Kidney transplantation in people living with human immunodeficiency virus: An overview of the Australian experience.

Kidney transplantation in people living with HIV (PLWHIV) is occurring with increasing frequency. Limited international data suggest comparable patient and graft survival in kidney transplant recipients with and without HIV. All PLWHIV aged ≥18 years who received a kidney transplant between 2000 and 2020 were identified by retrospective data initially extracted from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), with additional HIV-specific clinical data extracted from linked local health-care records. Twenty-five PLWHIV and kidney failure received their first kidney transplant in Australia between January 2000 and December 2020. Majority were male (85%), with median age 54 years (interquartile range, IQR 43-57). Focal segmental glomerulosclerosis was the most common primary kidney disease (20%), followed by polycystic kidney disease (16%). 80% of patients underwent induction with basiliximab and none with anti-thymocyte globulin (ATG). Participants were followed for median time of 3.5 years (IQR 2.0-6.5). Acute rejection occurred in 24% of patients. Two patients lost their allografts and three died. Virological escape occurred in 28% of patients, with a maximum viral load of 190 copies/mL. In conclusion, kidney transplantation in PLWHIV in Australia is occurring with increasing frequency. Acute rejection is more common than in Australia's general transplant population, but this does not appear to be associated with higher rates of graft failure or mortality out to four years.

Effect of lanthanum carbonate on serum calciprotein particles in patients with stage 3-4 CKD-results from a placebo-controlled randomized trial.

BACKGROUND: Calciprotein particles (CPP) are colloidal aggregates of calcium phosphate and the mineral-binding protein fetuin-A, and are potential mediators of cardiovascular disease in chronic kidney disease (CKD). Emerging evidence suggests non-calcium-containing phosphate binders may reduce serum CPP in patients with kidney failure who require dialysis; however, it is unclear whether similar interventions are effective in patients with earlier stages of CKD. METHODS: The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) was a multi-centre, placebo-controlled, randomized trial of lanthanum carbonate on cardiovascular markers in 278 participants with stage 3b/4 CKD. In this pre-specified exploratory analysis, primary (CPP-I) and secondary CPP (CPP-II) were measured in a sub-cohort of participants over 96 weeks. Treatment groups were compared using linear mixed-effects models and the relationship between serum CPP and pulse wave velocity (PWV) and abdominal aortic calcification (AAC) was examined. RESULTS: A total of 253 participants had CPP data for baseline and at least one follow-up timepoint and were included in this analysis. The mean age was 62.4 ± 12.6 years, 32.0% were female and the mean estimated glomerular filtration rate (eGFR) was 26.6 ± 8.3 mL/min/1.73 m2. Baseline median serum CPP-I was 14.9 × 104 particles/mL [interquartile range (IQR) 4.6-49.3] and median CPP-II was 3.3 × 103 particles/mL (IQR 1.4-5.4). There was no significant difference between treatment groups at 96 weeks in CPP-I [22.8% (95% confidence interval -39.2, 36.4), P = 0.65] or CPP-II [-18.3% (95% confidence interval -40.0, 11.2), P = 0.20] compared with a placebo. Serum CPP were not correlated with baseline PWV or AAC, or with the progression of either marker. CONCLUSIONS: Lanthanum carbonate was not associated with a reduction of CPP at 96 weeks when compared with a placebo in a CKD cohort.

Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells.

BACKGROUND: Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro. METHODS: This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays. RESULTS: In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {-62% [95% confidence interval (CI) -76 to -44], P < .0001 and -38% [-62 to -0.14], P < .001, respectively} compared with washout. Nine of 14 plasma cytokines/chemokines significantly decreased with high-dose SO, with consistent reductions in interleukin-6 (IL-6) and IL-8. Exposure of HASMC and HCAEC cultures to serum of SO-treated patients reduced calcification and markers of activation (IL-6, IL-8 and vascular cell adhesion protein 1) compared with washout. Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. Effects of CPP removal were confirmed in an independent cohort of chronic kidney disease patients. CONCLUSIONS: High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.

