NOTE: Title change to "Integrated Medical Model - Renal Stone Module" and end date change to 12/15/2015 per M. Urbina/JSC (Previous title "Probabilistic Analysis of Renal Stones in US Astronauts")--Ed., 10/8/15

NOTE: End date change per M. Urbina/JSC and PI (Ed., 9/17/15)

NOTE: Addition of ExMC 4.13 Gap per IRP Rev E (Ed., 3/19/14)

NOTE: End date shows as 5/31/2015 per JSC MTL dtd 12/28/12 (Ed. 1/25/13)

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Lifetime Surveillance of Astronaut Health (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the Glenn Research Center (GRC) Integrated Medical Model (IMM) team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0 L/day and 2.5 L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects, and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of spaceflight to assess the likelihood of renal stone formation.

Once completed, The Renal Stone Formation Simulation Module (RSFSM) will provide a state-of-the-art computational capability that can not only be used to more directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios but also help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future.

The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task is designed to inform NASA's Integrated Medical Model (IMM) with the likelihood and associated uncertainty of astronauts developing kidney stones upon long-term exposure to microgravity, as well as upon re-entry to a gravitational field. The computational module will be able to assess the effects of various design reference mission scenarios, thus allowing mission planners, medical kit designers, and clinicians to compare the efficacy of various countermeasures devised to reduce the probability of developing renal stone incident during the mission. The understanding that these simulations provide will also help to improve the astronauts' screening protocols.

The benefits of developing this computational capability is not limited to space applications but will extend back to impact clinical and scientific medicine on Earth. As a state-of-the-art research tool and virtual hypothesis-tester, RSFSM will expand the current level of understanding of renal stone disease. It will also serve as a tool to help improve clinical procedures for screening and treating nephrolithiasis on Earth and devise physical and/or pharmaceutical interventions to help the nearly 15 million Americans who currently suffer from this ailment today.

For the PBE renal stone formation simulation studies, four subjects were considered based on their published 1g and microgravity biochemical profiles, namely -- 1g normal, microgravity astronaut, and 1g recurrent and microgravity stone-formers. Parametric simulations were performed to assess the impact of alterations in renal biochemistry of the astronauts due to microgravity exposure on the risk of critical CaOx renal stone formation during long duration missions and to quantify the efficacy of using citrate and pyrophosphate dietary supplements and increased hydration as possible countermeasures for reducing this risk.

Through comprehensive numerical case studies performed by the PBE model the following assessments were made:

1. The PBE model was successful in clearly distinguishing between a 1g normal and a 1g recurrent stone-former based on their published 24 hr urine biochemical profiles.

2. The predicted CaOx crystal aggregate size distribution for a microgravity astronaut were closer to those of a recurrent stone-former on Earth than a normal risk free subject in 1g underscoring the detrimental effect of space altered renal biochemistries.

3. Due to microgravity renal biochemical alterations, the increase in risk level for developing renal stone in microgravity was relatively more significant for a normal person going to space than a stone former. However, numerical predictions also clearly underscore that the stone-former subject has still by far the highest absolute risk of critical stone formation during space travel.

4. For stone-formers both on Earth and in Space depletion of calcium and oxalate is an important factor to be considered. This points to the shortcoming of the relative supersaturation levels determined by the 24 hr urine measurements performed distal to the growth process as a definitive measure of the risk.

5. Agglomeration was found to be a crucial mechanism for stone size enhancement both in 1g and microgravity.

6. Citrate was found to be an effective inhibitor of both growth and agglomeration. Our numerical predictions indicate that urine, due to its normal citrate content, is already, to a large extent, inhibited against growth and agglomeration of CaOx crystals. Any additional increase in citrate beyond its average normal urinary levels on Earth through dietary supplements is beneficial but only to a limited extent. However, the model also predicts that any decline in the citrate levels during space travel below its normal urinary values on Earth could easily move the microgravity astronaut subject into the stone-forming risk category. So the current results strongly recommend for use of citrate as a dietary countermeasure to prevent the adverse effect of any space-induced hypocitraturia during the future missions.

