Elevated Serum Alkaline Phosphatase Research Articles

Defining the clinical spectrum and genotype-phenotype correlations for CCDC115-CDG: A patient report and review of the literature.

Liver involvement in systemic immunoglobulin light-chain (AL) amyloidosis is diagnosed by an increase in liver size and/or elevated serum alkaline phosphatase (ALP) levels. However, novel diagnostic approaches that reflect the organ-specific characteristics of liver involvement are needed. Shear wave elastography (SWE) is a noninvasive and repeatable technique for measuring tissue stiffness. In this study, we evaluated the clinical significance of SWE and serum biochemistry tests in the diagnosis of AL amyloidosis with liver involvement. Twenty-five patients with systemic AL amyloidosis were examined. Eight patients were diagnosed with liver involvement according to the current consensus criteria. In patients with and without liver involvement, hepatic shear wave velocity (SWV) was 1.93 ± 0.39 versus 1.36 ± 0.11 m/sec (p = 0.00099), and the gamma-glutamyltranspeptidase (γ-GTP) level was 165 ± 131 versus 36 ± 28 U/L (p = 0.00222). Receiver-operating characteristic curve analysis showed that SWV and γ-GTP levels had favorable diagnostic accuracy for liver involvement. Of note, two patients with liver involvement who achieved organ response showed a decrease in both SWV and γ-GTP levels. These results suggest that SWV and γ-GTP are useful for establishing accurate organ-specific diagnosis and response criteria for liver involvement in AL amyloidosis.

Disclosure: L.K. Ereifej: None. J. Azocar villalobos: None. L.E. Aguirre: None. E. Lewiecki: None.Introduction: Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) combined with clinical risk factors is a robust predictor of fracture risk and the need for pharmacologic therapy to reduce fracture risk. However, these static assessments do not reveal the dynamics of bone metabolism and do not predict the rate of bone loss. This is a report of a patient with osteopenia and high bone turnover markers (BTMs) with a rapid rate of bone loss. Case presentation: A 51-year-old woman who had premature menopause at age 41 years was referred by her gastroenterologist for evaluation of persistent elevation of serum alkaline phosphatase (ALP) (248 U/L, normal range 46-116 U/L) and bone specific ALP (29.6 ug/L, normal range 7-24 ug/L), with normal liver enzymes and no evidence of chronic liver or kidney disease. She complained of generalized musculoskeletal pain but was otherwise healthy, with no known fracture. The clinical work-up was significant for high fasting serum C-telopeptide (CTX) (1546 pg./mL) and procollagen type I intact N-terminal propeptide (P1NP) (180 mcg/L) Other lab tests were within normal limits, including TSH, PTH, vitamin D, phosphorus, magnesium, serum calcium, celiac panel, ESR, CRP, ferritin, ANA, and an overnight 1 mg dexamethasone suppression test. A whole-body nuclear bone scan showed no localized increased bone activity. DXA showed osteopenia, with the lowest relevant T-score -2.4 at left 33% radius. FRAX showed low fracture risk, below the treatment threshold. She was managed with non-pharmacologic therapy with plans to return in 2 years for a repeat DXA. The follow-up DXA showed a statistically significant decrease in BMD at left total hip, with the lowest relevant T-score now -3.1 at left 33% radius. Secondary osteoporosis work up was still unremarkable. The patient was then treated with IV zoledronic acid. Six months later there was a substantial reduction of CTX to 485 pg/mL and ALP to 159 U/L. A third DXA 12 months after zoledronic acid showed improvement in BMD by 11% at left total hip with a numerical improvement at the left 33% radius T-score to -2.8. Conclusion: This patient illustrates the association of high BTMs and rapid bone loss, suggested a need for closer observation and perhaps earlier intervention than in patients with lower BTMs.References;Vilaca T, Gossiel F, Eastell R. Bone Turnover Markers: Use in Fracture Prediction. J Clin Densitom. 2017 Jul-Sep;20(3):346-352. doi: 10.1016/j.jocd.2017.06.020. Epub 2017 Jul 14. PMID: 28716498.Bandeira F, Costa AG, Soares Filho MA, Pimentel L, Lima L, Bilezikian JP. Bone markers and osteoporosis therapy. Arq Bras Endocrinol Metabol. 2014 Jul;58(5):504-13. doi: 10.1590/0004-2730000003384. PMID: 25166041.Presentation: Monday, July 14, 2025

