Apolipoprotein L1 (APOL1) and Nephropathy

Posted on Scarica PDF

Alanís Yael Szyferman

DOI: 10.69097/43-01-2026-05

Alanis Yael Szyferman1, Soledad Kleppe1, Fabrizio Cristiano2,3, Juan C. Conde-Manotas4, Andrés Cadena-Bonfanti4, Gustavo Aroca-Martinez4, Carlos G. Musso1,4

1 Research Department. Universidad del Hospital Italiano de Buenos Aires, Argentina
2 Department of Neuroscience, Imaging and Clinical Science, Gabriele d’Annunzio University of Chieti and Pescara, Chieti, Italy
3 Nephrology and Dialysis Unit, Ortona Hospital, ASL 2 Lanciano Vasto Chieti, Italy
4 Facultad de Ciencias de la Salud. Universidad Simón Bolívar, Barranquilla. Colombia

Corresponding author:
Alanís Yael Szyferman
E-mail: alanisyael18@gmail.com

 

Abstract

Introduction. End-stage renal disease exhibits a disproportionate prevalence among Black individuals and older adults within the United States and worldwide. A significant genetic contributor to this disparity is the Apolipoprotein L1 (APOL1) gene, found exclusively in populations of African ancestry.
Materials and Method. We aim to perform a narrative review regarding the current understanding of APOL1 and its complex role in kidney disease pathogenesis.
Results. The G1 and G2 APOL1 risk alleles are strongly associated with an elevated risk for non-diabetic chronic kidney disease (CKD), including hypertensive nephropathy, focal segmental glomerulosclerosis, and HIV-associated nephropathy, in individuals who are homozygous or compound heterozygous for these variants. While 10-15% of African Americans carry two APOL1 risk alleles, approximately 80% remain disease-free, suggesting incomplete penetrance and the involvement of additional risk factors. In this condition, renal damage could be induced through different mechanisms such as altered cellular ion transport, mitochondrial dysfunction, and the requirement for additional stressors or “second hits”.
Conclusion. The increased susceptibility to end-stage renal disease (ESRD) in individuals of African ancestry is influenced by variations in the APOL1 gene.

Keywords: Apolipoprotein L1, kidney diseases, genetics

Introduction

Studies in the United States have revealed that the risk of developing end-stage renal disease (ESRD) is significantly higher in Black individuals and older adults. Specifically, Black individuals are almost three times more likely to develop this condition compared to White individuals, and those aged 75 and older are almost three times more likely to develop it compared to those aged 45 to 64 [1, 2].

Apolipoprotein L1 (APOL1) is a gene observed exclusively within populations of African ancestry. The APOL1 risk alleles, G1 and G2, which are characterized by two linked single nucleotide polymorphisms (G1) and a deletion (G2), respectively, are strongly associated with an elevated risk for non-diabetic chronic kidney disease in homozygous or compound heterozygous individuals, following an autosomal recessive inheritance pattern [3–12].

In African Americans, 50% carry at least one G1 or G2 allele, while 10-15% are homozygous or compound heterozygous for these risk alleles. Despite a significant risk of chronic kidney disease associated with G1 and G2 APOL1 variants, approximately 80% of individuals with two risk alleles will remain disease-free [8].

It is worth mentioning that Chen et al. found that even though the prevalence of hypertension, coronary heart disease, atrial fibrillation/flutter, stroke, and heart failure was similar between Black individuals with high-risk and low-risk APOL1 genotypes, significant disparities emerged when comparing Black and White participants. Black participants, regardless of APOL1 genotype (high or low risk), exhibited a higher prevalence of hypertension, diabetes mellitus, and overall cardiovascular disease compared to White participants. Moreover, APOL1 risk variants were identified as risk factors for end-stage renal disease, but not for mortality, and this association remained consistent across different age groups [1].

 

APOL1

APOL1, a recently evolved gene present only in humans and certain primates, circulates as part of high-density lipoprotein and protects against Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness, by inducing lysosomal swelling and lysis of the parasite [8].

The APOL1 gene is located at chromosome 22, and encodes apolipoprotein L1, a protein expressed across a range of tissues and cell types [1, 3, 10]. The APOL1 messenger RNA is expressed in various tissues, including liver, lung, placenta, and endothelial cells, with weaker expression in heart and pancreas, and potential expression in macrophages [4]. The majority of APOL1 present in human plasma is secreted by the liver, and circulates as part of high-density lipoprotein class 3, specifically the dense subclass 3a, and is largely absent from other HDL classes [5, 8]. Beyond its well-established association with kidney disease, APOL1 plays a key role in lipid metabolism, particularly as a structural component of high-density lipoprotein (HDL) particles. APOL1 is primarily secreted by the liver and circulates in HDL subclass 3a, where it participates in the reverse cholesterol transport (RCT) pathway, promoting cholesterol efflux from macrophages and peripheral tissues toward the liver for excretion. Variants in APOL1 (G1 and G2), although evolutionarily selected for their protective role against Trypanosoma brucei rhodesiense, may alter HDL composition and function, leading to reduced anti-atherogenic capacity. This dysfunction could contribute to endothelial injury, vascular inflammation, and accelerated atherosclerosis in carriers of APOL1 risk alleles, potentially linking renal and cardiovascular pathogenesis within the same genetic framework. While findings remain partially inconsistent – some studies not demonstrating a direct causal link – emerging evidence supports that APOL1 variants may impair HDL-mediated cholesterol trafficking and anti-inflammatory functions, offering a unifying explanation for the increased cardiovascular and renal risk in individuals of African ancestry. Understanding this dual role of APOL1 in both lipid handling and kidney injury may help nephrologists interpret the broader systemic implications of APOL1 genotypes and design integrated approaches to patient care (Figure 1) [15].

Schematic representation of the role of APOL1 in high-density
Figure 1. Schematic representation of the role of APOL1 in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport. APOL1, primarily secreted by the liver, is incorporated into HDL3a particles that mediate cholesterol efflux from macrophages to the liver. APOL1 risk variants (G1, G2) may alter HDL composition, impair cholesterol trafficking, and reduce its anti-atherogenic capacity, contributing to endothelial injury, vascular inflammation, and increased cardio-renal risk.

The APOL1 protective effect against Trypanosoma brucei rhodesiense explains the high frequency of APOL1 risk variants in sub-Saharan Africa [4, 8, 10]. Thomson et al. found that the G1 variant of the APOL1 gene was most prevalent in West Africa, while the G2 variant was distributed more evenly across the globe [3, 5]. Genetic variation in the APOL1 gene is a major contributor to the disparity in non-diabetic kidney disease rates between African Americans and European Americans. Approximately 30% of African Americans chromosomes carry either the G1 or G2 APOL1 allele, which are mutually exclusive on single chromosomes. Around 10-12% of African Americans inherit two APOL1 risk alleles, while 49% lack any risk variants. In contrast, these risk variants are infrequent in European Americans, with roughly 0.3% carrying the G1 allele and 0.1% carrying the G2 allele [4]. The G1 allele was found in approximately 40% of Yoruba (West Africa) chromosomes but was absent in European, Japanese, and Chinese individuals. Similarly, G2 was detected in only three Yoruba subjects and not in the other groups [6]. North American studies have reported APOL1 allele frequencies between 20% and 39%, while Asian and some Latin American studies have shown considerably lower frequencies, ranging from 1.9% to 9.4% (Figure 2) [3].

Global prevalence of APOL1 risk variants (G1 and G2)
Figure 2. Global prevalence of APOL1 risk variants (G1 and G2). The map illustrates regional differences in APOL1 allele frequencies: dark red (>30%) in Sub-Saharan Africa, orange (10-30%) in North America and Afro-descendant regions, yellow (1-9%) in some Latin American populations, and light grey (<1%) in Europe, Asia, and Oceania. This distribution reflects the evolutionary pressure exerted by Trypanosoma brucei rhodesiense exposure.

 

APOL1 and kidney disease

APOL1 gene variants in African Americans significantly increase the risk of hypertensive kidney disease, lupus nephritis, sickle cell nephropathy, focal segmental and global glomerulosclerosis, characterized by interstitial scarring and arteriolar changes, and HIV-associated collapsing glomerulosclerosis [3–12]. In Afro-descendant patients with chronic kidney disease, the prevalence of APOL1 gene mutations is 20-22% for the G1 variant and 13-15% for the G2 variant [3].

In the population-based Dallas Heart Study, APOL1 risk variants were associated with an increased prevalence of microalbuminuria and a decreased glomerular filtration rate among African American participants. However, no statistically significant difference in proteinuria or estimated glomerular filtration rate was observed between individuals with two APOL1 nephropathy risk variants and those with less than two [7].

In kidney transplant patients, no significant difference in renal allograft survival was observed between recipients of kidneys from donors carrying one APOL1 nephropathy risk variant and those receiving kidneys from donors without such variants, while it was found significantly reduced renal allograft survival in recipients of deceased donor kidneys from African Americans with two APOL1 nephropathy risk variants compared to those receiving kidneys from African American donors with fewer than two risk variants [4]. Additionally, it has been suggested that APOL1 expression across podocytes, endothelial cells, and immune cells may independently or synergistically contribute to the complex pathogenic processes affecting renal allograft survival [12]. Recent evidence also suggests that APOL1 variants may influence cardiovascular risk beyond their established renal effects. As a structural component of high-density lipoproteins (HDL), APOL1 participates in reverse cholesterol transport, facilitating cholesterol efflux from peripheral macrophages to the liver. Alterations in APOL1 structure or expression could impair HDL function, potentially reducing its anti-atherogenic capacity. This dysfunctional HDL phenotype may contribute to endothelial injury, vascular inflammation, and accelerated atherosclerosis in APOL1 risk allele carriers. Although the literature remains inconsistent – some studies failing to confirm a direct causal relationship – the possibility of a link between APOL1 variants, altered lipid metabolism, and cardiovascular disease warrants further investigation [13].

 

APOL1 damaging mechanisms

It has been hypothesized several potential mechanisms by which APOL1 variants may induce nephropathy in native kidneys:

  • The APOL1 protein present in individuals homozygous for APOL1 risk alleles, may exhibit reduced HDL binding, leading to its filtration and reabsorption within the proximal nephron, culminating in kidney damage. In this sense, circulating APOL1 has been implicated in recurrent focal segmental glomerulosclerosis post-transplantation, a condition responsive to plasmapheresis [4].
  • Abnormal HDL levels may contribute to renal microvascular disease, frequently observed in focal segmental glomerulosclerosis and hypertension-attributed end-stage renal disease [4].
  • The requirement of two APOL1 risk alleles for phenotype development may be explained by a multimerization model. This model proposes that wild-type APOL1 interacts with an unknown factor to antagonize APOL1 toxicity. In the presence of a single APOL1 risk allele, the formation of APOL1 multimers containing at least one wild-type subunit is sufficient to maintain the inhibitory binding of the toxicity-blocking factor. Conversely, when two risk alleles are present, multimers predominantly lack wild-type APOL1, leading to the manifestation of toxicity [8].
  • APOL1 podocyte expression may result in cellular dysfunction or injury. Given APOL1 structural and functional similarities to the Bcl2 family of apoptosis-related proteins, APOL1-induced podocyte apoptosis could lead to glomerulosclerosis. These pathways could contribute to subclinical APOL1-associated kidney disease in native kidneys, as well as to graft dysfunction post-donation in the context of cold ischemia and nephrotoxic agents, such as calcineurin inhibitors [4].
  • Since nephropathy does not manifest in all individuals who present two APOL1 risk variants inheritance, this suggests that additional genetic and/or environmental factors (second hit) are necessary for developing this disease. This ‘second hit’ may interact with APOL1 risk variants, resulting in renal damage. For example, the presence of HIV infection (60-70% HIV-associated collapsing focal segmental glomerulosclerosis carry the high-risk APOL1 genotype) or variations within the podocin gene (NPHS2) may represent second hits [7]. Another potential ‘second hit’ is serum suPAR, a predictive biomarker for kidney disease in individuals with the high-risk APOL1 genotype, which could bind podocyte integrins and APOL1, potentially leading to renal damage [8].
  • Interferon treatment in some individuals with this genotype has induced proteinuria and focal segmental glomerulosclerosis. These findings strongly suggest that viral infections, by an interferon-mediated mechanism, are a crucial second hit for kidney disease development. Interferon strongly induces APOL1 RNA and protein expression in cultured human podocytes and endothelial cells, due to multiple STAT-binding sites on APOL1 regulatory regions [8].
  • It has been proposed that risk variant APOL1-induced toxicity is mediated by impaired late endosome-lysosome fusion (a VAMP8-mediated process), and subsequent disruption of autophagy flux [8].
  • APOL1 variants mediate kidney disease pathogenesis by exerting ion channel activity, consequently resulting in the NLRP3 upregulated activation as cytotoxicity mediator and STING function as immune mediators inducer, both of which are nephropathy determinants (Figure 3) [12].
APOL1 Damaging Mechanisms.
Figure 3. APOL1 Damaging Mechanisms.

 

APOL1 and pre-eclampsia

The life course of APOL1-related disease may begin in utero. In the CKiD and NEPTUNE cohorts, children carrying APOL1 risk variants (RVs) showed a higher likelihood of preterm birth. Although population studies do not confirm a general association between APOL1 and preterm delivery, fetal APOL1 RVs have been linked to an increased maternal risk of pre-eclampsia, particularly among U.S.-born women, suggesting that environmental factors may modulate this risk. Some evidence indicates an additive effect, where even a single maternal APOL1 RV increases susceptibility, but the highest risk occurs when the fetus carries a high-risk APOL1 genotype; mismatches between maternal and fetal genotypes may further influence outcomes. This association likely reflects the high placental expression of APOL1, as demonstrated in transgenic mice, where APOL1 expression in the placenta induced a pre-eclampsia-like phenotype – even in wild-type dams carrying APOL1-positive fetuses. Additionally, fetal APOL1 RVs have been associated with small-for-gestational-age infants in pre-eclamptic pregnancies. Collectively, these findings suggest that APOL1 genotyping could serve as a risk-stratification tool for pregnant women of African ancestry, and that pre-eclampsia or preterm birth might act as second hits predisposing to early-onset kidney disease in childhood [14].