Relationship Between Dietary Phosphate Intake and Biomarkers of Bone and Mineral Metabolism in Australian Adults With Chronic Kidney Disease.

OBJECTIVE: Higher serum phosphate is associated with increased adverse outcomes including cardiovascular disease. Abnormalities of bone and mineral metabolism in chronic kidney disease (CKD), including higher serum phosphate, are important risk factors for increased cardiovascular disease. Associations between dietary phosphate intake and biochemical and cardiovascular parameters in non-dialysis CKD patients, however, have not been adequately studied. This study aimed to explore associations between phosphate intake and biomarkers of bone and mineral metabolism and intermediate cardiovascular markers in adults with stage 3-4 CKD. DESIGN AND METHODS: One hundred thirty-two participants enrolled in the IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease trial were invited to participate in this sub-study. At baseline, dietary phosphate intake and its source (animal, plant, or a mixture of animal and plant) were determined using a 7-day self-administered diet food record, and measurements were made of serum and urinary phosphate, serum calcium, parathyroid hormone, fibroblast growth factor-23, and the intermediate cardiovascular markers pulse wave velocity (PWV) and abdominal aortic calcification. The relationships between dietary phosphate intake and these bone metabolism and cardiovascular markers were explored using Pearson's correlation and linear regression. The effect of source of phosphate intake was analyzed using compositional data analysis. RESULTS: Ninety participants (age 64 ± 12 years, 68% male, estimated glomerular filtration rate 26.6 ± 7.6 mL/min/1.73 m2, daily phosphate intake 1,544 ± 347 mg) completed the study. Correlations among dietary phosphate intake and biochemical measures, PWV, and abdominal aortic calcification ranged from r = -0.13 to r = +0.13. Linear regression showed no association between dietary phosphate measurements and biochemical or cardiovascular parameters. Source of phosphate intake was associated with PWV (P = .01), but not with other biomarkers of bone and mineral metabolism. Higher PWV values were associated with higher intake of plant-based relative to animal-based phosphate (1.058 [1.020-1.098], P = .003). CONCLUSION: Levels of total dietary phosphate intake measured by dietary food record show no statistically significant relationship with biochemical markers of bone and mineral metabolism or intermediate cardiovascular markers. Higher PWV levels associated with higher intake of plant-based relative to animal-based phosphate intake were an unexpected finding and further research is needed in this area.

Outcomes following parathyroidectomy for secondary hyperparathyroidism in patients with chronic kidney disease: a single-centre study.

BACKGROUND: Surgical parathyroidectomy may be required for severe and refractory secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Parathyroidectomy is associated with long-term survival benefit despite an increase in short-term morbidity and mortality. Global variation in practice exists, with limited Australian data on outcomes following parathyroidectomy. AIM: To evaluate clinical outcomes of patients with chronic kidney disease undergoing surgical parathyroidectomy for secondary hyperparathyroidism. METHODS: We conducted a retrospective study of patients who underwent parathyroidectomy for SHPT between January 2010 and December 2019 at a single tertiary referral centre in Melbourne, Australia. Biochemical markers and medications were assessed 12 months pre- and post-surgery. Clinical outcomes, including hospital readmission, cardiovascular events and mortality were assessed following surgery. RESULTS: During the 10-year study period, 129 patients underwent parathyroidectomy for SHPT (mean age 50.7 ± 15 years; 109 (85%) on dialysis). Significant immediate post-operative complications were seen in eight (6%) patients, requiring admission to the intensive care unit (n = 6) or return to theatre (n = 2). Within the first 6 months, 24 (19%) patients required hospital readmission. Within 12 months post-parathyroidectomy, 100 (78%) and 103 (80%) patients experienced at least one episode of hypercalcaemia (corrected calcium >2.6 mmol/L) or hypocalcaemia (corrected calcium <2.1 mmol/L) respectively. Over a 12-month period, there were six (5%) deaths and eight (6%) patients experienced a major cardiovascular event. CONCLUSION: Significant fluctuations in serum calcium levels are common post-parathyroidectomy; however, long-term morbidity and mortality in our cohort were lower than previously reported, highlighting that parathyroidectomy in a carefully selected cohort is safe for severe SHPT refractory to medical treatment.

