Interventions to Attenuate Cardiovascular Calcification Progression: A Systematic Review of Randomized Clinical Trials.

BACKGROUND: Cardiovascular calcification, characterized by deposition of calcium phosphate in the arterial wall and heart valves, is associated with cardiovascular morbidity and mortality and is commonly seen in aging, diabetes, and chronic kidney disease. Whether evidence-based interventions could significantly attenuate cardiovascular calcification progression remains uncertain. METHODS AND RESULTS: We conducted a systematic review of randomized controlled trials involving interventions, compared with placebo, another comparator, or standard of care, to attenuate cardiovascular calcification. Included clinical trials involved participants without chronic kidney disease, and the outcome was cardiovascular calcification measured using radiological methods. Quality of evidence was determined by the Cochrane risk of bias and Grading of Recommendations, Assessment, Development, and Evaluations assessment. Forty-nine randomized controlled trials involving 9901 participants (median participants 104, median duration 12 months) were eligible for inclusion. Trials involving aged garlic extract (n=6 studies) consistently showed attenuation of cardiovascular calcification. Trials involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (n=14), other lipid-lowering agents (n=2), hormone replacement therapies (n=3), vitamin K (n=5), lifestyle measures (n=4), and omega-3 fatty acids (n=2) consistently showed no attenuation of cardiovascular calcification with these therapies. Trials involving antiresorptive (n=2), antihypertensive (n=2), antithrombotic (n=4), and hypoglycemic agents (n=3) showed mixed results. Singleton studies involving salsalate, folate with vitamin B6 and 12, and dalcetrapib showed no attenuation of cardiovascular calcification. Overall, Cochrane risk of bias was moderate, and the Grading of Recommendations, Assessment, Development, and Evaluations assessment for a majority of analyses was moderate certainty of evidence. CONCLUSIONS: Currently, there are insufficient or conflicting data for interventions evaluated in clinical trials for mitigation of cardiovascular calcification. Therapy involving aged garlic extract appears most promising, but evaluable studies were small and of short duration.

Atrial Fibrillation in Kidney Failure: Challenges in Risk Assessment and Anticoagulation Management.

Management of atrial fibrillation (AF) is a clinical conundrum in people with kidney failure. Stroke risk is disproportionately high, but clinicians have a limited armamentarium to improve outcomes in this population in whom there is a concurrently high bleeding risk. Direct oral anticoagulants may have a superior benefit-risk profile compared with vitamin K antagonists in people on hemodialysis. Although research has predominantly focused on identifying a safe and effective oral anticoagulation option to reduce stroke risk in people with kidney failure (and predominantly those on hemodialysis), it remains uncertain how clinicians discriminate between people who would derive net clinical benefit as opposed to net harm. The recommended CHA2DS2-VASc score cutoffs provide poor discriminatory value, and there is an urgent need to identify robust markers of thromboembolic risk in kidney failure. There is increasing data to challenge the prior dogma of risk equivalence across AF type, and the American Heart Association highlights moving beyond AF as a binary entity to consider the prognostic significance of AF burden. Implantable cardiac monitor studies reveal high rates and varied burden of subclinical and paroxysmal AF in people on hemodialysis. The association between AF burden and the proarrhythmic environment of hemodialysis with cyclical volume loading, offloading, and electrolyte changes is not well studied. We review the significance of AF burden as a contributor to thromboembolic risk, its potential as the missing link in risk assessment, and updated evidence for anticoagulation in people with kidney failure.

Magnetic Resonance Imaging (MRI) Analysis of Tissue Sodium Concentration in Chronic Kidney Disease.

Human body sodium is regulated by the kidneys and extrarenal mechanisms. Stored skin and muscle tissue sodium accumulation is associated with kidney function decline, hypertension, and a pro-inflammatory and cardiovascular disease profile. In this chapter, we describe the use of sodium-hydrogen magnetic resonance imaging (23Na/1H MRI) to dynamically quantify tissue sodium concentration in the lower limb of humans. Real-time quantification of tissue sodium is calibrated against known sodium chloride aqueous concentrations. This method may be useful for investigating in vivo (patho-)physiological conditions associated with tissue sodium deposition and metabolism (including in relation to water regulation) to enlighten our understanding of sodium physiology.