 

APOL1 treatment

The growing understanding of the molecular basis of APOL1-mediated nephropathy has fostered the development of several targeted therapeutic strategies aimed at reducing APOL1 expression, inhibiting its cytotoxic function, and modulating downstream inflammatory pathways [10]. These interventions are grounded in the observation that APOL1-induced injury is driven by elevated expression and aberrant channel activity of the high-risk G1 and G2 variants, which promote podocyte dysfunction, inflammation, and cell death. Therefore, reducing APOL1 levels or blocking its pore-forming activity is hypothesized to attenuate the initial pathogenic cascade. Among the most advanced compounds is Inaxaplin (VX-147), a small-molecule inhibitor designed to block APOL1 pore function and prevent cationic dysregulation within podocytes. In a Phase 2 study [15] treatment with Inaxaplin in patients carrying two APOL1 risk variants and focal segmental glomerulosclerosis resulted in a clinically meaningful reduction in proteinuria after 13 weeks, suggesting that selective inhibition of APOL1 function may slow the progression of nephropathy and potentially redefine the therapeutic approach for genetically determined glomerular disease. In parallel, antisense oligonucleotides (ASOs) targeting APOL1 mRNA have demonstrated preclinical efficacy by silencing APOL1 gene expression, thereby reducing the accumulation of toxic protein in podocytes and mitigating kidney injury [16]. This gene-specific strategy directly addresses the pathogenic source and may complement small-molecule inhibitors in patients with high-risk genotypes. Beyond direct APOL1 modulation, recent findings highlight the potential of downstream pathway inhibition. Wu et al. identified both the NLRP3 inflammasome and the STING (stimulator of interferon genes) signaling pathway as critical effectors operating downstream of APOL1 channel activity within podocytes. Inhibiting STING may represent a particularly promising strategy, given its role in amplifying interferon production, which in turn induces APOL1 overexpression and perpetuates cellular toxicity. STING blockade, therefore, could interrupt this pathogenic feedback loop and limit the inflammatory milieu driving APOL1-associated renal damage. Similarly, pharmacologic inhibition of NLRP3 inflammasome activation may attenuate pyroptosis and inflammatory cytokine release, thereby preserving podocyte viability [17].

Other approaches under investigation include JAK-STAT pathway inhibitors, such as baricitinib, which suppress cytokine-driven APOL1 transcription and have shown beneficial effects in experimental models of inflammatory podocytopathy. Collectively, these strategies reflect a multifaceted therapeutic paradigm – ranging from direct genetic and molecular inhibition of APOL1 to modulation of its downstream signaling effectors [18]. While most agents remain in early clinical or preclinical phases, these emerging data collectively underscore a paradigm shift in the management of APOL1-associated kidney diseases – from non-specific immunosuppression toward precision nephrology, grounded in genetic stratification and mechanistic understanding (Table 1). The integration of APOL1 genotyping into clinical practice will be crucial for patient selection and for guiding the application of these novel therapies, ultimately improving renal outcomes and addressing long-standing health disparities in populations of African ancestry.

Agent Mechanism/Target Development Phase Key Reference(s)
Inaxaplin (VX‑147) Small-molecule APOL1 function/pore inhibitor; reduces proteinuria Phase 2/3 Egbuna et al., N Engl J Med 2023
APOL1 Antisense Oligonucleotide APOL1 mRNA silencing (reduces APOL1 expression) Preclinical/early clinical Aghajan et al., JCI Insight 2019
Baricitinib (JAK inhibitor) Blocks cytokine-induced JAK-STAT signaling and APOL1 upregulation Experimental/repurposing Nystrom et al., JCI Insight 2022
STING pathway inhibitors Attenuate interferon-stimulated APOL1 expression and inflammatory signaling Preclinical Wu et al., Immunity 2021
NLRP3 inflammasome blockers Inhibit inflammasome activation/pyroptosis downstream of APOL1 Preclinical Wu et al., J Clin Invest 2021
Table 1. Drugs under investigation for APOL1-mediated kidney disease.

 

Transplant implications

In the context of kidney transplantation, donor APOL1 genotype has emerged as a more consistent predictor of allograft outcomes than recipient genotype, particularly with respect to long-term graft survival. Several cohorts have shown that kidneys procured from deceased African American donors who carry two APOL1 renal-risk alleles display a significantly shorter allograft survival, even after adjusting for donor age, cold ischemia time, and HLA matching [19]. In contrast, the recipient’s APOL1 risk status has not reliably correlated with five-year graft loss in most studies, suggesting that the intrinsic “health” of the graft – shaped by donor APOL1 expression – is the critical determinant. Case reports further support the donor-risk paradigm: Chang et al. described instances of de novo collapsing focal segmental glomerulosclerosis (FSGS) occurring in recipients of kidneys from donors later found to harbor two high-risk APOL1 alleles. In several of those cases, viral infections (e.g. CMV or BK viremia) served as plausible “second hits”, triggering glomerular injury in a graft already genetically predisposed. These findings reinforce a “two-hit” model of APOL1 injury, wherein a high-risk donor background requires additional stressors to precipitate overt graft disease [20]. Because of this evidence, transplant programs increasingly consider APOL1 genotyping in donor evaluation, especially among donors of African ancestry. Some guidelines recommend counseling recipients about the increased graft risk when the donor carries a high-risk genotype [21]. However, the use of APOL1 genotyping in recipient decision-making remains controversial: the presence of the risk alleles in recipients has not consistently translated into worse short- or intermediate-term allograft survival across studies. Going forward, large-scale prospective studies (such as the APOLLO (APOL1 Long-term Kidney Transplantation Outcomes) study) are poised to clarify the magnitude of risk conferred by donor APOL1 status and to refine allocation strategies that balance graft utility with equity [22]. Meanwhile, the evidence supports that donor high-risk APOL1 genotype should be considered a relevant risk factor in transplant planning, while recipient genotyping must be interpreted with caution and in the context of broader immunologic, hemodynamic, and environmental influences.

 

Discussion

Testing for APOL1 genetic variants is recommended in selected clinical scenarios where the results may clarify diagnosis, prognosis, or influence management decisions. The strongest indications include unexplained non-diabetic proteinuric chronic kidney disease (CKD), particularly in patients of African ancestry with focal segmental glomerulosclerosis (FSGS) or glomerulosclerosis on biopsy without another clear etiology; HIV-associated nephropathy (HIVAN) or other forms of collapsing glomerulopathy, in which APOL1 high-risk genotypes markedly increase disease susceptibility and accelerate progression; early-onset CKD or a family history of ESRD in individuals of African or Afro-Caribbean descent, where APOL1 testing can assist in genetic counseling and risk stratification; and evaluation of living kidney donors of African ancestry, as donor – but not recipient – APOL1 genotype has been linked to long-term allograft survival. Routine population screening is not currently recommended, as the majority of individuals carrying two risk alleles do not develop kidney disease, highlighting the influence of “second-hit” factors such as viral infections, interferon exposure, or inflammatory stressors. Nonetheless, APOL1 testing is increasingly integrated into precision nephrology programs, helping clinicians tailor surveillance, manage secondary risk factors, and inform transplant counseling [23]. Interpretation of APOL1 genotyping requires a nuanced understanding of its probabilistic – not deterministic – nature. The presence of a high-risk genotype, defined by two risk alleles (G1/G1, G2/G2, or G1/G2), substantially increases the probability and rate of CKD progression, particularly in non-diabetic etiologies such as focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, and HIV-associated nephropathy. However, penetrance is incomplete: only a fraction (≈15-20%) of high-risk individuals develop clinically evident kidney disease, underscoring the importance of environmental and inflammatory “second hits” – for instance, viral infections, interferon exposure, or ischemic injury – that interact with the genetic background to precipitate renal damage. APOL1 results must always be interpreted in conjunction with histopathologic findings, clinical phenotype, and comorbid conditions. A biopsy can delineate specific glomerular lesions (e.g., collapsing FSGS, microvascular changes) that support APOL1-mediated pathology, while clinical context – such as hypertension, diabetes, or viral infection – helps differentiate genetic susceptibility from acquired injury. In transplant settings, donor high-risk status predicts reduced allograft survival, whereas recipient genotype alone does not consistently correlate with five-year graft outcomes. APOL1 genotyping refines risk stratification rather than providing a binary diagnosis. Its optimal use lies in integrated interpretation, combining genetic, histologic, and clinical dimensions to inform prognosis, surveillance intensity, and therapeutic decision-making – especially within precision nephrology and transplant counseling frameworks [24]. Genetic counseling for individuals tested for APOL1 risk variants should emphasize that the high-risk genotype confers susceptibility but not certainty of disease. Incomplete penetrance must be clearly explained to avoid undue anxiety or stigma. Counseling should also address ethical and psychosocial implications, including potential effects on insurability, employability, and family planning, which vary across jurisdictions and regulatory frameworks. Importantly, patients should be encouraged to focus on modifiable risk factors that can mitigate disease expression, such as optimal blood pressure control, renin-angiotensin-aldosterone system (RAAS) inhibition, and dietary sodium and protein moderation. Incorporating APOL1 education into broader CKD prevention programs can foster informed decision-making while minimizing genetic discrimination and promoting equitable access to testing and follow-up care [25].

In addition, we have reviewed the most recent literature on genetic testing in CKD and glomerular disease [26]. On this basis, we now propose a set of clear indications for practicing nephrologists facing isolated patients affected by CKD or specific nephropathies, which we have summarized in Box 1. This recommendation is based on the following factors, Prognosis / risk stratification, In Elliott et al. 2024 [26], both monogenic diagnoses (6.5% of patients) and high-risk APOL1 genotypes (5.5%) independently predicted faster eGFR decline and higher kidney failure risk [26]. Actionability, NKF 2024 consensus says nephrologists should actively integrate genetic testing into routine evaluation of suspected hereditary nephropathies, into donor assessment, and into longitudinal care planning, and provide algorithms for symptomatic and at-risk individuals [27]. Clinical utility in real-world CKD: A large prospective CKD panel study (>1,600 adults; RenaCARE) showed that ~21% had a positive genetic finding; in ~49% of those, the genetic result replaced or reclassified the working diagnosis, and physicians reported it changed management in >90% [28].

 

BOX 1. When should a clinical nephrologist order genetic testing?

  1. CKD with unclear or atypical etiology (test broadly).
  • Adults or children whose routine clinical, serologic and imaging work-up does not yield a clear cause (“CKD of unknown etiology”).
  • Includes patients with descriptive biopsy labels only (e.g. “FSGS”, “interstitial nephritis”, “nephrosclerosis”) without an upstream driver.
  • In the 5,727-patient cohort of Elliott et al. [26], a monogenic kidney disorder was found in 6.5% and a high-risk APOL1 genotype in 5.5%, and both were independently associated with higher kidney-failure risk (HR 1.72 and 1.67, respectively). Early genetic diagnosis therefore refines prognosis and therapy [29].

2. When a monogenic kidney phenotype is suspected.

2a. Stereotyped phenotypes with well-defined genes

  • Persistent hematuria ± deafness/ocular signs → suspect COL4A3–COL4A5 (Alport spectrum).
  • Steroid-resistant, collapsing or recurrent FSGS (child or young adult).
  • Cystic kidney disease not fully compatible with “typical” late-onset ADPKD.
  • CAKUT, especially bilateral or syndromic in pediatrics [27].

2b. Early-onset disease

  • CKD/proteinuria/hematuria/HTA before 30-40 yrs without another explanation, higher monogenic yield across all 3 JCI 2024 cohorts and in 2025 frameworks [29].

2c. Kidney-plus presentations

  • Kidney disease plus neurosensory, skeletal, endocrine, metabolic, neurologic, ocular or developmental features, think single-gene or ciliopathy [30].
  1. Positive family history.
  • ≥1 first or second degree relative with CKD, ESKD or transplant [29].
  1. APOL1 testing in ancestry or phenotype appropriate patients.
  • West African, Afro-Caribbean, African-American, Afro-Latin ancestry and collapsing FSGS or FSGS-like lesions, disproportionately aggressive “hypertensive” CKD or rapid eGFR loss.
  • In living donor evaluation in these ancestries, as recommended by the NKF working group (2024) and reiterated in 2025 updates and the KDIGO APOL1 conference report [27].
  1. Before accepting a related living kidney donor when hereditary disease is suspected.
  • Donors biologically related to a recipient with proven or suspected COL4A, UMOD, PKD, or APOL1 mediated kidney disease should do targeted testing (familial variant or APOL1). This is now part of responsible donor evaluation in NKF 2024/2025 and in recent donor-genetics reviews [31].
  1. When the molecular result changes management.
  • To start a gene- or pathway-directed therapy (complement, CoQ10, RNAi, upcoming APOL1 drugs).
  • To stop futile immunosuppression in monogenic podocytopathies
  • To anticipate recurrence post-transplant and to organize cascade testing in the family [29].
  1. Pediatric CKD
  • In children 30-50% of CKD can be genetic (CAKUT, podocyte, ciliopathy, metabolic), so a broad exome is recommended [32].

Note: The most recent evidence (KDIGO 2024 on CKD evaluation, the NKF 2024/2025 report on genetics in nephrology, and 2025 studies combining exome sequencing with polygenic risk scores, PRS) shows that even in “unselected” CKD cohorts clinically actionable genetic findings are identified in ≈20% of patients. Together with the ongoing reduction in sequencing costs and the emergence of targeted mechanism based therapies (APOL1 inhibitors, complement directed drugs, CoQ10 pathway defects, etc), this strongly suggests that the threshold for ordering genetic studies will decrease in the near future.

 

Conclusion

The increased susceptibility to end-stage renal disease (ESRD) in individuals of African ancestry is influenced by variations in the APOL1 gene. While the precise molecular pathways leading to renal damage are still being investigated, current theories suggest that these variants may exert their effects through mechanisms such as altered cellular ion transport, mitochondrial dysfunction, and the requirement for additional stressors or “second hits”. The ongoing investigation into these complex mechanisms is crucial, as it directly informs the development of targeted therapies. Promising interventions, including agents that directly modulate APOL1 protein activity or inhibit downstream inflammatory cascades, offer the potential to mitigate disease progression and address the significant health disparities observed in APOL1-associated kidney disease. APOL1 genotyping represents a pivotal step toward precision nephrology, linking genetic risk with targeted prevention and emerging therapies. While a high-risk genotype increases susceptibility to kidney injury, its expression depends on environmental and clinical modifiers, underscoring the need for integrated interpretation and personalized management. Ongoing translational research and clinical trials promise to transform APOL1 from a genetic marker of risk into a therapeutic target, bridging discovery and clinical care for populations most affected by kidney disease.