Changes in bone microarchitecture following parathyroidectomy in patients with secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) has a significant effect on bone, affecting both trabecular and cortical compartments. Although parathyroidectomy results in biochemical improvement in mineral metabolism, changes in bone microarchitecture as evaluated by high-resolution imaging modalities are not known. Magnetic resonance imaging (MRI) provides in-depth three-dimensional assessment of bone microarchitecture, as well as determination of mechanical bone strength determined by finite element analysis (FEA). METHODS: We conducted a single-centre longitudinal study to evaluate changes in bone microarchitecture with MRI in patients with SHPT undergoing parathyroidectomy. MRI was performed at the distal tibia at baseline (time of parathyroidectomy) and at least 12 months following surgery. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. RESULTS: Fifteen patients with CKD (12 male, 3 female) underwent both MRI scans at the time of surgery and at least 12 months post-surgery. At baseline, 13 patients were on dialysis, one had a functioning kidney transplant, and one was pre-dialysis with stage 5 CKD. Seven patients received a kidney transplant following parathyroidectomy prior to follow-up MRI. MRI parameters in patients at follow up were consistent with loss in trabecular and cortical bone thickness (p = 0.006 and 0.03 respectively). Patients who underwent a kidney transplant in the follow-up period had reduction in trabecular thickness (p = 0.05), whereas those who continued on dialysis had reduction in cortical thickness (p = 0.04) and mechanical bone strength on FEA (p = 0.03). CONCLUSION: Patients with severe SHPT requiring parathyroidectomy have persistent changes in bone microarchitecture at least 12 months following surgery with evidence of ongoing decline in trabecular and cortical thickness.

Reduction of Calciprotein Particles in Adults Receiving Infliximab for Chronic Inflammatory Disease.

Patients with chronic inflammatory diseases (CID) experience accelerated loss of bone mineral density, which is often accompanied by increased vascular calcification. These disturbances can be attenuated by therapies for inflammation, such as the tumor necrosis factor inhibitor infliximab. Calciprotein particles (CPP) are circulating colloidal aggregates of calcium and phosphate together with the mineral-binding protein fetuin-A, which have emerged as potential mediators of vascular calcification. The precise origins of serum CPP are unclear, but bone turnover may be an important source. In this longitudinal observational study, we studied patients with CID undergoing treatment with infliximab to assess the temporal relationship between bone turnover and circulating CPP. Ten patients with active CID receiving infliximab induction therapy and an additional 3 patients with quiescent CID on maintenance infliximab therapy were studied for 8 weeks with repeated measures of bone turnover markers as well as CPP (calciprotein monomers [CPM], primary CPP [CPP-I], and secondary CPP [CPP-II]). Therapeutic response was appraised using validated disease activity scores. At baseline, those with active CID had elevated markers of bone resorption and suppressed bone formation markers as well as higher CPM and CPP-I compared with those with quiescent CID. In responders, there was an early but transient reduction in resorption markers by week 1, but a more sustained increase in bone formation markers compared with non-responders at week 8. This was accompanied by reductions in CPM (ß = -6.5 × 103 AU [95% CI -11.1, -1.8], p = 0.006) and CPP-I (ß = -23.4 × 104 particles/mL [95% CI -34.8, -11.9], p < 0.001). In contrast, no significant changes in any markers were observed in non-responders or those receiving maintenance therapy. Thus, CPP have a dynamic association with changes in bone turnover in response to infliximab therapy, adding to accumulating evidence of the role of bone as a determinant of systemic levels. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Risk factors for major adverse kidney events in the first year after acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) survivors are at increased risk of major adverse kidney events (MAKEs), including chronic kidney disease (CKD), end-stage kidney disease (ESKD) and death. High-risk AKI patients may benefit from specialist follow-up, but factors associated with increased risk have not been reported. METHODS: We conducted a retrospective study of AKI patients admitted to a single centre between 2012 and 2016 who had a baseline estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 and were alive and independent of renal replacement therapy (RRT) at 30 days following discharge. AKI was identified using International Classification of Diseases, Tenth Revision codes and staged according to the Kidney Disease: Improving Global Outcomes criteria. Patients were excluded if they were kidney transplant recipients or if AKI was attributed to intrinsic kidney disease. We performed Cox regression models to examine MAKEs in the first year, defined as the composite of CKD (sustained 25% drop in eGFR), ESKD (requirement for chronic RRT or sustained eGFR <15 mL/min/1.73 m2) or death. We examined secondary outcomes (CKD, ESKD and death) using Cox and competing risk regression analyses. RESULTS: We studied 2101 patients (mean ± SD age 69 ± 15 years, baseline eGFR 72 ± 23 mL/min/1.73 m2). Of these, 767 patients (37%) developed at least one MAKE (429 patients developed CKD, 21 patients developed ESKD, 375 patients died). MAKEs occurred more frequently with older age [hazard ratio (HR) 1.16 per decade, 95% confidence interval (CI) 1.10-1.24], greater severity of AKI (Stage 2 HR 1.38, 95% CI 1.16-1.64; Stage 3 HR 1.62, 95% CI 1.31-2.01), higher serum creatinine at discharge (HR 1.04 per 10 µmol/L, 95% CI 1.03-1.06), chronic heart failure (HR 1.41, 95% CI 1.19-1.67), liver disease (HR 1.68, 95% CI 1.39-2.03) and malignancy (non-metastatic HR 1.44, 95% CI 1.14-1.82; metastatic HR 2.26, 95% CI 1.80-2.83). Traditional risk factors (e.g. diabetes and cardiovascular disease) had limited predictive value. CONCLUSIONS: More than a third of AKI patients develop MAKEs within the first year. Clinical variables available at the time of discharge can help identify patients at increased risk of such events.

