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Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2016 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 12/31/2015  
Task Last Updated: 05/01/2017 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information.
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Antonsen, Erik  
Center Contact: 281.483.4961 
erik.l.antonsen@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: End date is 12/31/2015 per D. Griffin/GRC (Ed., 11/18/15)

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)

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits: Nephrolithiasis constitutes as one of the most common diseases that has afflicted man for centuries. Indeed, one of the first evidences of renal stones in humans was found in an Egyptian mummy at El- Amrah dating back to 4800 B.C. Today, approximately 5% of the U.S. population develops clinically significant urinary calculi in their lifetime. However, renal stone disease is not only a concern on Earth, but could conceivably pose as a serious risk to the astronauts’ health and safety in space. The physiological, environmental, and dietary conditions imposed by space travel and weightlessness can easily increase this risk as a recent survey of renal stone formation in U.S. astronauts has revealed 14 recorded episodes. Russian medical science investigators have also noted multiple stone events among the Soviet cosmonauts. The most serious one was an in-flight renal stone occurrence that nearly caused the the Russian mission to be aborted.

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.

Task Progress & Bibliography Information FY2016 
Task Progress: In this work analytical Population Balance Equation (PBE) and Computational Fluid Dynamics (CFD) models were developed to predict the steady state size distribution of nucleating, growing, and agglomerating calcium oxalate (CaOx) renal calculi during their transit through the kidney in 1g and microgravity based solely on the renal biochemical profile of the subject as input. The PBE 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 with excellent agreements.

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.

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kassemi M, Thompson D, Goodenow D, Gokoglu S, Myers J. "Effect of Dietary Countermeasures and Impact of Gravity on Renal Calculi Size Distributions Predicted by PBE System and PBE-CFD Models." Exploration Medical Capability Session, 2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016.

2016 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 8-11, 2016. , Feb-2016

Abstracts for Journals and Proceedings Kassemi M, Thompson D, Goodenow D, Gokoglu S, Myers J. "Coupled CFD-PBE Prediction of Renal Stone Size Distributions in the Nephron under Weightlessness and Upon Reentry into a Gravitational Field." Presented at ExMC session, 2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017.

2017 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 23-26, 2017. , Jan-2017

Articles in Peer-reviewed Journals Kassemi M, Griffin E, Thompson D. "Numerical assessment of CaOx renal calculi development in space using PBE coupled to urinary flow and species transport." Int J Heat Mass Transf. 2018 Jun;121:1146-58. Epub 2018 Mar 7. https://doi.org/10.1016/j.ijheatmasstransfer.2018.01.035 , Jun-2018
Articles in Peer-reviewed Journals Kassemi M, Thompson D. "Prediction of renal crystalline size distributions in space using a PBE analytic model. 1. Effect of microgravity-induced biochemical alterations." Am J Physiol Renal Physiol. 2016 Sep 1;311(3):F520-30. Epub 2016 Jun 8. http://dx.doi.org/10.1152/ajprenal.00401.2015 ; PubMed PMID: 27279490 , Sep-2016
Articles in Peer-reviewed Journals Kassemi M, Thompson, D. "Prediction of renal crystalline size distributions in space using a PBE analytic model. 2. Effect of dietary countermeasures." Am J Physiol Renal Physiol. 2016 Sep 1;311(3):F531-8. Epub 2016 Jun 8. http://dx.doi.org/10.1152/ajprenal.00402.2015 ; PubMed PMID: 27279491 , Sep-2016
Papers from Meeting Proceedings Kassemi M, Griffin E, Thompson D. "Coupled PBE-CFD Predictions of Renal Stone Size Distributions in the Nephron in Microgravity." 46th International Conference on Environmental Systems, Vienna, Austria, July 10-14, 2016.