7. Pyrophosphate was also found to be an effective direct inhibitor of growth. Results indicate that minimal pyrophosphate concentrations in urine can move the maximum CaOx aggregate size predicted for the microgravity astronaut from a near critical value of 140 microns to a definitively safe range below 10 microns. These promising predictions suggest that more comprehensive experimental assessment of use of pyrophosphate and other similar inhibitors such as phytic acid, and osteopontin as dietary countermeasures for the space program are warranted.

8. Hydration can act as an effective promoter or inhibitor of renal stone development in 1g and microgravity. Our results indicate that dehydration during space travel that may cause astronaut urinary volumes below 1.5 liters/day can easily move a preflight non-stone-former to the population densities and renal stone size ranges resembling the 1-g recurrent stone formers. Augmented hydration levels that produce up to 3 liters/day urinary output were also simulated and numerical results indicate that urinary volumes from 2.5 - 3 liters/day can serve as an excellent and effective countermeasure. Thus based on our results, a ½ liter increase in urine output from the current guideline level of 2.0 liters/day to 2.5 liters/day is recommended because it is predicted that it will provide considerable inhibitive benefits, moving the astronaut well into a risk free range.

In this work, we only investigated the effect of variation in the direct inhibitive action by citrate and pyrophosphate. For the citrate case there is also an indirect inhibition due to speciation. This contribution was included in our model only at a fixed level representative of a standard urine biochemistry. In order to consider the impact of indirect inhibition as a function of citrate concentration, the use of speciation codes such as JESS or Equil2 is required to account for the bounding of calcium ions with citrate in forming soluble complexes that lowers the supersaturation levels of CaOx. Coupling of JESS computations with the current PBE renal stone model will be undertaken as part of our ongoing work in this area with the goal of providing a more comprehensive assessment of both direct and indirect inhibition potentials of the citrate and hydration countermeasures in near future.

There are two main factors that will determine whether a critical stone incident will occur or not. First is the renal biochemistry that dictates the rate of stone size enhancement due to growth and agglomeration and the second is the residence time of renal calculi that is determined by their transport through the nephron by the urinary flow. The lag that might occur due to nonslip boundary condition (in both 1g and microgravity) or due to gravity effects in upward flowing tubules (only in 1g) or due to nucleation and growth on Randall plaque surfaces or on injured sections of the nephron could not be included in the present “lumped” PBE transport analysis.

In order to consider these important transport effects, a two-phase PBE-CFD Renal Calculi Formation & Transport model was developed by coupling the PBE for nucleating, growing, and agglomerating renal calculi to a CFD model that solves for flow of urine, conservation of species, and transport of renal calculi in the nephron using a Eulerian two-phase mathematical framework.

Parametric simulations were performed using the PBE-CFD model to study steady state stone size and volume fraction distributions in the four main sections of the nephron under weightlessness conditions. These sections are: the tubule (distal, tube of Henle, proximal); the Inner Medullary Collecting Duct (IMCD); the Outer Medullary Collecting Duct (OMCD); and the Duct of Bellini (DoB). The CFD results reiterated that agglomeration has a profound effect on the renal stone size distributions by decreasing the population of smaller stones and increasing the number and sizes of the larger stones in all four segments of the nephron. More importantly, it was found that due to the retarding effect of the wall on the urinary flow, the volume fraction of the CaOx crystals is dramatically increased at the walls of tubule and IMCD segments. Thus for these first two nephron segments, a mixed-suspension mixed-product removal (MSMPR) continuous crystallizer model as adopted by many of the previous theoretical work is not valid.

Our numerical results further show that mixing due to the cascading transition between the nephron segments produces quite uniform volume fraction distributions in the OMCD, and DoB nephron segments. Simulations using measured astronaut urinary calcium and oxalate concentrations in microgravity as input indicate that under nominal conditions the largest stone sizes developed in Space will be still considerably below the critical range for problematic stone development. However, our results also imply that since the highest stone volume fraction occurs next to the tubule and duct walls, there may be an increased propensity for wall adhesion, for example, on existing Randall Plaque surfaces or injured sections of the nephron, with a greater risk of evolution towards critical sizes. More detailed CFD models that can rigorously capture the urine-crystal-wall interactions are needed to provide a deeper understanding of renal stone formation that leads to a critical retention scenario.

