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Perspective

Modular Strategies for Nephron Replacement and Clinical Translation

by
Natalia Stepanova
1,2,* and
Yevheniia Tamazenko
3
1
State Institution “O.O. Shalimov National Scientific Center of Surgery and Transplantology of the National Academy of Medical Science of Ukraine”, 03065 Kyiv, Ukraine
2
Dialysis Medical Center LLC “Nephrocenter”, 03057 Kyiv, Ukraine
3
State Institution “Territorial Medical Association of the Ministry of Internal Affairs of Ukraine for the City of Kyiv and the Kyiv Region”, 04050 Kyiv, Ukraine
*
Author to whom correspondence should be addressed.
Kidney Dial. 2025, 5(3), 41; https://doi.org/10.3390/kidneydial5030041
Submission received: 19 July 2025 / Revised: 28 August 2025 / Accepted: 28 August 2025 / Published: 1 September 2025
(This article belongs to the Special Issue Research Advances in Blood Purification: New Techniques, Drugs and Indications)
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Abstract

End-stage chronic kidney disease remains a global challenge, with dialysis and transplantation offering only partial or limited solutions. Recent advances in bioengineering have introduced modular strategies that aim to restore kidney function not by replicating the entire organ, but by rebuilding it one segment at a time. Platforms such as kidney organoids, implantable bioartificial kidneys, 3D-bioprinted tissues, and decellularized scaffolds each target specific nephron functions, from filtration to endocrine signaling. This Perspective examines how these technologies can be integrated into interoperable systems that reflect the nephron’s native structure and functional complexity. We assess translational readiness across key benchmarks, including vascular integration, hormonal responsiveness, immune compatibility, and implantability, and discuss the ethical, regulatory, and design considerations that will shape their clinical future. Collectively, these modular strategies offer a pathway toward more personalized, scalable, and physiologically relevant approaches to kidney replacement.

1. Introduction

Chronic kidney disease (CKD) affects more than 850 million people globally, with the number of patients needing kidney replacement therapy (KRT) expected to reach 5.4 million by 2030 [1,2]. These burdens fall disproportionately on low- and middle-income countries, where access to dialysis and transplantation is often limited [3]. Existing options, dialysis and kidney transplantation, are life-sustaining but not curative. Dialysis only partially replaces kidney function and is associated with high morbidity, poor quality of life, and reduced survival [4,5]. Kidney transplantation offers superior outcomes but is constrained by a severe shortage of donor organs, risk of graft failure, and the need for lifelong immunosuppression [6,7].
In response to these limitations, a new wave of technologies has emerged aimed at replicating key nephron-level functions using biological or bioengineered systems [8,9]. Rather than attempting to recreate an entire kidney, many of these approaches focus on modular restoration of specific physiological functions, leveraging advances in stem cell biology, biofabrication, and device engineering.
Several efforts have already laid the foundation for this conceptual shift. In 2018, the Kidney Health Initiative (KHI) released a landmark roadmap calling for transformative innovation in KRT [10]. That same year, a Perspective by Salani et al., published in the American Journal of Kidney Diseases, highlighted advances in wearable and implantable artificial kidneys, efforts that reflect a parallel push to improve dialysis through engineering and miniaturization [8]. More recently, Bonandrini et al. provided a comprehensive review of cell-based and bioartificial kidney technologies, marking a shift toward regenerative strategies aimed at restoring nephron-level function [9]. Collectively, these works show growing support for the idea that next-generation therapies may not require full organ regeneration. Instead, they may come from combining modular technologies to restore kidney function.
In this Perspective, we build on that evolving paradigm by introducing a function-oriented framework for evaluating emerging nephron replacement strategies, structured around the physiological roles of discrete nephron segments. Our aim is to provide a translational synthesis that highlights opportunities for functional synergy across platforms. The discussion focuses on four principal technological modalities: kidney organoids, implantable bioartificial kidneys (iBK), three-dimensional (3D) bioprinted renal tissues, and decellularized scaffolds. Each is examined in terms of its ability to replicate core nephron functions, its segmental specialization, and its readiness for clinical translation. Ethical and regulatory considerations are also addressed, given their importance to responsible development and deployment.
Although not yet formalized in clinical nomenclature, we use the term “nephron replacement strategies” to describe biologically or bioengineered interventions that aim to restore kidney function beyond the limits of conventional KRT. To guide the reader through this conceptual framework, Figure 1 maps each nephron segment to corresponding bioengineering strategies, offering a visual reference for the discussion that follows.

2. Modular Building Blocks for Nephron Replacement

As introduced above, four platforms currently dominate the field of modular kidney replacement. Although they differ in their mechanisms, maturity, and functional focus, they collectively represent the most promising avenues for next-generation, modular kidney support. Table 1 provides a comparative overview of their principal advances and remaining barriers.

