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Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73m(2); 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

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.

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.

Background Calciphylaxis is a rare disease, predominantly affecting patients with chronic kidney disease (CKD) and associated with significant morbidity and mortality due to progressive cutaneous calcification, necrotic ulceration and infection. Clinical registries have been established to better understand the risk factors, optimal treatments and disease outcomes of calciphylaxis. Methods We established a prospective, Internet-based clinical registry for the online notification of calciphylaxis cases in Australia. Seven institutions participated, with data recorded on patient characteristics, biochemical parameters, treatments and disease outcomes. Results Between 2014 and 2019, 47 cases of calciphylaxis were registered. The mean patient age was 66 ± 11 years and body mass index was 35 ± 9 kg/m2, with a higher proportion of females (51%). Eighty-seven percent of patients had end-stage kidney disease (ESKD), with 61% on hemodialysis or hemodiafiltration, with a median dialysis vintage of 4.8 [interquartile range (IQR) 1.7–7.4)] years. Five patients had CKD not requiring dialysis and two were kidney transplant recipients. Diabetes was present in 76% of patients and the cause of ESKD in 60%; 34% received vitamin K antagonists (VKAs) before diagnosis. The median parathyroid hormone level at diagnosis was 32 (IQR 14–50) pmol/L. The most common site of calciphylaxis was the lower limbs (63%), with 19% of patients having more than one area involved. Ten patients (22%) had a resolution of calciphylaxis and 25 died, with 50% mortality at a median of 1.6 (IQR 0.2–2.5) years from diagnosis. Conclusions The Australian Calciphylaxis Registry highlights risk factors for calciphylaxis, including diabetes, obesity and VKA use. Resolution of calciphylaxis is uncommon despite multimodal therapy and mortality from calciphylaxis in the first year following diagnosis remains high.

IntroductionPatients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD.Methods and analysisWe outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population—the IMpact of Phosphate Reduction On Vascular End-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels.Ethics and disseminationEthical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.Trial registration numberACTRN12610000650099.

Patients with chronic kidney disease (CKD) undergoing hemodialysis experience a high annual mortality rate (7% per year) with 25% of all deaths due to sudden cardiac death (SCD) [(1)][1]. There has been conjecture as to the mechanism of SCD. This prospective study (Identification and

Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) have a high risk of sudden cardiac death (SCD). A unique risk factor may be a longer interval between HD sessions (interdialytic period). Inherent in conventional HD (thrice-weekly) are two 48-hour short breaks (SIDP) and one 72-hour long break (LIDP) between HD sessions.We used an implantable cardiac monitor (ICM) to define the incidence and timing of significant arrhythmias in an HD population.Fifty CKD patients undergoing HD with left ventricular ejection fraction35% had an ICM inserted, with intensive follow-up to record SCD events and predefined bradyarrhythmias and tachyarrhythmias.Mean age of the patients was 67 ± 11 years; 72% were male, and the mean follow-up was 18 ± 4 months. There were 8 unexpected SCDs (16%), all during the LIDP. The terminal event was severe bradycardia with asystole in each recorded case. No episodes of polymorphic ventricular tachycardia (VT) occurred. A total of 7686 arrhythmia events were recorded in 43 patients (86%), including bradycardia in 15 patients (30%), sinus arrest in 14 (28%), second-degree atrioventricular block in 4 (8%), nonsustained VT in 10 (20%), and new-onset paroxysmal atrial fibrillation in 14 (28%). The LIDP was the highest-risk period for all arrhythmias (P.001). The arrhythmia event rate per hour was greatest during the first pre-HD period of the week compared with any other peri-HD period (P.001).Risk of SCD and significant arrhythmias is greatest during the LIDP. SCD was attributable to severe bradycardia and asystole. Interventions to prevent this type of SCD or shorten the LIDP deserve further evaluation.URL: https://www.anzctr.org.au (Unique identifier: ACTRN12613001326785).

Studies have shown that dual therapy with angiotensin-converting enzyme inhibitors (ACEI) and either angiotensin II receptor blockers or aldosterone receptor antagonists is more effective in reducing proteinuria than either agent used alone. The questions that remain are as follows: (1) Which of these agents should be used as dual therapy with the ACEI? (2) Does a higher level of blockade of the renin-angiotensin-aldosterone system with triple therapy offer an advantage over dual blockade? A 3-mo randomized, double-blind, placebo-controlled study was performed in 41 patients with proteinuria >1.5 g/d. Four treatment groups were compared: (1) Ramipril + spironolactone placebo + irbesartan placebo, (2) ramipril + irbesartan + spironolactone placebo, (3) ramipril + irbesartan placebo + spironolactone, and (4) ramipril + irbesartan + spironolactone. The percentage change in protein excretion differed according to treatment arm (ANOVA: F(3,35) = 8.6, P < 0.001). Pair-wise comparison showed that greater reduction in protein excretion occurred in treatment regimens that incorporated spironolactone. The reduction in proteinuria at 3 mo was as follows: Group 1, 1.4%; group 2, 15.7%; group 3, 42.0%; and group 4, 48.2%. The reduction in proteinuria among patients who were taking spironolactone-containing regimens was sustained at 6 and 12 mo. This study suggests that aldosterone receptor blockade offers a valuable adjuvant treatment when used with ACEI therapy for the reduction of proteinuria. Results suggest no advantage of triple blockade over dual blockade of the renin-angiotensin-aldosterone system to reduce proteinuria.

