
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39300159
72256
10.1038/s41598-024-72256-8
Article
Novel extracorporeal treatment for severe neonatal jaundice: a mathematical modelling study of allo-hemodialysis
Maheshwari Vaibhav 1
Díaz-González de Ferris Maria Esther 2
Filler Guido guido.filler@lhsc.on.ca

3
Kotanko Peter 14
1 https://ror.org/032g46r36 grid.437493.e 0000 0001 2323 588X Renal Research Institute, New York, NY USA
2 https://ror.org/0130frc33 grid.10698.36 0000 0001 2248 3208 University of North Carolina at Chapel Hill, Chapel Hill, NC USA
3 https://ror.org/02grkyz14 grid.39381.30 0000 0004 1936 8884 Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario, 800 Commissioners Road E, London, ON N6A 5W9 Canada
4 https://ror.org/04a9tmd77 grid.59734.3c 0000 0001 0670 2351 Icahn School of Medicine at Mount Sinai, New York, NY USA
19 9 2024
19 9 2024
2024
14 2191010 11 2023
5 9 2024
© The Author(s) 2024
2024
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Severe Neonatal Jaundice (SNJ) causes long-term neurocognitive impairment, cerebral palsy, auditory neuropathy, deafness, or death. We developed a mathematical model for allo-hemodialysis as a potential blood purification method for the treatment of SNJ in term or near-term infants. With allo-hemodialysis (allo-HD), the neonate’s blood flows through hollow fibers of a miniature 0.075 m2 hemodialyzer, while the blood of a healthy adult (“buddy”) flows counter-currently through the dialysate compartment. We simulated the kinetics of unconjugated bilirubin in allo-hemodialysis with neonate blood flow rates of 12.5 and 15 mL/min (for a 2.5 kg and 3.5 kg neonate, respectively), and 30 mL/min for the buddy. Bilirubin production rates in neonate and buddy were set to 6 and 3 mg/kg/day, respectively. Buddy bilirubin conjugation rate was calculated to obtain normal steady-state bilirubin levels. Albumin levels were set to 1.1, 2.1, 3.1 g/dL for the neonate and 3.3 g/dL for the buddy. Model simulations suggest that a 6-h allo-hemodialysis session could reduce neonatal bilirubin levels by > 35% and that this modality would be particularly effective with low neonatal serum albumin levels. Due to the high bilirubin conjugation capacity of an adult’s healthy liver and the larger distribution volume, the buddy’s bilirubin level increases only transiently during allo-hemodialysis. Our modelling suggests that a single allo-hemodialysis session may lower neonatal unconjugated bilirubin levels effectively. If corroborated in ex-vivo, animal, and clinical studies, this bilirubin reduction could lower the risks associated with SNJ, especially kernicterus, and possibly avoiding the morbidity associated with exchange transfusions.

Subject terms

Paediatric research
Isolation, separation and purification
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pmcIntroduction

Neonatal hyperbilirubinemia, defined as total serum bilirubin level above 5 mg/dL (86 µmol/L), affects up to 60% of term and up to 80% of preterm neonates within the first two weeks of life and usually resolves without consequences within 3–5 days after birth1. However, Severe Neonatal Jaundice (SNJ), defined as a serum bilirubin level > 20 mg/dL (342 µmol/L) after 72 h of life, accounts for up to 35% of hospital readmissions after birth2. In 2016, SNJ accounted for 1,309 deaths per 100,000 live births and over 110,000 disability-adjusted life years2. In other studies, at least 481,000 term/near-term neonates were affected by SNJ annually, with 114,000 neonates dying and an additional 63,000 neonates surviving with kernicterus3. Phototherapy and exchange transfusion prevent and treat SNJ, but these modalities are scarce in some less resourced countries4, which also have a higher prevalence of glucose-6-phosphate dehydrogenase deficiency, blood group incompatibilities, late referrals, and delayed diagnosis of SNJ5. In fact, the prevalence of kernicterus in less-resourced regions such as sub-Saharan Africa, Latin America, Eastern Europe, Central and South Asia regions was estimated as high as 0.73/1000, significantly higher than in well-resourced countries (0.1/1000 live births)6. Sunlight therapy may reduce rehospitalization rates for SNJ, but it is understudied, and while filtered-sunlight phototherapy had a similar bilirubin-lowering effect as conventional phototherapy, there was no difference in treatment failure requiring exchange transfusion4. Exchange transfusions have their own risks.