2.1. Kidney Organoids

Kidney organoids are 3D structures derived from pluripotent stem cells (PSCs) that mimic aspects of early nephron development and architecture [11,12]. Over the past decade, they have become central to regenerative nephrology, serving as platforms for disease modeling, drug testing, and potentially future transplantation [11,12].
Modern kidney organoids typically contain glomerular-like podocytes, proximal and distal tubule segments, loop of Henle-like regions, and interstitial cell populations [13,14]. Morphologically, they resemble fetal kidneys in the first and second trimesters but remain immature and lack integration with vasculature and urinary drainage systems [14]. As such, they are not yet capable of supporting full renal function. Key limitations include the following:
  • Absence of a vascular network, which restricts nutrient delivery and size;
  • Lack of a urine drainage system, precluding physiological excretion;
  • Cellular heterogeneity and presence of off-target populations, reducing reproducibility [13,15,16].
Recent advances have begun to address these barriers. Microfluidic organ-on-chip platforms improve endothelial integration and podocyte maturation [17,18]; genetic co-differentiation with endothelial progenitors enables vascularization, renin production, and limited erythropoietin expression [19,20]. In addition, in vivo transplantation into immunodeficient mice has enhanced structural maturity and host integration [20]. ECM modifications and refined protocols have also improved tissue organization and nephron segmentation [21,22].
Although organoids remain preclinical, these developments bring them closer to translational relevance. Importantly, they offer a scalable and biologically human-compatible platform that may contribute modular components, such as glomerular or tubular segments, to hybrid systems. From a modular perspective, organoids are best viewed not as standalone solutions but as functional subunits within a broader nephron replacement strategy.

2.2. iBK Devices

iBKs represent one of the most advanced nephron replacement platforms, combining engineered filtration membranes with living renal epithelial cells to replicate core kidney functions [23,24]. Unlike conventional dialysis, iBKs aim to deliver continuous, physiological therapy without the need for external power, vascular access maintenance, or immunosuppression [8,25,26].
The most mature system in this space is the iBK developed by The Kidney Project. It consists of two functional modules: a silicon nanopore hemofilter that mimics glomerular filtration and a bioreactor seeded with proximal tubule epithelial cells to support solute reabsorption and metabolic activity [8,23,25]. These components are designed to operate passively within the patient’s circulation, offering a self-contained alternative to dialysis infrastructure [8,26].
Recent preclinical studies have shown that the iBK bioreactor can maintain stable function for up to seven days in large-animal models, without thrombosis, device occlusion, or mechanical failure [27]. These results validate the hemofilter’s biocompatibility, structural durability, and physiological integration under in vivo conditions.
Despite its promise, the iBK faces several key engineering and biological challenges:
  • Sustaining epithelial cell viability and function under physiological shear stress;
  • Preventing fibrosis and immune rejection in the absence of systemic immunosuppression;
  • Ensuring long-term durability of membrane materials and preventing device fouling or occlusion;
  • Achieving tight coupling between filtration and reabsorption to fully mimic nephron-level homeostasis [24,28,29].
From a translational perspective, the iBK stands out as the most clinically mature platform in the nephron replacement landscape, with active support from KidneyX, NIH, and the FDA as it progresses toward first-in-human evaluation.

2.3. 3D Bioprinted Renal Tissues

3D bioprinting offers a highly customizable platform for engineering kidney tissue, distinguished by its bottom-up fabrication approach and spatial control over cell placement and architecture [30,31]. Unlike organoid or scaffold-based systems, bioprinting enables the construction of nephron-mimetic structures, including glomeruli, tubules, and interstitial compartments, using bioinks composed of renal cells and extracellular matrix-based hydrogels [30,32].
Recent advances have demonstrated multi-compartmental constructs that incorporate both epithelial and endothelial cells, recapitulating elements of the filtration–reabsorption axis [33,34]. Bioinks now often include stromal support cells and ECM signals to better mimic the renal microenvironment. However, several critical barriers remain:
  • Achieving hierarchical vascularization;
  • Maintaining long-term cell viability under physiological pressure;
  • Scaling constructs to clinically relevant sizes without compromising function;
  • Integrating bioprinted tissues with host vasculature and immune environments [30,35,36].
Despite these barriers, 3D bioprinting holds strong potential for modular nephron replacement. Its ability to generate anatomically organized, functionally distinct units makes it well-suited for ex vivo testing and for integration into hybrid systems that combine bioprinted segments with other engineered components [10,32,36].

2.4. Decellularized Kidney Scaffolds

Decellularized kidney scaffolds are created by removing all cellular material from donor kidneys, using chemical, enzymatic, or physical methods, while preserving the organ’s 3D ECM structure and vascular architecture [37,38]. The ECM provides both structural and biochemical cues, supporting cell adhesion, migration, and differentiation due to its retention of key proteins and signaling molecules [37,39].
Recent improvements in decellularization techniques have helped retain ECM integrity while reducing immunogenic material [40]. Recellularization efforts now use kidney-specific cell types such as podocytes, proximal tubule epithelial cells, and glomerular endothelial cells. These are often delivered through the preserved vasculature to promote even distribution and segment-specific function [41]. In parallel, stem-cell-derived renal progenitors and endothelial cells are being used to rebuild nephron and vascular compartments [40,42]. Perfusion bioreactors are critical to this process. They supply controlled flow, oxygen, and mechanical stimulation to support cell survival, maturation, and organization within the scaffold [40]. Some studies also report hypoxia-induced erythropoietin expression after recellularization [43].
Despite promising progress, major challenges persist:
  • Efficient and selective recellularization of glomerular, tubular, and vascular compartments;
  • Sourcing sufficient quantities of autologous or immunocompatible cells;
  • Achieving functional integration and perfusion after implantation;
  • Controlling immune responses and fibrosis in vivo [37,38,39].
Nonetheless, decellularized scaffolds provide a structurally accurate and potentially patient-specific foundation for nephron replacement [39,40,41]. Their preserved anatomy and bioactive matrix make them well-suited for integration into hybrid systems that combine living and engineered components. If current barriers are overcome, they may help bridge the divide between whole-organ engineering and modular therapeutic strategies.