NOTE: Title change to "Integrated Medical Model - Renal Stone Module" and end date change to 12/15/2015 per M. Urbina/JSC (Previous title "Probabilistic Analysis of Renal Stones in US Astronauts")--Ed., 10/8/15

NOTE: End date change per M. Urbina/JSC and PI (Ed., 9/17/15) (Ed., 9/17/15)

NOTE: End date change per M. Urbina/JSC and PI (Ed., 9/17/15)

NOTE: Addition of ExMC 4.13 Gap per IRP Rev E (Ed., 3/19/14)

NOTE: End date shows as 5/31/2015 per JSC MTL dtd 12/28/12 (Ed. 1/25/13)

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Longitudinal Study of Astronaut Health. (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the Glenn Research Center (GRC) Integrated Medical Model (IMM) team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0 L/day and 2.5 L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects, and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of space flight to assess the likelihood of renal stone formation.

Once completed, The Renal Stone Formation Simulation Module (RSFSM) will provide a state-of-the-art computational capability that can not only be used to more directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios but also help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future.

The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task is designed to inform NASA's Integrated Medical Model (IMM) with the likelihood and associated uncertainty of astronauts developing kidney stones upon long-term exposure to microgravity, as well as upon re-entry to a gravitational field. The computational module will be able to assess the effects of various design reference mission scenarios, thus allowing mission planners, medical kit designers, and clinicians to compare the efficacy of various countermeasures devised to reduce the probability of developing renal stone incident during the mission. The understanding that these simulations provide will also help to improve the astronauts' screening protocols.

The benefits of developing this computational capability is not limited to space applications but will extend back to impact clinical and scientific medicine on Earth. As a state-of-the-art research tool and virtual hypothesis-tester, RSFSM will expand the current level of understanding of renal stone disease. It will also serve as a tool to help improve clinical procedures for screening and treating nephrolithiasis on Earth and devise physical and/or pharmaceutical interventions to help the nearly 15 million Americans who currently suffer from this ailment today.

This deterministic model for renal stone formation was developed using the rigorous frame work of the Population Balance Equation (PBE). The model is amenable to analytical solutions based on two simplifying but acceptable assumptions. Therefore, it can provide fast solutions to accommodate the numerous Monte Carlo generated parametric simulations that are required in future by the Probabilistic Risk Assessment (PRA) analyses.

The model was verified through comparison with the published results provided by several MSRPP crystallization experiments including an in-vitro calcium oxalate experiment related to renal stone formation. Four subjects were considered based on their published 1g and microgravity biochemical profiles, namely--1g normal, microgravity astronaut, and 1g recurrent and microgravity stone-formers.

The research was carried out in two phases. In Phase I, simulations were performed to assess the impact of biochemical alterations induced by Space travel on development of renal stones and risk of a critical renal formation for the astronauts. In Phase II, numerical simulations were performed to examine and assess the efficacy of several dietary countermeasures such as use of citrates and increased hydration in reducing the risk of critical renal stone development for the astronauts.

From the results of the comprehensive Phase I case studies involving the four above-mentioned subjects the following assessments were made:

1. The model was successful in clearly distinguishing between a 1g normal and a 1g recurrent stone-former based on their published 24 hr urine biochemical profiles.

2. The predicted stone size distribution and maximum stone size for a microgravity astronaut were closer to those of a recurrent stone-former on Earth than a normal risk free subject in 1g underscoring the detrimental effect of space altered renal biochemistries.

3. Due to microgravity renal biochemical alterations, the relative change in risk level for developing renal stone in microgravity was more significant for a normal person going to space than a stone former -- an important issue to consider for astronaut screening.

4. For stone-formers both on Earth and in Space depletion of calcium and oxalate is an important factor to be considered and points to the shortcoming of the relative supersaturation levels determined by the 24 hr urine measurements performed distal to the growth process as a definitive measure of the risk.

