Coincidence or Causality: Parathyroid Carcinoma in Chronic Kidney Disease-Case Report and Literature Review.

Parathyroid carcinoma (PC) associated with primary hyperparathyroidism (PHPT) has been well investigated in recent years. Data regarding PC evolution in secondary hyperparathyroidism (SHPT) due to chronic kidney disease (CKD) are, however, scarce. Most features that raise the suspicion of PC in PHPT are part of the usual SHPT evolution in CKD, mirroring the natural changes undergone by the parathyroid glands. Therefore, pre-surgically establishing the malignant or benign character of the lesions is cumbersome. We present two cases of PC in end-stage renal disease, one of which was bilateral, diagnosed after total parathyroidectomy in a high-volume parathyroid surgery center. A literature review of the data was also performed. A systematic search of the PubMed/MEDLINE database until January 2024 identified 42 cases of PC associated with SHPT. Understanding the PC features in CKD might improve associated bone and mineral disease management, and reduce the risk of metastasis, parathyromatosis, or recurrence. Irradiation, prolonged immunosuppression, long dialysis vintage, and genotype may predispose to the malignant transformation of chronically stimulated parathyroids. Despite postsurgical diagnosis, favorable outcomes occurred when distant metastases were absent, even without "en bloc" resection. Further research is warranted to delineate specific diagnostic and therapeutic approaches tailored to this particular patient subpopulation.

Preptin: A New Bone Metabolic Parameter?

Preptin is a 34-aminoacid peptide derived from the E-peptide of pro-insulin-like growth factor 2 (pro-IGF2) that is co-secreted with insulin and upregulates glucose-mediated insulin secretion. High serum preptin levels were described in conditions associated with insulin resistance, such as polycystic ovary syndrome and type 2 diabetes mellitus (T2M). Insulin and also IGF2 are known to be anabolic bone hormones. The "sweet bone" in T2M usually associates increased density, but altered microarchitecture. Therefore, preptin was proposed to be one of the energy regulatory hormones that positively impacts bone health. Experimental data demonstrate a beneficial impact of preptin upon the osteoblasts. Preptin also appears to regulate osteocalcin secretion, which in turn regulates insulin sensitivity. Preptin is greatly influenced by the glucose tolerance status and the level of physical exercise, both influencing the bone mass. Clinical studies describe low serum preptin concentrations in osteoporosis in both men and women, therefore opening the way towards considering preptin a potential bone anabolic therapy. The current review addresses the relationship between preptin and bone mass and metabolism in the experimental and clinical setting, also considering the effects of preptin on carbohydrate metabolism and the pancreatic-bone loop.

Thyroid, Gonadal and Adrenal Dysfunction in Kidney Transplant Recipients: A Review for the Clinician.

While chronic kidney disease-associated mineral and bone disorders (CKD-MBD) prevail in the endocrinological assessment of CKD patients, other endocrine abnormalities are usually overlooked. CKD is associated with significant thyroid, adrenal and gonadal dysfunction, while persistent and de novo endocrinological abnormalities are frequent among kidney transplant recipients (KTR). Low T3 levels prior to transplantation may help identify those at risk for delayed graft function and are often found in KTR. Thyroid surveillance after kidney transplantation should be considered due to structural anomalies that may occur. Despite the rapid recovery of gonadal hormonal secretion after renal transplantation, fertility is not completely restored. Testosterone may improve anemia and general symptoms in KTR with persistent hypogonadism. Female KTR may still experience abnormal uterine bleeding, for which estroprogestative administration may be beneficial. Glucocorticoid administration suppresses the hypothalamic-pituitary-adrenal axis in KTR, leading to metabolic syndrome. Patients should be informed about signs and symptoms of hypoadrenalism that may occur after glucocorticoid withdrawal, prompting adrenal function assessment. Clinicians should be more aware of the endocrine abnormalities experienced by their KTR patients, as these may significantly impact the quality of life. In clinical practice, awareness of the specific endocrine dysfunctions experienced by KTR patients ensures the correct management of these complications in a multidisciplinary team, while avoiding unnecessary treatment.