46th International Conference on Environmental Systems, Vienna, Austria, July 10-14, 2016. Paper # 2016-276. https://ntrs.nasa.gov/archive/nasa/casi.ntrs.nasa.gov/20170000238.pdf , Jul-2016

Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2015 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 12/31/2015  
Task Last Updated: 09/17/2015 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Antonsen, Erik  
Center Contact: 281.483.4961 
erik.l.antonsen@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: End date is 12/31/2015 per D. Griffin/GRC (Ed., 11/18/15)

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)

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits: Nephrolithiasis constitutes as one of the most common diseases that has afflicted man for centuries. Indeed, one of the first evidences of renal stones in humans was found in an Egyptian mummy at El- Amrah dating back to 4800 B.C. Today, approximately 5% of the U.S. population develops clinically significant urinary calculi in their lifetime. However, renal stone disease is not only a concern on Earth, but could conceivably pose as a serious risk to the astronauts’ health and safety in space. The physiological, environmental, and dietary conditions imposed by space travel and weightlessness can easily increase this risk as a recent survey of renal stone formation in US astronauts has revealed 14 recorded episodes. Russian medical science investigators have also noted multiple stone events among the Soviet cosmonauts. The most serious one was an in-flight renal stone occurrence that nearly caused the the Russian mission to be aborted.

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.

Task Progress & Bibliography Information FY2015 
Task Progress: In FY 2014-2015 effort, an analytical Population Balance Equation model was developed to predict the steady state size distribution of nucleating, growing, and agglomerating renal calculi during their transit through the kidney in 1g and microgravity based solely on using the renal biochemical profile of the subject as input.

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

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kassemi M, Griffin E, Thompson D. "Effect of Gravitational Field and Countermeasures on Renal Calculi Development & Size Distributions in the Nephron." 2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015.

2015 NASA Human Research Program Investigators’ Workshop, Galveston, TX, January 13-15, 2015. 2015 HRP IWS - Integrated Pathways to Mars, #0326. , Jan-2015

Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2014 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 09/30/2015  
Task Last Updated: 01/30/2014 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Watkins, Sharmi1a  
Center Contact: 281.483.0395 
sharmila.watkins@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: Title change to "Integrated Medical Model - Renal Stone Module" 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)

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits: Nephrolithiasis constitutes as one of the most common diseases that has afflicted man for centuries. Indeed, one of the first evidences of renal stones in humans was found in an Egyptian mummy at El- Amrah dating back to 4800 B.C. Today, approximately 5% of the U.S. population develops clinically significant urinary calculi in their lifetime. However, renal stone disease is not only a concern on Earth, but could conceivably pose as a serious risk to the astronauts’ health and safety in space. The physiological, environmental, and dietary conditions imposed by space travel and weightlessness can easily increase this risk as a recent survey of renal stone formation in U.S. astronauts has revealed 14 recorded episodes. Russian medical science investigators have also noted multiple stone events among the Soviet cosmonauts. The most serious one was an in-flight renal stone occurrence that nearly caused the abortion of the Russian mission.

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.

Task Progress & Bibliography Information FY2014 
Task Progress: A combined transport-kinetics model for nucleation, growth, and agglomeration of calcium oxalate crystals was developed in the framework of the population balance equation whereupon the nephron was treated as a continuous crystallizer. The model was used to investigate the growth rates and size distributions of renal calculi based on parametric simulation case studies for normal and stone-forming subjects in 1g and microgravity. To investigate the transport effects of gravity on the formation and development of renal calculi in the nephron, the Population Balance Equation (PBE)-agglomeration model was further incorporated into the multipurpose computational fluid dynamics (CFD) code Ansys-Fluent and coupled to the Navier-Stokes and species equations that describe the urinary flow and transport of calcium and oxalate ions through the nephron. Numerical results indicate that the typical renal biochemistry of normal subjects on Earth as exemplified by low urinary calcium and oxalate concentrations, higher relative velocities between urinary flow and the calculi, and lower reaction rates due to presence of normal concentration of inhibitors will lead to surface reaction limited crystal growth rates. However, in microgravity, due to the possibility of increased supersaturation levels arising from lower urine volumes and higher calcium and oxalate concentrations, a negligible relative velocity between the stone and the urinary flow, and the lower inhibitor concentrations, the stone growth will be limited by the transport of ions in the bulk liquid. The numerical simulations further indicate that:

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.

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
Papers from Meeting Proceedings Kassemi M, Iskovitz I. "Prediction of Renal Stone Development and Size Distribution in Microgravity Using Population Balance Equation." Paper AIAA-1574858, Session: ICES513, Computational Modeling for Human Health and Performance Analysis, presented at 43rd AIAA International Conference on Environmental Systems, Vail, CO, July 14-18, 2013.