 

Bibliography

  1. Chen TK, Coresh J, Daya N, Ballew SH, Tin A, Crews DC, Grams ME. Race, APOL1 Risk Variants, and Clinical Outcomes among Older Adults: The ARIC Study. J Am Geriatr Soc. 2021 Jan;69(1):155-163. https://doi.org/10.1111/jgs.16797.
  2. Perez JPZ, Torres JV, Suárez MRU, Ochoa MPP, Hoyos GA, Henao OO. Modelo ideal de nefroprevención para Colombia: Ideal nefroprevention model for Colombia. Rev Colomb Nefrol. 2021 Aug 18;8(3):e431– https://doi.org/10.22265/acnef.8.3.431.
  3. Duran CE, Ramírez A, Posada JG, Schweineberg J, Mesa L, Pachajoa H, Estacio M, Manzi E, Aros V, Díaz L, Garcia VH. Prevalence of APOL1 Risk Variants in Afro-Descendant Patients with Chronic Kidney Disease in a Latin American Country. Int J Nephrol. 2019 Dec 18;2019:7076326. https://doi.org/10.1155/2019/7076326. Erratum in: Int J Nephrol. 2020 Nov 17;2020:8706297. https://doi.org/10.1155/2020/8706297.
  4. Reeves-Daniel AM, DePalma JA, Bleyer AJ, Rocco MV, Murea M, Adams PL, Langefeld CD, Bowden DW, Hicks PJ, Stratta RJ, Lin JJ, Kiger DF, Gautreaux MD, Divers J, Freedman BI. The APOL1 gene and allograft survival after kidney transplantation. Am J Transplant. 2011 May;11(5):1025-30. https://doi.org/10.1111/j.1600-6143.2011.03513.x.
  5. Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011 Nov;22(11):2129-37. https://doi.org/10.1681/ASN.2011040388.
  6. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010 Aug 13;329(5993):841-5. https://doi.org/10.1126/science.1193032.
  7. Freedman BI, Langefeld CD, Turner J, Núñez M, et al. Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease. Kidney Int. 2012 Oct;82(7):805-11. https://doi.org/10.1038/ki.2012.217.
  8. Beckerman P, Susztak K. APOL1: The Balance Imposed by Infection, Selection, and Kidney Disease. Trends Mol Med. 2018 Aug;24(8):682-695. https://doi.org/10.1016/j.molmed.2018.05.008.
  9. Markowitz GS, Nasr SH, Stokes MB, D’Agati VD. Treatment with IFN-α, -ß, or -δ is associated with collapsing focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010 Apr;5(4):607-15. https://doi.org/10.2215/CJN.07311009. Epub 2010 Mar 4. Erratum in: Clin J Am Soc Nephrol. 2010 Jul;5(7):1353.
  10. Vivante A. Genetics of Chronic Kidney Disease. N Engl J Med. 2024 Aug 15;391(7):627-639. https://doi.org/10.1056/NEJMra2308577. PMID: 39141855.
  11. Gbadegesin RA, Ulasi I, Ajayi S, Raji Y, et al; H3Africa Kidney Disease Research Network. APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans. N Engl J Med. 2025 Jan 16;392(3):228-238. https://doi.org/10.1056/NEJMoa2404211.
  12. Bruggeman LA, Azhibekov T, O’Toole JF. Moving Toward a Common Pathogenic Mechanism and Therapeutic Targets for APOL1 Nephropathies. Am J Kidney Dis. 2022 Jun;79(6):901-903. https://doi.org/10.1053/j.ajkd.2022.02.011.
  13. Cubedo J, Padró T, Alonso R, Mata P, Badimon L. ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia. J Lipid Res. 2016 Jun;57(6):1059-73. https://doi.org/10.1194/jlr.P061598.
  14. Itoku A, Isaac J, Wilson S, Reidy K, Kaskel F. APOL1 Nephropathy Risk Variants Through the Life Course: A Review. Am J Kidney Dis. 2024 Jul;84(1):102-110. https://doi.org/10.1053/j.ajkd.2023.12.014.
  15. Egbuna O, Chertow GM. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. Reply. N Engl J Med. 2023 Jun 29;388(26):2491. https://doi.org/10.1056/NEJMc2304780. PMID: 37379148
  16. Aghajan M, Booten SL, Althage M, Hart CE, wt al. Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1-transgenic mice. JCI Insight. 2019 Jun 20;4(12):e126124. https://doi.org/10.1172/jci.insight.126124.
  17. Wu J, Raman A, Coffey NJ, Sheng X, et al. The key role of NLRP3 and STING in APOL1-associated podocytopathy. J Clin Invest. 2021 Oct 15;131(20):e136329. https://doi.org/10.1172/JCI136329. PMID: 34651582; PMCID: PMC8516463
  18. Nystrom SE, Li G, Datta S, Soldano KL, Silas D, Weins A, Hall G, Thomas DB, Olabisi OA. JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight. 2022 Jun 8;7(11):e157432. https://doi.org/10.1172/jci.insight.157432.
  19. Freedman BI, Moxey-Mims MM, Alexander AA, et al. APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale. Kidney Int Rep. 2019 Dec 13;5(3):278-288. https://doi.org/10.1016/j.ekir.2019.11.022.
  20. Chang JH, Husain SA, Santoriello D, Stokes MB, Miles CD, Foster KW, Li Y, Dale LA, Crew RJ, Cohen DJ, Kiryluk K, Gharavi AG, Mohan S. Donor’s APOL1 Risk Genotype and “Second Hits” Associated With De Novo Collapsing Glomerulopathy in Deceased Donor Kidney Transplant Recipients: A Report of 5 Cases. Am J Kidney Dis. 2019 Jan;73(1):134-139. https://doi.org/10.1053/j.ajkd.2018.05.008.
  21. Merle JL, Kuo MC, Gacki-Smith J, Agrawal A, Friedewald J, Gordon EJ, Smith JD. Contextual factors of implementing APOL1 genetic testing into living kidney donor clinical evaluation. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2025 Jul;68(7):758-768. https://doi.org/10.1007/s00103-025-04068-8. Epub 2025 Jun 11. PMID: 40498120; PMCID: PMC12254160.
  22. Ojo AO, Adu D, Bramham K, Freedman BI, Gbadegesin RA, Ilori TO, Jefferson N, Olabisi OA, Susztak K, Young BA, Cheung M, King JM, Grams ME, Jadoul M, Ulasi II; Conference Participants. APOL1 kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2025 Jun 23:S0085-2538(25)00429-6. https://doi.org/10.1016/j.kint.2025.05.017. Epub ahead of print. PMID: 40582702
  23. Bruggeman LA, Azhibekov T, O’Toole JF. Moving Toward a Common Pathogenic Mechanism and Therapeutic Targets for APOL1 Nephropathies. Am J Kidney Dis. 2022 Jun;79(6):901-903. https://doi.org/10.1053/j.ajkd.2022.02.011. Epub 2022 Feb 28. PMID: 35240248
  24. Freedman BI, Limou S, Ma L, Kopp JB. APOL1-Associated Nephropathy: A Key Contributor to Racial Disparities in CKD. Am J Kidney Dis. 2018 Nov;72(5 Suppl 1):S8-S16. https://doi.org/10.1053/j.ajkd.2018.06.020.
  25. Rasmussen LV, Agrawal AH, Botsford P, Powers A, Schnoebelen J, Xinos S, Harper G, Thanner J, McCabe S, Moore S, Wicklund CA, Duquette D, Gordon EJ. Challenges of Integrating APOL1 Genetic Test Results into the Electronic Health Record. Appl Clin Inform. 2023 Mar;14(2):321-325. https://doi.org/10.1055/s-0043-1767680. Epub 2023 Apr 26. PMID: 37186083; PMCID: PMC10132929.
  26. Elliott MD, Vena N, Marasa M, Cocchi E, Bheda S, Bogyo K, et al; CureGN Consortium. Increased risk of kidney failure in patients with genetic kidney disorders. J Clin Invest. 2024 Sep 3;134(17):e178573. https://doi.org/10.1172/JCI178573. PMID: 39225089; PMCID: PMC11364380.
  27. https://www.kidney.org/press-room/national-kidney-foundation-unveils-recommendations-genetic-testing-kidney-disease.
  28. Dahl NK, Bloom MS, Chebib FT, Clark D, Westemeyer M, et al. The Clinical Utility of Genetic Testing in the Diagnosis and Management of Adults with Chronic Kidney Disease. J Am Soc Nephrol. 2023 Dec 1;34(12):2039-2050. https://doi.org/10.1681/ASN.0000000000000249.
  29. Lin MR, Wu IW, Chou WH, Lin YF, Hung KY, Kojima K, Shido K, Kinoshita K, Chang WC, Wu MS. Whole exome sequencing and polygenic risk assessment for kidney functions and clinical management in both hospital-based cohort and population-based Asian cohorts. J Biomed Sci. 2025 Aug 6;32(1):72. https://doi.org/10.1186/s12929-025-01168-0. PMID: 40770708; PMCID: PMC12330128.
  30. Naama Elefant, Maddalena Marasà, Hila Milo Rasouly. Beyond Kidney Genes: Broad Clinical Implications of Genetic Testing for Nephrology Patients. Seminars in Nephrology, Volume 45, Issue 4, 151660. https://doi.org/10.1016/j.semnephrol.2025.151660.
  31. Franceschini, D.L. Feldman, et al. Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group. American Journal of Kidney Diseases, Volume 84, Issue 6, 751 – 766. https://doi.org/10.1053/j.ajkd.2024.05.010.
  32. Abraham W Aron, Neera K Daahl. Clinical Genetic Testing in Nephrology: Core Curriculum 2024. American Journal of Kidney Diseases, Volume 84, Issue 5, 632 – 645. https://doi.org/10.1053/j.ajkd.2024.05.011.

Bidirectional Interaction Between the Gastrointestinal System and the Kidney: Pathophysiological and Clinical Perspective

Posted on Scarica PDF

DOI: 10.69097/43-01-2026-09

Emre Leventoğlu1, Derya Cevizli1, Yavuz Emre Parlar2

1 Konya City Hospital, Department of Pediatric Nephrology, Konya, Turkey
2 Sincan Training and Research Hospital, Department of Gastroenterology, Ankara, Turkey

Corresponding author:
Emre Leventoğlu, MD
Address: Konya City Hospital, Department of Pediatric Nephrology, Konya, Turkey
Phone: +90 332 310 50 00, +90 506 608 66 86
E-mail: dremrelevent@gmail.com

 

Abstract

The gastrointestinal (GI) system and the kidneys, though anatomically separate, are functionally interconnected through shared responsibilities in maintaining fluid-electrolyte balance, acid-base homeostasis, immune regulation, and hormonal signaling. Disruptions in one system often lead to secondary complications in the other, highlighting the need for a comprehensive understanding of their bidirectional interactions. Kidney involvement in GI diseases commonly results from mechanisms such as fluid loss, malabsorption, systemic inflammation, and exposure to toxins, as seen in conditions like inflammatory bowel disease (IBD), celiac disease, liver failure, and enteric infections. Conversely, GI complications frequently arise in the context of chronic kidney disease (CKD), dialysis, and immunosuppressive therapies post-transplantation, manifesting as symptoms including uremic gastropathy, anorexia, and enteropathy. This review explores these interactions under two main categories: renal complications of GI diseases and GI manifestations of kidney disorders. It also discusses the underlying pathophysiological mechanisms and clinical implications, emphasizing the importance of an integrated, multidisciplinary approach. By highlighting current knowledge gaps, the review aims to foster future research in this complex and clinically significant area. Understanding these bidirectional interactions can inform individualized patient care and improve outcomes in both GI and renal disease contexts.

Keywords: Gastrointestinal system, Kidney diseases, Gut-kidney axis

Overview of Gastrointestinal System and Kidney Interactions

The gastrointestinal (GI) system and kidneys are two distinct systems that play critical roles in maintaining intracorporeal homeostasis. Although there is no direct anatomical connection between these systems, there is a close cooperation through many physiological processes such as fluid-electrolyte balance, acid-base regulation, immune responses and hormonal signaling. Therefore, pathological conditions affecting one system can also influence the other [1]. This interaction is seen clinically in the form of kidney dysfunction that develops during GI diseases and GI complications that occur in kidney diseases [2].

Kidney involvement in GI diseases is often mediated by fluid and electrolyte loss, malabsorption, toxin exposure, or systemic inflammation. In particular, kidney function may be directly or indirectly affected in inflammatory bowel diseases (IBD), celiac disease, liver failure and enteric infections [3–6]. Similarly, the GI system can be significantly affected by kidney diseases. Complications such as uremic gastropathy, enteropathy and anorexia are common in patients with chronic kidney disease (CKD), and treatments such as hemodialysis and peritoneal dialysis may further exacerbate GI symptoms [7, 8]. In addition, post-transplant infections due to immunosuppression and drug side effects may also lead to GI complications [9, 10]. The main interactions between the GI system and the kidneys are shown in Figure 1.

In this review, kidney involvement in GI system diseases and GI complications arising in kidney diseases will be examined under two separate headings; the pathophysiological basis and clinical reflections of this interrelationship will be discussed (Table 1). The aim is to better understand these complex interactions in pediatric and adult patients and to draw attention to the importance of a multidisciplinary approach. It is also aimed to lay the groundwork for future research by revealing the knowledge gaps in these areas.

Bidirectional interactions between gastrointestinal system and the kidney.
Figure 1. Bidirectional interactions between gastrointestinal system and the kidney.
  Mechanisms of Kidney Involvement in GI Diseases
Upper GI System Disorders
GERD Use of PPI and associated ATIN
  Use of PPI and PPI-related nephropathy
H. pylori Infection Systemic inflammation induced by persistent infection
Immune complex-mediated kidney injury due to mucosal IgA secretion
  Metabolic disturbances such as insulin resistance and dyslipidemia due to H. pylori
Malabsorption Syndromes
Inflammatory Bowel Diseases Nephrolithiasis and nephrocalcinosis due to enteric hyperoxaluria
Glomerulonephritis due to antigen-specific immune responses
AKI and CKD due to systemic inflammation, medication toxicity, and malnutrition
Celiac Disease IgAN due to galactose-deficient IgA1
CKD due to increased intestinal permeability and immune activation
Diabetic nephropathy due to high prevalence of T1DM
Nephrolithiasis due to intestinal malabsorption or altered renal handling
UTI due to impaired urinary tract motility, dysfunction of the bladder, changes in gut microbiota
Liver Diseases
Primary Hyperoxaluria Nephrolithiasis/nephrocalcinosis and associated CKD due to hepatic enzyme deficiencies in glyoxylate metabolism
Wilson’s Disease Tubular dysfunctions due to copper deposition
Glomerular involvement due to immune complex-mediated mechanisms
Drug-induced nephrotoxicity caused by chelation therapy
Chronic Liver Disease Decreased kidney perfusion and reduced GFR due to splanchnic vasodilation, activation of RAAS system and sympathetic nervous system
Systemic inflammation due to impaired hepatic detoxification
Hepatorenal syndrome due to advanced liver disease
Enteric Infections
STEC-HUS Endothelial damage and subsequent thrombotic microangiopathy due to systemic dissemination of Shiga toxins
GI System Involvement in Kidney Diseases
Idiopathic Nephrotic Syndrome Edema of the bowel wall due to hypoalbuminemia
Mesenteric arterial thrombosis due to hypercoagulable state
Spontaneous bacterial peritonitis due to immunosuppression
Peptic ulcer disease and drug-related mucosal injury due to steroid therapy
Polycystic Kidney Disease Polycystic liver disease due to ADPKD
Congenital hepatic fibrosis due to ARPKD
Chronic Kidney Disease Uremic gastropathy or delayed gastric emptying due to uremia
GI bleeding due to mucosal fragility and platelet dysfunction
Abdominal discomfort or paralytic ileus due to bowel wall edema
Systemic inflammation due to translocation of endotoxins
Alterations in the gut microbiome (dysbiosis) due to uremia
Constipation due to restricted fluid intake, dietary limitations, and phosphate binders
Protein-energy wasting and deficiencies in essential nutrients due to decreased appetite
Kidney Replacement Therapies Hypotension-related gut hypoperfusion, mesenteric ischemia and colonic angiodysplasia-related bleeding due to hemodialysis
Increased intra-abdominal pressure, leading to early satiety, gastroesophageal reflux, abdominal fullness, or hernias due to peritoneal dialysis
Bacterial or sclerosing encapsulating peritonitis
Nausea, diarrhea, oral ulcers, and anorexia due to immunosuppressive therapy
Opportunistic infections due to immunosuppressive therapy
Table 1. Mechanisms of kidney involvement in GI system diseases and GI involvement arising in kidney diseases. GI: Gastrointestinal, GERD: Gastroesophageal reflux disease, PPI: Proton-pump inhibitor, ATIN: Acute tubulointerstitial nephritis, IgA: Immunoglobulin A, AKI: Acute kidney injury, CKD: Chronic kidney disease, IgAN: Immunoglobulin A nephropathy, T1DM: Type 1 diabetes mellitus, UTI: Urinary tract infection, GFR: Glomerular filtration rate, RAAS: Renin-angiotensin-aldosterone system, STEC-HUS: Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome, ADPKD: Autosomal dominant polycystic kidney disease, ARPKD: Autosomal recessive polycystic kidney disease.