5. Agglomeration was found to be a crucial mechanism for stone size enhancement both in 1g and microgravity.

In the Phase II research, the renal stone formation model was used to assess the impact of citrate and pyrophosphate dietary supplements and increased hydration as countermeasures for reducing the risk of critical renal stone development for the astronauts during their future long-duration missions. The results of the comparative Phase II numerical case studies indicate the following assessments for the microgravity astronaut subject:

1. Citrate was found to be an effective inhibitor of both growth and agglomeration. Our numerical predictions indicate that urine, due to its normal citrate content, is already, to a large extent, inhibited against growth and agglomeration of CaOx crystals. Any additional increase in citrate beyond the average normal 1g urinary levels through dietary supplements is beneficial but only to a limited extent. However, the model also predicts that any decline in the citrate levels below the normal 1g urinary values during space travel could easily move the microgravity astronaut subject into the stone-forming risk category. So the current results strongly recommend for use of citrate as a dietary countermeasure to prevent the adverse effect of any space-induced hypocitraturia during the future missions.

2. Pyrophosphate was also found to be an effective direct inhibitor of growth. Results indicate that minimal pyrophosphate concentrations in urine can move the maximum stone size predicted for the microgravity astronaut from a near critical value of 140 microns to a definitively safe range below 10 microns. These promising predictions suggest that more comprehensive experimental assessment of use of pyrophosphate and other similar inhibitors such as phytic acid, and osteopontin as dietary countermeasures for the space program are warranted.

3. Hydration can act as an effective promoter or inhibitor of renal stone development in 1g and microgravity. Our results indicate that dehydration below the level of 1.5 liters/day urinary output during space travel can easily move a preflight non-stone-former to the stone population densities and renal stone size ranges resembling 1-g recurrent stone formers. Augmented hydration up to 3 liters/day urinary output levels were also simulated and numerical results indicate that hydration levels from 2.5-3 liters/day can serve as excellent and effective countermeasure. Thus based on our results, a ½ liter increase in hydration level from the current guideline level of 2.0 liters/day to 2.5 liters/day is recommended because it is predicted that it will provide considerable inhibitive benefits, moving the astronaut well into a risk free range.

There are two main factors that will determine whether a critical stone incident will occur or not. First is the renal biochemistry that dictates the rate of stone size enhancement due to growth and agglomeration and the second is the residence time of renal calculi that is determined by their transport through the nephron by the urinary flow. The lag that might occur due to nonslip boundary condition (in both 1g and microgravity) or due to gravity effects in upward flowing tubules (only in 1g) could not be included in the present “lumped” transport analysis. In order to consider these important transport effects the PBE renal stone model needs to be coupled to a two-phase CFD model for stone and urine transport through the nephron. While a coupled CFD-PBE analysis was outside the scope of the analytical model it is part of our ongoing parallel CFD renal stone model development effort.

Finally, we only investigated the effect of variation in the direct inhibitive action by citrate and pyrophosphate. For the citrate case there is also an indirect inhibition due to speciation. This contribution was included in our model only at a fixed level as for an average urine. In order to consider the impact of indirect inhibition as a function of citrate concentration, the use of speciation codes such as JESS or Equil2 is required to account for the bounding of calcium ions with citrate in forming soluble complexes that lowers the supersaturation levels of CaOx. Coupling of JESS computations with the current PBE renal stone model will be undertaken as part of our ongoing work in this area with the goal of providing a more comprehensive assessment of both direct and indirect inhibition potentials of the citrate and hydration countermeasures in near future.

Two papers have been submitted to American Journal of Physiology - Renal Physiology:

Kassemi, M. and Thompson, P. "Prediction of Renal Stone Size Distributions in Microgravity Using a PBE Analytical Model: 1. Effect of Space-Induced Biochemical Alterations " Submitted AJP-Renal, Sep-2015

Kassemi, M. and Thompson, D. "Prediction of Renal Stone Size Distributions in Microgravity Using a PBE Analytical Model: 2. Effect Dietary Countermeasures" Submitted AJP-Renal, Sep-2015

NOTE: End date change per M. Urbina/JSC and PI (Ed., 9/17/15)

NOTE: Addition of ExMC 4.13 Gap per IRP Rev E (Ed., 3/19/14)

NOTE: End date shows as 5/31/2015 per JSC MTL dtd 12/28/12 (Ed. 1/25/13)

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Longitudinal Study of Astronaut Health. (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the Glenn Research Center (GRC) Integrated Medical Model (IMM) team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0L/day and 2.5L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects, and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of space flight to assess the likelihood of renal stone formation.

