Clinical Kidney Journal, 2023, vol. 16, no. 2, 230–244 https:/doi.org/10.1093/ckj/sfac212 Advance Access Publication Date: 20 September 2022 CKJ Review CKJ REVIEW Novel strategies in nephrology: what to expect from the future? Sidar Copur1 , Cem Tanriover1 , Furkan Yavuz1 , Maria J. Soler2,3 , Alberto Ortiz 4 , Adrian Covic5 and Mehmet Kanbay 6 1 Department of Medicine, Koc University School of Medicine, Istanbul, Turkey, 2 Department of Nephrology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Spain, 3 Nephrology and Kidney Transplant Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain, 4 Department of Medicine, Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz, Madrid, Spain, 5 Nephrology Clinic, Dialysis and Renal Transplant Center, ‘C.I. PARHON’ University Hospital, and ‘Grigore T. Popa’ University of Medicine, Iasi, Romania and 6 Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey Correspondence to: Mehmet Kanbay; E-mail: mkanbay@ku.edu.tr ABSTRACT Chronic kidney disease (CKD) will become the fifth global case of death by 2040. Its largest impact is on premature mortality but the number of persons with kidney failure requiring renal replacement therapy (RRT) is also increasing dramatically. Current RRT is suboptimal due to the shortage of kidney donors and dismal outcomes associated with both hemodialysis and peritoneal dialysis. Kidney care needs a revolution. In this review, we provide an update on emerging knowledge and technologies that will allow an earlier diagnosis of CKD, addressing the current so-called blind spot (e.g. imaging and biomarkers), and improve renal replacement therapies (wearable artificial kidneys, xenotransplantation, stem cell-derived therapies, bioengineered and bio-artificial kidneys). Keywords: artificial kidney, bioengineering, chronic kidney disease, induced pluripotent stem cells, xenotransplantation INTRODUCTION the USA (71% on dialysis and 29% with a kidney transplant) [2], whereas, in Europe the estimated ESRD population is over 1 mil- There are currently 850 million persons in the world with lion people, with considerable variations across individual coun- chronic kidney disease (CKD), and CKD is predicted to become tries [3, 4]. the fifth global cause of death by 2040 and the second cause of Kidney transplantation was first performed in 1954 by Dr death in counties with long life expectancy by 2100 [1]. Moreover, Joseph Murray and is the current gold standard for treatment. CKD is the leading chronic condition with increased incidence, However, there are still fewer donors than the relentlessly in- prevalence and overall health impact. The terminal stage of CKD, creasing waiting list [5]. Chronic hemodialysis was introduced referred as end-stage renal disease (ESRD) or kidney failure, is in 1960 by Dr Belding Scribner, and despite being the major form defined by an estimated glomerular filtration rate (eGFR) be- of renal replacement therapy (RRT) it is associated with numer- low 15 mL/min/1.73 m2 by the Kidney Disease: Improving Global ous short- and long-term complications. Importantly, the life Outcomes (KDIGO), affecting approximately 800 000 patients in expectancy of patients in dialysis in their twenties is 40 years Received: 30.7.2022; Editorial decision: 14.9.2022 © The Author(s) 2022. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 230 Novel strategies in nephrology 231 Figure 1: General overview of the novel strategies in nephrology. (Diagnostics will be further elaborated in detail in Fig. 2.) shorter than for the general population [6]. Peritoneal dialy- Imaging: assessing nephron number as a determinant sis is less frequently utilized, and beside specific complications of kidney disease and kidney fibrosis (peritonitis, cellulitis, metabolic disturbances) it is limited by al- Imaging techniques have the advantage of being non-invasive most inexorable membrane failure [7]. and, thus, may be safely repeated to evaluate changes, provid- Thus, overall, the treatment of ESRD patients remains sub- ing information for both kidneys and potentially combining optimal, due to a shortage of kidney donors and multiple sig- functional with morphological information. The most interest- nificant complications associated with both dialysis modalities, ing advances relate to estimation of nephron number, overall although multiple alternatives have been considered over the kidney functions, fibrosis and new functional magnetic reso- years. Some of the recent developments have the potential to nance imaging (MRI), as well as ultrasound techniques such as revolutionize the field of nephrology in the upcoming decades. diffusion-weighted MRI (DWI or DW-MRI), blood oxygenation In addition, a large proportion of patients with CKD, especially level–dependent MRI (BOLD-MRI), perfusion MRI, hyperpo- those with stage 2 and stage 3 CKD, are older individuals who larized (HP) carbon 13 MRI (13C MRI) and contrast-enhanced will never require any form of renal replacement therapy mainly ultrasound (CEUS). since these patients die earlier of cardiovascular diseases. Thus, Functional nephron number is considered an important de- the real increase in the need of RRT is much less. The main terminant of kidney health and disease susceptibility through- benefits of new drugs such as sodium–glucose cotransporter 2 out life [14, 15]. In humans, nephron number varies widely and (SGLT2) inhibitors and mineralocorticoid receptor antagonists a low nephron endowment at birth and/or a loss of nephrons (MRAs) are in this group of kidney disease patients. throughout life is strongly associated with kidney disease [15]. In this review, we aim to describe the novel diagnostic meth- Novel technologies to measure nephron number are under de- ods in nephrology such as the advancements in kidney imag- velopment, and functional nephron number has the potential to ing and modalities utilized to estimate renal function as well be used as a clinical biomarker [14]. Nephron number, when used as the novel therapeutic approaches in kidney disease includ- as a biomarker, could provide important information regarding ing wearable artificial kidneys, xenotransplantation, stem cell- the progression of kidney disease and provide early detection of derived therapies, bioengineering models and medications on CKD onset or assessment of recovery after acute kidney injury, the rise (Fig. 1). improve the evaluation and assessment of donor organs, predict graft survival times, predict the risk of drug-induced nephrotox- icity, and help develop strategies for dosing and toxicity testing NOVEL DIAGNOSTIC METHODS for a wide range of therapeutic drugs [14]. Novel diagnostic methods that would allow an earlier diagnosis New methods