Summary: Primary biliary cholangitis is a chronic, immunologically mediated, progressive liver dis ease characterized by progressive destruction of small bile ducts, resulting in cholestasis, liver fi brosis with the development of liver cirrhosis and all of its complications. These ultimately lead to liver failure, resulting in death or the need for a liver transplant. Early and eff ective treatment is a key factor in infl uencing the prognosis. The dis ease mainly aff ects women, accounting for 90% of cases. Dia gnosis is possible based on an elevation of serum alkaline phosphatase (ALP) above 1.5-times the normal level for 6 months and in combination with the presence of antimitochondrial antibodies (AMA) ≥ 1 : 40 or specifi c antinuclear antibodies (ANA) sp100, gp210, or a combination of elevated serum ALP with typical histological fi ndings found during liver biopsy. Although ursodeoxycholic acid (UDCA) remains the treatment of choice, unfortunately some patients do not tolerate this treatment or do not respond adequately to it. Second-line treatment is currently available – peroxisome proliferator-activated receptor (PPAR) agonists, delta (PPAR-) or dual agonists (PPAR-/ ). Seladelpar (PPAR-) and elafi branor (PPAR-/ ) are promising treatment alternatives due to their anti- -inflammatory and antifi brotic properties. Key words: primary biliary cholangitis – alkaline phosphatase – AMA antibodies – ANA antibodies – ursodeoxycholic acid – elafi branor – seladelpar

Sarcoidosis is a multisystemic inflammatory disease characterized by heterogeneous clinical manifestations and granuloma formation in the organs involved. Diagnosing systemic sarcoidosis requires a multidisciplinary approach and the exclusion of other pathologies; after diagnosis, organ involvement and disease extent are further assessed. Genetic factors influence not only the risk of sarcoidosis development but also the disease course, which is highly variable and unpredictable. The clinical course of systemic sarcoidosis is highly variable, ranging from a self-limited disease that does not require long-term therapy to a rapidly progressive, symptomatic disease requiring immunosuppression. The liver is a commonly affected organ in sarcoidosis; while most patients with systemic sarcoidosis have hepatic granulomas, a minority will experience significant liver disease. In hepatic sarcoidosis, granulomas can cause a cholestatic liver injury, exemplified by elevated serum alkaline phosphatase and gamma‐glutamyl transferase, though neither is pathognomonic and there are no hepatic sarcoid-specific biomarkers to monitor disease activity. Patients with ongoing hepatic inflammation require the initiation of the disease-modifying agents to prevent fibrosis and decompensation. This review article summarizes the existing literature on etiology, risk factors, pathogenesis, clinical features, and the management of hepatic sarcoid.

Calcineurin inhibitors (CNIs) are essential medications for many people living with solid-organ transplants. CNI therapy helps prevent organ transplant rejection, though it requires monitoring to ensure efficacy and safety. Here we report a case of a young kidney transplant recipient who developed a severe and debilitating complication of CNI therapy that resolved following CNI dose reduction. CNI-induced pain syndrome (CIPS) may affect as many as 1 in 20 people treated with CNIs, including many of the 62 900 people in the United Kingdom who require CNI therapy following organ transplantation. Clinical presentation, severity and duration are variable, though the condition is often associated with elevated serum alkaline phosphatase levels. Limited awareness of CIPS, compounded by the potential for severe symptoms to develop even when CNI blood levels are within the standard therapeutic range, risks delayed recognition and significant patient suffering, as this case report highlights. Appropriate clinical suspicion of CIPS is thus imperative to limit patient harm and resource use associated with this under-recognised and potentially serious condition.

Association Between Serum Alkaline Phosphatase Levels and Sarcopenia in US Adults: A Cross-sectional Study.