Dietary Phosphate Consumption in Australians With Stages 3b and 4 Chronic Kidney Disease.

OBJECTIVE: Dietary phosphate modification is a common therapy to treat hyperphosphatemia in individuals with chronic kidney disease (CKD). However, current dietary intake and common food sources of phosphate typically consumed by individuals with CKD are not well characterized. This study examined a cohort of CKD patients to determine total dietary intake and common food sources of phosphate, including phosphate additives. DESIGN AND METHODS: Participants with CKD stages 3b and 4 recruited to a substudy of the "IMPROVE-CKD (IMpact of Phosphate Reduction On Vascular End-points in Chronic Kidney Disease) Study" completed a 7-day self-administered diet record at baseline. Diet histories were analyzed and daily phosphate intakes determined using FoodWorks V.9 (Xyris). The proportion of phosphate contributed by each food group was determined using the AUSNUT 2011-2013 Food Classification System. Ingredient lists of packaged food items consumed were reviewed to determine frequency of phosphate-based additives. RESULTS: Ninety participants (mean eGFR 26.5 mL/min/1.73 m2) completed this substudy. Mean phosphate intake of participants was 1544 ± 347 mg/day, with 96% of individuals exceeding the recommended daily intake of phosphate (1000 mg/day). The highest sources of dietary phosphate were milk-based products (25%) and meat and poultry products/dishes (25%). Phosphate-based food additives were identified in 39% (n = 331/845) of packaged foods consumed by participants. CONCLUSION: Dietary phosphate intakes of Australians with CKD are high and come from a variety of sources. Managing dietary phosphate intake requires a patient-centered, tailored approach with an emphasis on maintaining nutritional adequacy and awareness of phosphate additives.