have been suggested to measure nephron of CKD are an unmet clinical need. Reliance on the current eGFR number ex vivo in the intact kidney: cationized ferritin-enhanced threshold to diagnose CKD means that by the time CKD is diag- MRI (CFE-MRI) [16], light sheet microscopy after optical clearing nosed, over 50% of the functional kidney mass has been lost and [17] and computed tomography (CT) [18]. However, the utiliza- the combined risk of CKD progression and premature death is tion of these tools in vivo and in the clinics necessitates them already increased by around 2- to 7-fold, while current interven- being non-destructive and relatively non-invasive, and thus far tions decrease the risk of adverse outcomes by 20%–40% [8, 9]; in only CFE-MRI has been used in vivo [14]. other words, diagnosis is too late. While CKD may be diagnosed CFE-MRI uses ferritin filled with an iron oxide [14]. Following earlier based on high albuminuria values, most patients progress intravenous injection, the ferritin is cationized and bound to to CKD category G3 while having physiological albuminuria, as the glomerular basement membrane. The accumulation of evidenced by epidemiological data that show that G3 is the most ferritin in the glomeruli allows its detection, mapping of the common category of CKD [10], i.e. albuminuria did not allow an entire kidney in vivo and co-localization of glomeruli with other earlier diagnosis (i.e. G1 or G2) for most patients that progressed structures such as the microvasculature. To support the use of to G3. This subclinical stage of CKD progression, potentially last- nephron number as a clinical parameter, the cationized ferritin ing decades, as evidenced by those forms of CKD in which we molecule of CFE-MRI has been modified to form radiolabeled have a tool that allows an earlier diagnosis (e.g. sonography for cationic ferritin (RadioCF), a radiotracer used in positron emis- autosomal dominant polycystic kidney disease) is in fact the sion tomography (PET) to map functioning glomeruli in vivo blind spot for CKD diagnosis [11–13]. Several approaches are un- in the kidney [19]. RadioCF-PET accurately quantifies nephron der study to address the blind spot in CKD, mainly using imaging mass in animals and had the potential for clinical transla- and assessment of biomarkers in biological fluids (Fig. 2). tion [19]. Radio-CF is formed by integration of a radioisotope, 232 S. Copur et al. Figure 2: Novel diagnostic methods in nephrology. CFE-MRI: cationized ferritin-enhanced MRI; RadioCF-PET: radiolabeled cationic ferritin-positron emission tomog- raphy; CKD: chronic kidney disease; AKI: acute kidney injury; GBM: glomerular basement membrane; KRIS: Kidney Risk Inflammatory Signature; THSD7A: throm- bospondin type-1 domain–containing 7A antibodies; NAD: nicotinamide adenine dinucleotide; FAT1: glomerular antigen-protocadherin FAT1; ESRD: end-stage renal disease; DKD: diabetic kidney disease; HST: hematopoietic stem cell transplantation; PCX: podocalyxin; KIM-1: kidney injury molecule 1; TNF-α: tumor necrosis factor- α; 8-OHdG: 8-oxo-7,8-dihydro- 2 -deoxyguanosine; L-FABP: liver-type fatty acid binding protein; IGFBP-7: insulin-like growth factor-binding protein-7; TIMP-2: tissue inhibitor of metalloprotease-2; DIKI: drug-induced kidney injury; CNA35-CT: collagen-binding adhesion protein-35 CT; ESMA-based MRI: elastin-specific contrast agent MRI; DW-MRI: diffusion-weighted MRI; BOLD-MRI: blood oxygen level–dependent MRI; HP-13C MRI: hyperpolarized carbon 13 MRI; plus sign: advantages; minus sign: disadvantages/limitations (indicated in red color). Cu-64, to the cationic ferritin (CF) and has been shown to bind ing integrated into clinical practice [25–27] mainly due to the functional glomeruli when given intravenously [19]. RadioCF- cost and technical factors involved in MRI recalibration and op- PET can map and measure the areas of functional nephron eration. An additional major setback of this technique for now loss making it a diagnostic tool that can also predict CKD is the lack of adequate characterization of findings in different progression [14]. CKD stages and in various kidney diseases. MRI has been used to assess the functional status of both kid- Specific techniques have been designed to assess kidney fi- neys. Multiparametric MRI may evaluate diverse aspects of kid- brosis and its dynamics in both kidneys simultaneously in vivo ney function and vascularization [20]. A novel imaging modality [28]. These include fluorescent CNA35 CT, which takes advan- is sodium MRI. Compared with “normal MRI,” which is a map tage of a collagen binding peptide, and elastin-specific contrast of hydrogen atoms in the body, sodium MRI is a map of sodium agent MRI (ESMA)-based molecular MRI of elastin [28]. For in- atoms in the body. The kidney has a baseline gradient of sodium stance, collagen-binding adhesion protein (CNA35) which has concentrations from the cortex to the medulla (corticomedullary high affinity for type I and III collagen molecules has been uti- sodium gradient) [21, 22]. The first study of sodium MRI on hu- lized as a tool to visualize collagen deposition in mouse sub- man kidneys demonstrated that the sodium gradient increases jects and has a potential to be utilized in human subjects as linearly from cortex to medulla which is followed by linear de- a non-invasive method of fibrosis assessment [29, 30]. On the crease until renal pelvis [23, 24]. Although alterations in the other hand, ESMA-based MRI, which is a small peptide specific sodium gradient have been demonstrated on multiple clinical to elastin, component of extracellular matrix, has been shown and pre-clinical trials, the sodium MRI technique is far from be- to demonstrate kidney fibrosis in mouse models as well as the Novel strategies in nephrology 233 efficiency of anti-fibrotic therapies [31]. These techniques will participants, CKD273 performed better than traditional mark- eventually also test a potential impact of anti-fibrotic therapies, ers and correlated better than albuminuria with eGFR and bet- a current unmet need. ter predicted rapid CKD progression [37]. Similar findings were In addition, novel MRI techniques allow to generate imaging observed in another study conducted on 2087 participants, in biomarkers that can improve the management of kidney disease which CKD273 added to the prediction of CKD G3 after account- [20]. MRI enables to measure kidney volumes, blood flow in renal ing for baseline eGFR, albuminuria and covariables [38]. In a ran- arteries, renal water content and tissue oxygenation [20]. DWI, or domized controlled trial in diabetic patients without albumin- DW-MRI, can detect the displacement of water molecules within