 

Material and Methods

This article is a narrative review that examines the bidirectional interactions between the GI system and the kidneys, focusing on the underlying pathophysiological mechanisms and associated clinical outcomes, comprehensively reviewing of the current literature. Methodological rigor and principles of reproducibility were applied during both the literature selection and manuscript preparation processes. The literature search was conducted using the PubMed, Scopus, and Web of Science databases, covering publications from January 2000 to December 2024. Results were limited to studies published in English. The keywords and their combinations used were: “gastrointestinal system”, “kidney diseases”, “gut-kidney axis”, “renal replacement therapies”, and “microbiota”. The study included case reports and original research examining GI system findings or mechanisms in different stages of kidney disease, as well as review articles directly related to the topic. Publications and abstracts with limited relevance to the topic or that did not directly examine the kidney-GI relationship were excluded from the study.

In this narrative review, experimental studies such as animal models were used to understand potential biological pathways. While observational studies were evaluated to determine the relationships between the GI system and the kidneys in human populations, interventional studies provided the strongest evidence for potential effects. Unless supported by evidence from multiple study types, definitive causal statements were avoided, and neutral terms such as associated or linked were used.

 

Kidney Involvement in Gastrointestinal Diseases

Upper Gastrointestinal System Disorders

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is a common chronic condition characterized by the retrograde flow of gastric contents into the esophagus, resulting in symptoms such as heartburn, regurgitation, and, in some cases, esophagitis. The pathophysiology of GERD involves a combination of factors including lower esophageal sphincter dysfunction, impaired gastric emptying, and increased intra-abdominal pressure. GERD affects a significant proportion of the global population and often requires long-term pharmacological management, particularly with proton pump inhibitors (PPIs), which are the mainstay of treatment. Although PPIs are effective in controlling acid-related symptoms and healing mucosal damage, their long-term use has raised concerns regarding potential adverse effects, including those on kidney functions [11].

One of the most recognized renal complications associated with PPIs is acute tubulointerstitial nephritis (ATIN). In a pediatric study, 11.1% of patients with ATIN had a history of PPI use [12]. This is an immune-mediated hypersensitivity reaction characterized by interstitial inflammation and tubular injury. Clinically, PPI-induced ATIN may present with non-specific symptoms such as fatigue, nausea, or subtle kidney dysfunction, often leading to underdiagnosis. Histological confirmation through kidney biopsy typically reveals interstitial edema, lymphocytic infiltration, and eosinophils [12].

Recent studies have identified an association between chronic PPI use and an increased risk of CKD and kidney failure in adults. Although a direct causal relationship is still under investigation, repeated or subclinical episodes of ATIN, as well as PPI-induced alterations in magnesium homeostasis and gut microbiota, have been proposed as contributing mechanisms [13]. The risk of PPI-related nephropathy appears to be more pronounced in elderly patients, individuals with pre-existing kidney impairment, and those using PPIs for prolonged periods without appropriate clinical indication. Importantly, PPI-related kidney injury may be partially reversible if recognized early and the offending agent is discontinued [14].

These findings underscore the need for cautious and evidence-based prescribing of PPIs, emphasizing regular reassessment of their indication and duration. In patients requiring long-term acid suppression, kidney function should be periodically monitored, and alternative therapies may be considered when appropriate.

Helicobacter pylori Infection

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonizes the gastric mucosa and is a well-established cause of chronic gastritis, peptic ulcer disease, and gastric malignancies. Beyond its GI manifestations, H. pylori infection has been increasingly studied for its potential systemic effects, including those on kidney function [15].

Several epidemiological and experimental studies have suggested a link between chronic H. pylori infection and kidney impairment, although the exact mechanisms remain incompletely understood, and pediatric data are limited. One proposed pathway involves systemic inflammation induced by persistent infection. H. pylori stimulates the release of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, which may contribute to endothelial dysfunction and glomerular injury, particularly in individuals with pre-existing susceptibility [16]. A second pathway is the activation of the immune complex-mediated mechanism due to mucosal immunoglobulin A (IgA) secreted against H. pylori. Chronic H. pylori infection has been associated with the development of immune-mediated renal diseases, including IgA nephropathy (IgAN). Molecular mimicry and immune cross-reactivity between bacterial antigens and kidney tissues may play a role in this association [17]. In addition, H. pylori may contribute to metabolic disturbances such as insulin resistance and dyslipidemia, which are recognized risk factors for CKD [18]. Although a direct causal relationship has not been definitively established, the cumulative evidence indicates that chronic infection could act as a modifiable risk factor in the progression of kidney dysfunction [18]. Moreover, in kidney transplant recipients, H. pylori infection is of particular clinical relevance due to the immunosuppressed state, which may alter the typical presentation and increase the risk of GI complications such as peptic ulcer disease and bleeding. Additionally, chronic H. pylori infection may contribute to systemic inflammation, potentially affecting graft function and long-term outcomes. Some studies in adults have suggested that pre-transplant screening and eradication of H. pylori may reduce the incidence of post-transplant GI morbidity and support better kidney graft survival [19]. In a study evaluating adult patients with membranous nephropathy and H. pylori infection, the mean proteinuria value before eradication therapy was 2.42 ± 3.24 g/day, while three months after eradication therapy, the proteinuria level decreased to 1.26 ± 1.73 g/day (p = 0.031) [20]. In another study, a high urine albumin-to-creatinine ratio was detected in adult patients with H. pylori-positive peptic ulcers, and a significant 51.5% decrease in the albumin-to-creatinine ratio was observed in these patients after eradication therapy [21]. These results suggest that eradication therapy is beneficial in alleviating kidney damage and reducing the risk of CKD.

Overall, while further research is needed to clarify the causal pathways, current data highlight a possible connection between H. pylori infection and renal involvement through systemic inflammation, immune dysregulation, and metabolic derangement. These findings raise important considerations regarding the evaluation and management of H. pylori in patients with or at risk of kidney disease.

Malabsorption Syndromes

Inflammatory Bowel Diseases

Inflammatory bowel diseases (IBD), which include Crohn’s disease and ulcerative colitis, are chronic immune-mediated conditions of the GI tract. While ulcerative colitis is typically limited to the colon with continuous mucosal inflammation, Crohn’s disease may affect any segment of the GI tract and is characterized by transmural, patchy inflammation. IBD frequently begins in adolescence or early adulthood and follows a relapsing-remitting clinical course. Although primarily affecting the GI system, IBD is associated with numerous extraintestinal manifestations involving the skin, joints, eyes, liver, and kidneys. Several mechanisms contribute to kidney involvement in IBD, including metabolic disturbances related to malabsorption, drug-induced nephrotoxicity, immune-mediated glomerular disease, and structural complications such as nephrolithiasis and nephrocalcinosis [22].

Kidney involvement is increasingly recognized in children with IBD, yet remains underdiagnosed. One of the most clinically significant kidney complications is enteric hyperoxaluria, particularly in patients with Crohn’s disease involving the terminal ileum or those who have undergone ileal resection. Under normal physiological conditions, dietary calcium binds to oxalate in the intestinal lumen, forming insoluble complexes that are excreted in the feces. However, in IBD with fat malabsorption, unabsorbed fatty acids bind calcium, leaving oxalate unbound and more readily absorbed in the colon. This process is exacerbated by increased intestinal permeability and alterations in gut microbiota, particularly the depletion of Oxalobacter formigenes, a commensal bacterium that degrades oxalate. The result is enteric hyperoxaluria, which increases the risk of calcium oxalate nephrolithiasis and nephrocalcinosis. In chronic cases, nephrocalcinosis can lead to tubulointerstitial nephritis, interstitial fibrosis, and eventually CKD. Therefore, regular monitoring of kidney functions and urinary parameters is essential, especially in patients with extensive small bowel disease or surgical resections [23].

Emerging evidence suggests that glomerulonephritis (GN) in IBD may result either from antigen-specific immune responses originating in the inflamed gut or from shared genetic and environmental risk factors. GN appears both as an extraintestinal manifestation and as a potentially unrelated co-existing condition, with IgAN being the most frequently reported subtype. Although pediatric data are limited, the observed reduction in proteinuria with enteric budesonide therapy in adult patients with IgAN supports a pathogenic link between intestinal and kidney inflammation [24]. A study utilized bioinformatic and machine learning approaches to identify shared immune-infiltrating features, cross-talk genes, and pathways between IgAN and IBD using datasets from the Gene Expression Omnibus. Immune infiltration analyses revealed no major differences in immune cell profiles between the two diseases. Ten diagnostic cross-talk genes were identified, among which FDX1 and NFKB1 were notably elevated in the kidneys of IBD mouse models. Pathway analysis revealed 15 shared signaling pathways, highlighting lipid metabolism as a key contributor. These findings shed light on common immune mechanisms underlying IBD and IgAN, offering potential targets for further research [25].

The risk of acute kidney injury (AKI) and CKD is increased in IBD. The mechanisms underlying this association are not fully understood, but factors such as systemic inflammation, medication toxicity, and malnutrition may contribute. In an adult study assessing the prevalence of AKI and CKD in IBD, the results showed that individuals with IBD had a higher risk for both AKI (HR = 1.96) and CKD (HR = 1.57) compared to those without IBD, even after adjusting for demographic, lifestyle and health factors. Similar risks were found for Crohn’s disease and ulcerative colitis. Younger participants had stronger associations between IBD and kidney outcomes [26]. However, in another study, analyses based on genome-wide association data from individuals of European descent revealed that genetic predisposition to Crohn’s disease was significantly associated with an increased risk of CKD, while no such causal association was observed for ulcerative colitis. Furthermore, inverse Mendelian randomization analysis showed that genetic predisposition to CKD did not increase the risk of developing IBD, Crohn’s disease or ulcerative colitis. These findings suggest that Crohn’s disease has a unidirectional causal effect on CKD and underscore the need for routine renal function monitoring in patients with Crohn’s disease [27]. In a cross-sectional study of pediatric patients, one-quarter of 56 IBD patients had evidence of kidney disease, either previously diagnosed or detected by ultrasonography. Kidney length was significantly reduced compared to healthy peers. Use of infliximab was associated with smaller kidneys, while enteral nutrition correlated with preserved kidney size. These findings suggest that children with IBD are at risk for CKD, especially in severe cases, highlighting the need for early renal monitoring in this population [28].

Celiac Disease

Celiac disease is a chronic, immune-mediated enteropathy triggered by the ingestion of gluten – a protein found in wheat, barley, and rye – in genetically susceptible individuals. The pathophysiology involves an inappropriate immune response primarily in individuals carrying HLA-DQ2 or HLA-DQ8 alleles. Upon gluten exposure, tissue transglutaminase (tTG) modifies gluten peptides, increasing their affinity for HLA-DQ2/DQ8 molecules on antigen-presenting cells. This leads to the activation of gluten-specific CD4+ T cells in the lamina propria, resulting in the production of pro-inflammatory cytokines and tissue-damaging immune responses. Concurrently, anti-tTG autoantibodies are produced, which serve as both diagnostic markers and contributors to mucosal injury. The intestinal mucosa displays characteristic histological changes, including villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes, ultimately leading to malabsorption [29]. Celiac disease can present with both GI symptoms and a wide range of extraintestinal manifestations, including anemia, growth failure, osteoporosis, and even neurologic or renal involvement.

To investigate the association between celiac disease and kidney disease, genome-wide association from non-overlapping European cohorts was used and a Mendelian randomization study examining ten kidney traits was conducted. The analysis showed that genetic liability to celiac disease was causally associated with an increased risk of IgAN, chronic GN and a modest decrease in estimated glomerular filtration rate [30]. Although pediatric data are limited, findings from a meta-analysis have also shown that adult population with celiac disease have a significantly increased risk of developing kidney diseases, including IgAN and CKD. These findings highlight the need for greater clinical awareness and routine renal monitoring in patients with celiac disease to support early detection and prevention of kidney-related complications [4].

The IgAN is the most common primary GN worldwide, characterized by the deposition of IgA – particularly galactose-deficient IgA1 (Gd-IgA1) – in the glomerular mesangium. This triggers mesangial proliferation, inflammation, and eventually leads to varying degrees of proteinuria, hematuria, and progressive kidney dysfunction. Although the precise pathogenesis remains incompletely understood, IgAN is believed to result from a multi-hit process involving abnormal IgA1 glycosylation, the formation of autoantibodies against Gd-IgA1, and immune complex deposition in the kidney [31]. A potential link between IgAN and celiac disease has been increasingly recognized, given their shared immunological features and genetic predispositions – particularly involving HLA-DQ2/DQ8 alleles. In celiac disease, chronic mucosal inflammation and increased intestinal permeability may facilitate enhanced systemic exposure to dietary antigens and microbial components, leading to overproduction of aberrantly glycosylated IgA1. Moreover, mucosal immune activation in the gut-associated lymphoid tissue may promote the generation of nephritogenic IgA immune complexes that subsequently deposit in the glomeruli. Some studies have also suggested that a gluten-free diet may reduce proteinuria in patients with both IgAN and celiac disease, supporting the idea of gut-kidney axis involvement [4]. In a case series, kidney biopsies from nine IgAN patients, four of whom had celiac disease, were analyzed for the presence of IgA-tTG co-deposits. Circulating tTG antibodies were measured and frozen tissue sections were examined for colocalization of IgA and tTG. Among the celiac patients, three showed IgA-tTG deposits in the kidney, including two people who had not yet been diagnosed with celiac disease at the time of biopsy. Interestingly, no such deposits were observed in the patient on a gluten-free diet with known celiac disease [32].

In celiac disease, CKD may not only arise as a consequence of IgAN, but also through gut-kidney axis dysregulation, where increased intestinal permeability and immune activation contribute to systemic inflammation and kidney injury. Compromise of the intestinal barrier integrity may allow bacterial lipopolysaccharides to translocate into the systemic circulation. This translocation promotes systemic inflammation and uremic toxicity, both of which are recognized drivers in the onset and progression of CKD [7].