Bone microarchitecture in patients undergoing parathyroidectomy for management of secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) leads to complex bone disease, affecting both trabecular and cortical bone, and increased fracture risk. Optimal assessment of bone in patients with CKD is yet to be determined. High-resolution magnetic resonance imaging (MRI) can provide three-dimensional assessment of bone microarchitecture, as well as determination of mechanical strength with finite element analysis (FEA). METHODS: We conducted a single-centre, cross-sectional study to determine bone microarchitecture with MRI in CKD patients with SHPT undergoing parathyroidectomy. Within two weeks of surgery, MRI was performed at the distal tibia and biochemical markers of SHPT (parathyroid hormone [PTH] and alkaline phosphatase [ALP]) were collected. Trabecular and cortical topological parameters as well as bone mechanical competence using FEA were assessed. Correlation of MRI findings of bone was made with biochemical markers. RESULTS: Twenty patients with CKD (15 male, 5 female) underwent MRI at the time of parathyroidectomy (16 on dialysis, 3 with functioning kidney transplant, one pre-dialysis with CKD stage 5). Median PTH at the time of surgery was 138.5 pmol/L [39.6-186.7 pmol/L]. MRI parameters in patients were consistent with trabecular deterioration, with erosion index (EI) 1.01 ±â€¯0.3, and trabecular bone volume (BV/TV) 10.8 ±â€¯2.9%, as well as poor trabecular network integrity with surface-to-curve ratio (S/C) 5.4 ±â€¯2.3. There was also evidence of reduced cortical thickness, with CTh 2.698 ±â€¯0.630 mm, and FEA demonstrated overall poor bone mechanical strength with mean elastic modulus of 2.07 ±â€¯0.44. CONCLUSION: Patients with severe SHPT requiring parathyroidectomy have evidence of significant changes in bone microarchitecture with trabecular deterioration, low trabecular and cortical bone volume, and reduced mechanical competence of bone.

Vascular calcification in skin and subcutaneous tissue in patients with chronic and end-stage kidney disease.

BACKGROUND: Vascular calcification (VC) is well described in large- and medium-sized vessels in patients with chronic kidney disease (CKD), especially in those with end-stage kidney disease (ESKD) on dialysis. Medial calcification is particularly prevalent in this population and contributes to arterial stiffness and increased cardiovascular mortality and morbidity. Apart from in the setting of calciphylaxis, few studies have assessed skin and subcutaneous calcification and associations with abnormalities of bone and mineral metabolism in patients with CKD. METHODS: We performed a single-centre observational study to evaluate incisional skin tissue samples from three anatomical sites in patients with different stages of CKD undergoing elective surgery. We compared these samples to skin samples of a control cohort without CKD. Staining for calcification was performed with von Kossa method. A subgroup of skin samples were assessed by RT-PCR for upregulation of pro-calcific gene transcripts for tissue non-specific alkaline phosphatase (TNAP) and Runt-related transcription factor 2 (RUNX2). RESULTS: Forty-five patients were evaluated, 34 with CKD (including ESKD) and 11 control patients. VC was identified in 15 skin samples (13 CKD/ESKD and 2 controls). VC was present in the dermal and subcutaneous tissues of the neck, abdomen and arm samples. Two different histological types of VC were identified: speckled medial calcification and internal elastic lamina calcification. Presence of perieccrine calcification was identified in 14 samples, 10 with concurrent VC. There were no significant differences in serum parathyroid hormone, phosphate or calcium in patients with or without VC. Expression of TNAP or RUNX2 was not increased in samples from patients with ESKD or those with histological evidence of calcification. CONCLUSION: This study reports the novel finding of dermal and subcutaneous calcification in multiple anatomical locations in 38% of patients with advanced CKD/ESKD undergoing elective surgery but free from calciphylaxis.

Residual kidney function in nocturnal vs conventional haemodialysis patients: a prospective observational study.

