Renal Colic

Renal colic is characterized by severe, acute pain originating in the flank or back, typically radiating to the groin. This intense pain is primarily caused by the obstruction of the urinary tract, most commonly due to the passage of kidney stones (nephrolithiasis) from the kidney into the ureter. It represents a significant and distressing medical emergency for many individuals worldwide.

Biological Basis

The underlying biological mechanism of renal colic involves the formation of calculi (stones) within the kidneys, which can then migrate and obstruct the flow of urine through the ureter. This obstruction leads to increased pressure within the urinary tract and distension of the renal capsule, triggering nociceptive pain signals. Kidney stones are predominantly composed of calcium oxalate or calcium phosphate, but can also be made of uric acid, struvite, or cystine. Genetic predisposition plays a role in the formation of various stone types. For instance, genes involved in urate transport and metabolism, such asSLC22A12, SLC17A1, NIPAL1, FAM35A, ABCG2, and SLC2A9, have been identified in studies related to gout and renal underexcretion of uric acid, a condition that can lead to uric acid stone formation.^[1] Additionally, the STC1gene, which encodes stanniocalcin 1, is involved in calcium and phosphate homeostasis and may influence renal stone formation.^[1]

Clinical Relevance

Clinically, renal colic presents with sudden onset excruciating pain, often accompanied by nausea, vomiting, and hematuria (blood in the urine). Diagnosis typically involves symptom assessment, urinalysis, and imaging studies such as computed tomography (CT) scans or ultrasound to locate the stone and assess the degree of obstruction. Management strategies focus on pain relief, often with non-steroidal anti-inflammatory drugs (NSAIDs) or opioids, and facilitating stone passage. Depending on stone size and location, interventions may range from conservative management (hydration, alpha-blockers) to surgical procedures like lithotripsy (shock wave or ureteroscopic) or ureteral stenting. Renal colic carries a high risk of recurrence, necessitating preventive measures such as dietary modifications, increased fluid intake, and sometimes medication to prevent future stone formation.

Social Importance

Renal colic is a prevalent condition with considerable social and economic impact. Its high incidence worldwide contributes significantly to emergency department visits, hospital admissions, and healthcare costs associated with diagnosis, treatment, and follow-up care. The severe pain experienced by individuals with renal colic can lead to significant reductions in quality of life, loss of productivity, and considerable personal distress. Understanding the genetic underpinnings and risk factors associated with kidney stone formation and renal colic is crucial for developing more effective prevention strategies and personalized treatment approaches.

Limitations

Challenges in Study Design and Statistical Interpretation

Genetic association studies, while powerful, are often constrained by their design and statistical power. Many investigations rely on sample sizes that, despite being large, may still be modest for detecting variants with very small effect sizes, common in complex traits . Similarly, the expression of FANCM in renal glomeruli and arteries is influenced by variants like rs3783702 and rs10138997 , highlighting the broad impact of genetic variation on kidney function. ^[2]

Variations affecting RASGRF1 activity, such as rs139147290 , could impair the kidney’s cellular homeostasis, potentially making it more susceptible to injury, inflammation, or abnormal proliferation—processes often linked to conditions that lead to renal colic. For example, ifRASGRF1 variants lead to altered cell cycle regulation, this could impact tissue repair or contribute to conditions where cells behave abnormally, such as in stone formation or inflammatory responses within the kidney. Genes like HIST1H2BF and HIST1H4E encode histone proteins that regulate DNA binding and chromatin structure, influencing cell cycle and cellular responses to inflammation in the kidney and intestine. ^[1]Furthermore, conditions like acute kidney injury (AKI), which can contribute to chronic kidney disease and potentially predispose to renal colic, have been linked to genetic factors, including variants inBBS9, a gene involved in ciliary function critical for renal recovery from injury. ^[3]

Beyond cellular signaling, other genetic factors contribute to the complex etiology of renal health, with implications for conditions like renal colic. Imbalances in calcium and phosphate homeostasis are directly relevant to kidney stone formation, a primary cause of renal colic. TheSTC1gene, for instance, encodes stanniocalcin 1, a hormone highly expressed in the renal nephron that influences local calcium and phosphate balance and possesses anti-inflammatory properties.^[4] Similarly, variations impacting extracellular matrix components, such as those near the ACAN gene (variant rs111283115 ), could affect renal structural integrity and development, potentially contributing to conditions that increase susceptibility to kidney problems. ^[1] The interplay of such diverse genetic influences, including those affecting fundamental cellular processes like those regulated by RASGRF1, underscores the complex genetic underpinnings of kidney health and disease susceptibility.