Diabetic kidney disease is increasingly observed in children as the prevalence of type 1 diabetes mellitus (T1DM) rises. Celiac disease, which shares genetic susceptibility with T1DM – especially via HLA-DR3-DQ2 and DR4-DQ8 – coexists in 3-12% of pediatric cases [7]. Celiac disease may also be an independent risk factor for both microvascular and macrovascular complications, potentially through mechanisms like intestinal malabsorption, micronutrient deficiencies such as folate, B vitamins, and hyperhomocysteinemia [33]. These findings support routine screening for celiac disease in T1DM patients and highlight the need for further research into the gut-kidney and gut-vascular axes in this context.

The association between celiac disease and urolithiasis was first reported in the 1970s, with studies identifying hyperoxaluria in over half of affected children [34]. More recent data confirm an elevated risk of recurrent kidney stones – particularly oxalate stones – in individuals with celiac disease. Stone formation requires urinary supersaturation with certain solutes, but in celiac disease, this may be exacerbated by intestinal malabsorption or altered renal handling of compounds like oxalate, calcium, and citrate. These imbalances promote crystallization and stone development [35]. Additionally, gut microbiota dysbiosis plays a role; reduced levels of butyrate-producing bacteria like Roseburia lead to increased intestinal oxalate absorption and inflammation, further promoting lithogenesis [36]. This complex interplay between gut permeability, immune activity, and microbial metabolism may explain the higher prevalence of kidney stones in celiac disease.

Individuals with celiac disease have a higher frequency of urinary tract infections (UTIs). This is due to a variety of factors, including impaired urinary tract motility, dysfunction of the bladder, changes in gut microbiota that can promote urinary contamination, reduced immune defense mechanisms, and dysregulated immune responses. In a study evaluating the association between celiac disease and UTIs in the absence of anatomical abnormalities, 22.7% of 97 patients with celiac disease reported at least one episode of UTI, with a female predominance. In the majority of cases, the UTI occurred before the diagnosis of celiac disease. Notably, the cumulative probability of being UTI-free by the age of 18 years was significantly lower in women with celiac disease compared to the general population [37]. These findings point to a possible increased risk of UTIs in female celiac disease patients and potentially warrant closer clinical attention.

Liver Diseases

Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a group of rare, autosomal recessive metabolic disorders characterized by hepatic enzyme deficiencies involved in glyoxylate metabolism. These defects lead to the overproduction of oxalate in the liver, which subsequently binds with calcium to form calcium oxalate crystals. While oxalate is normally a minor end-product excreted by the kidneys, in PH, its excessive hepatic production surpasses kidney excretion capacity, resulting in crystal deposition in any organ. PH is classified into three types based on the specific hepatic enzyme affected. PH type 1 (PH1), the most severe and common form, results from mutations in the AGXT gene encoding the liver-specific enzyme alanine: glyoxylate aminotransferase. PH type 2 (PH2) is due to defects in GRHPR, and PH type 3 (PH3) involves mutations in HOGA1; both are also expressed in the liver but tend to present with milder clinical manifestations [38].

In PH, calcium oxalate crystals deposit primarily in the kidney tubules and interstitium, resulting in nephrocalcinosis and nephrolithiasis. The mechanical damage caused by the crystals, combined with inflammation and fibrosis, contributes to the development of tubulointerstitial nephritis. Progressive accumulation and stone formation ultimately lead to a decline in glomerular filtration rate and CKD. In many patients with PH1, this progression leads to kidney failure at an early age [38]. To date, distinct clinical forms of PH1 have been identified. Infantile oxalosis typically manifests within the first six months of life, presenting with nephrocalcinosis and early-onset kidney failure. In contrast, childhood-onset cases more commonly begin with symptoms related to kidney stone formation, such as renal colic, hematuria, or urinary tract infections. Additional presentations include disease recurrence following kidney transplantation and, in rare instances, recurrent kidney stones appearing later in adulthood [39]. A nationwide study evaluating the overall clinical characteristics of patients with PH1 found that 92.4% of patients had nephrolithiasis/nephrocalcinosis even at the time of diagnosis. Although individuals with infantile oxalosis were diagnosed at a younger age compared to individuals with childhood-onset PH1, they exhibited more advanced CKD or kidney failure requiring dialysis at the time of diagnosis [40]. Therefore, given the risk of early and progressive kidney involvement in PH, even in asymptomatic stages, timely evaluation of kidney function is essential; close collaboration between nephrology and gastroenterology is crucial to ensure comprehensive and coordinated patient care.

Wilson’s Disease

Wilson’s disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, which encodes a copper-transporting ATPase responsible for incorporating copper into ceruloplasmin and excreting excess copper into the bile. Defective ATP7B leads to the accumulation of free copper in various tissues, most notably the liver, central nervous system, and cornea. Clinical manifestations are highly variable and age-dependent, ranging from hepatic dysfunction in children and adolescents to neurological and psychiatric symptoms in older individuals [41].

Although kidney involvement is less commonly recognized, it is a relevant extrahepatic manifestation of Wilson’s disease, particularly in untreated or advanced cases. Copper deposition in the kidneys may lead to tubular dysfunction, which can be present as aminoaciduria, low-molecular-weight proteinuria, hypercalciuria, or renal tubular acidosis, particularly the distal type. In some patients, nephrolithiasis and hypophosphatemia have also been reported [42]. Moreover, glomerular involvement, although rare, may manifest as proteinuria or even nephrotic syndrome, and IgAN potentially due to immune complex-mediated mechanisms [43]. Chelation therapy with agents such as D-penicillamine may also influence kidney function, either by improving copper overload or, conversely, causing drug-induced nephrotoxicity in some cases [44]. Thus, regular monitoring of kidney parameters should be performed in the management of Wilson’s disease, especially in patients receiving long-term chelation therapy.

Chronic Liver Diseases

Chronic liver disease encompasses a wide range of progressive liver disorders that lead to sustained liver inflammation, fibrosis, and ultimately cirrhosis. It can result from various etiologies including viral hepatitis (especially hepatitis B and C), autoimmune hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), metabolic and genetic disorders (such as Wilson’s disease or alpha-1 antitrypsin deficiency), and biliary tract diseases like primary sclerosing cholangitis. Over time, continuous liver damage impairs hepatic synthetic, metabolic, and detoxifying functions, potentially leading to complications such as portal hypertension, hepatic encephalopathy, ascites, coagulopathy, and increased susceptibility to infections [7].

Chronic liver disease and kidney involvement are closely interconnected through complex systemic and local mechanisms. As chronic liver disease progresses, portal hypertension develops, leading to splanchnic vasodilation. This vasodilation reduces the effective circulating blood volume, resulting in decreased kidney perfusion. In response, the body activates compensatory systems such as the renin-angiotensin-aldosterone system, the sympathetic nervous system, and antidiuretic hormone, which together cause renal vasoconstriction and subsequently a significant drop in glomerular filtration rate [5]. Furthermore, impaired hepatic detoxification allows bacterial endotoxins and inflammatory cytokines to enter the circulation, enhancing systemic inflammation and exacerbating kidney dysfunction. Additional contributing factors include acidosis, hyponatremia, hypoalbuminemia, and sepsis, all of which can further impair kidney function [45].

Hepatorenal syndrome (HRS) is a form of functional kidney failure that occurs in individuals with advanced liver disease, most commonly cirrhosis, in the absence of other identifiable structural kidney abnormalities. Based on the duration and progression of kidney dysfunction, HRS is currently classified into two main types: HRS-AKI and HRS-CKD [46].

HRS-AKI is characterized by:

  • A rapid decline in kidney function, typically identified by an acute rise in serum creatinine (≥0.3 mg/dL within 48 hours or ≥50% from baseline within seven days) in patients with cirrhosis and ascites.
  • It usually occurs following precipitating events such as infections, GI bleeding, or excessive diuretic use.

HRS-CKD refers to:

  • A gradual and sustained impairment in kidney function lasting three months or longer,
  • Long-standing portal hypertension and diuretic-resistant ascites.

Management of HRS includes prompt identification and treatment of precipitating factors such as infections, GI bleeding, or excessive diuretic use, administration of albumin together with vasoconstrictors such as terlipressin, and early evaluation for liver transplantation when indicated [46]. Given the intricate interplay between the liver and kidneys, early recognition and collaborative management of renal dysfunction in patients with chronic liver disease is essential to improve outcomes and guide appropriate therapeutic strategies.

Enteric Infections

Shiga toxin-producing Escherichia coli

Shiga toxin-producing Escherichia coli (STEC) infection is primarily a GI illness characterized by abdominal cramping, watery diarrhea that often progresses to bloody diarrhea (hemorrhagic colitis), and, in some cases, fever and vomiting. The GI manifestations are largely attributed to the direct mucosal damage caused by Shiga toxins, which are released by the bacteria in the colon. These toxins disrupt the intestinal epithelial barrier, leading to inflammation, epithelial cell apoptosis, and capillary hemorrhage. Colonoscopy or histological examination in severe cases may reveal mucosal edema, ulcerations, and hemorrhagic lesions predominantly in the distal colon. Importantly, while the GI symptoms are self-limiting in most patients, a subset – particularly young children and the elderly – are at risk for extraintestinal complications such as STEC-hemolytic uremic syndrome (HUS) (STEC-HUS) [47].

The pathogenic mechanism of kidney involvement in STEC-HUS is primarily driven by the systemic dissemination of Shiga toxins, particularly Stx2, following disruption of the intestinal epithelial barrier. Once in circulation, Shiga toxins exhibit high affinity for globotriaosylceramide (Gb3) receptors, which are abundantly expressed on endothelial cells within the kidney glomeruli. Upon binding to Gb3, the toxins are internalized and inhibit protein synthesis by inactivating the 60S ribosomal subunit, leading to endothelial cell apoptosis and dysfunction. This endothelial injury initiates a prothrombotic state characterized by platelet activation, increased release of von Willebrand factor, and reduced production of antithrombotic mediators such as prostacyclin and nitric oxide. The result is widespread microvascular thrombosis, particularly in glomerular capillaries, which manifests clinically as thrombotic microangiopathy. The ensuing microthrombi cause mechanical damage to erythrocytes, leading to microangiopathic hemolytic anemia, while the consumption of platelets contributes to thrombocytopenia. Concurrently, the glomerular filtration barrier becomes compromised, resulting in AKI, typically presenting with oliguria or anuria, elevated serum creatinine, and signs of fluid and electrolyte imbalance. Proteinuria and hematuria are frequently observed in urinalysis [47]. There is no specific therapy for STEC-HUS, and treatment is primarily supportive, focusing on fluid and electrolyte management, blood pressure control, and, in severe cases, renal replacement therapy. While most pediatric patients recover fully with appropriate supportive care, a subset may develop long-term complications such as CKD, hypertension, or proteinuria [48].

As can be seen, the kidney pathology in STEC-HUS illustrates the critical role of the gut-kidney axis, wherein enteric infections can precipitate severe extraintestinal consequences. STEC-HUS remains one of the leading causes of AKI in children and poses significant clinical challenges due to its rapid onset and potential for long-term renal sequelae.

 

Gastrointestinal System Involvement in Kidney Diseases

Idiopathic Nephrotic Syndrome

Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children and also affects adults, though with differing histopathological profiles. It is defined by the classic triad of massive proteinuria (>3.5 g/day), hypoalbuminemia, and generalized edema. In pediatric populations, minimal change disease is the most frequent histological subtype, while in adults, focal segmental glomerulosclerosis and membranous nephropathy are more common. Although the precise pathogenesis of INS remains incompletely understood, immune dysregulation – particularly involving T and B-cell dysfunction and circulating permeability factors – has been implicated in podocyte injury and proteinuria [49]. While the kidney manifestations are central to the diagnosis, INS is increasingly recognized as a multisystem disorder, including those affecting the GI system. GI involvement is often secondary to the systemic consequences of hypoalbuminemia, edema, thrombotic tendency, and immunosuppressive therapy [50].

One of the most common GI manifestations in INS is edema of the bowel wall, which may lead to abdominal discomfort, nausea, vomiting, and even paralytic ileus. In severe cases, bowel wall thickening can mimic conditions such as IBD or ischemia on imaging studies [51]. Additionally, the hypercoagulable state associated with INS increases the risk of mesenteric arterial thrombosis, a rare but life-threatening complication that can present with acute abdominal pain [52]. Moreover, patients with INS are at increased risk for infections, including spontaneous bacterial peritonitis, especially in those with ascites. The use of corticosteroids and other immunosuppressants further compromises GI immunity and mucosal defense, predisposing to opportunistic infections, peptic ulcer disease, and drug-related mucosal injury [53]. Malabsorption of fat-soluble vitamins (particularly vitamin D) may also occur due to protein loss and intestinal edema, contributing to metabolic bone disease in the long term [54]. Therefore, GI assessment and monitoring are essential components of comprehensive care in patients with INS, particularly in those with persistent hypoalbuminemia or GI symptoms.

Polycystic Kidney Diseases

Polycystic kidney disease (PKD) comprises a group of inherited disorders characterized by the progressive development of fluid-filled cysts in the kidneys, ultimately leading to kidney failure. The two main genetic forms are autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD), each with distinct clinical and genetic profiles. ADPKD is the most common hereditary kidney disorder, typically caused by mutations in the PKD1 or PKD2 genes. It usually manifests in adulthood with bilateral kidney enlargement, hypertension, and gradual loss of kidney function. ARPKD, in contrast, is a rarer and more severe form, caused by mutations in the PKHD1 gene and often present in infancy or early childhood with enlarged echogenic kidneys. While kidney manifestations are the hallmark of both forms, GI involvement is an important aspect of the disease, particularly in relation to hepatic and biliary complications [55].

In ADPKD, one of the most frequent extrarenal manifestations is polycystic liver disease (PLD), which occurs in up to 80% of patients over the age of 30 [56]. Although often asymptomatic, extensive liver cysts may cause abdominal distension, early satiety, gastroesophageal reflux, and even mechanical bowel compression. Cyst infection or hemorrhage can also cause acute abdominal pain and mimic intra-abdominal sepsis [57]. In ARPKD, the most prominent GI-related manifestation is due to congenital hepatic fibrosis, which can lead to portal hypertension. This may result in splenomegaly, esophageal varices, hematemesis, and ascites, posing serious risks, especially in pediatric patients. The combination of hepatobiliary and kidney dysfunction in ARPKD is sometimes referred to as a hepatorenal fibrocystic disease [58]. In both forms of PKD, GI symptoms may also arise from complications of CKD, such as uremic gastropathy, anorexia, and nausea, or from treatment-related factors, including immunosuppressive therapy following transplantation [57]. Thus, careful GI assessment is essential in the multidisciplinary management of PKD patients, particularly those with advanced disease or hepatic involvement.

Chronic Kidney Diseases

Chronic kidney disease is a progressive condition characterized by a sustained reduction in glomerular filtration rate and the accumulation of uremic toxins. While the kidney and cardiovascular consequences of CKD are well known, GI involvement is also frequent and significantly affects morbidity, nutritional status, and quality of life. Many of the GI manifestations in CKD stem from uremia-related metabolic disturbances, chronic inflammation, altered intestinal permeability, and the effects of therapeutic interventions [59].

