Endocrine disorders linked to chronic kidney disease: Mechanisms and clinical implications

Abstract

Chronic kidney disease (CKD) is a progressive condition that disrupts multiple endocrine axes, contributing to a broad range of hormonal imbalances, including mineral and bone disorder, gonadal dysfunction, thyroid abnormalities, insulin resistance, and elevated prolactin levels. These disturbances not only exacerbate comorbidities such as cardiovascular disease, anemia, diabetes, and sarcopenia, but may also accelerate the decline of renal function. This article aims to provide a comprehensive overview of the pathophysiology, clinical impact, and management strategies for endocrine disorders in CKD. A narrative literature search was conducted using PubMed, EMBASE, the Cochrane Library, and Scielo through July 2025, focusing on 141 studies addressing endocrine complications in CKD. The prevalence of hormonal dysfunction increases with CKD progression, affecting over 70% of patients in advanced stages. Disruptions in calcium and phosphate homeostasis lead to secondary hyperparathyroidism, vascular calcification, and bone fragility. Thyroid hormone alterations and testosterone deficiency contribute to reduced muscle mass, fatigue, and cardiovascular risk. Impaired glucose metabolism complicates glycemic control, particularly in dialysis and post-transplant populations. Diagnostic interpretation is often challenged by altered hormone clearance and protein binding. Therapeutic approaches require individualized strategies, including dietary and pharmacological correction of mineral imbalances, cautious hormone replacement, and use of agents such as dopamine agonists or sodium-glucose cotransporter-2 inhibitors. A multidisciplinary approach integrating nephrology and endocrinology is essential to improve outcomes and quality of life in this population.

Key Words: Chronic kidney disease; Endocrine dysfunction; Hormonal imbalance; Chronic kidney disease-mineral and bone disorder; Hypogonadism; Insulin resistance

Core Tip: Chronic kidney disease disrupts multiple endocrine pathways, leading to mineral and bone disorders, thyroid dysfunction, hypogonadism, insulin resistance, and prolactin elevation. These hormonal disturbances exacerbate cardiovascular disease, anemia, sarcopenia, and impaired quality of life. This narrative review synthesizes current evidence on mechanisms, diagnostic challenges, and therapeutic strategies for endocrine complications in chronic kidney disease. By highlighting the bidirectional relationship between kidney and endocrine dysfunction, it underscores the need for integrated nephrology-endocrinology management to optimize patient outcomes.

INTRODUCTION

Chronic kidney disease (CKD) is defined as a clinical condition characterized by persistent abnormalities in kidney structure or function lasting at least three months, with associated adverse consequences for health. To standardize diagnosis, prognosis, and treatment strategies, CKD is staged based on glomerular filtration rate (GFR; categories G1 to G5) and albuminuria levels (A1 to A3)[1]. Globally, CKD affects more than 700 million individuals, with a disproportionate burden in Asia, particularly in China and India. It ranks among the most prevalent chronic conditions in adults aged ≥ 65 years[2,3]. Beyond renal impairment, CKD is now recognized as a systemic disease with far-reaching consequences, including disruption of endocrine homeostasis. Hormonal dysregulation in CKD contributes to comorbid conditions such as type 2 diabetes mellitus (DM2), cardiovascular disease, and anemia, with direct implications for morbidity and mortality[4-6]. Notably, more than 25% of American adults present with overlapping cardio-renal-metabolic comorbidities, with CKD and DM2 being the most prevalent combination[7].

Despite this growing recognition, endocrine disturbances in CKD are often addressed in a fragmented manner[8-10]. While CKD-related mineral and bone disorder (MBD) has been incorporated into clinical practice guidelines, other hormonal alterations such as hypogonadism, thyroid dysfunction, and insulin resistance remain underexplored and poorly integrated into standard nephrology care[11,12].

This narrative review provides an integrative clinical perspective, examining the impact of CKD on key hormonal systems and elucidating the resulting pathophysiological and therapeutic implications. By synthesizing current evidence, the review aims to underscore the clinical relevance of endocrine dysfunction in CKD and advocate for its systematic inclusion in diagnostic and therapeutic frameworks for this complex multisystem disorder[13-15].

LITERATURE REVIEW

A narrative review was conducted to examine the pathophysiological mechanisms and clinical implications of endocrine disorders associated with CKD. The literature search was performed across four major databases: PubMed/MEDLINE, EMBASE, the Cochrane Library, and SciELO. The search strategy employed both Medical Subject Headings and free-text terms combined using Boolean operators. Key Medical Subject Headings terms included: “Kidney Diseases”, “Chronic Kidney Diseases of Uncertain Etiology”, and “Chronic Kidney Disease-Mineral and Bone Disorder”, in conjunction with terms such as “endocrine dysfunction”, “hormonal disturbances”, “thyroid disorders”, “insulin resistance”, “hypogonadism”, and “pathophysiology”. The final search was conducted in July 2025.

Inclusion criteria were limited to peer-reviewed articles published in English within the past ten years. Eligible studies included original research articles, randomized controlled trials, cohort studies, systematic reviews, and meta-analyses that addressed endocrine complications in the context of CKD. Exclusion criteria comprised non-peer-reviewed literature (e.g., conference abstracts, editorials, commentaries) and articles published prior to 2015.

This narrative format enabled an integrative synthesis of nephrological and endocrinological evidence, emphasizing hormonal axes commonly affected by CKD and their clinical relevance. A total of 141 articles that met the eligibility criteria were included in the final analysis, providing insights into underlying mechanisms, diagnostic considerations, and therapeutic implications of endocrine dysfunction in CKD.

EPIDEMIOLOGY

Progressive loss of renal function causes widespread endocrine disruption across all CKD stages, with manifestations becoming increasingly prominent as renal function declines, especially in stages 3 to 5 and among patients receiving dialysis[12,13,16].