Causes of Renal Colic

Renal colic, typically resulting from conditions affecting kidney function and urinary tract integrity, stems from a complex interplay of genetic predispositions, environmental factors, and comorbidities. These factors can contribute to the development of kidney stones or other obstructions that manifest as acute pain.

Genetic Determinants of Kidney Health and Urate Metabolism

Genetic factors play a significant role in influencing an individual’s susceptibility to conditions that lead to renal colic by affecting kidney function and the metabolism of substances like uric acid. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with traits related to kidney function, including estimated glomerular filtration rate (eGFR) and serum creatinine levels, as well as uric acid concentration.^[5] For instance, specific variants in genes such as MPPED2-DCDC5, CPS1, RGS14, STC1, RNASEH2C-OVOL1, and SLC6A13 have been linked to measures of kidney function. ^[5] The CPS1gene, coding for carbamoyl-phosphate synthase 1, notably exhibits divergent effects on renal function and cystatin C production, indicating its complex role in metabolic pathways relevant to kidney health.^[6]

Beyond general kidney function, genetic variants influencing uric acid metabolism are particularly relevant, given that high uric acid levels can lead to gout and urate kidney stones. GWAS of gout subtypes have identified loci inGCKR, SLC2A9, ABCG2, and CUX2as commonly associated with the pathogenesis of gout.^[1]Specifically for conditions characterized by renal underexcretion (RUE) of uric acid, additional loci inSLC22A12, NIPAL1, and FAM35A have been identified, with SLC22A12being a known urate reabsorption transporter.^[1]These genetic predispositions can alter the balance of uric acid excretion and reabsorption, increasing the risk for crystal formation in the kidneys that can obstruct urine flow and cause colic.

Environmental and Lifestyle Influences

Environmental and lifestyle factors are critical contributors to the development of conditions underlying renal colic, often by impacting metabolic processes and overall kidney health. Dietary habits, physical activity levels, alcohol consumption, and smoking have been identified as lifestyle-associated factors that can influence acquired risk factors relevant to kidney disease.^[7]Obesity, a significant lifestyle-related factor, is strongly linked to kidney disease, particularly in individuals with type 1 and type 2 diabetes.^[8] This connection highlights how widespread environmental factors can exacerbate underlying susceptibilities to kidney impairment.

These external influences can contribute to metabolic imbalances that predispose individuals to kidney stone formation or other renal complications. For example, specific dietary patterns can alter urine composition, leading to supersaturation of stone-forming minerals. While the direct mechanisms for renal colic are complex, these lifestyle elements contribute to a broader environment within the body that impacts kidney function and the likelihood of developing conditions that may precipitate colic.

Gene-Environment Interactions and Epigenetic Mechanisms

The development of conditions leading to renal colic often involves intricate interactions between an individual’s genetic makeup and their environment, sometimes mediated by epigenetic modifications. Research indicates that gene-environment interactions, rather than solely strong gene-gene interactions, may play a more significant role in triggering kidney disease, such as observed withAPOL1 variants in African Americans with nondiabetic nephropathy. ^[9] This suggests that certain genetic predispositions require specific environmental triggers to manifest their pathological effects on kidney health.

Furthermore, lifestyle-associated factors may indirectly influence acquired risk factors through epigenetic modification, although this area warrants further study.^[7]Epigenetic mechanisms, such as changes in DNA methylation or histone modifications, can alter gene expression without changing the underlying DNA sequence. For instance, histone genes and their expression levels in the kidney and intestine are noted for their potential role in reaction to inflammation, implying an epigenetic link to kidney function.^[1]These interactions demonstrate a dynamic interplay where environmental exposures can modulate genetic risk, affecting kidney physiology and increasing vulnerability to conditions like renal colic.