BACKGROUND: Residual kidney function (RKF) provides substantial volume and solute clearance even after dialysis initiation. Preservation of RKF is associated with improved outcomes including mortality in patients on both peritoneal and haemodialysis (HD). Factors predicting RKF loss are unclear, including HD modality. Nocturnal haemodialysis (NHD) may result in less aggressive fluid and solute shifts, however, retrospective data suggests frequent NHD may accelerate RKF decline. The aim of the study was to determine if decline in RKF differs between patients undergoing conventional haemodialysis (CHD) versus NHD. METHODS: A prospective observational study of incident HD patients was undertaken comparing patients undertaking CHD (4-5 h, 3 days/week) and NHD (8 h, 3-5 nights/week). Change in RKF was measured by urea and creatinine clearance (48-h interdialytic urine collection) and glomerular filtration rate (GFR) (Cr51-EDTA nuclear scan) at initiation of dialysis (baseline) and 12 months. RESULTS: A total of 18 incident HD patients were recruited (8 CHD, 10 NHD). Three patients withdrew after baseline (n = 15). Baseline RKF was similar between groups with mean nuclear GFR of 13.3 ± 4.1 mL/min in the CHD cohort vs 13.5 ± 4.6 mL/min in the NHD group (p = 0.89). Baseline urine volume was 2399 ± 950 mLs and 2794 ± 1662 mLs in the CHD and NHD, respectively (p = 0.57). Nuclear GFR declined from time 0 to 12 months to 9.3 ± 2.5 mL/min and 10.4 ± 4.3 mL/min in the CHD and NHD, respectively (p = 0.52). There was a significant decline in 48-h urine volume over 12 months with a mean volume of 1943 ± 1087.0 mLs in the CHD compared to 601.7 ± 315.3 mLs in the NHD (p = 0.01). No significant difference was found in other measures of RKF between groups over 12 months. CONCLUSION: This small prospective cohort study found that the loss of residual urine volume was greater in the NHD vs the CHD cohort but there was no difference in other measures of RKF.

Aortic Calcification and Arterial Stiffness Burden in a Chronic Kidney Disease Cohort with High Cardiovascular Risk: Baseline Characteristics of the Impact of Phosphate Reduction On Vascular End-Points in Chronic Kidney Disease Trial.

Chronic kidney disease (CKD) is associated with excess cardiovascular morbidity and mortality compared to the general population. Hyperphosphataemia, associated with vascular calcification and arterial stiffness, may play a key role in the pathogenesis of cardiovascular disease (CVD) associated with CKD, although phosphate reduction strategies have not consistently proven to beneficially affect clinically relevant outcomes. The IMpact of Phosphate Reduction On Vascular End-points in CKD (IMPROVE-CKD) study is an international, multi-centre, randomized, placebo-controlled trial investigating the effect of the phosphate binder lanthanum carbonate on intermediate cardiovascular markers in patients with stage 3b-4 CKD. The primary end-point is change in carotid-femoral pulse wave velocity (PWV, SphygmoCor) after 96 weeks. Secondary outcomes include change in abdominal aortic calcification (AAC, computed tomography), serum phosphate and fibroblast growth factor 23 (FGF-23). In total, 278 participants were recruited and randomized, mean age 63 ± 13 years, 69% male, 45% diabetes, 32% CVD, 33% stage 3b CKD and 67% stage 4 CKD. Mean estimated glomerular filtration rate and serum phosphate were 26.6 ± 8.3 mL/min/1.72 m2 and 1.25 ± 0.20 mmol/L, respectively. Median (interquartile range) intact and c-terminal FGF-23 levels were 133.0 (89.1-202) pg/mL and 221.1 (154.3-334.1) RU/mL, respectively. Mean PWV was 10.8 ± 3.6 m/s and 81% had AAC (median Agatston score 1,535 [63-5,744] Hounsfield units). PWV ≥10 m/s was associated with older age, diabetes, CVD, presence of AAC, higher systolic blood pressure (BP), larger waist circumference and higher alkaline phosphatase. AAC was associated with older age, male sex, diabetes, CVD, higher diastolic BP, dyslipidaemia (and use of statins), smoking, larger waist circumference and increased PWV. In conclusion, IMPROVE-CKD participants had high baseline risk for cardiovascular events, as suggested by high baseline PWV and AAC values.