Studies indicate that up to 70% of patients with advanced CKD (stages 4-5 or on dialysis) present with at least one clinically relevant endocrine disorder, commonly involving the parathyroid, thyroid, gonadal, adrenal, and pituitary axes, as well as glucose metabolism and prolactin regulation[16]. Hypogonadism is frequently observed in men with CKD and has been independently associated with increased cardiovascular risk, muscle wasting, and anemia[17]. Hypothyroidism and hyperprolactinemia have been documented in up to 50% of patients with end-stage kidney disease (ESKD)[12,13].

The rising epidemiological burden of CKD further underscores the clinical importance of its endocrine complications. Globally, over 673 million individuals are affected (8.54% prevalence), a 92% increase since 1990. Annual incidence approaches 19 million new cases. CKD now ranks as the 11^th leading cause of death, responsible for 1.5 million deaths in 2021, and imposes a substantial disability-adjusted life year burden (563.3 per 100000)[18]. Regions such as Central Asia, Latin America, and Mauritius show disproportionately high impact, driven by aging, urbanization, diabetes, and hypertension[19].

Importantly, the relationship between CKD and endocrine dysfunction is bidirectional. Not only does CKD promote hormonal imbalances due to impaired filtration and altered endocrine feedback, but certain endocrine disorders also contribute to the disease progression[20,21]. For instance, diabetes mellitus remains the leading global cause of CKD[22]. Secondary hyperparathyroidism (SHPT) promotes vascular calcification, left ventricular hypertrophy, and bone disease[23]. Additionally, conditions such as acromegaly can induce glomerular hyperfiltration, renal hypertrophy, and proteinuria, ultimately contributing to kidney injury[24].

PATHOPHYSIOLOGICAL MECHANISMS

Accumulation of uremic toxins

As nephron loss progresses, renal clearance of metabolic waste diminishes, resulting in systemic accumulation of uremic toxins. These include protein-bound solutes such as indoxyl sulfate and p-cresyl sulfate, as well as metabolic derivatives like trimethylamine N-oxide and asymmetric dimethylarginine[25,26].

Indoxyl sulfate and p-cresyl sulfate, derived from microbial metabolism of tryptophan and tyrosine, activate proinflammatory and fibrotic signaling cascades via reactive oxygen species and transforming growth factor beta 1. Trimethylamine N-oxide promotes endothelial dysfunction and renal fibrogenesis, while asymmetric dimethylarginine impairs nitric oxide synthesis, contributing to vascular stiffness and glomerular injury[26,27].

Hormonal and metabolic dysregulation

Declining renal function disrupts the clearance of metabolic hormones such as insulin, leptin, and adiponectin, fostering insulin resistance, altered adipokine signaling, and chronic low-grade inflammation[12,28]. The concomitant accumulation of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor alpha, further exacerbates systemic inflammation, contributing to cardiovascular complications and CKD progression[28,29].

The kidney is responsible for approximately 30% of endogenous insulin degradation through glomerular filtration, tubular reabsorption, and intracellular metabolism. With advancing CKD, particularly when GFR falls below 20 mL/minute, insulin clearance declines markedly, prolonging its half-life and promoting peripheral resistance[30]. Additional CKD-related factors such as uremia, oxidative stress, metabolic acidosis, and SHPT further impair insulin signaling, amplifying metabolic dysfunction[31].

Mineral and bone imbalance (CKD-MBD)

CKD disrupts mineral metabolism through phosphate retention, hypocalcemia, decreased calcitriol synthesis, and the development of SHPT[32]. Parathyroid hormone (PTH) levels may begin to rise as early as CKD stage G2, driven by hyperphosphatemia, calcitriol deficiency, and reduced renal catabolism, since the kidneys are responsible for approximately 20%-30% of circulating PTH clearance[33,34]. Persistent PTH elevation, further exacerbated by increased fibroblast growth factor 23 (FGF-23) and Klotho deficiency, contributes to the pathogenesis of renal osteodystrophy (ROD), vascular calcification, and an increased risk of skeletal fractures[35,36].

PTH exerts a dichotomous effect on bone, with intermittent elevations stimulating osteoblastic activity and bone formation, while sustained elevations promote osteoclastic resorption[34]. The latter leads to high-turnover lesions such as osteitis fibrosa (OF), characterized by increased bone turnover, cortical bone loss, and, in advanced cases, fibrous tissue replacement[33,35]. In contrast, excessive suppression of PTH, often resulting from the prolonged use of calcimimetics or active vitamin D analogs can induce adynamic bone disease (ABD), now the predominant form of low-turnover bone disease in CKD. ABD is defined by diminished osteoblastic activity and impaired bone formation, and is frequently associated with diabetes mellitus, protein-bound uremic toxins, and chronic inflammation-malnutrition syndromes. Both OF and ABD represent maladaptive skeletal responses to disrupted PTH regulation and contribute significantly to bone fragility and fracture susceptibility in CKD[34,37].

Renal tubular acidosis in CKD

Renal tubular acidosis (RTA) comprises a group of disorders characterized by impaired renal acid excretion despite the preservation or reduction of glomerular function. Among these, type 4 RTA is the most prevalent in the setting of CKD, particularly among individuals with DM2 and older adults[38,39].

Under physiological conditions, renal acid-base homeostasis is maintained through hydrogen ion secretion, bicarbonate reabsorption, and ammoniagenesis. In type 4 RTA, hypoaldosteronism or resistance to aldosterone signaling impairs epithelial sodium channel activity in the distal nephron. This disrupts the electrochemical gradient required for hydrogen ion and potassium excretion, resulting in hyperkalemia and metabolic acidosis. Hyperkalemia further worsens acidosis by suppressing ammoniagenesis in proximal tubular cells and inhibiting ammonium transport along the nephron, compromising acid buffering[38-40].