Pituitary hypoplasia and growth hormone deficiency in a patient with Coffin-Siris syndrome and severe short stature: case report and literature review.

Coffin-Siris syndrome (CSS) is a rare genetic disorder caused by the haploinsufficiency of one of the various genes that are part of the Brahma/BRG1-associated factor (BAF) complex. The BAF complex is one of the chromatin remodeling complexes, involved in embryonic and neural development, and various gene mutations are associated with cognitive impairment. CSS has a highly variable genotype and phenotype expression, thus lacking standardized criteria for diagnosis. It is generally accepted to associate 5th digit/nail hypoplasia, intellectual disability (ID)/developmental delay and specific coarse facial features. CSS patients usually display miscellaneous cardiac, genitourinary and central nervous system (CNS) anomalies. Many patients also associate intrauterine growth restriction, failure to thrive and short stature, with several cases demonstrating growth hormone deficiency (GHD). We report the case of a 4-year-old girl with severe short stature (-3.2 standard deviations) due to pituitary hypoplasia and GHD that associated hypoplastic distal phalanx of the 5th digit in the hands and feet, severe ID, coarse facial features (bushy eyebrows, bulbous nose, flat nasal bridge, dental anomalies, thick lips, dental anomalies, bilateral epicanthal fold) and CNS anomalies (agenesis of the corpus callosum and bilateral hippocampal atrophy), thus meeting clinical criteria for the diagnosis of CSS. Karyotype was 46,XX. The patient was started on GH replacement therapy, with favorable outcomes. Current practical knowledge regarding CSS diagnosis and management from the endocrinological point of view is also reviewed.

Salt, Not Always a Cardiovascular Enemy? A Mini-Review and Modern Perspective.

Dietary salt intake is a long-debated issue. Increased sodium intake is associated with high blood pressure, leading to salt-sensitive hypertension. Excessive salt intake leads to arterial stiffness in susceptible individuals via impaired nitric oxide action and increased endothelin-1 expression, overactivity of the renal sympathetic nervous system and also via aldosterone-independent activation of the mineralocorticoid receptor. Salt restriction in such individuals reduces blood pressure (BP) values. The optimal level of salt restriction that leads to improved cardiovascular outcomes is still under debate. Current BP and dietary guidelines recommend low sodium intake for the general population. However, a specific category of patients does not develop arterial hypertension in response to sodium loading. In addition, recent research demonstrates the deleterious effects of aggressive sodium restriction, even in heart failure patients. This mini review discusses current literature data regarding the advantages and disadvantages of salt restriction and how it impacts the overall health status.

Management of malignant struma ovarii: is aggressive therapy justified? Case report and literature review.

BACKGROUND: Struma ovarii (SO) is a rare ovarian teratoma containing predominantly thyroid tissue. In rare situations SO may develop malignancy. Most cases of malignant struma ovarii (MSO) are diagnosed after surgical removal, based on histopathological examination. There are still controversies regarding the extent of surgery and postoperative management in MSO, due to its unpredictable behavior, possible risk of metastasis and relatively high rate of recurrence. CASE PRESENTATION: We present the case of a patient diagnosed with a right ovarian cyst discovered incidentally during routine ultrasound examination. Its rapid growth and pelvic MRI raised the suspicion of a neoplastic process. She underwent total hysterectomy and bilateral adnexectomy. The anatomopathological diagnosis was MSO with follicular variant of papillary thyroid carcinoma. Prophylactic total thyroidectomy was performed, followed by radioactive iodine ablation (RAI), and suppressive therapy with levothyroxine. At 1 year follow-up, the patient was disease free. CONCLUSIONS: Even if latest literature reports consider that completion of local surgery with total thyroidectomy and RAI might be too aggressive in cases of MSO without extraovarian extension, in our case it was decided to follow the protocol for primary thyroid carcinoma, in order to reduce the recurrence risk.

Body composition, adipokines, FGF23-Klotho and bone in kidney transplantation: Is there a link?