Comorbidities and Age-Related Dynamics

Several existing health conditions, or comorbidities, significantly increase the risk for developing renal colic, alongside age-related physiological changes. Type 2 diabetes is a major comorbidity associated with kidney disease, often presenting with insulin resistance, hypertension, and microalbuminuria, all of which can impair renal function.^[8]Obesity further compounds this risk in diabetic individuals, directly contributing to kidney pathology.^[8]Similarly, gout, a condition characterized by high uric acid levels, is a strong risk factor for urate kidney stones, which are a common cause of renal colic.^[1]

Age is also a critical contributing factor, as the prevalence of kidney dysfunction and stone formation can increase with advancing age. While often adjusted for as a covariate in studies, the cumulative effect of age on kidney health, including changes in glomerular filtration rate and metabolic processes, can heighten susceptibility to conditions leading to renal colic.^[4]Additionally, the use of certain medications, such as uric acid-lowering therapies (e.g., allopurinol, benzbromarone, probenecid), are typically excluded in studies investigating baseline uric acid concentrations, implying their significant impact on the very metabolic pathways that, when dysregulated, can lead to conditions causing renal colic.^[5]

Biological Background

Renal Physiology and Homeostatic Regulation

Kidney function is crucial for systemic homeostasis, involving processes like filtration, reabsorption, and the activation of regulatory systems. Impaired kidney function, as seen in various kidney diseases, can activate the renin-angiotensin-aldosterone system (RAAS), a key hormonal cascade that regulates blood pressure and fluid balance^[2]. This system includes critical biomolecules such as renin and aldosterone, whose dysregulation can lead to chronic conditions like hypertension, further impacting kidney health and function^[2]. The efficient transport of molecules, including urate, is also vital, with transporters likeSLC22A12playing a role in urate reabsorption within the renal tubules^[1].

Monitoring renal health often involves markers like serum creatinine and Cystatin C (CyC), which are used to estimate the kidney’s filtration capacity ^[5]. However, the reliability of CyC as a kidney function marker can be compromised in contexts of acute disease or significant inflammation, where its levels may be influenced by factors beyond renal filtration^[6]. For example, Cystatin C secretion can be dynamically regulated in inflammatory conditions and is responsive to glucocorticoid treatment ^[6].

Cellular Pathways and Molecular Sensors

Within kidney cells, various molecular pathways maintain cellular integrity and respond to injury. One critical pathway involves calcium homeostasis, where proteins like RyR2 (ryanodine receptor 2) function as Ca2+ release channels on the sarcoplasmic reticulum membrane ^[3]. Abnormalities in RyR2function can disrupt calcium balance, contributing to cellular dysfunction and impacting processes like muscle contraction and electrical signaling^[3].

Cellular structures like cilia also play a significant role as signal transduction antennae, sensing damage and activating cell proliferation to promote recovery during kidney injury, such as ischemia/reperfusion^[3]. The proper functioning of ciliary proteins, like BBS9 (Bardet-Biedl syndrome protein 9), is essential for these protective mechanisms, and changes in BBS9 could contribute to higher complication rates concerning the kidney ^[3]. Additionally, Cystatin C, a potent cysteine protease inhibitor, is involved in immune regulation, with its secretion being induced by glucocorticoid agonists in inflammatory macrophages^[6].

Genetic Predisposition and Regulatory Networks

Genetic mechanisms contribute significantly to an individual’s susceptibility to kidney-related conditions. Genome-wide association studies (GWAS) have identified several loci associated with kidney function and disease, including specific susceptibility loci for gout, a condition often linked to kidney issues^[1]. Key genes like GCKR, SLC2A9, ABCG2, and CUX2are implicated in the pathogenesis of different gout subtypes, highlighting their role in metabolic regulation and transport processes^[1]. Furthermore, for renal underexcretion (RUE) gout, additional loci likeNIPAL1 and FAM35A have been identified, pointing to novel genetic contributors ^[1].

Beyond common variants, gene expression patterns themselves are subject to genetic influence and epigenetic modifications. For instance, the expression of the FANCM(Fanconi Anemia Complementation Group M) gene in renal glomeruli and arteries can differ based on an individual’s genotype at specific variants, such asrs3783702 and rs10138997 ^[2]. Certain histone genes in the kidney and intestine may influence cell cycle, cell amount, or response to inflammation by altering their expression levels, suggesting an epigenetic layer of regulation ^[1]. Familial clustering of diabetic kidney disease also points to strong genetic susceptibility^[10]. Genetic variants in various pathways can influence blood pressure and cardiovascular disease risk, further impacting kidney health^[11].