Genetic and environmental factors

Apolipoprotein L1 risk variants (G1, G2) increase CKD susceptibility and accelerate disease course in individuals of African ancestry through endocrine-inflammatory pathways. Expression is strongly induced in interferon-rich states, predisposing carriers to collapsing glomerulopathies in human immunodeficiency virus, parvovirus B19, and severe acute respiratory distress syndrome corona virus-2. In diabetic kidney disease, onset is unaffected, but proteinuric cases progress more rapidly. The interaction with hypertension and the renin-angiotensin-aldosterone system (RAAS) remains unresolved; however, genotyping refines prognostic accuracy at both population and individual levels. Cohort studies indicate that high-risk carriers may show differential blood pressure responses to RAAS modulation, while biomarkers predict faster progression. These insights enhance risk stratification and underscore the need to prioritise high-risk groups in future clinical trials[20,41].

Environmental toxins including aluminium, mercury, arsenic, and perfluorooctanoic acid act as nephrotoxic “second hits” and disrupt thyroid, steroid, and perfluorooctanoic acid vitamin D pathways. Mechanistic links to CKD, however, remain elusive, underscoring the need for mechanistic studies. Socioeconomic disparities further shape outcomes: Low-resource settings face restricted access to renal replacement and will likely encounter barriers to apolipoprotein L1-targeted therapies, in contrast to high-resource regions where early detection and standardized care improve prognosis[18,20,41].

Endocrine axes in CKD progression

CKD progression disrupts multiple hormonal systems, notably the mineral-bone axis, reproductive hormones, glucose metabolism, and erythropoiesis. These alterations stem from declining renal clearance, uremic toxin accumulation, chronic inflammation, and impaired endocrine feedback[42].

Key affected axes include disturbances in mineral metabolism, erythropoiesis, gonadal and thyroid function, as well as glucose homeostasis (Figure 1). Mineral metabolism is disrupted by elevated FGF-23 levels[28,43], Klotho deficiency[44], SHPT, and reduced calcitriol synthesis[45]. Erythropoiesis is impaired due to reduced erythropoietin production[18], bone marrow suppression associated with SHPT, and pro-fibrotic signaling involving PTH and FGF-23[34,46]. The gonadal axis is affected by suppressed gonadotropin-releasing hormone and elevated prolactin levels, with testosterone decline being common in dialysis patients[47]. The thyroid axis is characterized by impaired peripheral conversion of thyroxine (T4) to triiodothyronine (T3), elevated thyroid-stimulating hormone (TSH), and association with lower GFR[48]. Insulin resistance and glycemic variability result from impaired insulin clearance and altered glucose metabolism[28,49].

Figure 1 Hormone axes involved in chronic kidney disease. Overview of the mechanisms underlying the main endocrine pathways affected in chronic kidney disease. CKD: Chronic kidney disease; PO₄^3-: Phosphate; FGF-23: Fibroblast growth factor 23; PTH: Parathyroid hormone; sHPT: Secondary hyperparathyroidism; EPO: Erythropoietin; ROS: Reactive oxygen species; IL-6: Interleukin 6; TNF-α: Tumor necrosis factor alpha; Ca: Calcium; TSH: Thyroid-stimulating hormone; TRH: Thyrotropin-releasing hormone; T3: Triiodothyronine; T4: Thyroxine; GnRH: Gonadotropin-releasing hormone; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; TT: Total testosterone; FT: Free testosterone.

MAJOR ENDOCRINE DISORDERS LINKED TO CKD

CKD is associated with multiple endocrine disruptions, with varying prevalence and clinical relevance[13]. The most important and clinically impactful disorders include.

CKD-MBD

CKD-MBD is highly prevalent, especially in advanced stages[33,34], and refers to a systemic disorder which is characterized by a combination of the calcium-phosphate metabolism, PTH regulation, vitamin D synthesis, and bone structure, result from the reduced renal function[23].

SHPT arises from phosphate retention, hypocalcemia, and reduced vitamin D (calcitriol) synthesis due to impaired renal 1-α-hydroxylase activity. These alterations stimulate the parathyroid glands to secrete PTH, leading to increased bone resorption in an attempt to correct hypocalcemia[50,51].

Tertiary hyperparathyroidism may develop among patients on dialysis due to autonomous parathyroid hyperplasia, characterized by autonomous PTH secretion from glands that are not responding to normal regulatory feedback even after the underlying cause of the high PTH levels has been corrected[52].

Secondary and tertiary hyperparathyroidism are linked to bone pain, increased fracture risk, and vascular calcification. The latter significantly contributes to arterial stiffness, endothelial dysfunction, and cardiovascular events, which are leading causes of death in CKD[53,54].

Vitamin D deficiency

Vitamin D deficiency is highly prevalent in advanced CKD, resulting from impaired renal 1-α hydroxylase activity, which limits conversion of 25-hydroxyvitamin D into active calcitriol. This defect leads to a calcium malabsorption, enhanced PTH secretion, and exacerbating the SHPT, contributing to bone demineralization and systemic complications[55].

Beyond mineral metabolism, vitamin D has an important role in immune modulation. Its deficiency has been associated with increased systemic inflammation, greater susceptibility to infections, and endothelial dysfunction; these effects contribute to CKD progression and cardiovascular risk[55,56].

Hypogonadism

Hypogonadism affects up to 60% of dialysis patients and results from disruption of the hypothalamic-pituitary-gonadal axis[51]. It is characterized by reduced testosterone and estradiol and by diminished pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone, reflecting hypothalamic-pituitary-gonadal axis dysfunction[57-59].

In men, the pituitary LH secretion maintains its pulsatile character, but the amplitude of the pulses is reduced; baseline levels of LH are high due to feedback from low testosterone[57]. In women estradiol levels fail to increase and peak midcycle, leading to impaired ovulation and contributing to menstrual irregularities[59].

Clinically, hypogonadism manifests as infertility, decreased libido, chronic fatigue, anemia, and bone loss; all of which affect quality of life and physical function. Despite its significant impact, it is underdiagnosed and undertreated in the patients with CKD, due to the presence of other prominent symptoms and a lack of screening protocols in routine nephrology care[57,58].

Thyroid dysfunction

Low T3 syndrome, also known as non-thyroidal illness syndrome, alters peripheral conversion of T4 to T3 and changes in hormone-binding dynamics, without primary thyroid pathology[60]. The prevalence of low-T3 syndrome was 2.5 times higher in patients with advanced kidney disease compared to those with normal kidney function. This thyroid abnormality is highly prevalent in CKD and is found in up to 70% of patients with ESKD[61].