Hyaluronic acid (HA) is a ubiquitous component of extracellular matrix. After tissue injury, HA appears in greater abundance during the inflammatory response and the phase of clearance of cell and matrix debris, before collagen production and matrix degradation. The aim of this study was to examine whether normal rat renal fibroblasts were capable of HA synthesis and to determine the effect of HA on in vitro collagen production in a series of normal rat cortical fibroblast cultures. Fibroblast cultures from both renal cortex and medulla were established from adult Sprague-Dawley rats. HA synthesis was measured by radioimmunoassay, and incorporation of 3H-proline into collagen was used to determine collagen synthesis. Fibroblasts were defined on the basis of morphology and alpha smooth muscle actin immunohistochemistry. HA synthesis was measured in both renal cortical and medullary fibroblasts at passage 3 for both 24 and 48 h in 5 animals and expressed as a fraction of protein content. HA was synthesized by both cortical and medullary fibroblasts; however, cortical fibroblasts produced less HA than medullary fibroblasts at both 24 h (p = 0.05) and 48 h (p = 0.02). In normal cortical fibroblasts, exogenous HA suppressed overall total (cell and media) collagen production after a 22-hour labelling period (p = 0.002 compared to controls). Decreased collagen production was also found individually in cell (p = 0.02) and media fractions (p = 0.01). Both cortical and medullary fibroblasts are capable of synthesizing HA in vitro. Furthermore, the findings in this study suggest that HA may be an important mediator in reducing renal cortical fibroblast collagen production and may play an important role in limiting renal interstitial scarring.

Interstitial myofibroblasts (MF) are cells with features of both smooth muscle cells and fibroblasts. They have been universally recognized in situations of tubulointerstitial injury, where their presence has been shown to be a marker of disease progression. The objective of this study was to determine if functions of MF relevant to fibrogenesis can be modified in vitro by the phosphodiesterase inhibitor pentoxifylline (PTX). MF were obtained from sub-culture of normal rat kidney explant outgrowths maintained in DMEM + 20% fetal calf serum (FCS), supplemented with antibiotics. Cells were characterized on the basis of growth characteristics and immunohistochemistry. MF constituted >95% of cells at passage 3. Cell culture media was supplemented with the potential antagonist PTX alone (0, 1, 10, 100 μg/ml) and in combination with TGFβ1 (5 ng/ml). Population kinetics, proliferation and collagen production were determined from cell growth, [3H]thymidine incorporation and [3H]proline incorporation in collagenous proteins, respectively. Both serum-stimulated population growth and proliferation were reduced in a linear fashion by 1, 10 and 100 μg/ml PTX (all p < 0.05 versus 0 μg/ml). Effect of PTX on cell population growth was however reversible when PTX was removed. Basal collagen secretion was decreased by PTX at 10 and 100 μg/ml (p < 0.05 versus 0 μg/ml), although cell layer collagen remained unchanged. Collagen production (secreted and cell layer) was augmented by 5 ng/ml TGFβ1. These effects on collagen production were partially reduced when 100 μg/ml PTX was added. The authors conclude that myofibroblast function can be altered with agonists/antagonists. Attempts to down-regulate fibrogenic functions of MF may therefore offer a valuable therapeutic strategy.

Myofibroblasts, cells with both fibroblastic and smooth muscle cell features, have been implicated in renal scarring. In addition to synthetic properties, contractile features and integrin expression may allow myofibroblasts to rearrange and contract interstitial collagenous proteins. Myofibroblasts from normal rat kidneys were grown in cell-populated collagen lattices to measure cell generated contraction. Following detachment of cell populated collagen lattices, myofibroblasts progressively contracted collagen lattices, reducing lattice diameter by 42% at 24 h. Alignment of myofibroblasts, rearrangement of fibrils and β1 integrin expression were observed within lattices. We postulate that interstitial myofibroblasts contribute to renal scarring through manipulation of collagenous proteins.

Summary: Post-transplant lymphoproliferative disorder was diagnosed in six renal transplant recipients at the Royal Melbourne Hospital over a 5 year period to December 1994. This constituted a detection rate of 2.2%. All patients were treated with cyclosporine, azathioprine, prednisolone and orthoclone (OKT3). the median time of onset was 2 months (range 0.3 months-3 years) after transplant. Two patients who ultimately died presented with the diffuse form of the disease where immunoblasts massively infiltrated all organs. These tumours were monoclonal B cell lymphomas and Epstein-Barr virus (EBV) reactivation could be demonstrated. One patient developed a polyclonal B cell tumour with primary EBV infection and the remaining 3 patients tresented with T cell polyclonal proliferations and were EBV negative. No cytomegalovirus (CMV) infections, primary or reactionary were observed. Therapy in all cases consisted of reducing or ceasing immunosuppressive treatment and in three patients ganciclovir was used. Four polyclonal tumours responded to the treatment measures.