3. The Nephron as a Blueprint for Modular Kidney Replacement

Building on the strengths and limitations of current platforms, the next step is to align each technology with the native architecture and function of the nephron. The nephron comprises anatomically and functionally distinct subunits, including the glomerulus, proximal and distal tubules, loop of Henle, collecting duct, juxtaglomerular apparatus, and peritubular capillaries, that together mediate filtration, selective reabsorption, secretion, endocrine regulation, and urine excretion [44,45,46]. Each segment is characterized by region-specific cell populations, membrane transporters, and hemodynamic interfaces.
The nephron’s complex architecture and functional specialization pose both challenges and opportunities for tissue engineering and regenerative nephrology [47]. Framing nephron functions as discrete addressable units helps guide the development of focused replacement strategies. Table 2 provides an overview of this modular landscape, outlining physiological roles, cellular and molecular requirements, technological approaches, and the current status of each functional domain.

3.1. Glomerulus (Filtration)

The glomerulus serves as the nephron’s primary filtration barrier, forming an ultrafiltrate of plasma through a specialized tri-layered structure that excludes cells and high-molecular-weight proteins while allowing passage of water and small solutes [44,48]. This barrier consists of fenestrated glomerular endothelial cells, the glomerular basement membrane (GBM) composed of laminin, type IV collagen, and heparan sulfate proteoglycans, and podocyte foot processes bridged by slit diaphragm proteins such as nephrin and podocin. Filtration selectivity is governed by molecular size (~5–10 nm cutoff), electrostatic charge, and shape, while hydraulic permeability is modulated by capillary hydrostatic pressure, GBM thickness, and matrix compliance [48].
Technologies attempting to reproduce glomerular filtration fall into two major categories: biological constructs and mechanical analogues. Among the latter, the iBK hemofilter remains the most clinically advanced. It uses precision silicon nanopore membranes to achieve selective ultrafiltration under arterial pressure, operating without external pumps [8,24,28]. In vivo studies in large animals have shown short-term patency and protein retention, though challenges remain around long-term biocompatibility and fouling [27].
On the biological side, organoid-derived glomeruli and bioprinted glomerular units express structural markers and partially replicate podocyte architecture but lack continuous capillary loops and do not demonstrate physiologically relevant filtration capacity [13,49]. Decellularized glomerular scaffolds preserve native ECM and spatial architecture and support limited reseeding with podocytes and endothelial cells, though integration with upstream flow and physiologic pressure gradients, as well as demonstrable selective filtration, has not been achieved [37,38,50]. Thus, biological strategies remain at a preliminary stage, with no published reports confirming functional, pressure-responsive filtration analogous to that of native glomeruli.

3.2. Proximal Tubule (Reabsorption and Secretion)

The proximal tubule reabsorbs the majority of filtered water, electrolytes, glucose, and amino acids and serves as the primary site for organic ion secretion [51]. Its function depends on dense mitochondria, apical brush borders, and key transport proteins such as the sodium-glucose co-transporter 2 (SGLT2), sodium-hydrogen exchanger 3 (NHE3), and organic anion transporters 1 and 3 (OAT1/3), which together coordinate active reabsorption and secretion [51,52]. Proper function also requires strong apical-basal polarity and extensive vascular support.
Of all nephron segments, the proximal tubule has been modeled most successfully. Bioprinted proximal tubules and kidney-on-chip platforms reliably demonstrate transporter expression, polarized morphology, and functional reabsorption of glucose and albumin [53,54]. Under perfusion, epithelial monolayers form tight junctions and respond to fluid shear stress, simulating aspects of tubular flow [53,55]. Some platforms even allow drug screening and nephrotoxicity assays using human-derived cells [53,55,56].
Organoid-derived proximal segments also exhibit brush border markers, SGLT2 expression, and uptake of low-molecular-weight proteins [17,57,58]. However, they often lack proper tubule alignment, vascular proximity, and segmental specificity [16,57]. Recellularized proximal tubule scaffolds, using decellularized ECM, support improved polarity and survival but still require external flow and do not yet show long-term viability [38,59]. Functional integration with downstream segments is an active area of development.