uria, CKD273 predicted the development of albuminuria [39]. the tissue architecture [20]. This technique can inform about any Furthermore, the same CE-MS analysis of a single urine sam- changes in the renal microstructure such as renal fibrosis, cel- ple may be used to derive other peptidomics markers that pre- lular infiltration (inflammatory or tumorous) or edema as well dict the rapid loss of eGFR better than albuminuria in patients as changes in renal perfusion and in the water handling in the who do not fulfill current eGFR criteria for CKD (i.e. may allow an tubular compartment [20]. BOLD-MRI, which measures renal tis- earlier diagnosis of CKD than albuminuria) [40], or correlate with sue deoxyhaemoglobin levels voxel by voxel, is a promising tech- kidney fibrosis as detected in kidney biopsy [41] or provide infor- nique to monitor renal tissue oxygenation in humans [32]. It al- mation on the underlying cause of CKD and its prognosis [42, 43]. lows the monitoring of changes in renal oxygenation or changes The Kidney Risk Inflammatory Signature (KRIS) includes 17 in the capillary bed microstructure. In addition, T2 is altered by proteins directly involved in inflammation and correlated with several other factors such as hydration status, dietary sodium the 10-year risk of ESRD in diabetic kidney disease [44]. In this and susceptibility effects [20]. In addition, HP 13C MRI is a poten- study 194 circulating inflammatory proteins have been evalu- tial tool, not currently used in the clinic, for the non-invasive as- ated in three different cohorts comprised of type 1 and 2 dia- sessment of oxidative stress and mitochondrial pyruvate dehy- betic patients, revealing that 17 novel proteins enriched for TNF drogenase activity following renal ischemia–reperfusion injury Receptor Superfamily members are linked to early and late re- [33]. nal function decline leading to ESRD in diabetic subjects. Even Furthermore, CEUS has been a promising imaging modality though the major source, hypothesized to be white blood cells, for renal lesions. CEUS lacks nephrotoxicity, ionizing radiation, of those KRIS proteins is yet to be determined, their appear- and has the ability to evaluate the enhancement pattern of renal ance years prior to the onset of ESRD appears to be related to lesions quickly and in real time [34]. Some of the well-defined ap- overproduction rather that disrupted renal clearance. In addi- plications of CEUS are the differentiation of solid tumors, pseu- tion to their predictive role in ESRD, KRIS proteins provide a po- dolesions and complex cysts; characterization of complex cysts tential therapeutic intervention point as evidenced by a clinical with different malignant potential; and evaluation of tumor ab- trial conducted in one of those three cohorts demonstrating de- lation [34]. Microbubble contrast agents are safe with rare ad- cline in albuminuria consistent with the decline in KRIS proteins verse reactions [34]. in response to 24-week trial with 4 mg of baricitinib, a JAK-1/2 These approaches are promising tools to assess nephron inhibitor [45]. Additionally, certain metabolites of nicotinamide number, diverse kidney functions and kidney fibrosis and may adenine dinucleotide (NAD) have recently been correlated with be transitioned to clinical use if their safety, efficacy and regula- acute kidney injury (AKI) risk [46]. tory requirements are established. There are multiple ongoing clinical trials (NCT01550393, NCT02743273, NCT00690586, NCT04851145) investigating the role of proteomics and metabolomics in the field of nephrol- Biological fluid biomarkers ogy. However, these trials should demonstrate that proteomics Proteomics and metabolomics have recently been tested in the or metabolomics biomarkers offer additional information over field of nephrology with intriguing and promising results. In conventional biomarkers that are clinically relevant and may some cases, proteomic or metabolomic signatures themselves change therapeutic decision-making in a cost-effective manner. are used as biomarkers. In others, they are tools that are used It is important to emphasize that studies investigating novel to identify individual biomarkers that are then assessed using biomarkers need not only a detection cohort but also an inde- more conventional techniques. Additionally, both RNA and DNA pendent (second) validation cohort. in biological fluids may serve as biomarkers. These biomarkers In addition, multiple novel biomarkers have been identi- should correlate well with kidney disease, histopathology, pro- fied recently, sometimes using proteomics, although they are gression, outcomes or early disease, and allow for rapid, non- in diverse stages of translation to the clinic [47]. More than 40 invasive and specific measurements with high sensitivity and potential biomarkers have emerged in recent years and most specificity. can be sorted based on their association with features such as glomerular injury [podocalyxin (PCX)], tubular injury [kidney in- jury molecule 1 (KIM-1)], inflammation [tumor necrosis factor-α Proteomic and metabolomic analysis for the detection (TNF-α), TNF receptors-1 and -2) [48]] and oxidative stress [8-oxo- of biomarkers 7,8-dihydro- 2 -deoxyguanosine (8-OHdG)] [47]. CKD biomarkers Pontillo and Mischak identified 273 urinary peptides that dif- can be identified by a variety of conventional methods such as fer between patients with CKD and healthy subjects, namely solid-phase fluorescent immunoassay, liquid chromatography– the marker CKD273 which includes fragments of collagen and mass spectrometry, liquid chromatography–mass spectrometry, of proteins involved in inflammation and tissue repair, by us- high-performance liquid chromatography (HPLC) and enzyme- ing capillary electrophoresis-mass spectroscopy (CE-MS) on 230 linked immunosorbent assay (ELISA) [47]. Additionally, microflu- CKD patients and 379 control subjects [35, 36]. Further studies idics allow for short sample processing times along with a small have implicated the potential superiority of CKD73 in the pre- footprint, automated operation and a high degree of flexibility, diction and diagnosis of CKD over traditional markers leading and may potentially offer a robust, cost-effective and simple-to- to a letter of support of the US Food and Drug Administration operate instrument for early diagnosis of CKD and other patho- (FDA). According to a cross-sectional study conducted on 1990 logical events [47]. 