Current clinical practice guidelines recommend a native arteriovenous fistula (AVF) as the vascular access of first choice. Despite this, most patients in western countries start hemodialysis therapy using a catheter. Little is known regarding specific physician and system characteristics that may be responsible for delays in permanent access creation.Multicenter cohort study using mixed methods; qualitative and quantitative analysis.9 nephrology centers in Australia and New Zealand, including 319 adult incident hemodialysis patients.Identification of barriers and enablers to AVF placement.Type of vascular access used at the start of hemodialysis therapy.Prospective data collection included data concerning predialysis education, interviews of center staff, referral times, and estimated glomerular filtration rate (eGFR) at AVF creation and dialysis therapy start.319 patients started hemodialysis therapy during the 6-month period, 39% with an AVF and 59% with a catheter. Perceived barriers to access creation included lack of formal policies for patient referral, long wait times for surgical review and access placement, and lack of a patient database for management purposes. eGFR thresholds at referral for and creation of vascular accesses were considerably lower than appreciated (in both cases, median eGFR of 7 mL/min/1.73 m(2)), with median wait times for access creation of only 3.7 weeks. First assessment by a nephrologist less than 12 months before dialysis therapy start was an independent predictor of catheter use (OR, 8.71; P0.001). Characteristics of the best performing centers included the presence of a formalized predialysis pathway with a centralized patient database and low nephrologist and surgeon to patient ratios.A limited number of patient-based barriers was assessed. Cross-sectional data only.A formalized predialysis pathway including patient education and eGFR thresholds for access placement is associated with improved permanent vascular access placement.

Introduction: Chronic kidney disease (CKD) patients on haemodialysis (HD) have a high risk of sudden cardiac death (SCD). Traditional SCD risk factors donot adequately explain this but a unique risk factor may be a longer interval between HD sessions (interdialytic period, IDP). Inherent in conventional HD (thrice-weekly) are two 48-hour (short) breaks and one 72-hour (long) break between the start of HD sessions. Changes in electrolyte balance, ventricular repolarization (VR) and autonomic tone (AT) may be more profound after the longer IDP. Objectives:We used an implantable loop recorder (ILR) to define the incidence and timing of significant arrhythmias in a HD population, comparing the impact of the long vs short IDP (event time distribution-ETD). We used Ambulatory 24-hour Holter monitoring to evaluate markers of arrhythmic risk according to ETD. Methods: 50 CKD patients undergoing thrice-weekly conventional HD were recruited & underwent ILR insertion with regular fortnightly device follow-up. Pts with left ventricular ejection fraction 16 beats

This paper reports an isolated case of the exceedingly rare cutaneo-skeletal condition craniomandibular dermatodysostosis, in which focal glomerular sclerosis and end-stage renal failure developed and renal transplantation was required.

We examined the biopsy specimens of 62 patients with diabetic nephropathy to establish whether the myofibroblast (MF) has a role in progressive interstitial fibrosis and to ascertain whether a relationship existed between MF activity and severity of arteriolosclerosis. MF were identified by morphology and alpha smooth muscle actin (alpha SMA) immunostaining. Analysis of vascular injury was performed by counting the number of interstitial arterioles after staining endothelial cells with von Willebrand factor (VWF) antibody. Arteriosclerosis was quantified by using a computer-aided image analyzer to measure the arteriolar wall surface and total arteriolar surface area, and the ratio of wall to total surface area was expressed as the index of arteriosclerosis (IA). Fractional area of interstitium (IFA), alpha SMA, and collagen III (Coll III) were quantitated by point counting. Results were related to structural and functional parameters using rank correlation coefficients. There was a strong correlation between IFA and Coll III staining (r = 0.83; P0.001). The alpha SMA staining correlated with IFA (r = 0.56; P0.001) and Coll III (r = 0.47; P0.001), and there were significant correlations between alpha SMA and total urinary protein (r = 0.47; P0.001), renal function (plasma creatinine) at time of biopsy (r = 0.51; P0.001), and the percent change in plasma creatinine after 4 years (delta Cr) (r = 0.37; P = 0.01). The IA correlated significantly with Coll III (r = 0.29; P = 0.02), glomerular filtration rate (GFR) (r = 0.39; P = 0.008), and creatinine (r = 0.33; P = 0.01), but no correlation was observed between alpha SMA and IA (r = 0.16; P = 0.23) or IA and delta Cr (r = -0.04; P = 0.6). Strong correlations could be shown between arteriolar density, IFA (r = 0.75; P0.001), alpha SMA (r = -0.36; P = 0.034), and Coll III (r = -0.66; P0.0001). The MF appears to have a significant role in the progression of diabetic nephropathy. Ischemia secondary to arteriosclerosis may contribute to interstitial fibrosis through fibroblast modulation into MF.