Once completed, The Renal Stone Formation Simulation Module (RSFSM) will provide a state-of-the-art computational capability that can not only be used to more directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios but also help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future.

The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task is designed to inform NASA's Integrated Medical Model (IMM) with the likelihood and associated uncertainty of astronauts developing kidney stones upon long-term exposure to microgravity, as well as upon re-entry to a gravitational field. The computational module will be able to assess the effects of various design reference mission scenarios, thus allow mission planners, medical kit designers, and clinicians to compare the efficacy of various countermeasures devised to reduce the probability of developing renal stone incident during the mission. The understanding that these simulations provide will also help to improve the astronauts' screening protocols.

The benefits of developing this computational capability are not limited to space applications but will extend back to impact clinical and scientific medicine on Earth. As a state-of-the-art research tool and virtual hypothesis-tester, RSFSM will expand the current level of understanding of renal stone disease. It will also serve as a tool to help improve clinical procedures for screening and treating nephrolithiasis on Earth and devise physical and/or pharmaceutical interventions to help the nearly 15 million Americans who currently suffer from this ailment today.

1. The distribution of stone sizes and their respective population densities are both quite sensitive to the different biochemistries of normal and stone-forming subjects in 1g and microgravity.

2. Stone formers exhibit parabolic distributions with peak of stone populations shifting from 2 microns in 1g to about 5-7 microns in reduced-gravity and when precipitation is the main mechanism for growth.

3. Normal subjects exhibit a monotonic decrease in precipitating stone size populations from seed size to about 8 microns in microgravity.

4. As a result of the shift in the renal biochemistry upon exposure to microgravity, a normal subject in space can exhibit stone growth rates and size distributions that are comparable to a stone-former on Earth -- a finding that may prove important to the astronaut screening protocols.

5. Agglomeration is likely to be the most important and critical mechanism in development and enlargement of renal stones causing around ten-fold increase in the resulting stone sizes.

6. Stone size distribution is quite sensitive to the magnitude of the agglomeration coefficient – a quantity that unfortunately may vary substantially for different urine biochemistries and therefore not well-quantified in published literature.

7. The gravitational field plays an adverse effect increasing the transit time of renal calculi in the nephron with a possibility of a nearly two-fold stone size enhancement.

In summary, the results so far imply that while a typical stone-former may form considerably larger renal stones on Earth, the normal subject in microgravity tends to make significantly more stones below the 2 micron range by nucleation and precipitation. Agglomeration of these crystals in the nephron may result in a 10 fold further increase in the stone sizes in microgravity. The stones in this size range will still clear through the nephron. But unfortunately, upon re-entry into a gravitational field, further growth and agglomeration of the renal calculi combined with increased transit times due to the lagging of the stones behind the urinary flow in tubule sections where gravitational vector is acting in the adverse direction can result in size increases alarmingly close to the critical dimension for retention. In this case, the risk for a clinical stone occurrence may be greatly enhanced.

The development of the Renal Stone Formation Simulation Module (RSFSM) and its validation has been nearly completed in 2013. In the final year of the project (2014), this model will be used to perform a series of comprehensive parametric simulation case studies to investigate effect of hydration and inhibition. Furthermore, the core deterministic PBE model will be coupled to front and back end probabilistic wrapper models. Simulations performed using the combined deterministic-probabilistic model will be used to provide a probabilistic assessment of the risks of clinical stone incidents for future space mission scenarios.

NOTE: End date shows as 5/31/2015 per JSC MTL dtd 12/28/12 (Ed. 1/25/13)

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Longitudinal Study of Astronaut Health. (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the GRC IMM team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0L/day and 2.5L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of space flight to assess the likelihood of renal stone formation.

Once completed, The Renal Stone Formation Simulation Module (RSFSM) will provide a state-of-the-art computational capability that can not only be used to more directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios but also help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future.