Common uremic symptoms such as anorexia, nausea, vomiting, metallic taste, and weight loss are frequently reported and may reflect uremic gastropathy or delayed gastric emptying. In advanced stages, mucosal fragility and platelet dysfunction can predispose patients to GI bleeding, while bowel wall edema may cause abdominal discomfort or paralytic ileus [2]. Uremia also contributes to impaired gut barrier function, leading to increased intestinal permeability – often referred to as “leaky gut” – which facilitates the translocation of endotoxins and contributes to systemic inflammation through the gut-kidney axis [7].

Oral and esophageal manifestations, including dry mouth, oral ulcers, gingivitis, and uremic fetor, are commonly observed [60]. In parallel, CKD is associated with significant alterations in the gut microbiome (dysbiosis), including the proliferation of urease-producing and proteolytic bacteria. This dysbiosis increases the generation of gut-derived uremic toxins such as indoxyl sulfate and p-cresyl sulfate, which have been implicated in endothelial dysfunction, cardiovascular disease, and further progression of kidney injury [61].

Gastrointestinal motility disturbances are also common; constipation often results from fluid restriction, a low-fiber diet, oral iron supplementation, or use of phosphate binders. Conversely, diarrhea may occur due to certain medications such as magnesium-based antacids, antibiotics or infectious etiologies, especially in immunosuppressed patients [62]. Nutritional impairment is another major consequence of GI involvement in CKD. Reduced oral intake due to GI symptoms, combined with malabsorption and inflammation, can lead to protein-energy wasting and deficiencies in essential nutrients, including fat-soluble vitamins, vitamin B12, and folate. This contributes to muscle wasting, frailty, and increased vulnerability in elderly CKD patients [63].

In summary, the GI system plays a central and multifaceted role in the clinical course of CKD. A comprehensive understanding and management of GI involvement is essential to improve outcomes, reduce complications, and enhance the overall well-being of CKD patients.

Kidney Replacement Therapies

Kidney replacement therapies (KRT), including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation, are life-sustaining treatments for patients with kidney failure. Each modality has distinct physiological impacts and potential GI complications, which should be considered in patient management and nutritional planning. GI symptoms may arise due to the dialysis process itself, associated fluid shifts, metabolic changes, or immunosuppressive therapy [8].

Hemodialysis is the most commonly used modality for KRT. GI complications during or after dialysis sessions are frequent and may include nausea, vomiting, abdominal cramps, and hypotension-related gut hypoperfusion. HD is also associated with increased gut permeability, which can facilitate endotoxemia and systemic inflammation [64]. Constipation is common due to restricted fluid intake, dietary limitations, and phosphate binders [65]. Rare but serious GI complications include mesenteric ischemia and colonic angiodysplasia-related bleeding, particularly in long-term HD patients [66].

Peritoneal dialysis involves the instillation of dialysate into the peritoneal cavity, and its GI manifestations are often related to increased intra-abdominal pressure, leading to early satiety, gastroesophageal reflux, abdominal fullness, or hernias [67]. Peritonitis is a significant complication and may present with abdominal pain, fever, and diarrhea or paralytic ileus [68]. Chronic exposure of the peritoneum to dialysate can lead to sclerosing encapsulating peritonitis, a rare but severe condition causing intestinal obstruction [69]. Additionally, glucose absorption from dialysate may exacerbate dyslipidemia, insulin resistance, and obesity, contributing indirectly to metabolic complications that affect gut function [70].

While kidney transplantation restores kidney function and offers superior quality of life, it introduces unique GI risks, primarily due to immunosuppressive therapy. Common GI side effects of calcineurin inhibitors and mTOR inhibitors include nausea, diarrhea, oral ulcers, and anorexia [71]. Mycophenolate mofetil is particularly associated with diarrhea, colitis, and GI bleeding, sometimes mimicking IBD [72]. Strategies to mitigate drug-related GI adverse effects include dose splitting, using enteric-coated formulations, or switching to an alternative immunosuppressive class when feasible [72–74]. Opportunistic infections, such as cytomegalovirus colitis or Clostridioides difficile infections, are more frequent in the post-transplant setting. They should be considered in patients with new or worsening GI symptoms; cytomegalovirus infection can be initially screened with polymerase chain reaction (PCR) or antigen testing, while Clostridioides difficile should be evaluated with stool toxin assays or PCR [75, 76]. Moreover, long-term immunosuppression also increases the risk of GI malignancies, including colorectal and gastric cancers [77].

 

Conclusion

The complex and dynamic interplay between the GI system and the kidneys reflects a bidirectional relationship in which dysfunction in one organ system can significantly impact the other. GI symptoms are common across all stages of kidney disease and may arise from uremia, dialysis modalities, immunosuppressive therapies, or alterations in gut microbiota. Conversely, GI disorders such as infections, inflammatory conditions, and medication-induced mucosal injury can contribute to kidney injury through immune activation, systemic inflammation, or volume and electrolyte disturbances. Recognizing these interactions is crucial for early diagnosis, targeted management, and prevention of complications. A multidisciplinary approach that incorporates nephrologic and gastroenterologic expertise will be essential to optimize outcomes in patients affected by these intertwined organ systems.

 

Bibliography

  1. Nery Neto JAO, Yariwake VY, Câmara NOS, Andrade-Oliveira V (2023) Enteroendocrine cells and gut hormones as potential targets in the crossroad of the gut-kidney axis communication. Front Pharmacol 4:1248757. https://doi.org/10.3389/fphar.2023.1248757.
  2. Jose PA (2016) Gastrorenal communication: sniffing and tasting. Exp Physiol 101:457-8. https://doi.org/10.1113/EP085762.
  3. Corica D, Romano C (2016) Renal Involvement in Inflammatory Bowel Diseases. J Crohns Colitis 10:226-35. https://doi.org/10.1093/ecco-jcc/jjv138.
  4. Wijarnpreecha K, Thongprayoon C, Panjawatanan P, Thamcharoen N, Pachariyanon P, Nakkala K, et al (2016) Celiac disease and the risk of kidney diseases: A systematic review and meta-analysis. Dig Liver Dis 48:1418-1424. https://doi.org/10.1016/j.dld.2016.08.115.
  5. Kanduri SR, Velez JCQ (2024) Kidney dysfunction in the setting of liver failure: Core curriculum 2024. Am J Kidney Dis 83:386–401. https://doi.org/10.1053/j.ajkd.2023.08.013.
  6. Talarico V, Aloe M, Monzani A, Miniero R, Bona G (2016) Hemolytic uremic syndrome in children. Minerva Pediatr 68:441–455.
  7. Evenepoel P, Poesen R, Meijers B (2017) The gut-kidney axis. Pediatr Nephrol 32:2005–2014. https://doi.org/10.1007/s00467-016-3527-x.
  8. Karahan D, Şahin İ (2022) Comparison of gastrointestinal symptoms and findings in renal replacement therapy modalities. BMC Nephrol 23:261. https://doi.org/10.1186/s12882-022-02893-6.
  9. Serrano Pejenaute I, Lejarzegi Anakabe E, Madariaga L, Alonso Varela M, Santos-Diez Vázquez L, Herrero Goñi M (2022) Secondary immunosuppression in pediatric kidney transplant recipients. Exp Clin Transplant 20:258–264. https://doi.org/10.6002/ect.2021.0410.
  10. Zais IE, Sirotti A, Iesari S, Campioli E, Costantino A, Delbue S, et al (2024) Human cytomegalovirus-related gastrointestinal disease after kidney transplantation: A systematic review. Clin Transplant 38:e15218. https://doi.org/10.1111/ctr.15218.
  11. Al-Aly Z, Maddukuri G, Xie Y (2020) Proton pump inhibitors and the kidney: implications of current evidence for clinical practice and when and how to deprescribe. Am J Kidney Dis 75:497–507. https://doi.org/10.1053/j.ajkd.2019.07.012.
  12. Leventoğlu E, Uzun Kenan B, Büyükkaragöz B, Bakkaloğlu SA (2023). Clinical characteristics of children with acute tubulointerstitial nephritis: a single-center experience. Cureus 15:e36379. https://doi.org/10.7759/cureus.36379.
  13. Weir MR (2024) Proton pump inhibitors and kidney disease: fact or fiction? Am J Nephrol 55:499–508. https://doi.org/10.1159/000538755.
  14. Wang X, Wright Z, Patton-Tackett ED, Song G (2023). The relationship between gastroesophageal reflux disease and chronic kidney disease. J Pers Med 13:827. https://doi.org/10.3390/jpm13050827.
  15. Joob B, Wiwanitkit V (2014) Helicobacter pylori infection, chronic kidney disease, and peptic ulcer disease. J Chin Med Assoc 77:656. https://doi.org/10.1016/j.jcma.2014.07.008.
  16. Li Q, Lin X, Wu Z, He L, Wang W, Cao Q, Zhang J (2013) Immunohistochemistry analysis of Helicobacter pylori antigen in renal biopsy specimens from patients with glomerulonephritis. Saudi J Kidney Dis Transpl 24:751–758. https://doi.org/10.4103/1319-2442.113871.
  17. Jing S, Lin L, Li J, Pan J, Qiao X (2024) Causal relationship between Helicobacter pylori infection and IgA nephropathy: a bidirectional two-sample Mendelian randomization study. Ren Fail 46:2371055. https://doi.org/10.1080/0886022X.2024.2371055.
  18. Hata K, Koyama T, Ozaki E, Kuriyama N, Mizuno S, Matsui D, et al (2021) Assessing the relationship between Helicobacter pylori and chronic kidney disease. Healthcare (Basel) 9:162. https://doi.org/10.3390/healthcare9020162.
  19. Maioli ME, Frange RFN, Grion CMC, Delfino VDA (2022) Helicobacter pylori eradication in renal transplant candidates. J Bras Nefrol 44:215–223. https://doi.org/10.1590/2175-8239-JBN-2021-0097.
  20. Caliskan B, Yazici H, Caliskan Y, Ozluk Y, Gulluoglu M, Kilicaslan I, et al (2014) The effects of Helicobacter pylori eradication on proteinuria in patients with primary glomerulonephritis. Int J Nephrol 2014:180690. https://doi.org/10.1155/2014/180690.
  21. Pan W, Zhang H, Wang L, Zhu T, Chen B, Fan J (2019) Association between Helicobacter pylori infection and kidney damage in patients with peptic ulcer. Ren Fail 41:1028–1034. https://doi.org/10.1080/0886022X.2019.1683029.
  22. Seyedian SS, Nokhostin F, Malamir MD (2019). A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life 12:113–122. https://doi.org/10.25122/jml-2018-0075.
  23. Bianchi L, Gaiani F, Bizzarri B, Minelli R, Cortegoso Valdivia P, Leandro G, et al (2018) Renal lithiasis and inflammatory bowel diseases: an update on pediatric population. Acta Biomed 89:76–80. https://doi.org/10.23750/abm.v89i9-S.7908.
  24. Doumas SA, Tsironis C, Bolaji AA, Garantziotis P, Frangou E (2023) Glomerulonephritis and inflammatory bowel disease: a tale of gut-kidney axis dysfunction. Autoimmun Rev 22:103327. https://doi.org/10.1016/j.autrev.2023.103327.
  25. Yan Q, Zhao Z, Liu D, Li J, Pan S, Duan J, et al (2024) Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy. Ren Fail 46:2337288. https://doi.org/10.1080/0886022X.2024.2337288.
  26. Liu M, Zhang Y, Ye Z, Yang S, Zhou C, He P, et al (2023) Inflammatory bowel disease with chronic kidney disease and acute kidney injury. Am J Prev Med 65:1103–1112. https://doi.org/10.1016/j.amepre.2023.08.008.
  27. Li X, Ge Q, Yu C, Zhao W, Wu C, Liu Z, et al (2024) Assessment of the causal relationship between inflammatory bowel diseases and chronic kidney diseases: a two-sample bidirectional Mendelian randomization study among European population. Nephrology (Carlton) 29:738–747. https://doi.org/10.1111/nep.14371.
  28. Lauritzen D, Andreassen BU, Heegaard NHH, Klinge LG, Walsted AM, Neland M, Nielsen RG, Wittenhagen P, et al (2018) Pediatric inflammatory bowel diseases: should we be looking for kidney abnormalities? Inflamm Bowel Dis 24:2599–2605. https://doi.org/10.1093/ibd/izy166.
  29. Catassi C, Verdu EF, Bai JC, Lionetti E (2022) Coeliac disease. Lancet 399:2413–2426. https://doi.org/10.1016/S0140-6736(22)00794-2.
  30. Ge YM, Peng SL, Wang Q, Yuan J (2024) Causality between celiac disease and kidney disease: a Mendelian randomization study. Medicine (Baltimore) 103:e39465. https://doi.org/10.1097/MD.0000000000039465.
  31. Selvaskandan H, Jhaveri KD, Rizk DV (2024) Primary IgA nephropathy: new insights and emerging therapies. Adv Kidney Dis Health 31:180–193. https://doi.org/10.1053/j.akdh.2024.04.002.
  32. Nurmi R, Korponay-Szabó I, Laurila K, Huhtala H, Niemelä O, Mustonen J, et al (2021) Celiac disease-type tissue transglutaminase autoantibody deposits in kidney biopsies of patients with IgA nephropathy. Nutrients 13:1594. https://doi.org/10.3390/nu13051594.
  33. Mueller PW, Rogus JJ, Cleary PA, Zhao Y, Smiles AM, Steffes MW, et al (2006). Genetics of kidneys in diabetes (GoKinD) study: a genetics collection available for identifying genetic susceptibility factors for diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 17:1782–1790. https://doi.org/10.1681/ASN.2005080822.
  34. Salem A, Sawires H, Eskander A, Marwan R, Boshra E (2023) Risk factors for developing hyperoxaluria in children with Crohn’s disease. Pediatr Nephrol 38:781–789. https://doi.org/10.1007/s00467-022-05674-3.
  35. Ludvigsson JF, Zingone F, Fored M, Ciacci C, Cirillo M (2012) Moderately increased risk of urinary stone disease in patients with biopsy-verified coeliac disease. Aliment Pharmacol Ther 35:477–484. https://doi.org/10.1111/j.1365-2036.2011.04968.x.
  36. Denburg MR, Koepsell K, Lee JJ, Gerber J, Bittinger K, Tasian GE, et al (2020) Perturbations of the gut microbiome and metabolome in children with calcium oxalate kidney stone disease. J Am Soc Nephrol 31:1358–1369. https://doi.org/10.1681/ASN.2019101131.
  37. Fanos V, Verlato G, Matti P, Pizzini C, Maffeis C (2002) Increased incidence of urinary tract infections in patients with coeliac disease. Pediatr Nephrol 17:570–571. https://doi.org/10.1007/s00467-002-0881-7.
  38. Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369:649–658. https://doi.org/10.1056/NEJMc1311606.
  39. Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, Liutkus A, et al (2010). Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 77:443–449. https://doi.org/10.1038/ki.2009.435.
  40. Bakkaloğlu SA, Büyükkaragöz B, Pınarbaşı AS, Leventoğlu E, Saygılı S, Çomak E, et al (2024) Comprehensive evaluation of patients with primary hyperoxaluria type 1: a nationwide study. Nephrology (Carlton) 29:201–213. https://doi.org/10.1111/nep.14273.
  41. Lucena-Valera A, Ruz-Zafra P, Ampuero J (2023) Wilson’s disease: overview. Med Clin (Barc) 160:261–267. https://doi.org/10.1016/j.medcli.2022.12.016.
  42. Dang J, Chevalier K, Letavernier E, Tissandier C, Mouawad S, Debray D, Obadia M, Poujois A (2024). Kidney involvement in Wilson’s disease: a review of the literature. Clin Kidney J 17:sfae058. https://doi.org/10.1093/ckj/sfae058.
  43. Bhandari G, Tiwari V, Gupta A, Gupta P, Bhargava V, Malik M, et al (2021) IgA nephropathy with Wilson’s disease: a case report and literature review. Indian J Nephrol 31:474–477. https://doi.org/10.4103/ijn.IJN_227_20.
  44. Koraishy FM, Cohen RA, Israel GM, Dahl NK (2013) Cystic kidney disease in a patient with systemic toxicity from long-term D-penicillamine use. Am J Kidney Dis 62:806–809. https://doi.org/10.1053/j.ajkd.2013.04.017.
  45. Sansoè G, Aragno M, Wong F (2020) Pathways of hepatic and renal damage through non-classical activation of the renin-angiotensin system in chronic liver disease. Liver Int 40:18–31. https://doi.org/10.1111/liv.14272.
  46. Simonetto DA, Gines P, Kamath PS (2020) Hepatorenal syndrome: pathophysiology, diagnosis, and management. BMJ 370:m2687. https://doi.org/10.1136/bmj.m2687.
  47. Freedman SB, van de Kar NCAJ, Tarr PI (2023) Shiga toxin-producing Escherichia coli and the hemolytic-uremic syndrome. N Engl J Med 389:1402–1414. https://doi.org/10.1056/NEJMra2108739.
  48. Liu Y, Thaker H, Wang C, Xu Z, Dong M (2022) Diagnosis and treatment for Shiga toxin-producing Escherichia coli associated hemolytic uremic syndrome. Toxins (Basel) 15:10. https://doi.org/10.3390/toxins15010010.
  49. Campbell RE, Thurman JM (2022) The immune system and idiopathic nephrotic syndrome. Clin J Am Soc Nephrol 17:1823–1834. https://doi.org/10.2215/CJN.07180622.
  50. Kagaya S, Nagasawa T (2018) Abdominal involvement in minimal change nephrotic syndrome. Clin Exp Nephrol 22:481–482. https://doi.org/10.1007/s10157-017-1446-1.
  51. Wong EK, Brady M, Sheerin NS (2013) Severe intestinal oedema due to nephrotic syndrome. QJM 106:191–192. https://doi.org/10.1093/qjmed/hcr236.
  52. Ferjani M, Zaimi Y, Trad N, Hammi Y, Ayari M, Ayadi S, et al (2023) Mesenteric arterial thrombosis revealing relapse of nephrotic syndrome in young women. Int Med Case Rep J 16:633–639. https://doi.org/10.2147/IMCRJ.S401983.
  53. Takao H, Nishi K, Funaki T, Inoki Y, Osaka K, Nada T, et al (2023) Changes in patterns of infection associated with pediatric idiopathic nephrotic syndrome: a single-center experience in Japan. J Pediatr 254:11–16.e1. https://doi.org/10.1016/j.jpeds.2022.10.005.
  54. Yang SP, Ong L, Loh TP, Chua HR, Tham C, Meng KC, et al (2021) Calcium, vitamin D, and bone derangement in nephrotic syndrome. J ASEAN Fed Endocr Soc 36:50–55. https://doi.org/10.15605/jafes.036.01.12.
  55. Ma M (2021) Cilia and polycystic kidney disease. Semin Cell Dev Biol 110:139–148. https://doi.org/10.1016/j.semcdb.2020.05.003.
  56. Chebib FT, Torres VE (2016). Autosomal dominant polycystic kidney disease: core curriculum 2016. Am J Kidney Dis 67:792–810. https://doi.org/10.1053/j.ajkd.2015.07.037.
  57. Abu-Wasel B, Walsh C, Keough V, Molinari M (2013). Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J Gastroenterol 19:5775–5786. https://doi.org/10.3748/wjg.v19.i35.5775.
  58. Hartung EA, Guay-Woodford LM (2014) Autosomal recessive polycystic kidney disease: a hepatorenal fibrocystic disorder with pleiotropic effects. Pediatrics 134:e833–e845. https://doi.org/10.1542/peds.2013-3646.
  59. Cooper TE, Dalton A, Kieu A, Howell M, Jayanti S, Khalid R, et al (2021) The CKD bowel health study: understanding the bowel health and gastrointestinal symptom management in patients with chronic kidney disease: a mixed-methods observational longitudinal study (protocol). BMC Nephrol 22:388. https://doi.org/10.1186/s12882-021-02600-x.
  60. Velan E, Sheller B (2021) Oral health in children with chronic kidney disease. Pediatr Nephrol 36:3067–3075. https://doi.org/10.1007/s00467-020-04913-9.
  61. Rysz J, Franczyk B, Ławiński J, Olszewski R, Ciałkowska-Rysz A, Gluba-Brzózka A (2021) The impact of CKD on uremic toxins and gut microbiota. Toxins (Basel) 13:252. https://doi.org/10.3390/toxins13040252.
  62. Biruete A, Shin A, Kistler BM, Moe SM (2024) Feeling gutted in chronic kidney disease (CKD): gastrointestinal disorders and therapies to improve gastrointestinal health in individuals CKD, including those undergoing dialysis. Semin Dial 37:334–349. https://doi.org/10.1111/sdi.13030.
  63. Piccoli GB, Cederholm T, Avesani CM, Bakker SJL, Bellizzi V, Cuerda C, et al (2023) Nutritional status and the risk of malnutrition in older adults with chronic kidney disease – implications for low protein intake and nutritional care: a critical review endorsed by ERN-ERA and ESPEN. Clin Nutr 42:443–457. https://doi.org/10.1016/j.clnu.2023.01.018.
  64. March DS, Graham-Brown MP, Stover CM, Bishop NC, Burton JO (2017) Intestinal barrier disturbances in haemodialysis patients: mechanisms, consequences, and therapeutic options. Biomed Res Int 2017:5765417. https://doi.org/10.1155/2017/5765417.
  65. Kanai H, Kashiwagi M, Hirakata H, Nagashima A, Tada S, Yao T, et al (2000) Chronic intestinal pseudo-obstruction due to dialysis-related amyloid deposition in the propria muscularis in a hemodialysis patient. Clin Nephrol 53:394–399.
  66. Yu CC, Hsu HJ, Wu IW, Lee CC, Tsai CJ, Chou CC, et al (2009) Factors associated with mortality from non-occlusive mesenteric ischemia in dialysis patients. Ren Fail 31:802–806. https://doi.org/10.3109/08860220903180624.
  67. Kosmadakis G, Albaret J, da Costa Correia E, Somda F, Aguilera D (2018) Gastrointestinal disorders in peritoneal dialysis patients. Am J Nephrol 48:319–325. https://doi.org/10.1159/000494145.
  68. Lam D, Bargman JM (2013) Peritonitis in the patient on peritoneal dialysis: does the composition of the dialysis fluid make a difference? Clin J Am Soc Nephrol 8:1471–1473. https://doi.org/10.2215/CJN.07830713.
  69. Leventoğlu E, Büyükkaragöz B, Dalgıç A, Fidan K, Söylemezoğlu O, Bakkaloğlu SA (2022). Encapsulated peritoneal sclerosis in an adolescent with kidney transplant after long-term peritoneal dialysis. Exp Clin Transplant 20:112–114. https://doi.org/10.6002/ect.PediatricSymp2022.O35.
  70. Khan SF, Ronco C, Rosner MH (2019) Counteracting the metabolic effects of glucose load in peritoneal dialysis patients; an exercise-based approach. Blood Purif 48:25–31. https://doi.org/10.1159/000499406.
  71. Tielemans MM, van Boekel GAJ, van Gelder T, Tjwa ET, Hilbrands LB (2019) Immunosuppressive drugs and the gastrointestinal tract in renal transplant patients. Transplant Rev (Orlando) 33:55–63. https://doi.org/10.1016/j.trre.2018.11.001.
  72. Reinke P, Budde K, Hugo C, Petersen P, Schnuelle P, Fricke L, et al (2011). Reduction of gastrointestinal complications in renal graft recipients after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplant Proc 43:1641–1646. https://doi.org/10.1016/j.transproceed.2011.01.184.
  73. Cooper M, Salvadori M, Budde K, Oppenheimer F, Sollinger H, Zeier M (2012). Enteric-coated mycophenolate sodium immunosuppression in renal transplant patients: efficacy and dosing. Transplant Rev (Orlando) 26:233–240. https://doi.org/10.1016/j.trre.2012.02.001.
  74. Karakayali H, Yagmurdur MC, Emiroglu R, Moray G, Colak T (2002) Effects of mycophenolate mofetil on the gastrointestinal system and kidney graft function: early experience at one center. Transplant Proc 34:2093–2095. https://doi.org/10.1016/s0041-1345(02)02865-8.
  75. Lempinen M, Halme L, Sarkio S, Arola J, Honkanen E, Turunen U, et al (2009) CMV findings in the gastrointestinal tract in kidney transplantation patients, patients with end-stage kidney disease and immunocompetent patients. Nephrol Dial Transplant 24:3533–3539. https://doi.org/10.1093/ndt/gfp408.
  76. Saha S, Mara K, Pardi DS, Khanna S (2021) Long-term safety of fecal microbiota transplantation for recurrent Clostridioides difficile infection. Gastroenterology 160:1961–1969.e3. https://doi.org/10.1053/j.gastro.2021.01.010.
  77. Vrotniakaite K, Jaceviciute R, Rudminiene I, Laucyte-Cibulskiene A, Rainiene T, Jankevicius F, Zelvys A, Miglinas M (2014). Malignancy after renal transplantation: a single-center experience. Ann Transplant 19:456–463. https://doi.org/10.12659/AOT.890706.