3.3. Loop of Henle (Countercurrent Concentration)

The loop of Henle plays a pivotal role in generating the corticomedullary osmotic gradient, which enables water reabsorption in the collecting duct and supports urine concentration [45]. This is accomplished through a countercurrent multiplier mechanism, involving water efflux via aquaporin-1 (AQP1) in the thin descending limb, passive NaCl reabsorption in the thin ascending limb, and active Na+-K+-2Cl− cotransport (NKCC2) in the thick ascending limb of the loop. The net result is an axial osmolarity gradient that increases toward the inner medulla, allowing the kidney to concentrate urine up to ~1200 mOsm/kg H2O [45]. Replicating this gradient spatially and functionally remains a major bioengineering challenge.
Reconstructing this gradient-generating architecture remains one of the most formidable challenges in nephron bioengineering. Technologies targeting the loop have focused on microfluidic “loop-on-chip” systems that simulate opposing tubular flow and allow precise control of solute gradients. These platforms support unidirectional Na+ transport, segment-specific differentiation, and fluid shear exposure, which influence transporter expression and epithelial polarization [60,61]. However, while NKCC2 and AQP1 expression have been observed in some organoid-derived constructs, these models lack true anatomical curvature, peritubular capillaries, and interstitial fibroblasts, all essential for the spatial organization of the osmotic gradient [12,30,61]. None of the existing platforms successfully recreates the medullary interstitium, nor do they demonstrate dynamic osmotic concentration, water permeability gradients, or passive solute equilibration across countercurrent limbs [49,62]. Moreover, feedback regulation from the juxtaglomerular apparatus via the renin–angiotensin–aldosterone system (RAAS) or sodium sensing is absent, limiting physiological authenticity. Incorporation of gradient-generating scaffolds, ECM-based solute barriers, or co-culture with medullary interstitial cells, such as fibroblasts expressing urea transporters or prostaglandins, may help simulate the native environment and enable integration with downstream water-conserving modules [62,63]. Gradient-generating synthetic matrices or co-culture with medullary fibroblasts may be required to simulate the native interstitium.

3.4. Distal Tubule (Electrolyte Regulation)

The distal convoluted tubule plays a central role in fine-tuning sodium, potassium, calcium, and acid–base balance, acting as a key effector segment under hormonal regulation. It expresses the epithelial sodium channel (ENaC), the thiazide-sensitive sodium–chloride cotransporter (NCC), and TRPV5 calcium channels and responds dynamically to the aldosterone and parathyroid hormone to regulate systemic electrolyte and volume status [46,63]. The distal convoluted tubule also contributes to local feedback mechanisms, influencing JGA-mediated renin secretion via alterations in sodium load delivery.
In vitro systems, primarily organoid- and monolayer-based, have demonstrated segmental marker expression of ENaC, NCC, and TRPV5, with some models exhibiting partial transcriptional activation in response to hormone stimulation [64,65]. However, these responses are often transient and lack sustained ion flux measurements, limiting functional validation. Engineered epithelial sheets offer more stable polarization and transporter localization but fail to mimic the hormone–receptor coupling dynamics and downstream signaling pathways seen in vivo [66,67].
Critically, existing models do not recapitulate the interplay between the distal tubule and JGA via macula densa-mediated feedback. The absence of tubular–vascular alignment, sodium-sensing signal transduction, and renin modulation severely limits physiological realism. Integration of the distal convoluted tubule with upstream (loop of Henle) and downstream (collecting duct) segments, along with vascularized macula-densa-like interfaces, will be necessary to support functional nephron replacement and endocrine crosstalk. Moreover, mimicking flow-dependent ENaC activation and intracellular calcium dynamics remains an unmet technical goal [46].

3.5. Collecting Duct (Water and Acid–Base Regulation)

The collecting duct is the nephron’s terminal regulatory segment for water reabsorption, sodium handling, and acid–base homeostasis. It comprises principal cells, which respond to antidiuretic hormone (ADH) by translocating AQP2 channels to the apical membrane, and intercalated cells, which mediate proton secretion (via H+-ATPase) and bicarbonate reabsorption to regulate systemic pH [68]. Aldosterone also acts on this segment to promote sodium reabsorption via ENaC and potassium secretion through renal outer medullary potassium (ROMK) channels.
Organoid and organ-on-a-chip systems (OoCs) have demonstrated inducible AQP2 expression in response to ADH analogs, with some showing transient aquaporin trafficking and cell-surface insertion [66,67]. ENaC and H+-ATPase expression has also been observed, suggesting partial replication of segmental identity. However, these models lack essential physiological drivers: the axial osmotic gradient generated by the loop of Henle and proper interstitial compartmentalization to permit passive water movement.
Furthermore, intercalated cells remain underdeveloped in most systems, with limited data on their acid–base transport kinetics or regulation via systemic pH shifts. The collecting duct’s responsiveness to aldosterone and ADH remains poorly sustained over time, and no current model has integrated real-time electrolyte sensing, vasopressin-cAMP signaling cascades, or acid–base buffering feedback loops [49].