Pathophysiology of Kidney Dysfunction

Kidney dysfunction can manifest through various pathophysiological processes, ranging from acute injuries to chronic diseases like diabetic kidney disease and hypertensive kidney disease. Obesity and insulin resistance are recognized factors contributing to diabetic kidney disease, often preceding microalbuminuria and a faster decline in renal function^[12]. In acute contexts, such as post-cardiac surgery, the kidneys can suffer acute injury, where mechanisms like ischemia/reperfusion damage and ciliary dysfunction play a role in disease progression and recovery^[3].

The systemic consequences of kidney dysfunction extend beyond the organ itself. For example, the activation of the RAAS due to impaired kidney function can exacerbate hypertension, creating a vicious cycle that further damages renal tissues^[2]. Additionally, systemic inflammation, as seen in conditions like COVID-19, can significantly impact kidney function, where Cystatin C levels are dynamically regulated and correlate with patient outcomes, underscoring the kidney’s interconnectedness with broader systemic health and immune responses ^[6].

Pathways and Mechanisms

Renal Cell Signaling and Adaptive Responses

In renal cells, specific signaling pathways mediate growth, adaptation, and disease pathogenesis. High activation of the AKT pathway has been observed in human multicystic renal dysplasia, indicating its role in developmental anomalies.^[13]Similarly, mammalian target of rapamycin (mTOR) signaling plays a crucial role in compensatory renal hypertrophy, a mechanism by which the kidney adapts to reduced functional mass.^[14]Furthermore, impaired kidney function can activate the renin-angiotensin-aldosterone system (RAAS), a key regulatory mechanism for blood pressure and fluid balance that has implications for hypertensive kidney disease.^[2]

Genetic Regulation of Kidney Function and Metabolic Processes

Genetic regulation plays a significant role in determining kidney function and metabolic health. The glucocorticoid receptor directly targets CST3, leading to its glucocorticoid-responsive secretion, a mechanism observed in macrophages and cancer cells.^[6] Expression of the FANCM gene in renal glomeruli and arteries varies with genotypes like rs3783702 and rs10138997 , highlighting genetic influences on kidney disease susceptibility.^[2] Furthermore, genes such as ABCG2 and FTOare associated with chronic kidney disease (CKD), withABCG2having implications in gout andFTOlinking to metabolic disturbances like diabetes, hypertension, and hyperlipidemia.^[15]

Systemic Integration and Metabolic Dysregulation

Kidney health is deeply integrated with systemic metabolic and inflammatory processes. Obesity and insulin resistance are recognized factors contributing to diabetic kidney disease, reflecting a complex interplay of metabolic dysregulation.^[16] The FTOgene, for instance, is associated with a “triad” of diabetes, hypertension, and hyperlipidemia, underscoring its role in systemic metabolic disorders that can predispose to chronic kidney disease.^[15]Such interconnected metabolic pathways influence overall renal function, with markers like creatinine, a breakdown product of muscle creatine metabolism, used to estimate kidney filtration.^[6]

Molecular Dysregulation and Disease Susceptibility

Dysregulation of molecular pathways and genetic predispositions are central to kidney disease susceptibility. For example,APOL1gene-environment interactions are more likely to trigger kidney disease in African Americans with nondiabetic nephropathy than strongAPOL1-second gene interactions. ^[9] Genes like CHRM3, STAB1, WDR72, BHLHE22, ABCG2, ZMAT4, MAT2B, and RABGAP1have been associated with chronic kidney disease, highlighting a polygenic risk architecture.^[15]Understanding these complex genetic and environmental interactions, along with the specific signaling pathways involved in conditions like diabetic and hypertensive kidney disease, offers potential avenues for identifying therapeutic targets.^[8]

Clinical Relevance

The clinical relevance of understanding renal function, genetic predispositions, and associated conditions is paramount for comprehensive patient care, particularly in contexts like renal colic where acute events can impact long-term kidney health. Advanced diagnostic and prognostic tools, alongside a deeper understanding of genetic influences, enable more precise risk assessment, tailored treatment strategies, and proactive monitoring to prevent or mitigate disease progression.