43rd AIAA International Conference on Environmental Systems, Vail, CO, July 14-18, 2013. Paper AIAA-1574858. http://dx.doi.org/10.2514/6.2013-3319 , Jul-2013

Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 05/31/2015  
Task Last Updated: 05/28/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Watkins, Sharmi1a  
Center Contact: 281.483.0395 
sharmila.watkins@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: Title change to "Integrated Medical Model - Renal Stone Module" per M. Urbina/JSC (Previous title "Probabilistic Analysis of Renal Stones in US Astronauts")--Ed., 10/8/15

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)

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits: Nephrolithiasis constitutes as one of the most common diseases that has afflicted man for centuries. Indeed, one of the first evidences of renal stones in humans was found in an Egyptian mummy at El- Amrah dating back to 4800 B.C. Today, approximately 5% of the U.S. population develops clinically significant urinary calculi in their lifetime. However, renal stone disease is not only a concern on Earth, but could conceivably pose as a serious risk to the astronauts’ health and safety in space. The physiological, environmental, and dietary conditions imposed by space travel and weightlessness can easily increase this risk as a recent survey of renal stone formation in US astronauts has revealed 14 recorded episodes. Russian medical science investigators have also noted multiple stone events among the Soviet cosmonauts. The most serious one was an in-flight renal stone occurrence that nearly caused the abortion of the Russian mission.

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.

Task Progress & Bibliography Information FY2013 
Task Progress: In this year of the project, the Population Balance Equation model for renal stone formation involving nucleation and growth was developed. An agglomeration model was also developed and linked with the CFD code fluent for parametric analyses. Front and back end statistical wrapper models were also developed and used to analyze the risk of renal stone for the astronauts based on microgravity biochemistry profiles/data. The deterministic PBE model will be linked with the probabilistic front and back end models for unified simulations in the next phase of the research.

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.

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kassemi M, Iskovitz I. "Renal Stone Formation Module (RSFM): Predicting Renal Stone Size Distribution in Microgravity Using a Population Balance Approach." 2013 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-14, 2013.

2013 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-14, 2013. , Feb-2013

Papers from Meeting Proceedings Kassemi M, Iskovitz I. "Prediction of Renal Stone Development and Size Distribution in Microgravity Using Population Balance Equation." 43rd International Conference on Environmental Systems, Vail, CO, July 14-18, 2013. To be presented in Computational Modeling for Human Health and Performance Analysis session.

43rd International Conference on Environmental Systems, Vail, CO, July 14-18, 2013. Paper 1574858, Session: ICES513, Computational Modeling for Human Health and Performance Analysis. , Jul-2013

Papers from Meeting Proceedings Kassemi M, Iskovitz I. "Role of Transport and Kinetics in Growth of Renal Stones." 42nd International Conference on Environmental Systems, San Diego, CA, July 15-19, 2012.

Paper AIAA-2012-3449. 42nd International Conference on Environmental Systems, San Diego, CA, July 15-19, 2012. http://dx.doi.org/10.2514/6.2012-3449 , Jul-2012

Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 05/31/2015  
Task Last Updated: 08/23/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Watkins, Sharmi1a  
Center Contact: 281.483.0395 
sharmila.watkins@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: Title change to "Integrated Medical Model - Renal Stone Module" per M. Urbina/JSC (Previous title "Probabilistic Analysis of Renal Stones in US Astronauts")--Ed., 10/8/15

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)

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits: Nephrolithiasis constitutes as one of the most common diseases that has afflicted man for centuries. Indeed, one of the first evidences of renal stones in humans was found in an Egyptian mummy at El- Amrah dating back to 4800 B.C. Today, approximately 5% of the U.S. population develops clinically significant urinary calculi in their lifetime. However, renal stone disease is not only a concern on Earth, but could conceivably pose as a serious risk to the astronauts’ health and safety in space. The physiological, environmental, and dietary conditions imposed by space travel and weightlessness can easily increase this risk as a recent survey of renal stone formation in US astronauts has revealed 14 recorded episodes. Russian medical science investigators have also noted multiple stone events among the Soviet cosmonauts. The most serious one was an in-flight renal stone occurrence that nearly caused the abortion of the Russian mission.

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.