BACKGROUND: Kidney transplantation-associated mineral and bone disorder (KT-MBD) still represents a black box on the long-term due to scarce available data. We aimed to investigate the impact of non-classical bone regulating factors (body composition, adipokines, inflammatory markers, fibroblast growth factor 23-FGF23 and α-Klotho) in long-standing kidney transplant (KT) recipients compared to the general population. METHODS: Our cross-sectional study, enrolling 59 KT patients and age, sex and body mass index-matched healthy general population volunteers, assessed the predictive role of the body composition, serum adipokines (leptin, adiponectin, resistin), inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) and parathyroid hormone (PTH)-FGF23/α-Klotho axis upon bone mineral density (BMD) and osteocalcin, using correlation and linear multiple regression. RESULTS: The 59 KT recipients (mean transplantation span of 57.7 ± 7.2 months) had similar body composition but significantly lower BMD (p < 0.01) compared to the general population group. Total lean mass was independently associated with BMD in both groups. In KT patients, age, time spent on dialysis and PTH were the main negative independent predictors of BMD, after adjusting for possible confounders. Resistin and α-Klotho also negatively predicted lumbar bone density (p < 0.001), while adiponectin and α-Klotho positively predicted osteocalcin levels (p < 0.001) in KT recipients, independently of inflammatory markers. No significant associations were found between FGF23 and bone parameters in any of the groups. CONCLUSIONS: Age, PTH, time on dialysis and lean mass are among the main bone density predictors in long-standing KT patients. The bone impact of adipokine dysregulation and of α-Klotho merits further investigations in KT-MBD. Preserving lean mass for improved bone outcomes should be part of KT-MBD management on the long-term.

Reply to Campbell et al. Comment on "Hogas et al. Salt, Not Always a Cardiovascular Enemy? A Mini-Review and Modern Perspective. Medicina 2022, 58, 1175".

We thank Campbell et al. for their comment [...].

Bone mineral density predictors in long-standing type 1 and type 2 diabetes mellitus.

BACKGROUND: Despite the increased fracture risk, bone mineral density (BMD) is variable in type 1 (T1D) and type 2 (T2D) diabetes mellitus. We aimed at comparing independent BMD predictors in T1D, T2D and control subjects, respectively. METHODS: Cross-sectional case-control study enrolling 30 T1D, 39 T2D and 69 age, sex and body mass index (BMI) - matched controls that underwent clinical examination, dual-energy X-ray absorptiometry (BMD at the lumbar spine and femoral neck) and serum determination of HbA1c and parameters of calcium and phosphate metabolism. RESULTS: T2D patients had similar BMD compared to T1D individuals (after adjusting for age, BMI and disease duration) and to matched controls, respectively. In multiple regression analysis, diabetes duration - but not HbA1c- negatively predicted femoral neck BMD in T1D (ß= -0.39, p = 0.014), while BMI was a positive predictor for lumbar spine (ß = 0.46, p = 0.006) and femoral neck BMD (ß = 0.44, p = 0.007) in T2D, besides gender influence. Age negatively predicted BMD in controls, but not in patients with diabetes. CONCLUSIONS: Long-standing diabetes and female gender particularly increase the risk for low bone mass in T1D. An increased body weight partially hinders BMD loss in T2D. The impact of age appears to be surpassed by that of other bone regulating factors in both T1D and T2D patients.

New insights into the metabolic-bone crosstalk in active acromegaly.

INTRODUCTION: Body composition (BC) and adipokines share bone active properties and display an altered profile in acromegaly. The fibroblast growth factor 23 (FGF23)/α-Klotho system, also involved in bone metabolism, is upregulated in growth hormone (GH) excess states. Hence, we aimed to investigate their impact on bone in active acromegaly, compared to controls. MATERIAL AND METHODS: BC, bone mineral density (BMD) (via dual X-ray absorptiometry), serum adipokines (leptin, adiponectin, resistin), parathyroid hormone (PTH), FGF23, α-Klotho, and osteocalcin were assessed in a cross-sectional study enrolling 35 patients with active acromegaly (Acro), compared to 35 sex, age, and body mass index (BMI) one-to-one matched healthy controls (CTL). RESULTS: The Acro group had higher bone density scores (p < 0.05), lower visceral fat depots (p = 0.011), and lower serum leptin (p < 0.001) but elevated adiponectin (p < 0.001) and resistin (p = 0.001) concentrations when compared to the CTL group. α-Klotho was not related to the GH/IGF1 axis in the Acro group. Resistin was higher in both diabetic and non-diabetic Acro compared to CTL (p < 0.05). Age and BC were the main independent BMD predictors in regression analysis in both groups, while IGF1 was a positive predictor of osteocalcin levels in the Acro (ß = 0.48, p = 0.006). The correlations between adipokines, the FGF23/α-Klotho system, and bone parameters, respectively, were lost after adjusting for age and BC. CONCLUSIONS: Age and BC were the main independent BMD predictors in the acromegalic patients with active disease, while IGF1 was independently associated with serum osteocalcin concentrations. The role of α-Klotho in evaluating acromegaly and the associated osteopathy in the long-term appears to be limited. Our study is among the first to report significant serum resistin changes in patients with active acromegaly, opening new insights in the GH-mediated insulin resistance. The GH-resistin relationship merits further investigations.