234 S. Copur et al. Membranous nephropathy is the most common cause of in one study of 131 CKD patients not on dialysis and in another nephrotic syndrome in adults and in hematopoietic stem study conducted on 289 patients on hemodialysis [60, 61]. Ad- cell transplant (HST) patients. A flurry of autoantigens has ditionally, cell-free DNA was associated with AKI after cardiac been identified recently, following the description of anti- surgery or in patients with type 1 cardiorenal syndrome [62, 63]. phospholipase A2 receptor (PLA2R) antibodies, a biomarker that However, these data should be validated in large scale multi- according to guidelines can now replace kidney biopsy in pa- center clinical studies that address the added benefit on patient tients with membranous nephropathy [49]. Anti-protocadherin management of assessing cell-free DNA. FAT1 antibodies are found in over 80% of cases of mem- branous nephropathy following HST [50]. Patients with anti- NOVEL THERAPEUTIC ALTERNATIVES PLA2R antibody–negative primary membranous nephropathy may have anti-thrombospondin type-1 domain–containing 7A Novel therapeutic alternatives for ESRD include wearable artifi- antibodies [51, 52]. Additionally, anti-nephrin antibodies have cial kidneys, xenotransplantation, stem cell–based therapy, and been detected via serological and immunohistochemical studies bioengineered and bio-artificial kidneys. Of note, one of the main in a subset of biopsy-proven minimal change disease patients objectives of these novel therapeutic approaches should be to [53]. maintain patients at home and to avoid dialysis centers. Addi- The field of biomarkers of AKI is also very active; urinary tionally, novel medications to prevent CKD progression or treat insulin-like growth factor-binding protein-7 (IGFBP-7) and CKD complications are at advanced stages of clinical develop- tissue inhibitor of metalloprotease-2 (TIMP-2) testing are now ment or have already been approved for clinical use in some in clinical use under the brand name Nephrocheck [47, 54]. countries (Fig. 3). Kidney tubular injury results in the release of blood and urine The main aim for the development of novel therapeutic biomarkers [55]. Urinary KIM-1, liver-type fatty acid binding markers is to create a time frame for earlier treatment with pos- protein (L-FABP), IGFBP-7 and TIMP-2 are released from the sible reversal of disease or prevention of disease progression. proximal tubule, whereas uromodulin (UMOD) is secreted from Even though current therapeutic alternatives are mostly unben- the loop of Henle and neutrophil gelatinase-associated lipocalin eficial in this regard, novel therapeutic modalities have been de- (NGAL) originates from distal tubules [55]. These biomarkers veloped and testes along with the diagnostic modalities in hope could potentially localize specific segments of injured tubules. of reach that goal. Biomarkers involved in inflammation, repair and fibrosis [55] could also predict the transition from AKI to CKD, help dis- Wearable artificial kidneys tinguish between kidney dysfunction and injury, guide AKI management, and improve the diagnosis of diseases such as Existing hemodialysis is an imperfect treatment. It is socially ob- acute interstitial nephritis [55]. Furthermore, some biomarkers trusive to the patient, necessitating them to take several days are ready for use in clinical trials of AKI and could guide manage- out of the week to undergo a long treatment using bulky equip- ment in certain clinical settings. The Kidney Precision Medicine ment requiring significant water and electricity supply. Also, be- Project is an ongoing effort to build a kidney tissue atlas and cause it only occurs 3 days a week, it is at best a very imperfect increase the use of biomarkers to evaluate nephron health [55]. approximation of the continuously functioning normal kidneys [64]. Thus, current hemodialysis modalities cannot be consid- ered green techniques and are associated with dismal outcomes RNA biomarkers [6]. microRNAs (miRNA) are stable molecules and there are sev- The wearable artificial kidney (WAK) is an innovative eral examples of their potential use in the context of kidney approach to renal replacement therapy aiming to improve injury, including drug-induced kidney injury (DIKI) [56]. A cross- patients’ quality of life by allowing mobility and continuous laboratory program to identify urinary miRNA patterns associ- clearance of toxins without accumulation during inter-dialysis ated with cell- or cause-specific DIKI characterized biomarkers periods, with better hemodynamic stability, similar to healthy of glomerular, proximal tubule, thick ascending limb (TAL) of the kidneys. The minimum requirements for the dialysis system of loop of Henle or collecting duct (CD) injury in rats by exposing a WAK are pumping systems, a dialysate regeneration system, them to cell-specific toxins and confirming the location of in- dialysis membrane, batteries and a patient monitoring system creased expression by laser capture microdissection of nephron [65]. The initial effort for ambulation during hemodialysis segments [56]. Urinary miR-192-5p was identified as potentially sessions consisted of a WAK system enabling ambulation for up proximal tubule-specific. Urinary miR-221-3p, miR-222-3p and to one-third of the dialysis session [66]. Nevertheless, it lacked miR-210-3p increased following exposure to TAL toxins, and enough sorbent for full time treatment and patients had to be miR-23a-3p following the podocyte toxin doxorubicin. Thus, connected to a classical hemodialysis device for at least two- urinary miRNA panels from different nephron regions may con- thirds of the session duration. Next, another WAK system was tribute to the exploring the DIKI potential of novel drugs [56]. developed that had sorbent-containing minicartridges instead of requiring large amounts of dialysate; however, this system was limited by the requirement of minicartridges change four Cell-free DNA times daily, and by high infection risk due to transcutaneous Cell-free DNA methods have increasingly been used, along with arteriovenous shunts/fistula [67]. A few other WAK designs over other methods, especially in the field of hematology and oncol- the years did not undergo clinical trials [66, 68, 69]. Current ogy to detect malignancies and evaluate recurrences. Similarly, WAK models weigh under 5 kg and have long-lasting small bat- they have potential for use in the detection of renal cell carci- teries that avoid the need for continuous electrical connection, noma [57]. Though it is too early to draw conclusions, there is improved permeability membranes and advanced filtration potential for cell-free DNA to be used in the detection of acute re- materials that enable the reuse of dialysate solutions without jection in kidney transplant recipients [58, 59]. Additionally, high needing large quantities of water as in conventional hemodial- levels of cell-free