Subclinical hypothyroidism, characterized by increased TSH levels and normal free T4 (fT4), is frequently observed in CKD. It may represent an adaptative or early pathologic response, and its management remains controversial[60]. Patients with subclinical hypothyroidism had a significantly greater risk of CKD than those with euthyroidism[62].

Dialysis also affects thyroid hormone levels by altering the hormone-protein binding and renal clearance, leading to misinterpretation in the measured hormone levels, complicating diagnosis and masking clinically significant thyroid dysfunction[63]. In non-dialysis dependent and dialysis-dependent CKD patients, hypothyroidism and other thyroid functional test derangements have been associated with higher risk of cardiovascular disease[64].

Hypothyroidism has a direct effect on the activity of the RAAS, resulting in decreased cardiac output, decreased red cell production, increased peripheral vascular resistance, increased renal vasoconstriction, and diminished renal vasodilators; these changes leading to reduced GFR and contributing to CKD progression[65].

Prolactin elevation

Hyperprolactinemia in CKD is a frequent endocrine disorder highly prevalent in patients receiving dialysis, resulting from reduced renal clearance and impaired hypothalamic dopamine-mediated inhibition of pituitary prolactin release[47,66]. Hyperprolactinemia was present in 66% of dialysis-dependent patients, with levels positively correlated with CKD stage and creatinine, and negatively with testosterone[67].

Clinically the hyperprolactinemia may cause gynecomastia, galactorrhea, menstrual irregularities, decreased libido and emotional disturbances, especially in patients with ESKD. This condition is often considered benign in CKD, despite persistent increased levels of prolactin may have clinical consequences, especially when coexisting with other hormonal imbalances[47].

Insulin resistance and glucose metabolism

CKD promotes peripheral insulin resistance as a hallmark, is caused by chronic inflammation, oxidative stress, hyperparathyroidism and accumulation of uremic toxins, leading to impaired insulin signaling and glucose uptake, particularly in skeletal muscle and liver[68].

Insulin clearance is significantly reduced in advanced stages of the CKD due to diminished glomerular filtration and tubular metabolism, prolonging insulin half-life[69], this may lead to unpredictable hypoglycemia, particularly in patients with diabetes receiving insulin or insulin secretagogues; these events increase the risk of hospitalization and cardiovascular complications, underscoring the need for careful glycemic monitoring and adjustment of the antidiabetic therapy[28,70].

Importantly, patients without a prior diagnosis of diabetes may also experience significant glucose-lowering episodes, especially those with ESKD or during dialysis. Mechanisms include reduced renal gluconeogenesis, diminished clearance and degradation of insulin, nutritional deficiencies, and changes in glucose transport during dialysis procedures[30].

ENDOCRINE CONSIDERATIONS IN DIALYSIS AND TRANSPLANTATION

The transition to renal replacement therapy, whether hemodialysis (HD) or kidney transplantation, marks a pivotal phase in the management of advanced CKD. While these therapies are effective in managing uremia and prolonging survival, they do not completely resolve the underlying endocrine disruptions. Instead, they shift the hormonal landscape in distinct and clinically relevant ways. Dialysis patients continue to experience persistent hormonal imbalances, whereas transplant recipients often show partial restoration, albeit with new endocrine challenges[71].

HD and endocrine dysregulation

SHPT and mineral metabolism: SHPT is a hallmark endocrine complication in patients with CKD undergoing HD. Optimal therapeutic targets for PTH in stages G3-G5D remain controversial[72]. Current treatments include non-calcium phosphate binders, vitamin D analogues, and calcimimetics, while subtotal parathyroidectomy is considered in severe or refractory cases[72-74]. In parallel, FGFs, particularly FGF-23 and FGF19, function as central endocrine regulators in both dialysis and transplant populations. Elevated FGF-23 levels in dialysis are independently associated with cardiovascular morbidity and increased mortality risk. Conversely, FGF19 levels tend to decline after transplantation, reflecting alterations in bile acid metabolism and enterohepatic signaling, though the clinical significance of these findings remains under investigation[75,76].

Gonadal and thyroid axis dysregulation: Hypogonadism is frequently observed in men with an estimated GFR (eGFR) below 30 mL/minute/1.73 m². Guidelines recommend screening for testosterone deficiency in advanced CKD, although the role of androgen replacement therapy such as oxymetholone requires further validation[77]. Thyroid Dysfunction in dialysis is often masked by hemodilution and altered metabolism clearance. Pre-dialysis measurements frequently reveal low free T3 (fT3) and T4 fT4, with partial normalization post-dialysis. TSH may transiently decrease after sessions. To avoid diagnostic confusion, thyroid hormone assays should be obtained post-dialysis[78].

Insulin resistance and glycemic control: Insulin resistance is highly prevalent in patients with ESKD undergoing HD and contributes to significant glycemic variability, often manifesting as intradialytic hypoglycemia and interdialytic hyperglycemia. Although glycated hemoglobin remains the preferred marker for long-term glycemic assessment, its accuracy in this setting is limited by reduced red blood cell lifespan and the influence of erythropoiesis-stimulating agents. An glycated hemoglobin target of 7%-8% is generally recommended for most dialysis patients[76,79].

Glucose metabolism in ESKD is further affected by decreased insulin clearance and improved insulin sensitivity following dialysis initiation, partly due to the removal of uremic toxins such as guanidino compounds with insulin-sensitizing properties. These changes lower insulin requirements and increase the risk of hypoglycemia if antidiabetic therapy is not appropriately adjusted. In a cohort of over 58000 incident HD patients, hypoglycemia occurred in 16.8% of those with diabetes and 6.9% of those without. Severe episodes (glucose < 50 mg/dL) were more common in diabetics and independently associated with increased all-cause mortality[80]. These findings underscore the importance of individualized glycemic management to mitigate hypoglycemic risk and improve clinical outcomes in this vulnerable population.