3.6. Juxtaglomerular Apparatus (Endocrine and Autoregulatory Function)

The juxtaglomerular apparatus (JGA) is a specialized multicellular structure that couples tubular sodium sensing, arteriolar hemodynamics, and systemic endocrine signaling to regulate glomerular filtration and maintain circulatory homeostasis [69]. It comprises juxtaglomerular (granular) cells of the afferent arteriole, which synthesize and secrete renin; the macula densa of the distal tubule, which detects luminal NaCl concentrations; and extraglomerular mesangial cells that mediate paracrine communication. Through this architecture, the JGA orchestrates both tubuloglomerular feedback and activation of the RAAS in response to decreased renal perfusion, volume depletion, or sympathetic stimulation [69,70].
Functionally, the JGA serves as the kidney’s primary endocrine gateway. Upon renin release, a cascade ensues: angiotensinogen is converted to angiotensin I, then to angiotensin II, which promotes systemic vasoconstriction, sodium retention, aldosterone secretion, and restoration of blood pressure and volume [69,70]. The JGA thus provides the interface between local nephron sensing and systemic hemodynamic control, making its recreation essential for any nephron replacement system aiming to move beyond mechanical filtration.
Current in vitro models have made limited progress toward replicating this complexity. Kidney organoids have successfully generated renin-expressing cells from pluripotent stem cells, indicating partial endocrine differentiation [71]. However, these cells lack functional coupling to flow or sodium-sensing signals, and their secretory dynamics remain poorly defined [47]. Moreover, macula densa-like regions appear disorganized or absent, precluding accurate reconstruction of the sodium-feedback loop [72,73].
Efforts to mimic the functional topology of the JGA are underway in microfluidic and organ-on-chip systems, where pressure-sensitive flow interfaces and localized signaling gradients have been introduced. Yet these remain conceptual prototypes, and no model to date demonstrates regulated, feedback-responsive renin release, nor integration with downstream endocrine axes (e.g., aldosterone, ADH) [19,66].

3.7. Peritubular Capillaries (Microvascular Support)

Peritubular capillaries are essential for maintaining nephron function by supplying oxygen and nutrients, removing reabsorbed solutes, and supporting active transport processes across the tubular epithelium [74]. Originating from the efferent arteriole, these capillaries form an extensive, low-pressure vascular network around the tubules, enabling close exchange between blood and filtrate. They also participate in inflammatory signaling, endothelial–epithelial cross-talk, and regulation of renal oxygen tension, features critical for both kidney homeostasis and injury response [74,75].
Replicating peritubular microvasculature in vitro remains a major challenge. Current approaches have focused on vascularized organoids, endothelialized microfluidic chips, and scaffold reseeding with endothelial cells [14]. In co-culture models, endothelial networks have been shown to improve tubular cell polarization, tight junction formation, and mitochondrial density, particularly under perfused conditions. Vascular flow enhances epithelial survival and function by mimicking physiological shear stress and facilitating oxygen and nutrient delivery [76].
Despite this progress, most systems lack hierarchical vascular organization, long-term perfusion stability, and integration with functional tubular modules. While transient networks can be induced by co-culturing with angiogenic factors, they are often unstable and prone to regression. Whole-organ scaffold reseeding offers potential for anatomically accurate vascular regeneration but remains limited by incomplete endothelial coverage and thrombosis risk upon implantation [76,77,78].