The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task is designed to inform NASA's Integrated Medical Model (IMM) with the likelihood and associated uncertainty of astronauts developing kidney stones upon long-term exposure to microgravity, as well as, upon re-entry to a gravitational field. The computational module will be able to assess the effects of various design reference mission scenarios, thus allow mission planners, medical kit designers, and clinicians to compare the efficacy of various countermeasures devised to reduce the probability of developing renal stone incident during the mission. The understanding that these simulations provide will also help to improve the astronauts' screening protocols.

The benefits of developing this computational capability is not limited to space applications but will extend back to impact clinical and scientific medicine on Earth. As a state-of-the-art research tool and virtual hypothesis-tester, RSFSM will expand the current level of understanding of renal stone disease. It will also serve as a tool to help improve clinical procedures for screening and treating nephrolithiasis on Earth and devise physical and/or pharmaceutical interventions to help the nearly 15 million Americans who currently suffer from this ailment today.

In this year of the project, the previously developed combined transport-kinetics model for growth of calcium oxalate crystals is cast in the framework of the Population Balance Equation whereupon the nephron is treated as a continuous crystallizer. This report describes the present model formulations and some interesting results obtained during the preliminary parametric simulations. The model is used to investigate the growth rates and size distributions of renal calculi in the nephron based on parametric simulation case studies for normal and stone-forming subjects in 1G and microgravity. Simulation results seem to suggest that as a result of the shift in renal biochemistry upon exposure to microgravity, a normal subject in space can exhibit stone growth rates and size distributions that are comparable to a stone-former on Earth. Thus, the adverse effects of microgravity conditions may be relatively as consequential for a normal subject than an inherent stone former - a finding that may prove important to the astronaut screening protocols.

Numerical results also suggest that while a typical stone former on Earth or in Space may form a considerably larger number of renal stones in the range of 2-8 microns, the normal subject in microgravity tends to make significantly more stones below the 2 microns range. This may lead to an undesirable possibility for future long-duration missions, where the modified renal biochemistry of the astronauts in microgravity during space travel can instigate the formation of a large number of smaller stones that may become problematic upon reentry into a partial gravitational field.

NOTE: End date shows as 5/31/2015 per JSC MTL dtd 12/28/12 (Ed. 1/25/13)

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Longitudinal Study of Astronaut Health. (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the GRC IMM team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0L/day and 2.5L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of space flight to assess the likelihood of renal stone formation.

Once completed, The Renal Stone Formation Simulation Module (RSFSM) will provide a state-of-the-art computational capability that can not only be used to more directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios but also help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future.

The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task is designed to inform NASA's Integrated Medical Model (IMM) with the likelihood and associated uncertainty of astronauts developing kidney stones upon long-term exposure to microgravity, as well as, upon re-entry to a gravitational field. The computational module will be able to assess the effects of various design reference mission scenarios, thus allow mission planners, medical kit designers, and clinicians to compare the efficacy of various countermeasures devised to reduce the probability of developing renal stone incident during the mission. The understanding that these simulations provide will also help to improve the astronauts' screening protocols.

The benefits of developing this computational capability is not limited to space applications but will extend back to impact clinical and scientific medicine on Earth. As a state-of-the-art research tool and virtual hypothesis-tester, RSFSM will expand the current level of understanding of renal stone disease. It will also serve as a tool to help improve clinical procedures for screening and treating nephrolithiasis on Earth and devise physical and/or pharmaceutical interventions to help the nearly 15 million Americans who currently suffer from this ailment today.

The deterministic model has four important components: (i) nucleation and crystal growth from supersaturated solution; (ii) agglomeration to form larger stones; (iii) inhibition to growth and agglomeration by the urinary inhibitors; and (iv) transit and passage through the nephron. During the first 1.5 years of this task, the team developed the nucleation and growth model together with a preliminary phenomenological inhibition model. These models have been numerically verified for solution methodology’s uniqueness and stability, and validated against archival experimental data published in the literature.

However, the renal stone problem is not a single stone phenomena but a multiple interacting calculi event. Therefore, in order to be able to consider the size distribution of renal calculi that can interact with each other during growth and to properly capture the aggregation, agglomeration and breakage components of renal stone development, the team implemented a mathematical framework based on the Population Balance Equation (PBE) methodology used extensively by chemical engineers to model continuous chemical crystallizer operations. The preliminary development of the PBE mathematical framework is also completed and partially validated. This PBE model for renal stone includes the nucleation and growth component and the agglomeration and breakage components are currently being incorporated in the PBE.