Gene Therapies: Any Merit in Nephrology?

Posted on Scarica PDF

DOI: 10.69097/42-05-2025-06

Emre Leventoğlu1, Sevcan A. Bakkaloğlu2, Fatih Süheyl Ezgü3

1 Department of Pediatric Nephrology, Konya City Hospital, Konya, Turkey
2 Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
3 Department of Pediatric Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey

Corresponding author:
Emre Leventoğlu, MD
Department of Pediatric Nephrology, Konya City Hospital, Konya, Turkey
Phone: +90 312 202 52 26, +90 506 608 66 86
E-mail: dremrelevent@gmail.com

 

Abstract

Gene therapy is an innovative medical approach that involves altering or replacing defective genetic material to treat or potentially cure genetic disorders. This technique primarily uses viral or non-viral vectors to deliver genetic material into cells, aiming to restore normal gene function. The therapy has the potential to address a wide range of diseases, including genetic, cardiovascular, and neurodegenerative disorders. In this review, the focus will be on gene therapies related to kidney diseases. Topics to be covered include the use of messenger ribonucleic acid (mRNA) therapies for conditions such as hypertension and kidney cancer, as well as targeted gene therapies using small interfering RNA (siRNA) and adeno-associated viruses to treat glomerular diseases and prevent kidney damage. The application of gene therapies in treating well-known genetic conditions, such as Alport syndrome and cystinosis, will also be discussed. Additionally, the review will explore the progress of RNA interference (RNAi) therapies in acute kidney injury (AKI) and chronic kidney disease (CKD). Finally, the challenges and risks associated with gene therapy, including immune responses, insertional mutagenesis, and the high costs of treatment, will be examined. 

Keywords: Gene Therapy, Kidney Diseases, Molecular Nephrology, Nephrogenetics

Introduction to Gene Therapy

Gene therapies represent a cutting-edge approach in modern medicine, offering the potential to treat or even cure a range of genetic disorders by altering or replacing the genetic material within the cells. Gene replacement therapies generally use viral (adenovirus, or lentivirus) or non-viral vectors to transfer the new genetic material. These therapies aim to reconstitute the expression of the mutant genes responsible for recessively or dominantly inherited genetic disorders, such as cancer, cardiovascular, and neurodegenerative diseases. Some therapies are based on delivering genetic material without integrating into the patient’s genome. On the other hand, some therapies including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 (CRISPR-Cas9) can provide long-lasting or permanent potential therapeutic effects by inserting, removing, or altering genetic sequences [1].

 

Gene Therapy in Kidney Diseases

Chronic kidney disease (CKD) is a major global health problem, affecting approximately 10-15% of the adult population worldwide. Beyond its impact on morbidity and mortality, CKD significantly impairs patients’ quality of life and imposes a substantial economic burden on healthcare systems due to the high costs of long-term medical care and renal replacement therapies [2, 3]. While acquired causes remain prevalent, a growing body of evidence highlights the important role of genetic factors in the etiology of kidney diseases [4]. Advances in genetic sequencing technologies have dramatically increased the recognition of inherited kidney diseases, revealing that up to 20-30% of early-onset or familial cases have an identifiable genetic basis [5, 6]. Becherucci et al. developed a multi-stage diagnostic approach consisting of patient selection based on specific referral criteria, whole exome sequencing (WES), reverse phenotyping and multidisciplinary board evaluation to make the diagnosis of genetic kidney diseases more efficient and cost-effective. This method achieved a 67% diagnosis rate, confirming the clinical prediagnosis in 48% of cases and changing the diagnosis in 19%. Genetic diagnosis was achieved in 64% of children and 70% of adults. Cost analysis showed that early genetic testing resulted in cost savings of 20-41% per patient. Thus, a model of genetic diagnosis with high diagnostic success and economic advantage is possible [7]. However, current management strategies for many genetic kidney diseases remain largely symptomatic, aiming to slow disease progression and address complications rather than correct the underlying genetic defects. In this context, gene-based therapies have emerged as a promising frontier in nephrology, offering the potential to directly target the molecular causes of disease.

Messenger ribonucleic acid (mRNA) therapies for kidney diseases are still largely experimental, with preclinical studies showing promising results [8]. For instance, a study on hypertension showed that zilebesiran, a ribonucleic acid (RNA) interference (RNAi) drug, effectively lowers blood pressure by targeting hepatic angiotensinogen [9]. mRNA vaccines have also been explored for treating kidney cancer, showing promising results in early studies [10].

A targeted gene therapy using small interfering RNA (siRNA) may be delivered via specialized nanoparticles to treat kidney diseases. The nanoparticles, made of siRNA and cationic liposomes coated with PAI-1R, specifically target glomerular cells. When tested in a nephritic rat model, the therapy effectively reduced transforming growth factor-β1 (TGF-β1) levels in the glomeruli, improving glomerulosclerosis without affecting other organs. This approach shows promise for treating kidney diseases by specifically silencing mutant genes in the glomeruli [11]. Additionally, thymosin β4 (TB4), an actin-sequestering peptide, plays a crucial role in maintaining podocyte cytoskeleton integrity. A lack of endogenous TB4 exacerbates podocyte injury. Administration of an adeno-associated viral vector (AAV) encoding TB4, increased circulating TB4 levels, preventing adriamycin-induced podocyte loss and albuminuria. TB4 gene therapy also restored the disorganized actin cytoskeleton in vitro. These findings suggest that systemic gene therapy with TB4 expression could prevent podocyte injury and maintain glomerular filtration, offering a novel treatment strategy for nephrotic syndrome [12].