Community-acquired versus hospital-acquired acute kidney injury at a large Australian metropolitan quaternary referral centre: incidence, associations and outcomes.

BACKGROUND: There is increasing global incidence of acute kidney injury (AKI) and significant short- and long-term impacts on patients. AIMS: To determine incidence and outcomes of community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI) among inpatients in the Australian healthcare setting using modern health information systems. METHODS: A retrospective cohort study of adult patients admitted to a quaternary hospital in Melbourne, Australia, between 1 January 2018 and 31 December 2019 utilising an electronic data warehouse. Participants included adult patients admitted for >24 h who had more than one serum creatinine level recorded during admission. Kidney transplant and maintenance dialysis patients were excluded. Main outcomes measured included AKI, as classified by the Kidney Disease Improving Global Outcomes (KDIGO) criteria, hospital length of stay and 30-day mortality. RESULTS: A total of 6477 AKI episodes was identified across 43 791 admissions. Of all AKI episodes, 77% (n = 5011), 15% (n = 947) and 8% (n = 519) were KDIGO stage 1, 2 and 3 respectively. HA-AKI accounted for 55.9% episodes. Patients required intensive care unit admission in 22.7% (n = 1100) of CA-AKI and 19.3% (n = 935) of HA-AKI, compared with 7.5% (n = 2815) of patients with no AKI (P = 0.001). Patients with AKI were older with more co-morbidities, particularly chronic kidney disease (CKD). Length of stay was longer in CA-AKI (8.8 days) and HA-AKI (11.8 days) compared with admissions without AKI (4.9 days; P < 0.001). Thirty-day mortality was increased with CA-AKI (10.2%) and HA-AKI (12.8%) compared with no AKI (3.7%; P < 0.001). CONCLUSION: The incidence of AKI detected by the electronic data warehouse was higher than previously reported. Patients who experienced AKI had greater morbidity and mortality. CKD was an important risk factor for AKI in hospitalised patients.

Skin regulation of salt and blood pressure and potential clinical implications.

Sodium chloride, as salt, gives rise to hypertension. Nevertheless, individual susceptibility to the ramifications of sodium chloride is heterogeneous. The conventional nephron-centric regulation of sodium with neurohormonal inputs and responses is now expanded to include an intricate extrarenal pathway including the endothelium, skin, lymphatics, and immune cells. An overabundance of sodium is buffered and regulated by the skin interstitium. Excess sodium passes through (and damages) the vascular endothelium and can be dynamically stored in the skin, modulated by skin immune cells and lymphatics. This excess interstitially stored sodium is implicated in hypertension, cardiovascular dysfunction, metabolic disruption, and inflammatory dysregulation. This extrarenal pathway of regulating sodium represents a novel target for better blood pressure management, rebalancing disturbed inflammation, and hence addressing cardiovascular and metabolic disease.

Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis.

BACKGROUND AND OBJECTIVES: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. RESULTS: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. CONCLUSIONS: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.

Effect of nutritional calcium and phosphate loading on calciprotein particle kinetics in adults with normal and impaired kidney function.

Plasma approaches metastability with respect to its calcium and phosphate content, with only minor perturbations in ionic activity needed to sustain crystal growth once nucleated. Physiologically, calcium and phosphate are intermittently absorbed from the diet each day, yet plasma concentrations of these ions deviate minimally post-prandially. This implies the existence of a blood-borne mineral buffer system to sequester calcium phosphates and minimise the risk of deposition in the soft tissues. Calciprotein particles (CPP), endogenous mineral-protein colloids containing the plasma protein fetuin-A, may fulfill this function but definitive evidence linking dietary mineral loading with their formation is lacking. Here we demonstrate that CPP are formed as a normal physiological response to feeding in healthy adults and that this occurs despite minimal change in conventional serum mineral markers. Further, in individuals with Chronic Kidney Disease (CKD), in whom mineral handling is impaired, we show that both fasting and post-prandial levels of CPP precursors are markedly augmented and strongly inversely correlated with kidney function. This study highlights the important, but often neglected, contribution of colloidal biochemistry to mineral homeostasis and provides novel insight into the dysregulation of mineral metabolism in CKD.