SNJ can be treated with blood purification methods, for instance, with plasmapheresis7. Conventional hemodialysis would only affect free unconjugated bilirubin and is deemed insufficient for lowering total bilirubin concentrations, whereas the extraction of unconjugated bilirubin, which is heavily bound to albumin8, is enhanced with the use of albumin containing dialysates, when compared to traditional crystalloid hemodialysate. However, resource-intense treatments such as the Molecular Adsorbent Recirculating System (MARS), albumin dialysis system are rarely available in less-resourced countries.

Recently, allo-HemoDialysis (alloHD) was introduced as a novel dialytic treatment modality with the potential to increase access to kidney replacement therapy9. AlloHD is an alternative kidney replacement therapy where the blood of a healthy subject ("buddy") flows counter-currently to the patient's blood through a dialyzer9. Solutes and fluid from the neonate are transferred to the buddy and then cleared by his/her healthy kidneys (or liver for the conjugation of bilirubin), making alloHD a procedure where the buddy "donates" kidney/liver function intermittently to the neonate. Normally, unconjugated bilirubin cannot be dialyzed because of its very high plasma protein binding; however, in alloHD, the counter-currently flowing buddy blood contains albumin that has excess bilirubin binding capacity, thereby allowing for diffusion of the unconjugated bilirubin. Compared to conventional dialysis, the complexity of alloHD is drastically reduced.

An alloHD machine prototype for adults has been developed and tested in a porcine model of acute kidney injury10. A smaller version is technically feasible. Here we explore a mathematical model for alloHD to treat SNJ rapidly and effectively in neonates, possibly avoiding exchange transfusions and kernicterus. We hypothesized that with alloHD, the vast metabolic reserve of the buddy’s liver, greater distribution volume, and greater albumin mass would allow for an effective removal of neonatal unconjugated bilirubin. This novel intervention would also be feasible in less-resourced countries.

Results

We simulated alloHD for two scenarios: (A) 2.5 kg neonate with blood flow rate (Qpt) of 12.5 mL/min, and (B) 3.5 kg neonate with Qpt of 15 mL/min; both are dialyzed against a 70 kg buddy, with a buddy Qb of 30 mL/min (Fig. 1B). Model simulations suggest that a 6-h alloHD session can reduce neonatal total bilirubin levels by > 35%. Due to the high bilirubin conjugation capacity of an adult’s healthy liver and the higher distribution volume, the buddy’s bilirubin level increases only transiently to non-toxic levels during alloHD. The buddy bilirubin concentration starts to decrease during alloHD treatment, even though the buddy continues to receive unconjugated bilirubin from the neonate.Fig. 1 (A) Model schematic of alloHD to treat severe neonatal jaundice. Blood of the neonate flows through hollow fibers while blood of the buddy flows counter-currently in the dialysate compartment. For both neonate and buddy, unconjugated bilirubin is distributed in extracellular space, which is divided into plasma and interstitial spaces with different compartment albumin concentration. Cpl/is is the unconjugated bilirubin concentration in plasma/interstitial pool; Vpl/is is plasma/interstitial pool physiological volume, Qi is blood flow rate in the dialyzer for i∈pt,b, Ci,out is patient/buddy side bilirubin concentration at the exit of dialyzer; Gi, bilirubin is bilirubin production rate in patient/buddy. (B) Kinetics of unconjugated bilirubin in plasma (blue) and interstitial compartment (red) of the neonate (left panel) and the adult buddy (right panel) during a 6-h alloHD treatment. Solid and dotted lines respectively, correspond to alloHD of a 2.5 kg and 3.5 kg neonate at blood flow rate of 12.5 mL/min and 15 mL/min, respectively, dialyzed against a 70 kg buddy with blood flow rate of 30 mL/min.