DNA were associated with adverse outcomes ysis [70]. Among the five different WAK models currently under Novel strategies in nephrology 235 Figure 3: Novel therapeutic alternatives in nephrology. G-CSF: granulocyte colony stimulating factor. plus sign: advantages; minus sign: disadvantages/limitations (indicated in red color). development, three are based on peritoneal dialysis, one on ity should be improved and confirmed in longer and larger scale hemodialysis and one is a combined model [71, 72]. studies. Only a single human clinical trial (prospective, non- randomized) involving 10 subjects with a duration of 24 h has been conducted regarding the efficiency and adverse ef- Xenotransplantation: an old concept revisited fects of WAK [73]. No serious adverse events such as hemody- namic instability were observed and overall toxin clearance was Xenotransplantation was first postulated in 1667. However, achieved, but the trial was terminated because of the develop- clinical trials in the early 20th century were marred by limited ment of excessive amounts of carbon dioxide air bubbles. The success due to high rates of rejection, thrombotic complications targeted ultrafiltration rates were achieved with a mean blood and infection [75–77]. Given the ever-expanding waiting lists flow rate of 42 ± 24 mL/min and a mean dialysate flow rate for kidney transplantation, which is now over 100 000 patients of 43 ± 20 mL/min. Additionally, self-reported treatment satis- compared with a much lower number (∼35 000) of annual kidney faction and treatment-related quality of life were higher than transplantations performed in the USA, the concept of xeno- for traditional hemodialysis sessions. Major limitations in addi- transplantation has re-gained clinical and research attention tion to carbon dioxide bubbles were the considerable variations [78]. CRISPR/Cas9 and advances in the field of bioengineering in blood and dialysate flow rates and in toxin clearance. Addi- have allowed xenotransplantation across non-human species tionally, a pilot study with eight patients demonstrated similar with higher success and lower complication rates [79]. Pigs are outcomes [74]. Targeted ultrafiltration rates were achieved with the common choice as a source for kidneys due to their short a mean blood flow of 58.6 ± 11.7 mL/min and mean dialysate maturation period, low risk of xenozoonosis, advancement in flow of 47.1 ± 7.8 mL/min without significant hemodynamic ad- bioengineering studies, and relative physiology and size simi- verse effects. Two patients experienced clotting at the vascular larity to humans. Two 2022 clinical reports have been promising access despite the use of heparin similar to hemodialysis ses- [80, 81]. In a brain-dead patient, both kidneys were transplanted sions. In summary, WAK systems are promising but their qual- from pigs with 10 genetic modifications aimed at preventing 236 S. Copur et al. rejection. Despite the lack of hyperacute rejection and stable as intravenous infusion in terms of serum creatinine, cystatine urine output for 72 h until the termination of the trial, the C and reactive oxygen species after 8 weeks of therapy [101]. transplanted kidneys were unable to excrete creatinine at phys- Kidney organoids may be produced from pluripotent stem iological levels and histological examination revealed evidence cells. Efficient bioengineering protocols differentiate human for thrombotic microangiopathy with no evidence of cellular re- pluripotent stem cells into multipotent nephron progenitors jection or deposition of antibody or complement proteins [80]. In and, hopefully in the end, functional kidneys. Kidney organoids two further cases of genetically modified pig-to-human kidney formed in this procedure are organized into nephron-like struc- transplantations, GFR significantly improved within minutes tures and express markers for podocytes, proximal tubules, after transplantation [81]. Kidney biopsies performed at the 6th, loops of Henle and distal tubules [102–104]. Organoids may also 24th, 48th and 54th hours post-transplantation revealed no signs be considered to develop kidney disease models. For now, they of a hyperacute or antibody-mediated rejection reaction. How- are not able to mature beyond the second trimester stage. Even- ever, the follow-up period was limited to 54 h [81]. Overall, these tually, progress in this field is aimed at contributing to renal re- cases indicate that prevention of antibody-mediated hyperacute placement therapies in the future. rejection is feasible. However, the recent death of the recipient Finally, kidney rejuvenation strategies have been envisioned of the first ever heart transplant from genetically modified pigs, using Yamanaka factors in vivo (e.g. through kidney artery likely from a porcine virus and after initial apparent success of catheterization) or ex vivo (e.g. for kidneys from older transplant the procedure, adds a note of caution to the current limitations donors) [105]. of our understanding of the procedure and its complications. An alternative strategy would entail human organ generation Bioengineered and bio-artificial kidneys in animals whose organ size, anatomy and physiology are closer to humans (e.g. in pigs) [82]. With the demonstration of potential The concept of bioengineering an artificial kidney has been stud- interspecies organ generation with the use of xenogenic pluripo- ied for at least three decades [106]. The bio-artificial Renal As- tent stem cells, as shown by rat pluripotent stem cell-derived sist Device (RAD) was a hybrid system where a multi-fiber biore- on organogenesis-disabled mice via blastocyst complementa- actor consisting of the synthetic hollow fibers of a high-flux tion method, the potential role for of xenotransplantation has hemofiltration cartridge combined with porcine primary tubu- been questioned for human subjects without any clinical or pre- lar epithelial cells [107]. The RAD conducted active transport clinical study in that field. In any case, the ethical issues posed (differential reabsorption and secretion) as well as metabolic by xenotransplantation remain controversial. and endocrine functions [108], and improved hemodialysis per- formance in acutely uremic dogs [109]. In two clinical trials in the intensive care unit setting, the RAD maintained viability, dura- Stem cell-based therapy: an alternative approach bility and functionality in the clinical setting, and performed on the rise metabolic and endocrinologic activity [108]. All but one treated Stem-cell based therapies became popular after the discovery of patient improved 1–7 days following therapy, and 6 of the 10 pa- induced pluripotent stem cells by Yamanaka and colleagues