Adipokines, advanced glycation end products, and inflammation: Adipokines such as zinc-alpha-2-glycoprotein and adipolin are reduced, while free fatty acids are elevated, particularly in obese patients, contributing to insulin resistance[81]. Simultaneously, advanced glycation end products (AGEs) accumulate, promoting oxidative stress and vascular injury. Conventional HD provides limited clearance of AGEs, but adjunctive hemoadsorption with HA130 cartridges has shown promise in enhancing removal[82].

These disturbances coexist with a chronic pro-inflammatory state and endothelial dysfunction, forming a pathogenic triad in CKD-associated atherosclerosis. Such mechanisms are particularly exacerbated in patients with diabetic nephropathy and can be further aggravated by bioincompatible peritoneal dialysis solutions[82,83]. In addition, HD itself can provoke acute vascular responses, compromising endothelial integrity and, in some cases, inducing hypersensitivity-like reactions[71,84].

Hormonal dynamics after kidney transplantation

Kidney transplantation frequently restores endocrine homeostasis across multiple hormonal axes. Post-transplant, patients often experience resolution of SHPT and marked improvement in systemic symptoms such as fatigue, depression, pruritus, and sleep disturbances[73,85]. Although recipients generally report a higher quality of life than dialysis patients, full recovery to pre-CKD levels remains uncommon[86].

Post-transplant diabetes mellitus

Post-transplant diabetes mellitus remains a clinically significant complication. Current guidelines support cautious use of glucose-lowering agents such as metformin, adjusted according to eGFR, and sodium-glucose co-transporter 2 inhibitors (SGLT2i). However, their safety in immunosuppressed patients, particularly in regard to infection risk, warrants further research[74,80].

Bone demineralization and fracture risk

Bone disease persists despite initial PTH declines in up to 60% of patients[17]. Concurrent hypophosphatemia likely driven by residual FGF-23 activity exacerbates mineral imbalance. Bone mineral density tends to decrease in the early months post-transplant, particularly in those with prior prolonged dialysis. While several antiresorptives are contraindicated in patients with low eGFR, denosumab may be used with close monitoring of serum calcium[72,87].

Hypogonadism resolution

Testicular function typically improves after transplantation, leading to better body composition and hormonal recovery. However, recovery may be delayed in individuals with pre-existing gonadal injury or long-standing hypothalamic suppression due to uremia[86,87].

CLINICAL IMPLICATIONS AND COMPLICATIONS

Endocrine imbalances are central to the development of several complications in patients with CKD, including anemia, sarcopenia, vascular calcification, sexual dysfunction, and decreased quality of life. These alterations contribute to disease burden and, when left untreated, may accelerate CKD progression and worsen clinical outcomes[86,87].

Anemia

Anemia is highly prevalent in CKD, primarily resulting from reduced erythropoietin production and disrupted iron homeostasis, largely mediated by elevated hepcidin levels. It is associated with fatigue, reduced physical capacity, and increased cardiovascular risk. In diabetic patients, chronic inflammation further suppresses erythropoiesis, contributing to more severe anemia and cardiovascular compromise[88].

Inappropriately aggressive correction of hemoglobin using high doses of erythropoiesis-stimulating agents has been linked to a higher incidence of cardiovascular events, hospitalizations, and mortality[89].

Sarcopenia

Sarcopenia, defined by the progressive decline in muscle mass and function, is multifactorial in CKD and strongly influenced by hormonal disturbances. These include insulin resistance, vitamin D deficiency, and reduced activity of anabolic hormones such as testosterone and insulin-like growth factor 1[90,91].

Low serum testosterone levels are frequent in dialysis patients and correlate with reduced lean tissue mass and increased mortality[78]. Elevated levels of myostatin, an inhibitor of muscle growth, are also found in CKD, particularly under inflammatory conditions[92]. Sarcopenia increases the risk of falls, disability, prolonged hospitalization, and poor patient outcomes[93].

Cardiovascular calcification

Vascular calcification is highly prevalent in CKD and constitutes a strong independent predictor of cardiovascular morbidity and mortality[94]. Unlike atherosclerosis, medial arterial calcification in CKD represents a distinct pathophysiological entity[95], characterized by active transdifferentiation of vascular smooth muscle cells into osteoblast-like phenotypes[96,97].

This transformation is driven by systemic inflammation, uremic toxins, and chronic mineral metabolism disorders, such as persistent hyperphosphatemia, hypercalcemia, and SHPT[98-100]. In addition, the loss of endogenous inhibitors of ectopic mineralization, particularly fetuin-A, matrix Gla protein, and Gla-rich protein, further exacerbates mineral deposition in the vascular wall[101,102].

Together, these mechanisms contribute to pathological calcification of the arterial media, worsening cardiovascular outcomes and complicating therapeutic management[103,104].

Sexual dysfunction

Although not always systematically addressed, sexual dysfunction is frequent in patients with CKD, particularly in men undergoing dialysis. Hypogonadism, often marked by low testosterone levels and disrupted hypothalamic-pituitary signaling, is a contributing factor[105,106]. Its presence negatively affects emotional well-being, interpersonal relationships, and overall quality of life[107].

Quality of life

The cumulative burden of endocrine-related complications directly affects health-related quality of life in CKD. Anemia contributes to reduced energy levels and physical performance[88,89]. Sarcopenia is associated with frailty and functional dependency[87,88]. Together, these conditions can impair daily activities and mental health, leading to increased vulnerability and poorer long-term outcomes[108].

Consequences of unaddressed endocrine imbalances

Failure to recognize and treat these hormonal disturbances contributes to increased morbidity, higher healthcare utilization, and premature mortality[90]. The persistent presence of anemia, sarcopenia, and vascular calcification exacerbates systemic inflammation, impairs rehabilitation potential, and may hasten progression to ESKD[101,108]. Early identification and targeted management of these endocrine complications are essential to improving outcomes in this population[109].