In Fig. 2, we presented the effect of albumin concentration in the neonate on bilirubin kinetics during alloHD. Notably, for higher albumin concentration, alloHD efficacy is negligible because free bilirubin is sequestered by higher albumin concentration. In such a scenario, alloHD would be ineffective. However, for lower albumin concentrations, which are typical in SNJ, alloHD resulted in a significant drop in neonatal bilirubin concentration. We also modeled the effect of blood flow rates and found that neonatal blood flow rate had a significant effect on neonate bilirubin kinetics (Fig. 3A), while buddy blood flow rate had no material impact on neonate bilirubin levels (results not shown). The effect of dialyzer surface area on neonate’s bilirubin was negligible (Fig. 3B).Fig. 2 Effect of neonate albumin levels on kinetics of unconjugated bilirubin during alloHD in a 2.5 kg neonate (left panel) and the adult buddy (right panel). Lower albumin levels (typical in severe neonatal jaundice) in neonate results in excess free bilirubin, which is cleared effectively using alloHD, reflected as steep decline in bilirubin concentration. As neonate albumin concentration increases, alloHD efficacy saturates because of tight bilirubin-albumin binding.

Fig. 3 (A) Effect of neonate blood flow rate on neonate (left panel) and buddy (right panel) unconjugated bilirubin kinetics during alloHD. (B) Effect of dialyzer surface area on neonate (left panel) and buddy (right panel) unconjugated bilirubin kinetics during alloHD.

Discussion

We describe the mathematical modelling of alloHD for the treatment of SNJ in near term and term neonates, using realistic parameters for both the neonate and the adult buddy. Our mathematical modelling suggests that unconjugated bilirubin could potentially be cleared by alloHD and that a single alloHD session of 6 h could lower neonatal bilirubin levels effectively. In principle, this bilirubin reduction should lower the risks associated with SNJ, especially kernicterus and possibly avoid exchange transfusions. Of course, alloHD has only been performed as bench test using an adult machine, however, the model predictions form the adult alloHD could be verified on bench testing and animal testing10.

The effects of dialyzer surface area and buddy blood flow rates were negligible. In contrast, removal of unconjugated bilirubin could be improved with higher neonatal blood flow rates. In conventional hemodialysis, protein-bound uremic toxins kinetics are minimally affected by dialyzer surface area, which matches our model predictions. However, increasing dialysate flow (QD) in conventional hemodialysis improves removal of tightly bound protein-bound uremic toxins11; whereas we observed that increasing buddy blood flow rate in alloHD had no effect on bilirubin kinetics (results not shown). The primary reason for this difference is that we limited the neonatal blood flow rate Qpt to 5 mL/kg/min which is usually prescribed in this setting. Occasionally a higher Qpt of up to 7 mL/kg/min has been prescribed in neonates12. As simulated, increasing the neonatal Qpt increases the bilirubin removal from the neonate (Fig. 3A).

Our modelling makes some assumptions that can be challenged, for instance, the zero-liver bilirubin conjugation activity in the neonate. We were unable to find references that state that the activity of uridine-diphosphoglucuronic (UDP) glucuronosyltransferase, the key enzyme responsible for the conjugation of unconjugated albumin, in the term neonate is zero; however, deficiency of UDP glucuronosyltransferase in the neonate has been described13. Another assumption that can be challenged is the use of a two-compartmental model, as lymphoid circulation has been introduced as a third component14. However, adding complexity of compartmental models is unlikely to change the findings because the proportion of albumin in the lymphatic fluid of the neonate is small and alloHD duration is too short to affect albumin concentration in this compartment15. Furthermore, recent evidence suggests that the bilirubin production in a healthy adult is 4 mg/kg/day rather than 3 mg/kg/day owing to myoglobin degradation and other pathways. When modelling this higher production rate of 4 mg/kg/day, there was no material impact on neonatal or buddy bilirubin kinetics, because the buddy has a much larger pool of albumin to sequester most of bilirubin (data not shown). We did account for the fractional higher total body water of the neonate, and based on weight, the distribution of ¼ of the total extracellular fluid being intravascular and ¾ being interstitial matches the weight proportions of the neonate15. Finally, we made the assumption that there was no neonatal bilirubin conjugation activity.