FGF23 and primary hyperparathyroidism: is there a link?

INTRODUCTION: Data regarding the role of fibroblast growth factor 23 (FGF23) in primary hyperparathyroidism (PHPT) are scarce and discordant. Our study aimed to evaluate the prognostic impact of FGF23 upon the clinical and biochemical evolution of PHPT. MATERIAL AND METHODS: Forty-two patients with ages between 30 and 80 years, diagnosed with PHPT caused by a sporadic, solitary parathyroid adenoma, and referred to surgery (minimally invasive parathyroidectomy) were prospectively included in the study. Serum levels of FGF23, PTH, 25(OH)D3, calcium (Ca), phosphate (P), total procollagen type 1 N-terminal propeptide, and C-terminal telopeptide of type I collagen were determined at baseline (preoperatory), one day after surgery, and in 13 patients also prospectively at three, six, and 12 months. Bone mineral density (BMD) was also evaluated before surgery in all patients and 12 months after surgery in the 13 followed up patients. RESULTS: In the 42 PHPT patients with D hypovitaminosis (mean 25(OH)D3 levels of 16.2 ± 1.5 ng/mL), preoperatory serum FGF23 concentration was within the normal range (75.55 ± 3.39 pg/mL) and remained unchanged one day post operation (81.69 ± 4.67 pg/mL, p = non-significant). The 13 patients followed prospectively for up to 12 months after surgery also showed unmodified FGF23 levels (80.9 ± 11.03 pg/mL, p = non-significant), despite PTH and Ca normalisation and vitamin D replenishment. Preoperatory FGF23 negatively correlated with PTH (r = -0.37, p = 0.038), but not with 25(OH)D3, Ca, P, bone mass, or metabolism markers. CONCLUSIONS: In PHPT, correlations between FGF23 and PTH seem rather an epiphenomenon. Therefore, we think that FGF23 evaluation and dynamics are not informative regarding PHPT severity. (Endokrynol Pol 2020; 71 (4): 306-312).

FGF23 Beyond the Kidney: A New Bone Mass Regulator in the General Population.

Clinical studies investigating the relationship between fibroblast growth factor 23 (FGF23) and bone mass are controversial, especially in the healthy renal population. Our study is one of the forefronts investigating the relationship between FGF23 and bone mass parameters in the general population, according to age, sex, menopausal, and nutritional status. Cross-sectional study enrolling 123 volunteers between 20-80 years of age without primary osteoporosis under treatment nor secondary osteoporosis, where bone mass (bone mineral density-BMD, bone mineral content-BMC; assessed by Dual X-Ray Absorptiometry-DXA), body composition (DXA evaluation), and also the serum levels of FGF23, parathormone (PTH), 25(OH)D, bone resorption marker C-terminal telopeptide of type I collagen (CTx) and leptin were determined. FGF23 was negatively and independently associated with BMD and/or BMC in all groups. FGF23 contributed to up to 10% (p <0.05) of femoral neck BMD variance in postmenopausal women, but was not an accurate discriminator of normal versus low bone mass (AUC=0.622±0.076). FGF23 did not correlate with 25(OH)D, CTx, body weight, body composition parameters or leptin. FGF23 was independently associated with PTH in premenopausal women and men only. FGF23 was negatively associated with bone mass parameters in both sexes, but was not a fine discriminator between normal bone mass and osteopenia/osteoporosis. The mechanism through which FGF23 acts upon the bone seems independent of the nutritional status, requiring further investigation.