DIAGNOSTIC APPROACH

Routine biochemical monitoring is essential in CKD to detect and manage mineral and hormonal imbalances that develop with the disease progression. International guidelines, such as The Kidney Disease: Improving Global Outcomes guidelines 2017, recommend periodic assessment of serum calcium, phosphate, PTH, and 25-hydroxyvitamin D especially at CKD stage G3a to G5, with frequency tailored to disease progression and biochemical trends[109].

Contextual interpretation

Renal impairment alters hormone metabolism, clearance, and binding protein levels, requiring careful interpretation; for example, low serum T3 may reflect non-thyroidal illness syndrome rather than true hypothyroidism; elevated TSH may result from reduced renal clearance or altered glycosylation, not necessarily indicating hypothyroidism, complicating its diagnostic utility; dialysis may disturb hormone levels, especially TSH and thyroid hormones, emphasizing the need for post-dialysis sampling when possible[61,63]. Therefore, clinicians should interpret biochemical data with clinical context, symptomatology and longitudinal trends to avoid misclassification and unnecessary therapeutic interventions that may represent a risk in patients with CKD[109].

Core panels

Mineral metabolism markers: (Ca, Pi, PTH, vitamin D) should be evaluated at regular intervals, with frequency adjusted according to disease stage and biochemical trends. Serum calcium should be kept between 8.8-10.2 mg/dL; values < 8.8 suggest early CKD-related hypocalcemia, while > 10.2 may reflect ABD or overtreatment. Serum phosphate should remain within 2.5-4.5 mg/dL; sustained elevations > 4.5 mg/dL (from G3b) or > 5.5 mg/dL in dialysis (G5D) require treatment. Intact PTH should generally stay between 10-65 pg/mL; levels > 70 pg/mL in G3a-G5 and > 300 pg/mL in G5D suggest SHPT and call for evaluation of vitamin D, calcium, and phosphate status. 25 hydroxyvitamin D is often considered sufficient at ≥ 30 ng/mL and deficient below 20 ng/mL, though targets may vary by guideline[109].

Sex hormones: In adult men, total testosterone concentrations between 300 ng/dL and 1000 ng/dL are considered normal, and levels below 300 ng/dL may indicate biochemical hypogonadism. Free testosterone typically ranges from 47 pg/mL to 244 pg/mL; values under 47 pg/mL may indicate androgen deficiency despite a normal total testosterone[110]. Estradiol in men is normally ≤ 39 pg/mL, with bioavailable estradiol below 11 pg/mL linked to accelerated bone loss[111]. LH reference limits are 1.8-8.6 IU/L; LH values > 9.4 IU/L in the setting of low testosterone point to primary (testicular) hypogonadism, whereas LH in the lower half of its range with low testosterone suggests secondary (pituitary-hypothalamic) hypogonadism. Follicle-stimulating hormone normally ranges from 1.4 IU/L to 15.4 IU/L; values above this range support a diagnosis of primary gonadal failure in a man with clinical or biochemical hypogonadism[112].

Thyroid function tests: TSH has a standard adult reference interval of 0.4-4.0 mIU/L; subclinical hypothyroidism is defined by a TSH between 4.5 mIU/L and 10 mIU/L in the presence of normal fT4 and fT3. Overt hypothyroidism is generally diagnosed when TSH exceeds 10 mIU/L and fT4 falls below its normal range. fT4 reference values lie between 0.8 ng/dL and 1.8 ng/dL, and fT3 between 2.3 pg/mL and 4.2 pg/mL; in non-thyroidal illness syndrome, fT3 often “drops out” first with normal or low-normal fT4 and variable TSH levels. Persistent TSH elevation above 10 mIU/L or a fT4 below 0.8 ng/dL warrants levothyroxine replacement in symptomatic patients, following clinical judgment and guideline recommendations[113].

Bone biopsy and histomorphometry

Routine biochemical assays and imaging modalities often lack the specificity to distinguish between ROD subtypes, especially in cases of impaired mineralization or low bone turnover. According to the European consensus statement, iliac crest biopsy with quantitative histomorphometric analysis remains the diagnostic tool of choice for ROD. Histomorphometry provides precise classification of bone disease within the Turnover-Mineralization-Volume (TMV) framework, directly informs the choice between antiresorptive or anabolic therapies, and clarifies discordant findings among serum biomarkers and clinical presentation[114].

Integrating bone histomorphometry into the CKD-MBD diagnostic algorithm mitigates the risk of ABD from excessive PTH suppression of overuse of active vitamin D analogs, and ultimately guides safer, more effective management of mineral bone disorders in patients with advanced CKD[115].

Incorporation of emerging biomarkers in diabetic nephropathy

To enhance the diagnostic approach to endocrine disruptions in CKD, findings from diabetic nephropathy highlight the value of novel biomarkers that detect tubular injury, inflammation, and early filtration decline beyond albuminuria. Neutrophil gelatinase-associated lipocalin rises early in urine and serum during tubular stress and correlates with future albuminuria and GFR decline. Soluble tumor necrosis factor-alpha receptor 1 reflects endothelial inflammation and anticipates microalbuminuria and cardiovascular risk. Monocyte chemoattractant protein-1 elevation in urine mirrors monocyte recruitment and interstitial fibrosis. Kidney injury molecule-1, a marker of proximal tubular damage detectable within 12-24 hours after injury, associates with more rapid GFR decline when chronically elevated. Cystatin C, less influenced by muscle mass, provides a more accurate estimate of GFR and unmasked early filtration impairment when measured in serum or via its fractional excretion[116].

Integrating these biomarkers into multiparametric panels markedly improves diagnostic sensitivity, enabling earlier risk stratification and tailored therapeutic interventions in diabetic kidney disease, though clinical utility and cost effectiveness remain under evaluation. Moreover, plasma and urinary metabolomic profiling have identified dysregulated pathways, such as AGE accumulation and polyol pathway activation, that promise to yield additional markers for monitoring disease progression and response to novel treatments. The systematic inclusion of these emerging biomarkers in CKD protocols could bridge current gaps in early detection, guide individualized management, and ultimately improve clinical outcomes across the spectrum of endocrine and renal dysfunction[116].