The next steps for implementing the mathematical modelling presented in this manuscript consist of a bench test to prove the predicted bilirubin reductions, followed by a grant application and an animal model, likely a neonatal sheep model. We designed and built an alloHD machine prototype and performed a bench test to simulate the adult alloHD11. The mathematical modelling for an adult machine16 was accurate. We conducted animal studies using the prototype in a porcine model of acute kidney injury in which the alloHD machine performed as intended and kept the pigs with AKI alive. The results were presented at the 2024 conference of the European Renal Association17.

The effect of neonate albumin level plays a major role towards alloHD efficacy. For low neonatal albumin levels, as typically seen in SNJ patients and a known risk factor for kernicterus18, alloHD seems to be very effective in the removal of bilirubin, whereas its effectiveness with normal neonatal albumin levels would be limited. This finding is not surprising because lower albumin will lead to higher concentration of free unconjugated bilirubin which can be removed easily with alloHD. The albumin affinity to bind bilirubin is extremely high, and under healthy conditions, no free (non-albumin bound) unconjugated bilirubin is seen in the plasma8. The binding to albumin limits the escape of bilirubin from the vascular space and prevents its precipitation and deposition in tissues as well as removal in dialyzer8. To a lesser degree, especially in states of hypoalbuminemia, bilirubin binding also occurs with high-density lipoprotein (HDL)8. We did not consider HDL as an additional binding site in our model. The mean triglyceride/HDL ratio in healthy neonates has been reported as 3.13 whereas in healthy adults, it is < 2, suggesting that HDL levels are much lower in term neonates without distress19. We also assumed a set UDP glucuronosyltransferase activity in the buddy, which may be altered post-partum if the mother is considered as buddy. However, the impact of all these factors on the neonatal bilirubin removal is negligible.

The ability to practically implement our proposed alloHD modality in neonates with SNJ requires several considerations. We need to consider vascular access in the neonate (umbilical or femoral vessels), venous and arterial pressures, ultrafiltration, and anticoagulation. For instance, the arterial line blood aspiration pressure should be monitored if possible and kept between 150 and 200 mmHg to limit endothelial trauma20. This and the blood flow rates should be feasible with a umbilical vein catheter and/or femoral veins12. In our mass-transfer model, we did not consider the impact of arterial and venous pressures. Integration of miniature pressure monitors and controls of ultrafiltration are feasible with existing technologies. Vascular access for the buddy could be a simple 16-gauge or even 18-gauge canula in a peripheral vein. The next step will be ex-vivo bench tests followed by animal studies. Nonetheless, the current analysis demonstrates the fundamental feasibility of the concept of alloHD for the treatment of SNJ.

Our modeling study has limitations. As with any mathematical model, our kinetic model is influenced by parameter assumptions. Other limitations are the exclusion of the lymph compartment, the lack of data on interstitial albumin concentration and extrahepatic UDP glucuronosyltransferase activity in the neonate. We also did not explore the possible impact of albumin infusions. We went to great lengths to identify model parameters based on published literature and our own clinical experience with a variety of extracorporeal techniques. We believe that the assumptions shown in Table 1 are realistic and that the modelling results reliably suggest that alloHD may indeed be a feasible treatment modality of SNJ. Table 1 Assumptions for the alloHD model.