Aim: There is no definitive evidence to establish a causal relationship between elevated serum alkaline phosphatase (ALP) levels and sepsis susceptibility. This study employed observational and Mendelian randomization (MR) studies to investigate their potential correlation. Methods: This observational study used data from the eICU Collaborative Research Database (eICU-CRD) and included adult patients who were admitted to the ICU for a single episode, with an ICU stay of ≥ 24 h, and serum ALP records obtained within 24 hours of admission. Based on three quantiles of ALP, participants were divided into three groups (Units/L): ALP ≤ 59, 60 ≤ ALP ≤ 86, and ALP ≥ 87. Multivariate logistic regression (MLR) explored the association between serum ALP levels and sepsis susceptibility in the general population and subgroups categorized by sex, age, blood lactate, and APACHE IV scores. Meanwhile, this study utilized genome-wide association studies (GWAS) data of serum ALP levels (Neale lab, n = 13,586,006) and sepsis (UK Biobank, n = 12,243,539) to conduct MR analysis to validate their causal relationship by the inverse variance weighted (IVW) method. Results: The observational study comprised 4,458 patients. The sepsis susceptibility of the three groups was 11.1%, 12.5%, and 17.4%, respectively. MLR analysis revealed that sepsis susceptibility of the ALP ≥ 87 group was 1.748 times higher than the ALP ≤ 59 group (OR = 1.748, 95%CI: 1.399-2.183). There was a consistent correlation between them in sex, age, blood lactate, and the APACHE IV scores subgroup. MR study demonstrated a causal association between them (OR = 1.005, 95%CI: 1.002-1.008). Conclusions: Elevated serum ALP levels are significantly associated with sepsis susceptibility, and there is a causal relationship between them.

Urolithin (Uro)-B, a gut microbiota metabolite of ellagic acid, has recently gained considerable attention due to its beneficial bioactivities. This study investigated the potential hepatoprotective effect of Uro-B against alpha-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and explored the possible involved mechanisms. Mice were treated with Uro-B (50 and 100 mg/kg) for four days and received ANIT (75 mg/kg) once on the second day. Our data revealed that Uro-B reduced elevated serum transaminases, alkaline phosphatase, lactate dehydrogenase, and total bilirubin levels associated with ANIT injection. Histopathologically, Uro-B effectively ameliorated ANIT-induced disruption of the hepatic architecture as represented by repressed necro-inflammation and bile duct proliferation. Uro-B also maintained oxidant/antioxidant status that was dysregulated by ANIT. Mechanistically, Uro-B markedly activated Kelch-like ECH-associated protein 1 (Keap-1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling with subsequent upregulation of hepatic heme oxygenase-1 expression. On the other hand, Uro-B suppressed the ANIT-induced expression of nuclear factor kappa-B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). Interestingly, Uro-B repressed peroxisome proliferator-activated receptor alpha (PPARα) expression in the liver. These findings indicate a promising hepatoprotective effect of Uro-B against ANIT-induced CLI in mice. Uro-B modulated the interplay between Keap1/Nrf2, NF-κB/TNF-α, and PPARα signaling pathways, resulting in powerful antioxidant and anti-inflammatory effects.

Biliary obstruction is one of the common complications of chronic pancreatitis (CP). Different operative procedures were described for its management. The present study describes the technique and outcome analysis of intrapancreatic biliary ductoplasty for CP-induced biliary stricture. From March 2014 to March 2021, patients who underwent Frey's procedure with biliary ductoplasty (choledochoplasty) for CP-induced biliary stricture were analyzed retrospectively. During the study period, 148 patients underwent surgery for CP, of which 49 (33%) patients had associated biliary obstruction. Among the 49 patients with biliary obstruction, 43 patients underwent biliary ductoplasty along with Frey's procedure. On preoperative evaluation, elevated serum bilirubin and alkaline phosphatase were observed in 38 (88%) and 43 (100%) patients, respectively, and biliary stricture in 33 (77%) patients. The median duration of surgery was 250 minutes, with a median blood loss of 300 mL. Postoperative complications developed in five (12%) patients, with a median hospital stay of eight days. With a median follow-up of 29 months, recurrent biliary stricture was noted in one (2%) patient, and three patients had readmission for abdominal pain. Intrapancreatic biliary ductoplasty is a safe and feasible alternative procedure in patients with CP and biliary obstruction. This procedure is comparable to existing standard procedures without an increase in morbidity or mortality. This procedure seems to have a good long-term outcome with a low risk of recurrent biliary stricture.