Nephrotoxicity/renal failure after therapy with 90Yttrium- and 177Lutetium-radiolabeled somatostatin analogs in different types of neuroendocrine tumors: a systematic review.

BACKGROUND/OBJECTIVE: Data regarding the nephrotoxicity of the peptide receptor radionuclide therapy (PRRT) with Yttrium- and Lutetium-radiolabeled somatostatin analogs (RSA) are inconclusive. We aimed to evaluate the short- and long-term nephrotoxicity following PRRT usage in patients with all types of neuroendocrine tumors (NETs). METHODS: A systematic review of observational studies reporting data about nephrotoxicity after treatment with Yttrium and Lutetium RSA was performed. Data on serum creatinine, creatinine clearance, glomerular filtration rate (GFR) and need for renal replacement therapy were compiled. We included patients with progressive, inoperable symptomatic G1, G2 and G3 different types of NETs. After searching in three electronic databases PubMed, Scopus and the Cochrane Library, from 1 January 1978 to November 2018, data were extracted and summarized using a random-effects model. RESULTS: The final analysis included 34 studies, comprising 5386 participants, enrolling patients with G1, G2, G3 NETs and a follow-up from 12 up to 191 months. Compared with renal function before treatment, measured/estimated glomerular filtration rate (m/eGFR) values changed after PRRT, with a mean annual decrease following PRRT between 2 and 4 mL/min/1.73 m suggesting different grades of nephrotoxicity after PRRT. When compared, Y-RSA and the Y-RSA-Lu-RSA combination are associated with a higher m/eGFR decline compared to Lu-RSA alone. CONCLUSIONS: PRRT can be followed by potentially serious long-term nephrotoxicity, despite kidney protection. The use of the quantified renal function combined with a long follow-up period and personalized dosimetry-based PRRT can reduce nephrotoxicity, in order to use the whole PRRT potential in the management of NETs.

The Effects of Bariatric Surgery on Renal Outcomes: a Systematic Review and Meta-analysis.

BACKGROUND/OBJECTIVE: Although promising, data regarding the renal impact and safety of bariatric surgery (BS) are insufficient. We aimed at investigating the benefits and harms of BS for weight loss on kidney function. METHODS: A systematic review and meta-analysis of observational studies reporting data about the impact of BS (any techniques) on serum/plasma creatinine, creatinine clearance, glomerular filtration rate (GFR), proteinuria, nephrolithiasis, and need for renal replacement therapy (RRT)) was performed. Obese adults (non-chronic kidney disease (CKD), CKD or transplanted patients) that underwent BS for weight loss were included. After searching MEDLINE (inception to August 2017), the Cochrane Library (Issue 10-12, October 2017), and the websiteclinicaltrials.gov (August 2017), data were extracted and summarized using a random-effects model. RESULTS: The final analysis included 23 cohort studies, comprising 3015 participants. Compared with renal function before treatment, BS significantly decreased serum creatinine level (mean difference (MD), - 0.08 mg dl-1; 95% confidence interval (CI), - 0.10 to - 0.06); p < 0.001) and proteinuria (MD, - 0.04 g 24 h-1; 95% CI, - 0.06 to - 0.02; p < 0.001) in the overall group. GFR significantly improved 6 months or more after BS both in the hyperfiltration and CKD subgroups. Renal function also tended to improve in renal transplant patients. Data on nephrolithiasis and the need for RRT were scarce or not reported. CONCLUSIONS: BS apparently has positive effects on kidney function and tends to normalize GFR across different categories of renal impairment (hyperfiltration and CKD patients).

Modifications in the spectrum of bone mass predictive factors with menopausal status.