Parameter	Value	Justification/our approach	
Buddy weight	70 kg	The average weight of a mother (potential buddy) at delivery of the neonate was 68.8±13.7 kg24. Our approach: We chose 70 kg	
Birth weight	2.5–3.5 kg	Birth weight varies substantially between less and well-resourced countries	
		 The lowest average birth weight of a term neonate is in Pakistan, and the average in less-resourced countries is closer to 2.5 kg25. UNICEF defines low birth weight as < 2.5 kg	
		 By contrast, in a recent study of a well-resourced country, the average birth weight was 3.544 kg26	
		Our approach: We chose 2.5 kg as the lower weight and 3.5 kg as the upper weight for modelling	
Bilirubin production rate	6 mg/kg/day for neonate	These are the rates from the literature22 Buddy bilirubin conjugation rate was calculated to obtain normal steady state bilirubin levels. We only simulated unconjugated bilirubin because the conjugated form is readily excreted in bile and kidneys and is non-toxic	
	3 mg/kg/day for buddy	Our approach: We used both reported bilirubin production values for the neonate and buddy	
Blood flow rate	12.5 mL/min for a neonate with 2.5 kg	A blood flow rate of 2–5 mL/kg/min is recommended in neonates and infants12. From clinical experience, in a neonate with 2.5 kg body weight blood, flow rates as high as 31 mL/min can be achieved [calculated as QB = (birth weight[kg] + 10) × 2.5]20	
	15 mL/min for a neonate with 3.5 kg	In our calculations, a blood flow rate of > 30 mL/min of the buddy did not result in any increased unconjugated bilirubin clearance	
	30 mL/min for “buddy”	Our approach: We chose 5 mL/kg/min for a neonate	
Blood volume in the neonate	85–109 mL/kg	The neonate has a circulating blood volume of 85 mL/kg, but it rises after birth to a maximum of 105 mL/kg at one month of age27. Another figure states as much as 109 mL/kg in neonates delivered at term28 Our approach: We assumed 85 mL/kg as a minimum, allowing for an extracorporeal volume as low as 21 mL	
Extracorporeal volume	21.2–29.7 mL for hemodynamically unstable and	In a hemodynamically unstable infant, the extracorporeal volume must not exceed 10% of the blood volume to avoid the need for albumin or blood priming12	
	31.8–44.55 mL for hemodynamically stable neonates	- With a circulating blood volume of at least 85 mL/kg, the safe upper limit of the extracorporeal volume would be 21 mL	
		- In hemodynamically stable patients, 15% extracorporeal volume is tolerated20 Therefore, the extracorporeal volume can be as high as 41 mL in a hemodynamically stable neonate with 2.5 kg body weight	
		Our approach: We assumed 21 mL as the lower limit of extracorporeal volume for neonate. Buddy extracorporeal volume was twice of the neonate	
Hematocrit in the neonate	0.45–0.61	The average is 0.55 (normal values for hematocrit and hemoglobin in the in healthy term infants)29 Our approach: We use a neonate hematocrit of 0.55	
Hematocrit in the buddy	0.42–0.47	Our approach: We use 0.45, the average between healthy males and females	
Surface area of the dialyzer	0.075 m2 and 0.2 m2	Currently, the smallest hemodialysis filter has a surface area of 0.075 m2 with a priming volume of 27 mL including the tubing30. Given that the tubing will be smaller than the one used in CarpeDiem™ (a commercial continuous renal replacement therapy for neonates 2.5–10 kg), the extracorporeal surface area should be safe	
		We also considered a mini dialyzer with a surface area of 0.20 m2. Mini-dialyzer dialyzer mass transfer area coefficient for urea, KoA (dialyzer intrinsic efficacy property) was proportionally adjusted based on 1.8 m2 dialyzer with bilirubin KoA of 800 mL/min (high efficiency)	
		Our approach: We chose dialyzers with 0.075, 0.2, and 0.5 m2surface area	
Serum albumin concentrations	Maternal: 3.3 g/dL	Maternal (if the mother serves as buddy):	
	Neonatal: 3.1, 2.1, and 1.1 g/dL	- Serum albumin levels decrease during pregnancy. The average serum albumin in term women was higher at 3.36 g/dL31. We chose 3.3 g/dL	
		Neonatal:	
		 The average serum albumin level in a term neonate is 3.1 g/dL at 40 weeks of gestation18	
		 However, many neonates with severe neonatal jaundice often have lower albumin levels, which highlights the importance of unbound unconjugated bilirubin for kernicterus, which cannot currently be measured23	
		Our approach: We used 1.1, 2.1, and 3.1 g/dL	
Interstitial albumin mass		The interstitial albumin mass was reported to be 37%, but also some albumin was found in skin and other compartments32	
		Our approach:	
		In both neonates and buddies, we set the albumin mass in the interstitial compartment at 40%	
Number of compartments	Compartment 1: intravascular space;	Since unconjugated bilirubin is highly bound to serum albumin, its distribution volume (Vd) should be like that of albumin. The Vd of unconjugated bilirubin is the intravascular volume and the interstitial volume	
	Compartment 2: interstitial space	Our approach:	
		We chose a two-compartmental model	