Task Progress & Bibliography Information FY2012 
Task Progress: The Renal Stone Formation Simulation Module (RSFSM) developed as part of this task will provide state-of-the-art computational capability to directly investigate the renal stone size distributions and the statistical propensities for developing a critical stone incident for future mission scenarios and also to help to devise and evaluate different systematic chemical or physical intervention countermeasures for preventing their occurrence in future. The probabilistic risk assessment wrapper of RSFSM is driven by a series of coupled deterministic models that simulate the formation and transport of the renal stones.

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.

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Kassemi M, Iskovits I, Brock R. "A Combined Transport-Kinetics Model for Growth of Renal Calculi in 1G and Microgravity." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Articles in Peer-reviewed Journals Kassemi M, Brock R, Nemeth N. "A combined transport-kinetics model for the growth of renal calculi." Journal of Crystal Growth. 2011 Oct;332(1):48-57. http://dx.doi.org/10.1016/j.jcrysgro.2011.07.009 , Oct-2011
Project Title:  Integrated Medical Model -- Renal Stone Module Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP ExMC:Exploration Medical Capabilities
Start Date: 01/01/2011  
End Date: 08/08/2014  
Task Last Updated: 05/24/2012 
Download report in PDF pdf
Principal Investigator/Affiliation:   Kassemi, Mohammad  Ph.D. / NASA Glenn Research Center/Case Western Reserve University 
Address:  NASA Glenn Research Center 
21000 Brookpark Road, MS110-3 
Cleveland , OH 44135 
Email: mohammad.kassemi@nasa.gov 
Phone: 216-433-5031  
Congressional District: 10 
Web:  
Organization Type: NASA CENTER 
Organization Name: NASA Glenn Research Center/Case Western Reserve University 
Joint Agency:  
Comments: NOTE (Dec 2019): former affiliation included National Center for Space Exploration Research (NCSER), per information from J. McQuillen/GRC 
Co-Investigator(s)
Affiliation: 
Myers, Jerry  NASA Glenn Research Center  
Key Personnel Changes / Previous PI: NOTE: Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information
Project Information: Grant/Contract No. Directed Research 
Responsible Center: NASA JSC 
Grant Monitor: Watkins, Sharmi1a  
Center Contact: 281.483.0395 
sharmila.watkins@nasa.gov 
Solicitation / Funding Source: Directed Research 
Grant/Contract No.: Directed Research 
Project Type: GROUND 
Flight Program:  
TechPort: Yes 
No. of Post Docs:  
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) ExMC:Exploration Medical Capabilities
Human Research Program Risks: (1) ExMC:Risk of Unacceptable Health and Mission Outcomes Due to Limitations of In-flight Medical Capabilities (IRP Rev E)
Human Research Program Gaps: (1) ExMC 2.01:We do not know the quantified health and mission outcomes due to medical events during exploration missions (IRP Rev E) (Encompassed by Gap Med08 per IRP Rev I)
(2) ExMC 4.13:We have limited capability to screen for, diagnose, and treat renal stones during exploration missions (IRP Rev E)
Flight Assignment/Project Notes: NOTE: Title change to "Integrated Medical Model - Renal Stone Module" per M. Urbina/JSC (Previous title "Probabilistic Analysis of Renal Stones in US Astronauts")--Ed., 10/8/15

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

Task Description: The Exploration Medical Capability Element of the Human Research Program carries the risk of not being able to treat ill or injured crewmembers. Gap 4.13 in the Exploration Medical Capability Research Plan is the “Lack of lithotripsy or other capability to treat a renal stone.” The description of this gap states that, “Given the high probability of kidney stone formation in crew members during long duration missions the capability to perform Lithotripsy is highly desirable.”

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.

Rationale for HRP Directed Research: This research is directed because it contains highly constrained research, which requires focused and constrained data gathering and analysis that is more appropriately obtained through a non-competitive proposal.

Research Impact/Earth Benefits:

Task Progress & Bibliography Information FY2011 
Task Progress: New project for FY2011. Previous PI was Jerry Myers until January 2011. See project with title "Probabilistic Analysis of Renal Stones in US Astronauts" and PI=Myers for previous information

Bibliography Type: Description: (Last Updated: 03/08/2022) 

Show Cumulative Bibliography Listing
 
 None in FY 2011