TREATMENT STRATEGIES

Endocrine management in CKD must be tailored to the distinct pathophysiological features of each disorder. A consolidated overview of treatment strategies for the major endocrine disorders in CKD is presented in Table 1. It outlines key pathophysiological mechanisms, estimated prevalence, clinical complications, and current therapeutic approaches.

Table 1 Major Endocrine disorders in chronic kidney disease.

Disorder	Prevalence in CKD	Pathophysiological mechanism	Key complications	Clinical management
CKD-MBD	High (> 40%-80%)	Phosphate retention, ↓ Klotho, ↑ FGF-23, ↓ calcitriol	Bone fragility, vascular calcification, fractures	Non-calcium binders, vitamin D analogs, calcimimetics, parathyroidectomy
Vitamin D deficiency	Frequent in all CKD stages	↓ 1-α hydroxylase activity, impaired calcitriol synthesis	↑ PTH, ↓ calcium absorption, chronic inflammation	Active vitamin D analogs, calcifediol, monitor Ca/Pi
Hypogonadism	40%-60% in dialysis patients	HPG axis suppression, ↓ TT/FT, ↑ prolactin	Sexual dysfunction, anemia, fatigue	TRT if symptomatic, risk-benefit evaluation
Thyroid dysfunction	Up to 70% in ESRD	↓ T4→T3 conversion, ↑ TSH due to altered renal clearance	Fatigue, ↓ GFR, cardiovascular risk	Levothyroxine for overt/symptomatic hypothyroidism
Hyperprolactinemia	About 66% in dialysis	↓ Renal clearance, ↑ pituitary secretion, ↓ dopamine tone	Galactorrhea, libido loss, GnRH suppression	Dopamine agonists if symptomatic
Insulin resistance	Near-universal in advanced CKD	Inflammation, oxidative stress, ↓ insulin degradation	Hypoglycemia, CKD progression, ↑ CV risk	SGLT2 inhibitors, insulin dose adjustment

CKD: Chronic kidney disease; MBD: Mineral and bone disorders; FGF-23: Fibroblast growth factor 23; PTH: Parathyroid hormone; HPG: Hypothalamic-pituitary-gonadal axis; TT: Total testosterone; FT: Free testosterone; ESRD: End-stage renal disease; T4: Thyroxine; T3: Triiodothyronine; TSH: Thyroid-stimulating hormone; GnRH: Gonadotropin-releasing hormone; CV: Cardiovascular; Ca/Pi: Calcium/phosphorus product; TRT: Testosterone replacement therapy; GFR: Glomerular filtration rate; SGLT2: Sodium-glucose co-transporter type 2.

CKD-MBD management

Management of CKD-MBD aims to mitigate vascular calcification, bone fragility, and cardiovascular risk. Current strategies include dietary phosphate restriction and the use of phosphate binders; noncalcium binders (e.g., sevelamer, lanthanum) are preferred in patients with hypercalcemia or vascular calcification[117,118]. Active vitamin D analogs (e.g., calcitriol, paricalcitol) suppress PTH secretion but may exacerbate hypercalcemia and hyperphosphatemia, especially in stages G3a-G5; thus, their use requires careful monitoring[117], as excessive suppression of PTH may contribute to ROD[37]. Calcimimetics (e.g., cinacalcet) are effective in reducing PTH levels, are particularly useful in patients with hypercalcemia or refractory SHPT, and in patients receiving dialysis can reduce the need for surgical interventions. Parathyroidectomy remains a therapeutic option in patients with severe refractory hyperparathyroidism unresponsive to drug therapy[119].

Role of bone histomorphometry in therapeutic choice

Iliac crest biopsy interpreted via TMV classification enables clinicians to distinguish between histological subtypes of ROD and tailor treatment accordingly. In cases of high-turnover disease, typically OF, patients benefit from therapies that suppress PTH activity, including calcimimetics, active vitamin D analogs, and parathyroidectomy in refractory cases[114]. Low-turnover disease encompasses both ABD and osteomalacia. Management of ABD involves avoiding further antiresorptive agents and considering anabolic strategies such as teriparatide, provided renal function permits; osteomalacia requires correction of underlying causes, most commonly vitamin D deficiency or phosphate depletion, and may respond to sustained-release calcifediol of active vitamin D analogs[115].

Integrating TMV-guided biopsy interpretation into CKD-MBD management enables personalized treatment, reduces therapeutic missteps, and aligns with multidisciplinary care models that bridge nephrology and endocrinology[114].

Hypogonadism treatment

Testosterone replacement therapy is indicated in symptomatic men with confirmed biochemical hypogonadism, but only after a risk assessment. Treatment should begin just after evaluating serum morning testosterone levels, clinical symptoms and excluding reversible causes of functional hypogonadism such as obesity, poor controlled diabetes or chronic illness[120,121].

TRT has demonstrated that it improves sexual function, mood, and bone density, but in advanced CKD (stages 4-5 or dialysis) requires caution due to potential fluid retention, erythrocytosis, and cardiovascular risk; in addition, TRT may increase prostate-specific antigen (PSA) levels, thus, regular monitoring should be performed in this therapy[120-122].

Excessive or indiscriminate androgen therapy should be avoided in the advanced CKD due to the adverse effects and the altered pharmacokinetics of hormones. In individuals with borderline testosterone levels or nonspecific symptoms, lifestyle interventions may be the preferred lifestyle therapy before initiating TRT, such as weight reduction, glycemic control, and management of sleep apnea[120].

Thyroid dysfunction management

In thyroid abnormalities, most cases are asymptomatic and do not need any interventions. Reserve levothyroxine for overt hypothyroidism or symptomatic patients; avoid treating borderline TSH elevations without clinical correlation[123,124]. Moreover, subclinical cases may not benefit from intervention, and overtreatment may increase cardiovascular risk and lead to iatrogenic thyrotoxicosis[125].