4. From Platform to Patient: Strategic Pathways for Modular Nephron Replacement

As nephron replacement platforms mature, the critical next step is not improving individual components but integrating them into cohesive, interoperable systems that address clinical needs. To support that transition, we assess each platform’s readiness across six domains: in vitro function, vascular integration, hormone responsiveness, segment specificity, implantability, and preclinical validation (Figure 2).
The matrix highlights both achievements and persistent gaps. While progress has been made in filtration and reabsorption, essential nephron functions such as endocrine signaling, acid–base regulation, and immune modulation remain poorly replicated or entirely absent [29]. Structures such as the juxtaglomerular apparatus and peritubular capillaries have yet to be functionally reconstructed, and functional cross-talk between nephron segments is largely missing. These “orphan functions” are unlikely to be solved by a single technology and will require combinatorial strategies.
Beyond these missing elements, the next frontier is recreating the regulatory mechanisms that govern nephron physiology. These include autoregulation of glomerular blood flow, tubuloglomerular feedback, and the countercurrent gradient in the loop of Henle. Nephron replacement systems must also sense systemic inputs (blood pressure, circulating hormones, and autonomic innervation) and translate them into outputs such as urine volume, electrolyte balance, and drug excretion. Current platforms can reproduce isolated structures or molecular features, but they still lack the ability to respond dynamically to physiological signals.
Three clear trends emerge. First, in vitro function and segment specificity have been successfully demonstrated across many platforms, particularly organoids, OoCs, and 3D-bioprinted constructs. These models capture transcriptional identity and localized function [30] but remain isolated from systemic physiology.
Second, vascular integration and long-term perfusion remain major barriers. While endothelial co-culture and scaffold reseeding have produced partial capillary networks, no platform yet sustains stable, perfusable, hierarchical vasculature at a clinically relevant scale [76,78,79].
Third, implantability and in vivo validation have progressed mainly within device-based approaches, particularly the iBK. These systems have demonstrated filtration and mechanical durability in large-animal models. However, they lack segmental complexity and endocrine responsiveness. In contrast, biologically advanced constructs, such as organoids and bioprinted tissues, offer richer cellular architecture but remain non-implantable due to limitations in scalability, perfusion, and immune shielding [53].
These patterns suggest that future solutions will require a hybrid modular approach that combines the structural robustness of engineered devices with the cellular and functional complexity of biologically derived constructs. For example, iBK filtration units could be paired with proximal tubule modules derived from organoids or bioprinted tissues. Vascularized scaffolds could host multiple segments arranged in physiological sequence [17,31,38].
Modular nephron replacement systems may first serve as adjuncts to dialysis or bridge therapies for patients awaiting transplantation [26,80]. They may also benefit populations with acute kidney injury or early stage chronic disease, where even partial restoration of function can reduce dependence on conventional therapies [8,81]. These patient-centered applications should guide modular design, performance targets, and deployment models. In the long term, hybrid assemblies of engineered and biological modules may offer the most viable path toward clinically functional systems.
Regulatory frameworks must also be adapted to address the specific challenges posed by emerging bioengineered kidney platforms. Biological platforms, like organoids or decellularized constructs, face extensive review due to the use of living cells [82]. Agencies such as the FDA require long-term data on safety, sourcing, and reproducibility, potentially delaying trials by 5–10 years [83,84]. In contrast, mechanical systems like iBKs, built on biocompatible materials, face faster review (typically 3–5 years), as seen in the Kidney Project. However, hybrid systems that combine biological and mechanical components will likely require regulatory modifications to evaluate issues such as interoperability, durability, and long-term integration. Programs like KidneyX and the FDA’s Breakthrough Device designation are pivotal, but standardized guidance for modular bio-devices remains lacking.
To support real-world modular assembly, practical design standards will be essential. Organoid segments might be coupled to iBK membranes using vascular connectors or shared flow systems. Scaffolds could serve as structured platforms for stacking segment-specific modules. Designing “plug-and-play” interfaces for vascular coupling, tubular continuity, and immune protection will be key to future integration.
In summary, no single platform is sufficient. But by integrating biological complexity with engineered reliability, modular nephron systems could eventually support meaningful kidney function replacement in clinical settings. Translational success will ultimately depend not only on achieving core functional criteria, such as vascular integration and hormonal responsiveness, but also on meeting broader clinical and regulatory benchmarks, including immune compatibility, interoperability, scalability, and ethical readiness, which will determine long-term viability and real-world impact.

5. Outlook: Clinical Integration, Equity, and Ethical Imperatives

Modular nephron replacement is redefining the future of kidney care, offering targeted, function-specific alternatives to dialysis and transplantation. Rather than aiming to recreate the entire organ, the field is shifting toward assembling interoperable segments that restore essential nephron functions. Filtration and reabsorption are already being replicated by platforms like kidney organoids, iBKs, and bioprinted tubules. However, vascular integration, endocrine signaling, and immune regulation remain critical gaps that must be addressed before clinical deployment [36,40].
The clearest path forward lies in combining the strengths of multiple platforms into modular hybrid systems. These systems can be designed to replicate specific physiological tasks, such as ultrafiltration, solute reabsorption, or hormonal feedback, and tailored to individual patient needs. The resulting architectures may support scalable, adaptable interventions that bridge the gap between existing KRT options and future regenerative treatments [8,24,30].
Yet scientific progress alone will not be sufficient. The transition from lab to clinic must be guided by preclinical rigor, design interoperability, and ethical foresight [85,86]. The success of these technologies will depend not only on what they can do, but how they are implemented, regulated, and trusted by patients.
Ethical and social questions are emerging in parallel with technical innovation. For example, the sourcing of iPSCs for organoids and scaffold repopulation raises issues of informed consent, data privacy, and equitable inclusion of underrepresented populations [87,88]. Ensuring transparency in recruitment and governance will be essential to building public trust in regenerative therapies. In addition, clear frameworks for data governance, including how patient-derived iPSC lines are stored, shared, and reused, will be essential as biobanks expand. Questions also remain about post-implantation oversight: who is responsible for long-term monitoring, and how adverse outcomes are tracked and reported, particularly for cell-based constructs integrated into hybrid systems.
Access equity poses another major challenge. Advanced bioengineered therapies, such as silicon nanopore membranes or scaffold recellularization, risk replicating the financial burdens of dialysis if left to market forces [3,89]. To avoid deepening disparities, public–private partnerships, open-access manufacturing, and equitable pricing strategies should be embedded in translational planning from the outset [89].
Finally, these technologies will test societal boundaries. As nephron modules are integrated into the human body, the line between therapeutic intervention and biological augmentation may blur. Who gets access, how risks are governed, and what counts as ‘treatment’ will become pressing questions. To navigate this evolving landscape, a clear ethical framework, rooted in transparency, proportionality, and patient-centered care, must evolve alongside the science.