PURPOSE: Fat mass (FM) is a source of adipocytokines, with both positive and negative bone consequences. We aimed to investigate the role of body composition and adipokines as predictive factors for bone mass in women. METHODOLOGY: This cross-sectional study included 93 women (38 premenopausal and 55 postmenopausal). Bone mineral density (BMD) and body composition were assessed by dual-energy X-ray absorptiometry. Serum levels of leptin, adiponectin, resistin, and also of the phosphocalcic markers parathormone and vitamin D were measured. RESULTS: Only lean mass (LM) was an independent predictor of BMD in premenopausal women (r2 = 0.381, p < 0.001 for femoral neck BMD, r2 = 0.2, p < 0.01 for whole-body BMD) in both unadjusted and age-adjusted models. The effect of total FM upon BMD became nonsignificant when LM was added to the models assessed. In postmenopausal women, although LM, trunk-to-leg fat ratio, and resistin were initially associated with BMD in unadjusted models, only the trunk-to-leg fat ratio independently predicted BMD at various sites (r2 = 0.171, p < 0.01 for lumbar BMD, r2 = 0.078, p < 0.05 for radius BMD, r2 = 0.094, p < 0.05 for whole-body BMD) after adjusting for age. CONCLUSIONS: While in premenopausal women the effect of LM upon bone is prevalent, after menopause, the fat distribution reflected by trunk-to-leg fat ratio is a major determinant of bone mass at different sites. Our study also stresses that the relationship between total FM and BMD is not mediated by adipokines in women irrespective of menopausal status and body composition, but it is largely mediated by LM only in young premenopausal women.

Primary Prevention of Stroke in Chronic Kidney Disease Patients: A Scientific Update.

BACKGROUND: Although chronic kidney disease (CKD) is an independent risk factor for stroke, official recommendations for the primary prevention of stroke in CKD are generally lacking. SUMMARY: We searched PubMed and ISI Web of Science for randomised controlled trials, observational studies, reviews, meta-analyses and guidelines referring to measures of stroke prevention or to the treatment of stroke-associated risk factors (cardiovascular disease in general and atrial fibrillation (AF), arterial hypertension or carotid artery disease in particular) among the CKD population. The use of oral anticoagulation in AF appears safe in non-end stage CKD, but it should be individualized and preferably based on thromboembolic and bleeding stratification algorithms. Non-vitamin K antagonist oral anticoagulants with definite dose adjustment are generally preferred over vitamin K antagonists in mild and moderate CKD and their indications have started being extended to severe CKD and dialysis also. Aspirin, but not clopidogrel, has limited indications for reducing the risk for atherothrombotic events in CKD due to its increased bleeding risk. Carotid endarterectomy has shown promising results for stroke risk reduction in CKD patients with high-grade symptomatic carotid stenosis. The medical treatment of arterial hypertension in CKD often fails to efficiently lower blood pressure values, but recent data regarding the use of interventional procedures such as renal denervation, baroreflex activation therapy or renal artery stenting are encouraging. Key Messages: In the absence of clear guidelines and protocols, primary prevention of stroke in CKD patients remains a subtle art in the hands of the clinicians. Nevertheless, refraining CKD patients from standard therapies often worsens their prognosis.

Predictive Value for Galectin 3 and Cardiotrophin 1 in Hemodialysis Patients.

Patients with end-stage renal disease (ESRD) have an increased risk of all-cause mortality. The prognostic value of the new cardiac biomarkers, cardiotrophin 1 (CT-1) and galectin 3 (GAL-3), has not yet been defined in hemodialysis (HD) patients. The aim of this study was to determine the use of these novel biomarkers for predicting mortality in HD patients. Plasma GAL-3 and CT-1 concentrations were determined (at baseline) in 88 HD patients followed for 22.2 ± 4.7 months. During the follow-up period, 21 (23.9%) deaths were recorded. According to Cox analysis, the cutoff point for GAL-3 as a predictor of mortality was 23.73 ng/mL, while the cutoff point for CT-1 as a predictor of mortality was 36 pg/mL. In univariate analysis, only GAL-3 >23.73 ng/mL was an independent predictor of mortality (hazard ratio 2.60; 95% confidence interval, 1.09-6.18). In a multivariable Cox proportional hazards model, GAL-3 levels above the cutoff value remained an independent predictor of all-cause mortality. Our data suggest that similar to the general population, GAL-3 is an independent predictor of mortality in HD patients.