TSH trends should be interpreted cautiously because it levels fluctuate, as CKD alters thyroid hormone metabolism, renal clearance and binding proteins, leading to potential misclassification, emphasizing longitudinal monitoring over single measurements of TSH, especially in borderline or subclinical cases[60,123].

Prolactinemia approach

Hyperprolactinemia in CKD is often asymptomatic and may not require treatment[126]. Dopamine agonists (e.g., cabergoline, bromocriptine) may be considered in symptomatic cases with clinical manifestations such as sexual dysfunction, galactorrhea or infertility. However, the therapy should be individualized and carefully weighted, as the overall clinical benefit remains uncertain, and the possible adverse effects such as impulse control disorders, heart valve disease, and psychiatric symptoms[127].

Glucose control strategies

Glycemic management in CKD requires adjustment of pharmacologic agents based on renal function. Insulin and oral hypoglycemics should be adjusted as eGFR declines, with close monitoring for hypoglycemia[74]. SGLT2i are preferred in early CKD stages (eGFR > 30 mL/minute/1.73 m²) due to their nephroprotective and cardiovascular benefits[128,129]. Metformin is contraindicated when eGFR < 30 mL/minute/1.73 m², due to the risk of lactic acidosis[130]. Glucagon-like peptide-1 receptor agonists are recommended in patients who fail to achieve the glycemic target despite the use of metformin and SGLT2i, or when these agents are contraindicated[131].

Referral and multidisciplinary care

Referral to endocrinology in CKD should be guided by clearly defined scenarios, including refractory CKD-MBD, complex hypogonadism, persistent or uncertain thyroid dysfunction, clinically significant hyperprolactinemia, and inadequately controlled diabetes. Embedding such referral triggers within structured multidisciplinary pathways ensures timely specialist input and more precise therapeutic decision-making[117,120,130].

Multidisciplinary care should be initiated when the risk of kidney failure is high or when endocrine comorbidities complicate management, with teams integrating nephrologists, endocrinologists, dietitians, pharmacists, and allied health professionals. Coordinated interventions across pharmacological, nutritional, and educational domains, supported by shared decision-making, enhance continuity, individualization, and ultimately improve outcomes in patients with CKD and endocrine disorders[117,130].

FUTURE PERSPECTIVES

New paradigms in nephrology are changing the landscape for the management of CKD, particularly concerning endocrine-related complications[132,133]. Nonetheless, navigating the transition from bench to bedside remains particularly challenging. Key areas of emphasis include personalized hormone therapy, second-generation vitamin D analogs, artificial intelligence enabled predictive modeling, and the integration of endocrine and nephrology care models[134,135].

Personalized hormone replacement in CKD

Personalizing hormone therapy in CKD remains aspirational due to evidence gaps, pharmacokinetic variability, and regulatory inertia[17]. Menopausal hormone therapy may offer nephroprotective benefits, particularly in premature ovarian insufficiency, but conflicting cohort data suggest elevated CKD risk with early or prolonged use[136]. Cardiovascular outcomes remain unexamined in randomized trials, especially in high-risk transplant populations[137].

For men with CKD, TRT improves hormonal markers and symptoms, but evidence on body composition and long-term outcomes is inconsistent. Implementation is further hindered by the absence of stage-specific dosing protocols, limited access to specialized testing, and uncertainty in managing drug-drug interactions in transplant recipients[119,138].

Barriers to implementation also include the lack of stage-specific dosing algorithms, restricted availability of specialized assays, and knowledge gaps in the management of drug-drug interactions in this specific subset of the population. Economical barriers also remain: Price of hormone assays, individualized delivery systems, and specialist instruction restrict widespread implementation. Furthermore, variation in gender identity challenges standards of hormone estimation and inclusion in clinical algorithms[139].

Vitamin D analogs: Advancing safety, lagging outcomes

While novel vitamin D analogs such as paricalcitol and doxercalciferol have shown safer profiles, they still carry risks of hypercalcemia and lack validation in outcome-based trials. Extended-release calcifediol presents encouraging biochemical stability and PTH suppression, but whether this translates into reduced cardiovascular or renal events remains unknown[133]. Barriers to adoption include cost-effectiveness concerns, clinician inertia, and the absence of long-term safety data. Kidney Disease: Improving Global Outcomes guidelines remain inconclusive on target PTH levels or thresholds for vitamin D repletion, reflecting the need for standardized clinical endpoints[130].

AI in nephrology: Transformative yet underutilized

AI, including machine learning and deep learning, is poised to revolutionize nephrology through risk prediction and endocrine profiling. Tools like retinal imaging-based eGFR estimators and kidney failure risk equation integrated models offer precision forecasting[140,141]. However, translation into practice is slow. Key barriers include clinician trust deficits, ethical uncertainties, and limited regulatory frameworks; interoperability issues with electronic health records, delaying scalable deployment[134,135]; lack of external validation and data harmonization across healthcare systems[135]; and algorithmic bias due to underrepresentation of ethnic, gender-diverse, and rare disease populations[139,140]. Despite these limitations, AI holds potential for drug discovery, predictive diagnostics, and stratified care models if implementation challenges are systematically addressed[140,141].

Integrating endocrinologists: From recommendation to reality

Multidisciplinary care that includes endocrinologists is essential for managing CKD’s complex hormonal milieu. Endocrinologists contribute to risk assessment in diabetes, osteoporosis, menopause, and hypogonadism, conditions frequently overlooked in nephrology. However, integration remains uneven due to system-level fragmentation, referral delays, and limited cross-specialty education[133,137].

While the guidelines recommend comprehensive care, there is limited practical guidance for multidisciplinary care strategies across different specialties particularly in low-resource settings. A risk prediction tool may inform triage to multidisciplinary teams, though its implementation varies from center across institutions[130].

CONCLUSION

CKD disrupts multiple endocrine pathways through complex and interrelated mechanisms. Recognizing and managing endocrine disorders in CKD patients is essential for reducing complications, improving quality of life, and slowing disease progression. A multidisciplinary, individualized approach is key in navigating these overlapping pathologies.