Magnetic resonance imaging determination of tissue sodium in patients with chronic kidney disease.

Excess sodium is a major modifiable contributor to hypertension and cardiovascular risk. Knowledge of sodium storage and metabolism has derived mainly from indirect measurements of dietary sodium intake and urinary sodium excretion, however both attempt to measure body sodium and fluid in a two-compartment model of intracellular and extracellular spaces. Our understanding of total body sodium has recently included a storage pool in tissues. In the last two decades, sodium-23 magnetic resonance imaging (23 Na MRI) has allowed dynamic quantification of tissue sodium in vivo. Tissue sodium is independently associated with cardiovascular dysfunction and inflammation. This review explores (i) The revolution of our understanding of sodium physiology, (ii) The development and potential clinical adoption of 23 Na MRI to provide improved measurement of total body sodium in CKD and (iii) How we can better understand mechanistic and clinical implications of tissue sodium in hypertension, cardiovascular disease and immune dysregulation, especially in the CKD population.

Total Body Sodium Balance in Chronic Kidney Disease.

Excess sodium intake is a leading but modifiable risk factor for mortality, with implications on hypertension, inflammation, cardiovascular disease, and chronic kidney disease (CKD). This review will focus mainly on the limitations of current measurement methods of sodium balance particularly in patients with CKD who have complex sodium physiology. The suboptimal accuracy of sodium intake and excretion measurement is seemingly more marked with the evolving understanding of tissue (skin and muscle) sodium. Tissue sodium represents an extrarenal influence on sodium homeostasis with demonstrated clinical associations of hypertension and inflammation. Measurement of tissue sodium has been largely unexplored in patients with CKD. Development and adoption of more comprehensive and dynamic assessment of body sodium balance is needed to better understand sodium physiology in the human body and explore therapeutic strategies to improve the clinical outcomes in the CKD population.

Serum phosphate and mortality in incident dialysis patients in Australia and New Zealand.

AIM: Hyperphosphataemia is associated with increased adverse outcomes, including mortality. Re-examining this association using up-to-date data reflecting current and real-world practices, across different global regions and in both haemodialysis and peritoneal dialysis patients, is important. METHODS: We describe the association between serum phosphate and all-cause and cardiovascular mortality in incident dialysis patients between 2008 and 2018 using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Time-dependent Cox proportionate hazards models were used. Models were adjusted for available covariates and fitted for the overall cohort, and also each dialysis modality. RESULTS: 31 989 patients were followed over 97 122 person-years at risk (mean age at first dialysis 61 years, 38% female, 67% haemodialysis). We observed a U-shaped association between serum phosphate and all-cause mortality. In the fully adjusted model, categories of serum phosphate above and below 1.25-1.99 mmol/L were associated with progressively higher risk, reaching a hazard ratio of 2.13 (95% CI 1.93-2.36, p < .001) for serum phosphate ≥2.75 mmol/L, and 1.56 (95% CI 1.44-1.69, p < .001) for serum phosphate <1.00 mmol/L. Low and high levels of serum phosphate were also associated with increased risk of cardiovascular mortality, however the association with high serum phosphate was more pronounced ("J-shaped relationship"). The associations were consistent across sub-analyses of patients receiving haemodialysis and peritoneal dialysis treatment. CONCLUSION: In this large contemporary dialysis cohort, both high and low levels of serum phosphate were independently associated with increased risk of mortality. Future studies are required to determine whether treatment of abnormal serum phosphate levels improves mortality.

High-intensity physical exercise increases serum α-klotho levels in healthy volunteers.