The chemical speciation code, JESS has also been acquired through communications with its developers, Dr. Peter May (Murdoch University, Australia) and Dr. Kevin Murray (Insight Modeling Services, South Africa). JESS will be primarily used to account for changes in the kidney's relative supersaturation due to natural or augmented inhibition chemistry of the urine. It has been demonstrated to be more comprehensive in describing renal biochemical speciation than other existing speciation codes. Currently, the MATLAB sampling utility implemented in the probabilistic model, JESS, and the encoded deterministic renal stone growth model (written in C) are being coupled for preliminary simulations using MATLAB as the integrator.

Preliminary simulation results generated by model have pointed to two quite interesting and important trends:

1. The adverse effect of microgravity conditions seems to be relatively greater for a normal subject than an inherent stone-former - a finding that may prove important to the astronaut screening protocols. 2. Administration of natural chemical inhibitors such as citrates may provide an effective countermeasure to CaOx stone growth and reduce the risk of renal stone development in space even for inherent stone-formers. Although care must be taken that chemical inhibition of one type of crystal does not lead to other adverse effects such as promotion of other types of renal stone precipitation.

The above conclusions are, however, preliminary as important effects of agglomeration, inhibition, transport, and wall adhesion that may change the present predictions have not yet been fully incorporated. It is hoped that the future enhancements of the computational module can enable it to paint a broader and more complete picture of renal stone development in micro- and partial gravity environments.

NOTE: End date is 8/8/2014, per D. Griffin/GRC (Ed., 5/30/12)

During all spaceflight missions to date, renal stone incidence is actually lower than what would be expected in the general population or in the analog population utilized by the Longitudinal Study of Astronaut Health. (LSAH). After astronauts return to Earth, however, the incidence rate increases and surpasses both the rate of the general population and the LSAH analog population, with the astronaut incidence rate of calcium oxalate stones approximately doubling that of the general US population. If these trends persist with the reintroduction of even fractional gravity, renal stones during a Mars mission could become a serious problem, not only in terms of astronaut health, but also in terms of the resources required to adequately treat the condition. A Bayesian update analysis of the data above suggested an approximately 5% probability of at least one crewmember developing a renal stone during a Mars mission.

Given the nature of these data, the GRC IMM team developed a proof of concept probabilistic simulation of renal stone formation during a long duration exploration mission. While somewhat limited in scope, this simulation included both probabilistic and deterministic components. The deterministic components were developed to support the probabilistic analysis. Key findings from this work included:

1) As the stone grows larger, the governing equation says the rate of growth will increase, which is why the probabilistic analysis picks up the seed size as being influential.

2) The probabilistic model demonstrates identical sensitivity for Calcium and Oxalate, suggesting that a more detailed surface chemistry simulation needs to be conducted.

3) The sensitivities for the dwell time of a stone show pronounced differences between the 2.0L/day and 2.5L/day cases resulting in a 68.6% change in the probability of one stone reaching the effective diameter of a nephron from heterogeneous growth only. This result has a standard deviation of 0.237.

As part of the validation process for this module, the task underwent a subject matter expert review of the work done to date. The review was favorable with indication that an increase model fidelity was required, as outlined in Steps 1-3 below.

1. Determine expected incidence rate of renal stones during exploration missions and how this rate is affected by new countermeasure activities.

2. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program to develop medical kits appropriate to the level of risk of renal stone formation.

3. Provide a probabilistic simulation that allows the Exploration Medical Capabilities Element of the Human Research Program the ability to quantitatively evaluate the effect of different operations scenarios on the ability of a given medical kit to adequately treat an ill or injured crew member.

The GRC IMM task team is currently working to extend the capabilities of the deterministic model used as the parameter integration function to include both promoters, inhibitors, agglomeration, wall interaction effects and gravity components. Once this is matured, it will be wrapped with a probabilistic simulation representing the scenarios and physiological parameter variation typical of space flight to assess the likelihood of renal stone formation.