in tients survived past 30 days. One patient died within 12 h of RAD 2006 [83]. Pluripotent stem cells have the potential to differen- because of voluntary withdrawal from ventilatory life support tiate into almost all cell types in the body and are derived from and three other patients expired due to complications of comor- somatic cells by the introduction of Yamanaka factors (four spe- bidities unrelated to AKI or RAD therapy. Treatment with RAD cific genes encoding transcription factors, namely Oct3/4, Klf4, decreased granulocyte colony stimulating factor (G-CSF), inter- Sox2 and Myc) [84]. Stem-cell–based therapies have been on the leukin (IL)-6, IL-10 and IL-6/IL-10 ratios [108]. A second study rise in the last few decades. Multipotent stromal cells are the compared continuous venovenous hemofiltration together with choice so far and are derived from bone marrow (BM-MSCs), am- RAD in 40 patients versus conventional continuous renal re- niotic fluid (AFSCs), urine (USCs) or umbilical cord (UC-MSCs) placement therapy (CRRT) alone in 18 patients, observing a mor- [85]. Mesenchymal stem cells have been shown to differentiate tality rate of 33% in the RAD group and 61% in the CRRT group into mesangial cells when they are cultured with injured mesan- at Day 28 [110]. Furthermore, survival through Day 180 was sig- gial cells in vitro [86]. The main mechanisms of stem cell ther- nificantly higher in the RAD group and the risk for death was apy in kidney diseases include upregulation of autophagy, anti- approximately 50% of that in the CRRT group [110]. apoptotic properties, paracrine signaling and anti-inflammatory The RAD is the only bio-artificial kidney device tested in hu- properties. Extracellular vesicles secreted from stem cells may mans. There were limitations to its widespread use for kidney prevent high phosphorus-induced vascular calcification in CKD disease such as cell sourcing, times and costs of device manufac- patients and may prevent fibrosis and the resultant CKD in uni- turing, storage requirements and distribution related problems lateral ureteral obstruction through paracrine mechanisms [87, [107]. The Bioartificial Renal Epithelial Cell System (BRECS) is 88]. Stem cell therapy protects from cisplatin-induced nephro- an alternative technology, based on niobium-coated carbon and toxicity, AKI, diabetic nephropathy and oxidative stress through cryopreservable polycarbonate seeded with human renal tubu- the activation of autophagy [89, 90]. Anti-apoptotic and anti- lar epithelial cells derived from adult progenitor cells [111–113]. inflammatory properties of stem cells are beneficial for the treat- BRECS showed promising results in a porcine septic shock model ment of rhabdomyolysis or chromium- or adriamycin-induced [113] and in an anephric sheep model [114]. However, BRECS is AKI, diabetic nephropathy, renal artery stenosis, cardiorenal yet to be tested in human trials but there are no publications syndrome, lupus nephritis and obesity-induced AKI [91–100]. since 2017. Few clinical trials are yet to investigate the safety, efficiency Implantable bioartificial kidneys (iBKs) combine the pre- and applicability of stem cell therapy in human subjects with vious experiences with RAD bioengineering and the new CKD, though results appear promising as shown by a placebo- developments in miniaturization technology [115]. Similar to controlled clinical trial conducted on 200 Chinese patients with wearable artificial kidneys, iBK is potentially capable of pro- CKD and eGFR below 60 mL/min/1.73 m2 demonstrating effi- viding continuous dialysis throughout the day [116]. The iBK is ciency of bone marrow-derived mesenchymal stem cell therapy composed of a mechanical blood filter made with a silicon Novel strategies in nephrology 237 membrane and a bioreactor containing engineered renal to differentiate into every other cell type has yielded the most tubular epithelial cells making it a hybrid device capable of promising results for kidney re-cellularization [107]. Song et al. increased toxin clearance with improved cardiovascular sta- reported that the infusion of human umbilical venous endothe- bility and a higher quality of life. The bioreactor is responsible lial cells and rat neonatal kidney cells in a rat kidney scaffold for electrolyte balance as well as metabolic functions and the showed promising results [96]. After the decellularization of rat, silicon membrane provides glomerulus-like filtration. The iBK porcine and human kidneys by detergents the authors seeded is intended to connect into the patient’s systemic circulation rat kidney scaffolds with epithelial and endothelial cells and per- allowing the filtered waste to be removed directly into the fused these constructs in a whole-organ bioreactor to regener- bladder, thus eliminating the need for electrical pumps [116]. ate functional tissue. This novel structure produced rudimen- The iBK is currently in preclinical testing. The silicon cartridge tary urine both in vitro and in vivo following transplantation into was patent without an electrical pump or anticoagulants for rats [121]. up to 1 month in canine models [116, 117]. One of the major Even though Song et al. and several other authors [122, 123] drawbacks of iBK could be the durability and clotting of the have reported promising findings, the translation of kidney- blood filter, requiring patients to undergo frequent surgeries to derived scaffolds into the clinics still requires further techno- manipulate or change the device. In addition, the tubular cells logical advancements such as improvements in decellulariza- would need to maintain stability and viability against the high tion methods to avoid the disruption of the remaining matrix blood shear force that would be encountered in clinical use and strategies to prevent the host immunological response to [115]. The bioengineered artificial kidney, despite its limitations the decellularized scaffold [107]. and drawbacks, could become a potential alternative to renal replacement therapy and transplantation. Medications on the rise An organ-on-a-chip is a microfluidic cell culture platform that mimics the activities, mechanics and physiology of living In addition to the kidney and cardioprotective effects of SGLT2 human organs. The microfluidics system offers a physiologi- inhibitors and GLP1 receptor agonists, novel drugs have been cal cell microenvironment allowing long-term culturing while recently approved or have provided promising results in clin- maintaining cell phenotypes [116]. The organ-on-a-chip tech- ical trials for kidney protection (nonsteroidal MRAs, endothe- nology has provided the development of more advanced three- lin receptor