The recently discovered klotho proteins have roles in a diverse range of metabolic processes with the oldest protein, α-klotho, implicated in various cellular pathways in energy, glucose, and phosphate metabolism. Circulating soluble klotho (sKl), derived from membrane α-klotho cleavage, not only has effects on ion channels and insulin signaling pathways, but is inversely associated with mortality. Effects of physical exercise on sKl have not been well studied. The effect of a single high-intensity standardized exercise on sKl and serum phosphate (sPi) levels in healthy adults was investigated. A standard Bruce protocol treadmill exercise was undertaken by 10 fasting healthy volunteers. sKl, sPi, and blood glucose levels were measured in samples collected 1-week prior, immediately pre (Tpre), 0 (Tpost), 30 (T30), 240 (T240) min, and 1-week after exercise. Median (interquartile range) age of participants was 47.5 (44-51) years; five (50%) were male. All study participants achieved at least 90% predicted maximum heart rate (MHR). sKl increased acutely after exercise (Tpre median 448 pg/mL vs. Tpost median 576 pg/mL; p < 0.01). There was a nonsignificant sPi decline at T30 (Tpre 0.94 ± 0.12 mmol/L vs. T30 0.83 ± 0.22 mmol/L). Exercise led to a reduction in blood glucose by T240 with median glucose levels at Tpre, Tpost, T30, and T240 of 6.0, 6.5, 6.3, and 5.7 mmol/L, respectively. In conclusion, a single high-intensity exercise session is associated with a transient increase in sKl, a delayed reduction in blood glucose, and a nonsignificant decrease in sPi levels in healthy adults. The evaluation of long-term effects of cardiovascular fitness programs on sKl and sPi in healthy individuals and disease cohorts are required to identify potential lifestyle modifications to help improve chronic disease management and long-term outcomes.

Progression of arterial stiffness is associated with changes in bone mineral markers in advanced CKD.

BACKGROUND: Arterial stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD). There are limited prospective data however on progression of arterial stiffness in CKD, including evaluating associations with bone mineral markers such as fibroblast growth factor 23 (FGF23) and soluble α-klotho (sKl). METHODS: In this prospective, single-center, observational study, arterial stiffness [measured by pulse wave velocity (PWV)] and hormones influencing mineral homeostasis, including serum FGF23 and sKl, were compared between non-dialysis CKD stages 4/5 and healthy controls at baseline and 12 months (12 m). Abdominal aortic calcification (AAC) was quantitated using lateral lumbar radiography at baseline. RESULTS: Forty patients with CKD [mean estimated glomerular filtration rate (eGFR) 19.5 ± 6.7 mL/min/1.73m2] and 42 controls (mean eGFR 88.6 ± 12.9 mL/min/1.73m2) completed follow-up. There were no differences in age, gender and body mass index between groups. A significant increase in FGF23 [240.6 (141.9-1129.8) to 396.8 (160.3-997.7) pg/mL, p = 0.001] was observed in the CKD group but serum phosphate, corrected calcium, parathyroid hormone and sKl did not change significantly over 12 m. At baseline, CKD subjects had higher AAC prevalence [83.8% versus (vs.) 43.6%, p = 0.002] and higher aortic PWV [9.7(7.6-11.7) vs. 8.1 (7.2-9.7) m/s, p = 0.047] compared to controls. At 12 m, aortic PWV increased by 1.3 m/s (95% confidence interval, 0.56 to 2.08, p < 0.001) in the CKD cohort, with 30% of subjects showing progression from normal aortic elasticity to stiffening (PWV > 10 m/s). Serum FGF23 was associated with AAC, abnormal PWV and progression of PWV at 12 m. CONCLUSIONS: Arterial stiffness and serum FGF23, both of which are associated with increased cardiovascular risk, increased over one year in individuals with CKD. Additionally, a significant association was found between serum FGF23 and arterial calcification and stiffness. Larger clinical studies and further experimental work are warranted to delineate the temporal relationship as well as the pathological mechanisms linking FGF23 and vascular disease.

The Role of Secondary Calciprotein Particles in the Mineralisation Paradox of Chronic Kidney Disease.

Mineralisation paradox is prevalent in chronic kidney disease and ageing where increased vascular calcification is accompanied by reduced bone mineralisation and osteopenia. Secondary calciprotein particles (CPP2), colloidal nanoparticles containing hydroxyapatite crystal stabilised by a protein shell, have been implicated in vascular calcification in chronic kidney disease. Here, we describe the effect of CPP2 on osteoblasts and vascular smooth muscle cells (VSMC) mineralisation in an in vitro model system. The mineralisation paradox can be simulated in vitro by the addition of phosphate ions (Pi, 3 mM) and CPP2 (10 µg/ml of Ca equivalent). Pi alone induced osteoblast mineralisation but had no effect on VSMC mineralisation. CPP2 alone had no effect on mineralisation in either cell line, but when combined with elevated Pi, reduced osteoblast-like mineralisation (P < 0.001) whilst induced VSMC mineralisation (P < 0.001). These results suggest that in an in vitro system the synergistic interaction between Pi and CPP2 could mimic the mineralisation paradox, and may provide a potential mechanistic link to explain these clinical observations.

FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts.

In kidney disease, higher circulating levels of the mineral-regulating hormone fibroblast growth factor (FGF)-23 are predictive of disease progression but direct pathogenic effects on the kidney are unknown. We sought evidence of local renal synthesis in response to unilateral ureteric obstruction in the mouse, and pro-fibrotic actions of FGF23 on the fibroblast in vitro. Acute tubulointerstitial injury due to unilateral ureteric obstruction stimulated renal FGF23 synthesis by tubules, and downregulated inactivating proprotein convertases, without effects on systemic mineral metabolism. In vitro, FGF23 had divergent effects on fibroblast activation in cells derived from normal and obstructed kidneys. While FGF23 failed to stimulate fibrogenesis in normal fibroblasts, in those primed by injury, FGF23 induced pro-fibrotic signalling cascades via activation of TGF-ß pathways. Effects were independent of α-klotho. Tubule-derived FGF23 may amplify myofibroblast activation in acute renal injury, and might provide a novel therapeutic target in renal fibrosis.

Epigenetic Modifications to H3K9 in Renal Tubulointerstitial Cells after Unilateral Ureteric Obstruction and TGF-ß1 Stimulation.

Introduction: Epigenetic regulation of fibrogenesis through post-translational histone modifications (marks) may be a key determinant of progression in renal disease. In this study, we examined the distribution and acquisition of histone 3 Lysine 9 (H3K9) marks after injury and stimulation with the pro-fibrotic cytokine TGF-ß1. Our focus was on their presence in activated fibroblasts (myofibroblasts) and epithelial cells (epithelial-mesenchymal transition). Methods and Results: Immunofluorescent microscopy was used to examine global H3K9 acetylation (H3K9Ac) and tri-methylation (H3K9Me3) after unilateral ureteric obstruction (UUO) in mice. Confocal, super resolution microscopy and flow cytometry were used to determine the in vitro effect of TGF-ß1 on structural arrangement of these marks, and their relationship with α-smooth muscle actin (αSMA) expression, a marker of myofibroblasts and early EMT. The number of individual histone marks was increased 10 days after UUO (p < 0.05 vs. control), with both marks clearly seen in various cell types including proximal tubules and myofibroblasts. Sub-nuclear microscopy in primary rat renal fibroblasts and a proximal tubule cell line (NRK-52e) showed that H3K9Ac was co-localized with phosphorylated-Ser2 RNA polymerase II (pRNAPol II), while H3K9Me3 was not, consistent with permissive and repressive effects on gene expression respectively. In both cell types H3K9Ac was diffusely distributed throughout the nucleus, while H3K9Me3 was found in compartments resembling the nucleolus, and in the case of the fibroblast, also juxtapositioned with the nuclear membrane. TGF-ß1 had no effect on H3K9Ac marks in either cell, but resulted in a redistribution of H3K9Me3 within the fibroblast nucleus. This was unrelated to any change in mitogenesis, but was associated with increased αSMA expression. Conclusion: These findings highlight why it is important to consider the epigenetics of each cell individually, because whilst no overall enrichment occurred, renal myofibroblast differentiation was accompanied by distinct changes in histone mark arrangements.

Soluble klotho may be a marker of phosphate reabsorption.