6. Conclusions

Modular strategies for nephron replacement are no longer a theoretical vision but an emerging paradigm in kidney care, gradually moving from concept to practical possibility. Organoids, iBK, 3D bioprinted tissues, and decellularized scaffolds have each shown the capacity to reproduce important aspects of nephron physiology, particularly filtration and reabsorption. At the same time, challenges remain significant, especially in achieving vascular integration, hormonal responsiveness, immune compatibility, and clinical scalability. The most realistic future lies in combining these approaches into modular hybrid systems that can address different functions in a complementary way. Progress will depend on careful preclinical evaluation, standardized design principles, and early consideration of ethical and equity issues, to ensure that advances are safe and broadly accessible.
Taken together, modular nephron replacement offers a pathway toward expanding treatment options for patients with kidney disease. Although still at an early stage, steady progress in integration and translation may help build therapies that extend beyond the current limits of dialysis and transplantation.

Author Contributions

Conceptualization, writing—original draft preparation, visualization, N.S.; Writing—review and editing, Y.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

Author Natalia Stepanova is employed by the company Medical Center LLC “Nephrocenter”. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results. Both authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Kidneydial 05 00041 g001
Figure 1. Functional map of the nephron and corresponding nephron replacement strategies (created in https://BioRender.com, accessed on 19 August 2025). The nephron diagram (left) is color-coded by anatomical segment. Each strategy (right) is accompanied by colored dots that correspond to the nephron segments it aims to replicate. The dots indicate functional coverage, not anatomical reconstruction, and reflect the primary targets of each strategy based on current evidence.
Figure 1. Functional map of the nephron and corresponding nephron replacement strategies (created in https://BioRender.com, accessed on 19 August 2025). The nephron diagram (left) is color-coded by anatomical segment. Each strategy (right) is accompanied by colored dots that correspond to the nephron segments it aims to replicate. The dots indicate functional coverage, not anatomical reconstruction, and reflect the primary targets of each strategy based on current evidence.
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Figure 2. Translational readiness matrix for nephron replacement strategies (created in https://BioRender.com, accessed on 15 June 2025). Abbreviations: iBK, implantable bioartificial kidney. Supporting studies: Kidney organoids—in vitro function [8,11,13,14]; vascular integration [17,18,19,74,75,76]; hormone responsiveness [19,20,69,70,71]; segment specificity [11,13,14]; preclinical data [20,47,78]. iBK—in vitro function [8,22,23,24,25,51,52,53,54]; vascular integration [8,22,25,26,27,74,75,76]; segment specificity [22,23,24,51,52,53,54]; implantability [25,26,27]; preclinical data [26,27,28,78]. 3D bioprinting—in vitro function [29,30,31,32,33,51,52,53,54]; vascular integration [32,33,74,75,76]; segment specificity [29,31,32,33,51]; preclinical data [35,36]. Decellularized scaffolds—in vitro function [10,38,39,40,41,57]; vascular integration [39,40,41,48,74,75,76]; hormone responsiveness [43]; segment specificity [10,38,40,57]; preclinical data [10,38,41,48,57].
Figure 2. Translational readiness matrix for nephron replacement strategies (created in https://BioRender.com, accessed on 15 June 2025). Abbreviations: iBK, implantable bioartificial kidney. Supporting studies: Kidney organoids—in vitro function [8,11,13,14]; vascular integration [17,18,19,74,75,76]; hormone responsiveness [19,20,69,70,71]; segment specificity [11,13,14]; preclinical data [20,47,78]. iBK—in vitro function [8,22,23,24,25,51,52,53,54]; vascular integration [8,22,25,26,27,74,75,76]; segment specificity [22,23,24,51,52,53,54]; implantability [25,26,27]; preclinical data [26,27,28,78]. 3D bioprinting—in vitro function [29,30,31,32,33,51,52,53,54]; vascular integration [32,33,74,75,76]; segment specificity [29,31,32,33,51]; preclinical data [35,36]. Decellularized scaffolds—in vitro function [10,38,39,40,41,57]; vascular integration [39,40,41,48,74,75,76]; hormone responsiveness [43]; segment specificity [10,38,40,57]; preclinical data [10,38,41,48,57].
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Table 1. Overview of recent advances and major barriers across modular nephron replacement platforms.
Table 1. Overview of recent advances and major barriers across modular nephron replacement platforms.
PlatformKey AdvancesMajor Barriers
Kidney OrganoidsMulti-segment architecture; organ-on-chip vascular cues; in vivo maturationNo vasculature; no urine outflow; immaturity; heterogeneity
iBK DevicesFunctional hemofilter with tubule bioreactor; stable in large animals; no external powerCell viability under shear; fibrosis/immune risk; membrane durability
3D BioprintingCustom geometry; epithelial–endothelial constructs; ECM-based bioinksPoor vascularization; limited scaling; host integration issues
Decellularized ScaffoldsNative ECM and vasculature preserved; recellularization with renal cells; perfusion bioreactorsIncomplete reseeding; cell sourcing; immune rejection/thrombosis
Abbreviations: ECM, extracellular matrix; iBK, implantable bioartificial kidney.
Table 2. Segmental nephron functions, cellular requirements, and their corresponding replacement technologies.