We conclude that 6 h of alloHD for SNJ, with realistic blood flow rates of 5 mL/kg/min in the neonate and 30 mL/min in the buddy, should result in a significant reduction of neonatal bilirubin concentrations. Additionally, alloHD may be more effective in neonates with lower albumin levels, which are typically observed in near-term and term neonates with SNJ. If corroborated in ex vivo, animal, and clinical studies, this degree of bilirubin reduction could potentially lower the risks associated with SNJ, especially kernicterus, and possibly avoiding exchange transfusions.

Methods

Model description

Our mathematical model describes unconjugated bilirubin kinetics in SNJ, including bilirubin mass transfer from the neonate to an adult buddy and its elimination by the buddy’s liver. A block diagram of the two-compartmental model is shown in Fig. 1A. Both neonate and buddy are connected to the dialyzer, wherein the unconjugated bilirubin transfers from neonate blood to buddy’s blood. Unconjugated bilirubin is highly protein-bound thus distribution is primarily restricted to extracellular space, which is sub-divided into plasma and interstitial spaces (Fig. 1A). The model equations and symbols are presented in the Appendix. The model assumptions and their rationale are outlined in Table 1. The bilirubin-albumin equilibrium binding constant was assumed to be 2 × 107 M−1 which provides 99.99% bilirubin bound in the buddy21. The same binding constant was used for the neonate and the initial bilirubin free fraction was calculated based on neonatal albumin levels.

In the neonate, the hepatic bilirubin conjugation rate was set to zero, resulting in excess unconjugated albumin-bound bilirubin. Bilirubin production rates in the neonate and buddy were set to 6 and 3 mg/kg/day, respectively22. The buddy bilirubin conjugation rate was calculated to obtain normal steady state bilirubin levels. We only simulated unconjugated bilirubin because the conjugated form is readily excreted in bile and kidneys. Simulations are performed with albumin levels of 3.1, 2.1, and 1.1 g/dL in the neonate and 3.3 g/dL in the buddy, to reflect the high incidence of low albumin levels in infants with SNJ23. The model parameters are summarized and justified in Table 1.

Appendix

Mathematical model

Both neonate and buddy were connected to the dialyzer, wherein the unconjugated bilirubin spatial concentration distribution along the hollow fiber length was ignored, i.e., dialyzer was modelled as lumped model. Below, the model equations are described, where the suffix ‘i’ denotes the neonate patient or the buddy, i∈pt,b. Variables and parameters present in the model equations are described in Table 2. Table 2 Variables and states in the model.