A 3-month-old Golden retriever pup was presented with complaints of abdominal distension, lethargy and inappetence. On clinical examination pale mucous membrane, tachycardia and cardiac murmurs were observed. Haemato-biochemical examination revealed anaemia, leukocytosis, hypoalbuminaemia and elevated serum alkaline phosphatase. Radiographic findings indicated cardiac enlargement and ascites. Increased P wave duration and atrial tachycardia were the major findings on electrocardiography. Echocardiography revealed enlarged right chambers, collapsed left chambers and posteriorly placed tricuspid valves along with regurgitant flow diagnostic of Ebstein’s anomaly. Treatment was initiated with antibiotics, diuretics, ACE inhibitors and cardiac supportive. Pup succumbed to death the next day.

Background: Osteopenia, a condition indicative of reduced bone mineral content, is commonly observed among premature neonates. Early detection is crucial to initiate timely interventions and reduce the risk of long-term skeletal complications. Identifying reliable biochemical markers may enhance prediction and management strategies. Aim of the Study: The aim of this study was to assess whether serum alkaline phosphatase (ALP) levels can be used to predict osteopenia in premature infants. Patients and Methods: An observational cross-sectional study was conducted at the Neonatal Intensive Care Units of Baghdad Teaching Hospital and Children Welfare Teaching Hospital in Baghdad, Iraq. The study spanned six months, from October 1, 2024, to March 31, 2025. A total of 100 premature infants were enrolled. Osteopenia diagnosis was made by a senior pediatrician based on radiographic findings and supporting investigations. Serum ALP levels were measured twice during hospitalization. Results: Osteopenia was identified in 17% (17/100) of the premature infants. Infants diagnosed with osteopenia had significantly shorter gestational age and lower birth weight compared to those without the condition. Additionally, ALP levels in both the first and second samples were significantly elevated among osteopenic infants. Other associated factors included premature rupture of membranes and low Apgar scores at both one and five minutes after birth. Conclusions: Elevated serum alkaline phosphatase levels serve as a significant biochemical marker for predicting osteopenia in premature neonates. This marker may aid clinicians in early identification and management of at-risk infants.

The coexistence of Paget’s disease of bone (PDB) and rheumatoid arthritis (RA) is an uncommon clinical scenario, with limited cases reported in the literature. Both conditions independently affect bone metabolism – RA predominantly causes bone destruction, whereas PDB results in excessive and disorganized bone formation. This dual pathology complicates both diagnosis and management. We report the case of a 44-year-old female with seropositive RA who developed PDB, presenting with upper jaw swelling and elevated serum alkaline phosphatase levels. Histopathological examination revealed characteristic “jigsaw puzzle” trabeculae, confirming the diagnosis. Management required a multidisciplinary approach, including bisphosphonate therapy alongside continued disease-modifying antirheumatic drugs for RA, resulting in a favorable therapeutic response. This case highlights the importance of considering PDB as a differential diagnosis in RA patients with unexplained skeletal symptoms and underscores the need for early diagnosis and individualized treatment.

The Relationship Between Alkaline Phosphatase and Periodontitis: The Mediating Role of Cranial Bone Mineral Density.

Hepatotoxins, which may originate from chemicals, prescription medications, or medicinal plants, are a major cause of hepatotoxicity. This study aims to evaluate the protective role of ellagic acid (EA) in attenuating AsIII-induced hepatotoxicity in male rats. Forty male rats were used and divided into four groups (10 each). Group I: Negative control. Group II received 60 mg/kg/day of EA. Group III was intoxicated with AsIII at a dose of 10 mg/kg body weight for 14 days. Group IV was intoxicated with AsIII and treated daily with 60 mg/kg/day of EA, starting from Day 1 concurrently with AsIII for a total of 14 days. According to the study, AsIII intoxication (Group III) led to liver damage, as indicated by increased hepatocyte vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1) expression, and elevated serum biochemical markers-alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Hepatocyte damage was confirmed through histopathological examination. In contrast, Group IV demonstrated reduced liver damage, mild VEGF expression, HO-1 upregulation, and improvements in biochemical markers. Overall, the findings suggest that EA alleviated AsIII-induced hepatotoxicity via the HO-1 upregulation pathway, highlighting the therapeutic potential of EA in managing liver toxicity.