Magnetic resonance imaging based assessment of bone microstructure as a non-invasive alternative to histomorphometry in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) adversely affects bone microarchitecture and increases fracture risk. Historically, bone biopsy has been the 'gold standard' for evaluating renal bone disease but is invasive and infrequently performed. High-resolution magnetic resonance imaging (MRI) quantifies bone microarchitecture noninvasively. In patients with CKD, it has not been compared with results derived from bone biopsy or with imaging using dual energy X-ray absorptiometry (DXA). METHODS: Fourteen patients with end-stage kidney disease (ESKD) underwent MRI at the distal tibia, bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA; hip and spine) and transiliac bone biopsies with histomorphometry and microcomputed tomography (micro-CT). All patients had biomarkers of mineral metabolism. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: MRI indices of trabecular network integrity, surface to curve ratio (S/C) and erosion index (EI), correlated to histomorphometric trabecular bone volume (S/C r = 0.85, p = 0.0003; EI r = -0.82, p = 0.001), separation (S/C r = -0.58, p = 0.039; EI r = 0.79, p = 0.0012) and thickness (S/C, r = 0.65, p = 0.017). MRI EI and trabecular thickness (TbTh) also correlated to micro-CT trabecular separation (EI r = 0.63, p = 0.02; TbTh r = -0.60, p = 0.02). Significant correlations were observed between histomorphometric mineralization and turnover indices and various MRI parameters. MRI-derived trabecular parameters were also significantly related to femoral neck BMD. CONCLUSIONS: This study highlights the heterogeneity of bone microarchitecture at differing skeletal sites. MRI demonstrates significant, relevant associations to important bone biopsy and DXA indices and warrants further investigation to assess its potential to non-invasively evaluate changes in bone structure and quality over time.

Deterioration of Cortical Bone Microarchitecture: Critical Component of Renal Osteodystrophy Evaluation.

BACKGROUND: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the "Turnover Mineralization Volume" classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). METHODS: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman's or Pearson's rank correlation coefficients. RESULTS: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = -0.56; p = 0.03) by micro-CT and to TbTh (r = -0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. CONCLUSIONS: Deterioration of cortical -microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

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.

Is there a practical role for a virtual bone biopsy using high-resolution imaging of bone in patients with chronic kidney disease?

Renal osteodystrophy (ROD) refers to alterations in bone turnover, mineralisation, mass and microarchitecture in patients with chronic kidney disease (CKD) and represents the skeletal component of 'CKD-mineral and bone disorder'. Changes in bone structure lead to impaired bone quality, compromised bone strength and increased susceptibility to fractures with associated significant morbidity, mortality and financial cost. Diagnosis and management of ROD is hindered by the inadequacy of currently available diagnostic methods to interpret the complex pathophysiology. Bone biopsy, the perceived gold standard test to assess ROD, is invasive and suboptimal for disease screening and management in routine clinical practice. High-resolution imaging, such as high-resolution peripheral quantitative computed tomography and high-resolution magnetic resonance imaging provide accurate non-invasive quantification of bone microarchitecture and facilitate assessment of mechanical competence of bone, correlating with skeletal fragility. We discuss the potential for these imaging techniques in patients with CKD to provide quantification and assessment of bone structure and strength. When used in conjunction with serum biomarkers, these investigative tools may provide a non-invasive diagnostic virtual bone biopsy.

Emerging role of high-resolution imaging in the detection of renal osteodystrophy.

The term renal osteodystrophy refers to changes in bone morphology induced by chronic kidney disease (CKD) and represents the skeletal component of the entity 'chronic kidney disease - mineral and bone disorder'. Changes in turnover, mineralization, mass and microarchitecture impair bone quality, compromising strength and increasing susceptibility to fractures. Fractures are more common in CKD compared with the general population and result in increased morbidity and mortality. Screening for fracture risk and management of renal osteodystrophy are hindered by the complex, and still only partially understood, pathophysiology and the inadequacy of currently available diagnostic methods. Bone densitometry and bone turnover markers, although potentially helpful, have significant limitations in patients with CKD, and the 'gold standard' test of bone biopsy is infrequently performed in routine clinical practice. However, recent advances in high-resolution bone microarchitecture imaging may offer greater potential for quantification and assessment of bone structure and strength and, when used in conjunction with serum biomarkers, may allow non-invasive testing for a diagnostic virtual bone biopsy.