antagonists), treatment of consequences of CKD dimensional (3D) organ-level structures in vitro and the incorpo- [hypoxia-inducible factor (HIF) stabilizers] or specific causes of ration of dynamic mechanical and chemical signals [107]. It has CKD, such as voclosporin for lupus nephritis (Table 1). been used to replicate tubular or glomerular structures. Various glomerulus-on-a-chip and tubule-on-a-chip models have been Nonsteroidal MRA utilized for disease modeling, drug screening assays and in vivo regenerative medicine applications [116]. The glomerulus-on-a- Finerenone is a non-steroidal selective MRA that has emerged chip models the glomerular filtration barrier as both physical as a kidney and cardiovascular protective medication in patients forces and chemical stimuli influencing glomerular cell func- with diabetic kidney disease on angiotensin-converting enzyme tions can be modulated [107]. In the tubule-on-a-chip, tubular inhibitors (ACEi)/angiotensin receptor blockers (ARB) that may cells that are cultured in a 3D channel that represent the mi- also add protection to that offered by SGLT2 inhibitors [124]. A croenvironment of human kidney tubules and their functions of double-blind clinical trial with a median follow-up period of 3.4 reabsorption and secretion [107]. years and conducted on 7437 subjects with type 2 diabetes melli- The chip-based technology has helped conduct experiments tus and CKD with eGFR of 25–90 mL/min/1.73 m2 and microalbu- to better understand glomerular and tubular functions. Fu- minuria demonstrates that finerenone improved cardiovascular ture studies to produce next-generation chips combining both outcomes including hospitalization for heart failure, myocardial glomerular and tubular elements to generate a functional infarction, stroke and death from cardiovascular cause [125]. Ad- nephron that incorporates both filtration and reabsorption are ditionally, the risk for CKD progression has been reduced with necessary [116]. finerenone [126, 127]. Further analyses confirmed a beneficial A further bioengineering technology aims to generate a impact of finerenone on proteinuria, CKD progression and car- whole-kidney scaffold with a 3D geometry and vasculature [118]. diovascular outcomes [128, 129]. Indeed, finerenone has been After the decellularization of a kidney gathered from a patient approved by the US FDA and the European Medicines Agency with CKD, the recellularization of the scaffold with patient- (EMA) for the treatment of CKD G3 and G4 with albuminuria in specific progenitor cells would potentially result in the gener- type 2 diabetes in adults [130]. Given the mechanism of action ation of a new transplantable organ [118]. Kidney-derived scaf- of finerenone, its beneficial impact is expected to extend beyond folds are obtained by a process called ‘decellularization’ in which diabetic kidney disease to other forms of CKD. In addition, other detergents and enzymes remove the cellular components with- non-steroidal selective MRAs, such as apararenone (MT-3995), out affecting the extracellular matrix (ECM) [107, 119, 120]. The KBP-5074 and AZD9977, are undergoing clinical trials while esax- re-cellularization of the acellular matrix of the kidney is then erenone (CS3150) is approved in Japan for the treatment of hy- performed via different cell seeding processes [107]. Biological pertension [131]. Of note, as with other agents which antago- scaffolds allow signal exchange between the matrix and the cells nize the renin–angiotensin–aldosterone system hyperkalemia is resulting in the induction of migration, proliferation and differ- a risk and should be kept in mind while utilizing these medica- entiation [107]. However, the number of donor cells is limited, tions. and proper tissue/organ function requires advancements in the Aldosterone synthase inhibitors, mainly the inhibitor of al- re-cellularization technology [107]. Therefore, the correct repop- dosterone synthase enzyme or CYP11B2, have been investigated ulation and alignment of billions of cells for proper kidney func- for their potential role in the treatment of heart failure, hyper- tion is still in its early stages of development. tension and kidney diseases [132, 133]. LCI699, the first orally The use of either epithelial cells in combination with en- administered aldosterone synthase inhibitor (ASI), has shown dothelial cells or pluripotent stem cells that have the potential to lead a reduction in plasma aldosterone concentration along 238 S. Copur et al. Table 1: Medications that can be potentially used in nephrology. Medication Mechanism of action Advantages Finerenone Non-steroidal selective MRA • Better cardiovascular outcomes: • Decreases hospitalization for HF, MI, stroke and death risk • Reduces CKD progression • Declines proteinuria LCI699, fadrozole, RO6836191 Aldosterone synthase/CYP11B2 • Lead to reduction in plasma aldosterone inhibitors concentration along with an increase in plasma renin and deoxycortisol concentration • Beneficial in the treatment of primary hypertension Sparsentan, sitaxentan, zibotentan Endothelin receptor antagonists • Can be used to decrease proteinuria and kidney progression in CKD, FSGS, patients with scleroderma Daprodustat HIF prolyl hydroxylase inhibitor • Similar efficiency and cardiovascular event risk (HIF stabilizer) with darbepoetin alfa or epoetin alfa in anemia treatment • Can be administrated orally Voclosporin Calcineurin inhibitor • Voclosporin with MMF and low-dose steroids shows better kidney outcomes versus MMF and low-dose steroids HF: heart failure; MI: myocardial infarction; MMF: mycophenolate mofetil; FSGS: focal segmental glomerulosclerosis. with an increase in plasma renin and deoxycortisol concen- major problem in ERA, however patients on these medications tration [134]. Additionally, it has shown to be beneficial in the are reported to respond well to diuretic therapy. It is important treatment of primary hypertension. Similar effects have been to understand that the observed sodium—and water—retention observed with others ASIs such as fadrozole and RO6836191 in using ERA is attributed to the effect of ERA-B blockade and that phase 1 and 2 clinical trials [135, 136]. Future large-scale human selective ERA-A blockers are non-selective at the peak levels. randomized clinical trials are required for better understanding [144, 145] More selective ERA-A blockade might be the future of the clinical effects of ASIs and potential integration into clin- and is currently under investigation. ical practice. HIF stabilizers Endothelin receptor antagonists HIF prolyl hydroxylase inhibitors, also termed HIF stabilizers, are Endothelin receptor antagonists (ERAs) have a kidney protec- oral