Skeletal metastases portend a poor prognosis for patients with neuroendocrine tumors (NETs). Literature on peptide receptor radionuclide therapy (PRRT) specific to patients with skeletal metastases from NETs is scarce. This study assessed real-world clinical outcomes of 177Lu-DOTATATE PRRT in this patient subgroup. Methods: Data from consecutive patients with well-differentiated NETs and skeletal metastases treated with 177Lu-DOTATATE at our center from January 2014 until August 2024 were retrospectively reviewed. Safety, efficacy, progression-free survival (PFS), and overall survival (OS) outcomes were analyzed. Results: In total, 288 PRRT cycles were administered to 74 patients. The median number of PRRT cycles was 4 (interquartile range, 2-6), and the median cumulative activity was 21.3 GBq (interquartile range, 11.1-33.3 GBq). The best objective response rates, evaluated using modified M.D. Anderson criteria (bone metastases) and RECIST 1.1 (overall response), were 31% and 23%, respectively, for 62 evaluable patients. The skeletal metastases burden (≤10 vs. >10 sites) did not significantly affect objective response rates. Among the 23 patients with bone pain (31%), 39% reported complete resolution and 52% experienced a partial reduction after treatment. Grade 4 or 5 adverse events occurred in 12% of patients, with anemia, thrombocytopenia, leukopenia, and neutropenia each occurring in fewer than 5% of patients. Skeletal-related events were noted in 20% of patients. The median PFS and OS were 29 mo (95% CI, 18.0-39.9 mo) and 44 mo (95% CI, 32.8-55.2 mo), respectively. Multivariate Cox regression analysis revealed that higher cumulative activity (≥29.6 GBq) was the strongest independent predictor of improved PFS (hazard ratio [HR], 0.15; P < 0.001) and OS (HR, 0.11; P < 0.001), whereas serum alkaline phosphatase elevation (HR, 2.68; P = 0.048) and male sex (HR, 3.48; P = 0.007) were associated with worse OS rates. Conclusion: 177Lu-DOTATATE PRRT is an effective treatment modality for patients with skeletal metastases from NETs (regardless of metastatic burden), with a favorable safety profile and favorable survival outcomes. Serum alkaline phosphatase monitoring is essential in this patient cohort. Achieving an optimal cumulative activity is crucial to maximizing the survival benefit of patients receiving PRRT.

Abstract Solitary fibrous tumor (SFT) is a rare fibroblastic mesenchymal neoplasm with a low metastatic potential. The parapharyngeal area in the head and neck is one of the rarest subsites. Surgical excision remains the standard of care. The local recurrence rate stands at 4%, while the distant recurrence rate is 7% over a 5-year period. Radiation can be used in adjuvant, metastatic, and palliative settings. In metastatic disease, therapeutic options are limited, with the most common regimen used in the first line being a combination of dacarbazine and doxorubicin. With a better understanding of molecular biology, many centers use bevacizumab with temozolomide in the first line. A 50-year-old man underwent a wide excision of a mass in the parapharyngeal region in 2014. Histopathology showed a SFT with negative margins and a low mitotic index. He was under regular follow-up. He presented in January 2024 with abdominal discomfort and distension, fever, cough, and substantial weight loss. Clinically, he had hepatomegaly, lab investigations revealed transaminitis and elevated serum alkaline phosphatase. 18F fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDG PET CT) revealed multiple lung and liver metastases. Ultrasound-guided tru-cut biopsy of the liver lesion with immunohistochemistry (IHC) confirmed metastasis from SFT (positive for signal transducer and activator of transcription 6 and cluster of differentiation 34). He received bevacizumab and temozolomide for four cycles, and a PET CT scan showed progressive disease as per Choi's criteria. Treatment was changed to pazopanib 800 mg once daily as the patient was not keen on intravenous chemotherapy. The patient progressed clinically and radiologically. His programmed death-ligand 1 IHC showed a tumor proportion score of 0%. Next-generation sequencing 75 gene panel could not be done due to low tumor content in the block. The treatment was changed to doxorubicin. He received three cycles of doxorubicin and progressed clinically with deterioration of general health and hence offered the best supportive care. He succumbed to the illness in September 2024.

Disseminated 18 F-FDG-avid intraosseous lesions and clumps of malignant signet-ring cells on subsequent bone marrow aspirate were detected upon investigation of a 58-year-old man with intolerable bone pain, normocytic anemia, and elevated serum alkaline phosphatase. Immunohistochemistry and gastroscopic biopsy confirmed mucin-rich signet-ring cell adenocarcinoma [signet-ring cell gastric carcinoma (SRGC)]. Intriguingly, synchronous bone secondaries from SRGC tend to be hypermetabolic, regardless of the primary tumor 18 F-FDG-negativity, insinuating a reverse heterogeneity of tumor molecular biology. The identification of 18 F-FDG-avid myelophthisis on the setting of bone pain constitutes a caveat for suspicion of cancerous lesions from SRGC and should urge for bone marrow biopsy to improve treatment implications.