Background: Membrane-bound α-klotho functions as a co-receptor with fibroblast growth factor receptor at the renal tubule conferring specificity to fibroblast growth factor-23 (FGF-23), allowing it to inhibit tubular phosphate reabsorption at physiological concentrations. α-klotho also exists as a soluble protein. However, the complex interrelationships between soluble α-klotho (sKl), FGF-23 and phosphate reabsorption are poorly understood, with little known about the links between sKl, FGF-23 and phosphate reabsorption in chronic kidney disease (CKD). This study addresses this issue in a cohort of patients with and without CKD. Methods: We conducted a single-centre, cross-sectional study of contemporaneously obtained samples of blood and 24-h urine biochemistry along with sKl and intact FGF-23 (iFGF-23) from non-dialysis-dependent CKD patients and healthy volunteers. Pearson's correlation coefficients were used to determine correlations between natural log-transformed (Ln) sKl and iFGF-23 with other parameters of interest. Backward multivariate analysis was undertaken to evaluate the relationship between mineral parameters. Results: One hundred and sixteen participants (77 with CKD and 39 healthy volunteers) were studied, of which 74 (63.8%) were male. The median age was 61 (interquartile range 49-71) years. Those with CKD had lower sKl (408 versus 542 pg/mL), higher iFGF-23 (94 versus 41 pg/mL), higher fractional excretion of phosphate (25.05 versus 10.98%) and lower daily urinary phosphate excretion (UPE) (24.8 versus 32.3 mmol/L) compared with healthy volunteers (all P ≤ 0.002). Age correlated inversely and estimated glomerular filtration rate (eGFR) correlated positively with phosphate reabsorption and Ln(sKl), while the opposite was seen with Ln(iFGF23). Upon multivariate analysis, eGFR, Ln(sKl) and parathyroid hormone were independently associated with phosphate reabsorption, whereas Ln(iFGF-23) was not, after adjustment for age. Conclusions: Abnormalities in phosphate regulatory pathways are disturbed early in CKD. While iFGF-23 is associated with phosphate excretion on univariate analyses, sKl demonstrates a significant association with phosphate reabsorption independent of iFGF-23, and this relationship deserves further exploration.

Is there a role for newer biomarkers in chronic kidney disease-mineral and bone disorder management?

The current management of Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) relies largely on clinical judgement and assessment of biochemical parameters including serum calcium, phosphate and intact parathyroid hormone concentrations. In the past two decades, there has been a leap in the understanding of the pathophysiology of CKD-MBD, leading to the discovery of novel biomarkers. The potential utility of these markers in this clinical setting is an area of intense investigation. In the absence of any guidelines aiding the clinician's understanding and application of these markers, we summarise the current available literature surrounding fibroblast growth factor-23, α-Klotho, sclerostin and serum calcification propensity testing and their respective assays in the context of CKD-MBD management.

Changes in Markers of Mineral Metabolism After Living Kidney Donation.

BACKGROUND: Living kidney donors (LKDs) experience reduction in kidney function, however serum phosphate (sPi) levels are lower compared to patients with chronic kidney disease matched for reduced kidney function. Mineral metabolism adaptations that occur in LKDs have not been adequately investigated. To evaluate the effect of nephrectomy on markers of mineral metabolism in LKDs compared to healthy volunteers (HV) over 12 months. METHODS: Mineral parameters were evaluated in twenty-one adult LKDs and twenty HVs. Parameters included sPi, intact parathyroid hormone, fibroblast growth factor-23 (FGF23), soluble Klotho (sKl) and urinary phosphate, measured prior to donation (T0), 1 month (T1), 6 months (T6) and 12 months (T12) post-kidney donation. Statistical analyses were conducted on normalized variables and changes were assessed using 2-way analysis of variance. RESULTS: Mean ages of LKDs and HVs were 54.1 ± 14.7 and 52.6 ± 8.0 years, respectively. There were no baseline clinical or biochemical differences between LKDs and HVs. In LKDs at T1, serum creatinine increased (from 75 ± 12 to 114 ± 22 µmol/L), FGF23 increased (52 ± 15 to 70 ± 19 pg/mL) and sKl decreased (564 [469-662] to 424 [375-523] pg/mL), all P less than 0.001. Changes were sustained at T12. After donation, LKDs consistently demonstrated lower sPi compared with T0, with the maximal sPi change at T6 (-0.19 mmol/L difference, P < 0.001). Other markers of mineral metabolism were unchanged in LKDs. There were no mineral differences in HVs over 12 months. CONCLUSIONS: Prospective evaluation of mineral metabolism parameters in LKDs provides valuable insight into compensatory mechanisms after reduction in kidney function. Further reduction of sPi at T6 despite early alterations in FGF23 and sKl suggest adaptation of mineral metabolism continues long-term in LKDs.