Table 2. Segmental nephron functions, cellular requirements, and their corresponding replacement technologies.
Nephron FunctionPhysiological RoleCellular/Molecular RequirementsReplacement TechnologiesCurrent Status
Glomerulus (filtration)Initiates urine formation via selective, high-pressure filtration of blood; retains proteins and cells while allowing passage of water and small solutesPodocytes, glomerular endothelial cells, specialized GBM (collagen IV, laminin), slit diaphragm proteins (nephrin, podocin)Decellularized glomerular scaffolds; bioprinted glomerular units; PSC-derived organoid glomeruliProof-of-concept filtration achieved in vitro and in small animal models; physiological selectivity and sustained filtration rates remain suboptimal. Integration with vascular networks is a key challenge.
Proximal tubule (reabsorption/secretion)Reabsorbs ~65% of filtered water, glucose, amino acids, bicarbonate, and ions; secretes organic solutes and drugsProximal tubular epithelial cells with brush border, SGLT2, NHE3, rich mitochondrial content, tight junctions3D bioprinted tubules; organoid-derived proximal segments; recellularized scaffolds; microfluidic kidney-on-chip platformsFunctional reabsorption and secretion are demonstrated in vitro; models support drug screening and nephrotoxicity studies. Long-term maturation, polarity, and integration with downstream segments are active areas of research.
Loop of Henle (countercurrent concentration)Establishes medullary osmotic gradient via countercurrent multiplication, enabling urine concentrationThin and thick limb epithelial cells, aquaporins (AQP1, AQP2), Na-K-2Cl cotransporter (NKCC2), medullary interstitiumMicroengineered loop modules; segment-specific differentiation in organoidsEarly stage prototypes: partial recapitulation of countercurrent function. Full osmotic gradient generation and integration with adjacent segments remain to be achieved.
Distal tubule (electrolyte fine-tuning)Regulates sodium, potassium, calcium, and acid–base balance under hormonal control (aldosterone and PTH)Distal tubular epithelial cells, ENaC, NCC, calcium channels, hormone receptorsSegment-specific cell sheets; responsive bioartificial modules; engineered distal tubule constructsSegment identity and hormonal responsiveness were demonstrated in vitro. Integration with upstream and downstream modules and dynamic regulation is under development.
Collecting duct (water reabsorption/excretion)Final site for water reabsorption (ADH-regulated), acid–base homeostasis, and urine excretionPrincipal and intercalated cells, aquaporins (AQP2), ADH and aldosterone receptors, tight junctionsEngineered collecting duct arrays; organoid-derived collecting duct segments; responsive bioartificial modulesFunctional water reabsorption and hormone response are shown in vitro. Full integration with nephron modules and urine drainage systems remains a challenge.
Juxtaglomerular apparatus (endocrine/autoregulation)Senses tubular flow and sodium; regulates renin secretion and blood pressure (RAAS system); autoregulates GFR Juxtaglomerular cells (renin), macula densa, afferent arteriole, paracrine signaling moleculesOrganoid-based models; microfluidic feedback systemsExperimental models recapitulate some aspects of renin secretion and feedback. Full endocrine and autoregulatory function has not yet been achieved.
Peritubular capillaries (microvascular support)Supplies oxygen/nutrients, removes reabsorbed solutes, supports tubule metabolism and function; mediates oxygen sensing and EPO productionEndothelial cells, pericytes, angiogenic factors, basement membrane; peritubular interstitial fibroblast-like cells (EPO), HIF pathway componentsVascularized scaffolds; endothelialized microfluidic chips; co-culture systems; microfluidic models; scaffold-derived interstitial cell populationsMicrovascular networks are established in vitro; perfusion and stability over time are improving. Full integration with nephron modules and host vasculature remains a barrier. EPO expression is reported in organoid and scaffold studies under hypoxia, but physiologic oxygen sensing and regulated EPO secretion have not yet been achieved.
Abbreviations: ADH, antidiuretic hormone; AQP1, aquaporin 1; AQP2, aquaporin 2; ENaC, epithelial sodium channel; EPO, erythropoietin; GBM, glomerular basement membrane; GFR, glomerular filtration rate; HIF, hypoxia-inducible factor; iPSC, induced pluripotent stem cell; NCC, sodium chloride cotransporter; NKCC2, sodium-potassium-chloride cotransporter 2; NHE3, sodium-hydrogen exchanger 3; PTH, parathyroid hormone; PSC, pluripotent stem cell; RAAS, renin–angiotensin–aldosterone system; SGLT2, sodium-glucose cotransporter 2.
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Stepanova, N.; Tamazenko, Y. Modular Strategies for Nephron Replacement and Clinical Translation. Kidney Dial. 2025, 5, 41. https://doi.org/10.3390/kidneydial5030041

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Stepanova N, Tamazenko Y. Modular Strategies for Nephron Replacement and Clinical Translation. Kidney and Dialysis. 2025; 5(3):41. https://doi.org/10.3390/kidneydial5030041

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Stepanova, Natalia, and Yevheniia Tamazenko. 2025. "Modular Strategies for Nephron Replacement and Clinical Translation" Kidney and Dialysis 5, no. 3: 41. https://doi.org/10.3390/kidneydial5030041

APA Style

Stepanova, N., & Tamazenko, Y. (2025). Modular Strategies for Nephron Replacement and Clinical Translation. Kidney and Dialysis, 5(3), 41. https://doi.org/10.3390/kidneydial5030041

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