Assessment and Prognosis of Renal Function

The accurate assessment of renal function is critical in managing conditions impacting kidney health, such as renal colic. Biomarkers like plasmaCystatin C (CyC) and serum creatinine are widely utilized to estimate glomerular filtration rate (eGFR), with equations such as CKD-EPI providing quantifiable measures of kidney function ^[6]. ^[4]These eGFR calculations offer significant prognostic value, indicating potential outcomes, disease progression, and treatment response, especially for individuals with compromised renal status or those at risk of chronic kidney disease (CKD) following acute kidney events. For instance, a creatinine-Cystatin C (C2) ratio can be computed at various timepoints to further refine the assessment of renal health and predict future complications. ^[6]

Monitoring strategies that incorporate these markers are essential for tracking kidney function trajectories. Elevated Cystatin Clevels, for example, have been observed to be glucocorticoid responsive and can be indicative of underlying disease states, extending beyond a passive marker of renal function.^[6] The consistent application of these diagnostic utilities allows clinicians to identify patients at higher risk for adverse renal outcomes, guide treatment selection, and implement early interventions. This is particularly relevant in conditions where acute obstruction can rapidly alter kidney function.

Genetic Predisposition and Risk Stratification for Kidney Disease

Genetic factors play a substantial role in predisposing individuals to various renal conditions, influencing risk stratification and the potential for personalized medicine approaches. Genome-wide association studies (GWAS) have identified multiple loci associated with indices of renal function and CKD, underscoring the genetic architecture of kidney diseases. ^[4]For example, polygenic risk scores (PRS) for CKD have demonstrated utility in identifying high-risk individuals, providing a tool to predict disease onset or progression based on an individual’s genetic profile.^[17]Such risk stratification can inform prevention strategies, allowing for targeted screening or early lifestyle modifications in those genetically predisposed to kidney dysfunction.

Specific genetic variants, such as APOL1renal-risk variants, have been implicated in kidney disease in African American populations, highlighting the importance of ancestry-specific genetic insights in personalized medicine^[17]. ^[17]These genetic insights are not only valuable for predicting long-term implications of kidney disease but also for understanding treatment responses, such as in renal transplant outcomes.^[17] Integrating genetic risk information into clinical practice can lead to more nuanced patient management and potentially prevent severe complications by identifying individuals who may benefit most from intensive monitoring or prophylactic measures.

Associated Renal Conditions and Long-term Complications

Renal colic, typically caused by kidney stones, can be a gateway to various associated renal conditions and long-term complications, including acute kidney injury and progression to chronic kidney disease (CKD). Understanding the genetic and clinical factors related to these comorbidities is essential for comprehensive patient care. For instance, genetic susceptibility to diabetic kidney disease (DKD) has been elucidated through GWAS, which is crucial given the metabolic links between diabetes and kidney health, including kidney stone formation.^[4]

Furthermore, conditions such as congenital solitary functioning kidney, identified through GWAS, represent intrinsic renal abnormalities that can influence kidney health throughout a patient’s life and potentially exacerbate the impact of acute events like renal colic.^[18]Renal cell carcinoma (RCC), while distinct from renal colic, shares some risk factors like obesity and hypertension and represents another serious kidney pathology where genetic predisposition and early detection are crucial for prognosis.^[7]A comprehensive approach considering these overlapping phenotypes and potential complications allows for better long-term management and improved patient outcomes beyond the immediate resolution of renal colic.

Key Variants

RS ID	Gene	Related Traits
rs139147290	RASGRF1	renal colic

Frequently Asked Questions About Renal Colic

These questions address the most important and specific aspects of renal colic based on current genetic research.

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1. My dad had kidney stones; will I definitely get them too?

Not necessarily, but your risk is higher. Genetics play a significant role in kidney stone formation, and predispositions for certain stone types, like those involving uric acid or calcium, can run in families. Knowing your family history is important for early prevention.

2. If my family gets stones, can my diet still really help prevent them?

Yes, absolutely. While genetics influence your susceptibility, dietary modifications and maintaining high fluid intake are crucial preventive measures. These lifestyle changes can significantly reduce the chances of stone formation, even with a genetic predisposition.

3. I already had a kidney stone. Does that mean I’m just prone to getting more?

Unfortunately, yes, there’s a high risk of recurrence. Genetic factors can make certain individuals more susceptible to forming stones. However, proactive measures like increased fluid intake, dietary changes, and sometimes medication can help prevent future episodes.