Symbol	Description	Unit	
a1	Free bilirubin and albumin association rate constant	M−1 min−1	
a2	Bilirubin-albumin complex dissociation rate constant	min−1	
Cpl/is,i	Free bilirubin concentration in plasma/interstitial compartment in “i”, i∈pt,b where pt – patient and b – buddy	M	
Cdia,i	Free bilirubin concentration in/around the hollow fibers for “i”	M	
Ppl/is,i	Free albumin concentration in plasma/interstitial in “i”	M	
Pdia,i	Free albumin concentration in/around the hollow fibers for “i”	M	
PCpl/is,i	Albumin-bilirubin complex concentration in plasma/interstitial in “i”	M	
PCdia,i	Albumin-bilirubin complex concentration in/around the hollow fibers	M	
Gi	Free bilirubin production rate in “i”	moles/min	
Kip	Free bilirubin mass transfer coefficient between plasma and interstitial pool	L/min	
Kliver,i	Free bilirubin conjugation rate in liver of “i”	L/min	
KoA	Bilirubin mass transfer coefficient in dialyzer	L/min	
Qi	Plasma flow rate for “i”	L/min	
Vprime,i	Extracorporeal volume for “i”	L	

Plasma compartment

dCpl,idt=-QiCpl,i-Cdia,i-KipCpl,i-Cis,i+-a1Cpl,iPpl,i+a2PCpl,iVpl,i+Gi-Kliver,iCpl,idPpl,idt=-QiPpl,i-Pdia,i+-a1Cpl,iPpl,i+a2PCpl,iVpl,idPCpl,idt=-QiPCpl,i-PCdia,i+a1Cpl,iPpl,i-a2PCpl,iVpl,i

Interstitial compartment

dCis,idt=KipCpl,i-Cis,i+-a1Cis,iPis,i+a2PCis,iVis,idPCis,idt=a1Cis,iPis,i-a2PCis,iVis,i

Lumped Dialyzer model:

(A) Patient side (blood flow through hollow fibers)dCdia,ptdt=QptCpl,pt-Cdia,pt+-a1Cdia,ptPdia,pt+a2PCdia,ptVprime,pt-KoACdia,pt-Cdia,bdPdia,ptdt=QptPpl,pt-Pdia,pt+-a1Cdia,ptPdia,pt+a2PCdia,ptVprime,ptdPCdia,ptdt=QptPCpl,pt-PCdia,pt+a1Cdia,ptPdia,pt-a2PCdia,ptVprime,pt

(b) Buddy side (blood flow around hollow fibers)dCdia,bdt=QbCpl,b-Cdia,b+-a1Cdia,bPdia,b+a2PCdia,bVprime,b+KoACdia,pt-Cdia,bdPdia,bdt=QbPpl,b-Pdia,b+-a1Cdia,bPdia,b+a2PCdia,bVprime,bdPCdia,bdt=QbPCpl,b-PCdia,b+a1Cdia,bPdia,b-a2PCdia,bVprime,b

Author contributions

P.K. invented allo-hemodialysis. V.M. and P.K. conceived the study. Conceptualization was performed by all four authors. M.E.D.G.F. and G.F. developed the indications and provided the clinical parameters for neonatal applications. All authors prioritized the focus on severe neonatal jaundice. G.F. developed the table with the clinical assumptions. All authors agreed on the assumptions. V.M. performed the mathematical modelling based on the clinical assumptions. M.E.D.G.F. and G.F. performed the literature search. GF drafted the various stages of the manuscript, imported all the references from PubMed into EndNote and included them in the manuscript as well as formatting the references as per journal requirements and drafting the submission letter. M.E.D.G.F. and P.K. provided critical intellectual input and thoroughly edited the manuscript. P.K. organized the regular virtual meetings for the preparation of the study and the manuscript.

Data availability  

The datasets used and/or analyzed during the current study available from the corresponding author upon request.

Competing interests

PK is an employee of the Renal Research Institute, a wholly owned subsidiary of Fresenius Medical Care. At the time of model development, VM had been an employee of the Renal Research Institute. PK holds stock in Fresenius Medical Care. PK and VM are inventors on multiple patents in the kidney space. PK has received author honorarium from Henry Steward Talks. PK is on the editorial board of Blood Purification, Kidney and Blood Pressure Research, Frontiers in Nephrology and Kidney and Dialysis. MEDGF and GF declare that no financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

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