agents to treat CKD-associated anemia. Indeed, their ma- tive effect on CKD and proteinuria but are marred by sodium jor advantage over erythropoietin (EPO) analogs is the oral route retention and volume overload as a key safety issue. Bosentan of administration instead of subcutaneous injections. Some of and atrasentan are older ERA drugs that displayed some kidney them are in clinical use in China and Japan, and roxadustat protective actions in patients with CKD [137–139]. However, the was recently approved by the EMA. However, the FDA recently pivotal phase 3 trial of atrasentan for diabetic kidney disease rejected roxadustat and vadadustat based on safety concerns. was terminated and despite kidney protection, it did not offer HIF stabilizers do not appear to preserve kidney function and the cardiovascular protection associated to SGLT2 inhibition their cardiovascular safety record has been inconclusive regard- even though patients were carefully selected to minimize the ing blood pressure effects and cardiac hypertrophy. Although adverse impact of sodium retention [139, 140]. Sparsentan is it was initially hypothesized that by providing more stable and both an endothelin receptor-A inhibitor and an angiotensin lower EPO levels, they may be safer than current EPO derivatives, receptor blocker and was superior to irbesartan in reducing the cardiovascular safety appears to depend on the population proteinuria in patients with focal segmental glomerular sclero- being studied and the type of HIF stabilizer being utilized for as sis, without any significant adverse effect [141]. A clinical trial yet unclear reasons. Thus, roxadustat may even be safer than in immunoglobulin A nephropathy is ongoing (NCT03762850). EPO derivatives in non-dialysis and incident dialysis patients Sitaxentan reduced proteinuria and pulse wave velocity com- [hazard ratio (95% confidence interval) 0.79 (0.61, 1.02), 0.78 (0.62, pared with placebo in non-diabetic patients with proteinuria 0.98) and 0.78 (0.57, 1.05) for major adverse cardiovascular events [142]. Another clinical trial investigating zibotentan in patients (MACE), MACE+ and all-cause mortality, respectively] [146] while with scleroderma demonstrated beneficial effects on kidney dis- the most recent phase 3 clinical trials in dialysis and non- ease progression [143]. Since the main concern for ERA is sodium dialysis patients randomized to either daprodustat or injectable retention, it may be hypothesized that co-administration with erythropoiesis-stimulating agents (ESA) treatment evidenced SGLT2 inhibitors may improve the safety profile and potentially an influence of the geographic region regarding cardiovascu- enhance kidney protection. Indeed, a phase 2 clinical trial of lar safety: daprodustat was safer than ESA in Western Europe zibotentan and dapagliflozin for the treatment of CKD (ZENITH- and Asia [147, 148]. The dialysis trial randomized 2964 dialysis CKD Trial) is ongoing (NCT04724837). Sodium retention is a patients to either daprodustat or injectable ESA treatment and Novel strategies in nephrology 239 showed that daprodustat was non-inferior to either darbepoetin AUTHORS’ CONTRIBUTIONS alfa or epoetin alfa from an efficacy point of view [147]. Simi- S.C., C.T., F.Y. and M.K. contributed substantially to the con- lar findings have also been established over the course of few ception or design of the work; or the acquisition, analysis or other large scale clinical trials [149–152]. In 3872 CKD patients interpretation of data for the work. M.J.S, A.C., A.O. and M.K. not undergoing dialysis, a randomized clinical trial with a me- drafted the work or revised it critically for important intellectual dian follow-up of 1.9 years demonstrated that daprodustat was content. also non-inferior to darbepoetin alfa for the treatment of anemia without any overall change in major cardiovascular event risk [148]. Such finding has been validated in another clinical trial ETHICAL APPROVAL [153]. HIF stabilizers are novel agents that require further inves- tigation with large-scale studies covering different populations. This article does not contain any studies with human partici- pants or animals performed by any of the authors. Voclosporin DATA AVAILABILITY STATEMENT A randomized double-blind and placebo-controlled phase 3 clinical trial randomized 357 subjects with biopsy-proven No new data were generated or analyzed in support of this class III-IV-V active lupus nephritis to receive either placebo research. or voclosporin, a novel calcineurin inhibitor, with background mycophenolate mofetil (MMF) and rapidly tapered low-dose CONFLICT OF INTEREST STATEMENT corticosteroids. Voclosporin provided better kidney outcomes including urine protein to creatinine ratio and eGFR without A.O. has received grants from Sanofi, and consultancy or additional adverse effects [154]. Another clinical trial validated speaker fees or travel support from Advicciene, Astellas, As- the superior kidney outcomes (complete renal remission) both traZeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, in low and high dose (23.7 mg or 39.5 mg, each twice daily, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alex- respectively) voclosporin plus MMF (2 g/day) groups as com- ion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex pared with placebo plus MMF, while demonstrating a higher and Vifor Fresenius Medical Care Renal Pharma, and is Director risk for adverse events including deaths [155]. Surprisingly, of the Catedra Mundipharma-UAM of diabetic kidney disease more deaths were observed in the low-dose than in the placebo and the Catedra Astrazeneca-UAM of chronic kidney disease or high-dose groups (11.2%, 1.1% and 2.3%, respectively). Vo- and electrolytes. A.O. is the previous Editor-in-Chief of CKJ. closporin recently became the first drug approved by the FDA M.K. is member of the CKJ Editorial Board. M.J.S. is the current with an indication for active lupus nephritis. Editor-in-Chief of CKJ. The other authors declare that they have no conflict of interest. CONCLUSION In conclusion, multiple advances in several fronts of the fight REFERENCES against kidney disease are likely to result in earlier diagnosis 1. Jager KJ, Kovesdy C, Langham R et al. A single num- and intervention, increasing the chances of long-term success, ber for advocacy and communication-worldwide more more sustainable and patient-friendly modes of kidney replace- than 850 million individuals have kidney diseases. Nephrol ment therapy, and novel interventions to delay CKD progression Dial Transplant 2019;34:1803–5. http://dx.doi.org/10.1093/ and improve the management of CKD complications. 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