Gene therapies may be useful in Alport syndrome, a disease with a well-known genetic mechanism. It is caused by mutations in the genes for alpha 3, alpha 4, and alpha 5 chains of type IV collagen. This condition leads to symptoms such as hematuria, proteinuria, progressive kidney dysfunction, hearing loss, and eye problems. The mutation results in an abnormal collagen network in the glomerular basement membrane, impairing kidney function. Current conservative treatments, like angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or mineralocorticoid receptor antagonists have limited effectiveness. Gene therapy offers a potential solution by aiming to correct the mutations and restore normal collagen production. Advances in recombinant AAVs are making progress in kidney gene therapy, with ongoing research focused on developing effective treatments for Alport syndrome [13].

Investigational gene therapies can also be used to treat some clinical conditions that do not have a clear genetic basis. Acute kidney injury (AKI) is a serious condition with significant morbidity, even mortality and no definitive treatment. The RNAi is a potential solution by using engineered red blood cell-derived extracellular vesicles (REVs) to deliver therapeutic siRNAs to injured kidneys. The REVs, tagged with a peptide that binds to kidney injury molecule-1 (KIM-1), specifically targeted damaged kidney tubules in mouse models. They successfully delivered siRNAs targeting the transcription factors P65 and snail family transcriptional repressor 1 (Snai1), which are involved in inflammation and fibrosis. Therefore, anti-inflammatory and anti-fibrotic effects of this treatment lead to an improvement in kidney function and prevention of progression to chronic kidney disease (CKD) [14]. However, some patients may develop CKD despite all interventions. CKD is primarily driven by progressive fibrosis, making it essential to target and reverse the profibrotic processes in affected tissues. Nanoparticles offer a new method for delivering antifibrotic treatments directly to the kidneys. Chitosan nanoparticles coated with hyaluronan can deliver plasmid DNA encoding bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor/NK1 (HGF/NK1) to the kidneys. These nanoparticles promote cellular growth and reduce fibrosis by inhibiting fibrotic gene expression. When administered to mice with unilateral ureteral obstruction, the nanoparticles successfully delivered about 40-45% of the genetic material to the kidneys. This treatment reduced fibrosis, improved kidney function, and either reversed fibrosis and regenerated tubules or halted CKD progression and reduced collagen deposition [15].

Kidney transplantation is the best option among kidney replacement therapies in patients who develop kidney failure. However, ischemia-reperfusion injury can sometimes lead to adverse outcomes [16]. Normothermic machine perfusion (NMP) is a state-of-the-art method of organ preservation that overcomes the limitations of traditional hypothermic techniques in solid organ transplantation. It allows for the assessment and recondition of organs prior to transplantation and enables the delivery of therapeutic agents to organs. In a recent study, an oligonucleotide-based therapy, antagomir targeting microRNA-24-3p was successfully delivered to human kidneys during NMP. This treatment localized to the endothelium and proximal tubular cells of the kidney, showed specific interaction with the microRNA target and increased the expression of associated genes. It demonstrated a potential to target and block harmful microRNAs prior to transplantation [17]. Thus, it may be beneficial in increasing graft survival in kidney transplantation.

Investigational gene therapies have also been used in certain systemic diseases affecting the kidney such as cystinosis. Cystinosis, a lysosomal storage disorder caused by mutations in the CTNS gene, leads to cystine buildup due to the loss of cystinosin function. The kidneys are the most affected organs, with damage progressing to kidney failure. While cysteamine is the current treatment, it only lowers cystine levels without restoring kidney function and has significant side effects [18]. In a study, synthetic mRNA can successfully restore cystinosin expression in CTNS-/- kidney cells and zebrafish following delivery via lipofection. A single dose of CTNS mRNA reduced cellular cystine for up to 14 days in vitro and improved kidney function in zebrafish, enhancing tubular reabsorption, reducing proteinuria, and restoring key receptor functions. That study provides early evidence that mRNA-based therapies could offer a new approach to treating cystinosis by restoring cystinosin expression and improving kidney function [19]. In another study, hematopoietic stem cell (HSC) transplantation shows potential for treating cystinosis by delivering a functional CTNS gene to various organs. A clinical trial of allogeneic HSC transplantation in a cystinosis patient led to improved symptoms but severe complications, underscoring the risks. As a safer alternative, a Phase I/II trial is exploring autologous HSC transplantation, where a patient’s HSCs are genetically modified to express CTNS, potentially reducing risks and offering new treatment options [20].

As can be seen, gene therapies are being tested in the treatment of various diseases in the field of nephrology. However, so far, gene therapy has only been approved for the treatment of primary hyperoxaluria [21]. Primary hyperoxaluria (PH) type 1 (PH1) is a rare autosomal recessive genetic disorder caused by mutations in the AGXT gene. This condition impairs the enzyme alanine glyoxylate aminotransferase (AGT), leading to oxalate overproduction and subsequent kidney damage, including nephrocalcinosis, nephrolithiasis, chronic kidney disease, kidney failure. Systemic oxalosis may also be seen. Conventional medical treatments for PH1 are generally inefficacious except for pyridoxine in cases with pyridoxine-sensitive mutations. Current strategies mainly involve targeting the liver to block oxalate production. Lumasiran is the first RNAi therapy approved for PH1, receiving approval from the US Food and Drug Administration and the European Union in November 2020. The phase III trials demonstrated that lumasiran effectively lowers oxalate levels in urine and plasma across various patient groups, including children, adults, and those with advanced kidney disease with a good safety profile [22, 23]. Nedosiran, another RNAi therapy, reduces hepatic lactate dehydrogenase activity, a key factor in all genetic forms of PH. In a double-blind study with 35 participants with PH1 or PH 2 (PH2) received either nedosiran or placebo monthly for 6 months, nedosiran significantly reduced plasma oxalate in PH1 and was generally well tolerated [24]. It was first approved in the USA in 2023 for PH1 patients aged 9 years and older with relatively preserved kidney function [25].

 

Challenges and Risks of Gene Therapy

Gene therapy has made remarkable progress over the past 50-60 years, with new treatments now available for previously untreatable diseases. While advancements in gene editing technologies have significantly improved the precision and feasibility of these treatments, their clinical application is still carefully regulated due to potential risks. The immune system may react to the viral vector used in therapy, causing inflammation, fever, or more serious reactions [26]. Another potential side effect is called insertional mutagenesis, where the therapeutic gene integrates into the wrong part of the genome. This can disrupt the function of other genes and lead to cancer or other disorders [27]. Additionally, the therapy may affect non-target cells or tissues, resulting in unintended tissue damage [28]. Even if the therapeutic gene is placed in the right position, overproduction can lead to inflammation or tissue damage may occur [29]. Despite its effectiveness, there might be serious adverse events, such as thrombotic microangiopathy or immune hepatitis, associated with viral vector-based gene therapies [30]. The long-term effects of gene therapies are not yet fully understood. Factors such as the impact on future generations or the long-term presence of the therapeutic gene are still under investigation [31]. From an economic perspective, high costs for these therapies pose significant barriers to access. This issue may be exacerbated by complex health insurance systems. Recent discussions highlight the need for solutions to make these therapies more affordable and accessible, ensuring that advancements in gene therapy benefit all patients equally and fairly [32].

 

Conclusion

Gene therapy has made remarkable progress in recent years, offering promising therapeutic potential for a variety of genetic and acquired kidney diseases. However, despite the scientific progress, the high costs and limited accessibility of these therapies present significant challenges to widespread adoption. Moving forward, ongoing research is essential to refine the safety and efficacy of gene therapies, while addressing economic and logistical barriers to ensure equitable access for all patients. The future of gene therapy holds great promise, with the potential to transform the treatment landscape for kidney diseases, offering hope where conventional therapies have been limited.

 

Bibliography

  1. Steffin DHM, Hsieh EM, Rouce RH (2019) Gene Therapy: Current Applications and Future Possibilities. Adv Pediatr 66:37-54. https://doi.org/10.1016/j.yapd.2019.04.001.
  2. Sahu G, Arora P, Tiwari P, D’Cruz S, Tahlan A (2025) The impact of chronic kidney disease on health-related quality of life (HRQoL): key insights from a hospital-based cross-sectional study. J Bras Nefrol 47:e20240229. https://doi.org/10.1590/2175-8239-JBN-2024-0229en.
  3. Memirie ST, Habtemichael M, Hailegiorgis HG, Juhar LH, Berhane T, Tesfaye S, et al (2025) Out-of-pocket expenditure and financial risks associated with treatment of chronic kidney disease in Ethiopia: a prospective cohort costing analysis. BMJ Glob Health 10:e019074. https://doi.org/10.1136/bmjgh-2025-019074.
  4. Dai X, Yuan L (2025) Identification and validation of parthanatos-related genes in end-stage renal disease. Ren Fail 47:2519834. https://doi.org/10.1080/0886022x.2025.2519834.
  5. Connaughton DM, Kennedy C, Shril S, Mann N, Murray SL, Williams PA, et al (2019) Monogenic causes of chronic kidney disease in adults. Kidney Int 95:914-928. https://doi.org/10.1016/j.kint.2018.10.031.
  6. Torra R, Furlano M, Ortiz A, Ars E (2021) Genetic kidney diseases as an underrecognized cause of chronic kidney disease: the key role of international registry reports. Clin Kidney J 14:1879-1885. https://doi.org/10.1093/ckj/sfab056.
  7. Becherucci F, Landini S, Palazzo V, Cirillo L, Raglianti V, Lugli G, et al (2023) A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases. J Am Soc Nephrol 34:706-720. https://doi.org/10.1681/asn.0000000000000076.
  8. Granata S, Stallone G, Zaza G (2023) mRNA as a medicine in nephrology: the future is now. Clin Kidney J 16:2349-2356. https://doi.org/10.1093/ckj/sfad196.
  9. Khan RS, Frishman WH (2024) Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis. Cardiol Rev. https://doi.org/10.1097/crd.0000000000000645.
  10. Xu H, Zheng X, Zhang S, Yi X, Zhang T, Wei Q, Li H, Ai J (2021) Tumor antigens and immune subtypes guided mRNA vaccine development for kidney renal clear cell carcinoma. Mol Cancer 20:159.
  11. Liu X, Zhang J, Tang A, Xu L, Huang Y (2022) A novel peptide ligand-coated nano-siRNA-lipoplex technology for kidney targeted gene therapy. Am J Transl Res 14:7362-7377.
  12. Mason WJ, Jafree DJ, Pomeranz G, Kolatsi-Joannou M, Rottner AK, Pacheco S, et al (2022) Systemic gene therapy with thymosin β4 alleviates glomerular injury in mice. Sci Rep 12:12172. https://doi.org/10.1038/s41598-022-16287-z.
  13. Zhao Y, Zheng Q, Xie J (2024) Exploration of Gene Therapy for Alport Syndrome. Biomedicines 12:1159. https://doi.org/10.3390/biomedicines12061159.
  14. Tang TT, Wang B, Li ZL, Wen Y, Feng ST, Wu M, et al (2021) Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI. J Am Soc Nephrol 32:2467-2483. https://doi.org/10.1681/asn.2020111561.
  15. Midgley AC, Wei Y, Zhu D, Gao F, Yan H, Khalique A, et al (2020) Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy. J Am Soc Nephrol 31:2292-2311. https://doi.org/10.1681/asn.2019111160.
  16. Medyńska A, Kiliś-Pstrusińska K, Makulska I, Zwolińska D (2020) Kidney transplantation and other methods of renal replacement therapy in children: 30 years of observations in one center. Adv Clin Exp Med 29:611-613.
  17. Thompson ER, Sewpaul A, Figuereido R, Bates L, Tingle SJ, Ferdinand JR, et al (2022) MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys. Am J Transplant 22:1088-1100. https://doi.org/10.1111/ajt.16929.
  18. Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E (2016) Cystinosis: a review. Orphanet J Rare Dis 11:47. https://doi.org/10.1186/s13023-016-0426-y.
  19. Bondue T, Berlingerio SP, Siegerist F, Sendino-Garví E, Schindler M, Baelde HJ, et al (2023) Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis. Sci Rep 13:20961. https://doi.org/10.1038/s41598-023-47085-w.
  20. Jamalpoor A, Othman A, Levtchenko EN, Masereeuw R, Janssen MJ (2021) Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis. Trends Mol Med 27:673-686. https://doi.org/10.1016/j.molmed.2021.04.004.
  21. Gang X, Liu F, Mao J (2023) Lumasiran for primary hyperoxaluria type 1: What we have learned? Front Pediatr 10:1052625. https://doi.org/10.3389/fped.2022.1052625.
  22. Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O’Riordan WD, Cochat P, et al; ILLUMINATE-A Collaborators (2021) Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med 384:1216-1226. https://doi.org/10.1056/nejmoa2021712.
  23. Michael M, Groothoff JW, Shasha-Lavsky H, Lieske JC, Frishberg Y, Simkova E, et al (2023) Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial. Am J Kidney Dis 81:145-155.e1. https://doi.org/10.1053/j.ajkd.2022.05.012.
  24. Baum MA, Langman C, Cochat P, Lieske JC, Moochhala SH, Hamamoto S, et al; PHYOX2 study investigators (2023). PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2. Kidney Int 103:207-217. https://doi.org/10.1016/j.kint.2022.07.025.
  25. US Food and Drug (2023) Drug Approval Package: RIVFLOZA. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/215842Orig1s000TOC.cfm Accessed 23 December 2024.
  26. Ertl HCJ (2022) Immunogenicity and toxicity of AAV gene therapy. Front Immunol 13:975803. https://doi.org/10.3389/fimmu.2022.975803
  27. Hackett PB, Largaespada DA, Switzer KC, Cooper LJ (2013) Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Transl Res 161:265-283. https://doi.org/10.1016/j.trsl.2012.12.005.
  28. Waehler R, Russell SJ, Curiel DT (2007) Engineering targeted viral vectors for gene therapy. Nat Rev Genet 8:573-587. https://doi.org/10.1038/nrg2141.
  29. Uddin F, Rudin CM, Sen T (2020) CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front Oncol 10:1387. https://doi.org/10.3389/fonc.2020.01387.
  30. Schwotzer N, El Sissy C, Desguerre I, Frémeaux-Bacchi V, Servais L, Fakhouri F (2024) Thrombotic Microangiopathy as an Emerging Complication of Viral Vector-Based Gene Therapy. Kidney Int Rep 9:1995-2005. https://doi.org/10.1016/j.ekir.2024.04.024.
  31. Uddin F, Rudin CM, Sen T (2020) CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front Oncol 10:1387. https://doi.org/10.3389/fonc.2020.01387.
  32. Harrison PT, Friedmann T (2023) Cost of gene therapy. Gene Ther 30:737. https://doi.org/10.1038/s41434-023-00408-y.