4. Why do some people get different kinds of kidney stones?

Different genetic factors influence the type of stone formed. For instance, specific genes involved in how your body handles urate, likeSLC22A12 or ABCG2, can lead to uric acid stones. Other genes, such asSTC1, are related to calcium and phosphate balance, influencing those stone types.

5. My sibling eats the same as me but never gets stones. Why me?

Even within families, individual genetic variations can lead to different predispositions. While lifestyle plays a role, subtle genetic differences in how your body metabolizes substances like calcium or uric acid can make one sibling more susceptible to stone formation than another.

6. Does drinking water actually prevent stones, or is that just a myth?

It’s definitely not a myth; increased fluid intake is a crucial preventive measure. Drinking plenty of water helps dilute the concentration of stone-forming substances in your urine, making it less likely for crystals to form and accumulate into stones.

7. If I keep getting stones, could it lead to bigger kidney problems?

While renal colic is an acute issue, frequent stone formation can be a sign of underlying metabolic or genetic predispositions. Over time, recurrent stones can be associated with an increased risk of other kidney issues, so monitoring kidney health is important.

8. Can genetics help my doctor figure out the best way to prevent my stones?

Yes, understanding your genetic predispositions can be crucial. Knowing which specific genes, like those involved in urate transport or calcium homeostasis, might be influencing your stone formation can help tailor more effective and personalized prevention strategies, including diet or medication.

9. Can I predict if my kids might get kidney stones like me?

If you have a genetic predisposition, there’s an increased chance your children could inherit it. While not a certainty, understanding these genetic links can help you encourage preventive habits, like good hydration, from an early age for your kids.

10. This pain really affects my work. Is it really that common for people?

Yes, unfortunately, it’s a very common and severe condition globally. Renal colic significantly impacts quality of life, productivity, and can lead to frequent emergency visits and hospitalizations, highlighting its considerable social and economic importance.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[2] Kim HR, et al. “A Genome-Wide Association Study for Hypertensive Kidney Disease in Korean Men.”Genes (Basel). 2021.

[3] Westphal S, et al. “Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.”BMC Cardiovasc Disord. 2019.

[4] Kottgen, A. et al. “Multiple loci associated with indices of renal function and chronic kidney disease.”Nat Genet, 2009.

[5] Okada Y, et al. “Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations.” Nat Genet. 2012.

[6] Kleeman SO, et al. “Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.”Cell Genom. 2023.

[7] Hong, J. Y. et al. “Polygenic risk score model for renal cell carcinoma in the Korean population and relationship with lifestyle-associated factors.”BMC Genomics, 2024.

[8] van Zuydam, N. R. et al. “A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.”Diabetes, 2018.

[9] Langefeld, C. D. et al. “Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strongAPOL1-second gene interactions.” Kidney International, 2018.

[10] Seaquist ER, et al. “Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy.”N Engl J Med. 1989.

[11] Ehret GB, et al. “Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.”Nature. 2011.

[12] Maric-Bilkan C. “Obesity and diabetic kidney disease.”Med Clin North Am. 2013.

[13] Apostolou, A. et al. “High Activation of the AKT Pathway in Human Multicystic Renal Dysplasia.” Pathobiology, vol. 87, 2020, pp. 302–310.

[14] Chen, J.K. et al. “Role of mammalian target of rapamycin signaling in compensatory renal hypertrophy.” J. Am. Soc. Nephrol., vol. 16, 2005, pp. 1384–1391.

[15] Liu, T. Y. et al. “Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.”Science Advances, 2025.

[16] Karalliedde J, Gnudi L. “Diabetes mellitus, a complex and heterogeneous disease, and the role of insulin resistance as a determinant of diabetic kidney disease.”Nephrol Dial Transplant. 2016.

[17] Stapleton, C. P. “The Impact of Donor and Recipient Common Clinical and Genetic Variation on Estimated Glomerular Filtration Rate in a European Renal Transplant Population.” American Journal of Transplantation, 2019, PMID: 30920136.

[18] Groen In ‘t Woud, S. et al. “A Genome-Wide Association Study into the Aetiology of Congenital Solitary Functioning Kidney.” Biomedicines, 2022.