrate. Should a kidney stone be suspected in flight and particularly if ultrasonic treatments for kidney stones are used, an additional interaction is discussed in the NASA evidence report Risk of Performance Errors Due to Training Deficiencies (Barshi and Dempsey, 2016). These risks should be directly referenced in the report for improved clarity.
What Is the Overall Readability and Quality?
The overall readability and quality of the report are very good, with well-organized data presented in a thoughtful and concise manner.
Is the Breadth of the Cited Literature Sufficient?
The bibliography includes a good selection of the space life sciences literature on the risk of renal stone formation but is lacking sources from the urology literature on the stone formation process and current practices for preventing stones. Newer techniques for stone analysis, including micro-computed tomography and spectroscopy on stones from astronauts, could give additional information as to the differences in the stone formation process in flight as opposed to on Earth. Additionally, recent research evaluating technologies to study stones, identifying early miner-
alogical and cellular mechanisms, and assessing the effectiveness and potential side effects of treatments such as potassium citrate should be included. A few examples include (but are not limited to) Robinson et al., 2009; Williams et al., 2010; Boonla et al., 2014; Gul and Monga, 2014; Shoag and Eisner, 2014; Wang et al., 2014; Evan et al., 2015; and Zisman et al., 2015.
Is the Expertise of the Authors Sufficient to Fully Cover the Scope of the Given Risk? Is Input from Additional Disciplines Needed?
The authors have expertise in bone metabolism, human physiology, and biochemistry, which is important when discussing renal physiology. The report could be improved by including a practicing urologist and nephrologist who could update the report with current practices for treating and preventing stones on Earth as well as the current understanding of factors that contribute to renal stone formation.
Additional disciplines in the form of practicing urologists and nephrologists or experts in stone formation on Earth would greatly add to the report. As currently written, questions remain as to the current understanding of the stone formation process as well as to the standard practices for preventing stones on Earth. Aviation medicine has strict requirements for pilots with regard to the diagnosis of renal stones, and strategies to prevent stones may be possible to implement in spaceflight.
Has the Evidence Report Addressed Previous Recommendations Made by the IOM in the 2008 Letter Report?
The evidence report did not fully address the previous recommendations made by the IOM in the 2008 letter report. The propensity for renal stones pre-flight was brought up in the previous report, and the authors were encouraged to look for other factors that contribute to stone formation, including genetic predisposition and dietary factors. In addition, the report notes that the risk report focused on hypercalciuria, a focus that is continued in the 2017 version of the report. As noted in the current report, NASA has made an effort to address the real incidence (as opposed to symptomatic incidence) of renal stones, which was noted in the 2008 report. Data are still forthcoming on the real incidence of renal stones.