Abstract INTRODUCTION Ustekinumab is a monoclonal antibody commonly used in the management of Crohn’s disease (CD). ANCA-associated vasculitis (AAV), a type of vasculitis characterized by the presence of anti-neutrophil cytoplasmic antibodies, can arise from various etiologies, including drug-induced mechanisms. However, reports of ustekinumab-associated AAV are rare, with only one other documented case.We present a case of possible ustekinumab-induced AAV in a patient receiving treatment for CD, contributing to the growing understanding of biologic-induced vascular inflammation. CASE REPORT A 65-year-old male with a history of penetrating ileocolonic and perianal CD and chronic eczematous dermatitis presented with a two-week history of fatigue, night sweats, and high-grade fevers. Following multiple treatment failures, the patient started ustekinumab therapy in 2017. This led to clinical remission and endoscopic improvement for four years prior to presentation, with only mild inflammation on the latest colonoscopy. Upon presentation, the patient was febrile (39.3°C) with otherwise normal vital signs. Initial laboratory investigations revealed elevated serum creatinine (1.40 mg/dL), AST (88 U/L), ALT (152 U/L), alkaline phosphatase (251 U/L), and WBC count (17.52 thousand/uL). An extensive infectious workup, including a CT scan and a nuclear medicine white blood cell scan, was unrevealing.Rheumatology consultation found low suspicion for an autoimmune etiology following a positive antinuclear antibody (ANA) test (1:640) and a negative smooth muscle antibody test. A liver biopsy suggested possible drug-induced injury. A bone marrow biopsy and flow cytometry did not reveal evidence of malignancy. After these evaluations, no clear etiology was found, and the patient was ultimately discharged on antipyretics. Following persistent fevers after discharge, an outpatient ANCA panel returned positive for P-ANCA with an MPO &amp;gt; 8. A subsequent kidney biopsy confirmed MPO-ANCA-associated glomerulonephritis, revealing focal necrotizing glomerulonephritis with 17% crescents. The patient was started on rituximab and prednisone, and ustekinumab, thought by rheumatology consultants to be an inciting factor, was discontinued. Prednisone was tapered off, and rituximab was continued for 2 years before the patient experienced a flare of his CD. This led to the discontinuation of rituximab and initiation of upadacitinib for CD, chronic eczematous dermatitis, and vasculitis. DISCUSSION This case highlights the rare occurrence of potentially ustekinumab-induced AAV in patients treated for CD, underscoring the need for a high index of suspicion for uncommon adverse events. Understanding these potential risks can pave the way for future pathophysiological insights and improved clinical awareness.

Combination therapy with immune checkpoint inhibitors has become the standard first-line treatment for metastatic renal cell carcinoma (mRCC), leading to changes in second-line treatment options, such as nivolumab or tyrosine kinase inhibitors (TKIs). However, very few studies have compared the efficacy of these drugs in patients with mRCC, particularly those with bone metastases (BM), which are associated with a poor prognosis. This study compared the efficacy of nivolumab and TKIs as second-line treatments for mRCC patients with BM and examined the microenvironments of primary tumors and BM lesions. This multi-institutional retrospective study included 87 mRCC patients with BM who received either nivolumab or TKIs as second-line treatments. We analyzed tumor-infiltrating immune cells expressing CD8 and CD20, along with PD-L1, HIF2α, c-MET, VEGFR2, and AXL, in primary tumors and BM sites using immunohistochemistry. This analysis indicated that poor-risk classification, as per the International Metastatic RCC Database Consortium criteria (p<0.01), and elevated serum alkaline phosphatase levels (p=0.031) were significantly associated with poor prognosis. No significant difference in overall survival was observed between patients receiving nivolumab and those receiving TKIs. However, the objective response rate of patients with BM lesions was significantly higher when receiving TKIs than when receiving nivolumab (p=0.014). Immunohistochemistry revealed significantly higher VEGFR2 expression in BM lesions than primary tumors. TKIs could be a promising second-line treatment option for mRCC patients with bone-limited metastases.