Persistent uncertainties in optimal treatment approaches of secondary hyperparathyroidism and hyperphosphatemia in patients with chronic kidney disease.

PURPOSE OF REVIEW: This review is a critical analysis of treatment results obtained in clinical trials conducted in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT), hyperphosphatemia, or both. RECENT FINDINGS: Patients with CKD have a high mortality rate. The disorder of mineral and bone metabolism (CKD-MBD), which is commonly present in these patients, is associated with adverse outcomes, including cardiovascular events and mortality. Clinical trials aimed at improving these outcomes by modifying CKD-MBD associated factors have most often resulted in disappointing results. The complexity of CKD-MBD, where many players are closely interconnected, might explain these negative findings. We first present an historical perspective of current knowledge in the field of CKD-MBD and then examine potential flaws of past and ongoing clinical trials targeting SHPT and hyperphosphatemia respectively in patients with CKD.

Continuous Renal Replacement Therapy Might Mask Immobilization-Induced Hypercalcemia in Critically Ill Patients.

Immobilization and prolonged bed rest are harmful to the skeleton, which suffers increased resorption, and contribute to reducing survival rates among patients in critical care units. We report a patient who presented hypercalcemia 10 days after continuous venovenous hemofiltration has ended. Investigative tests showed an increase of serum C-terminal telopeptide of type I collagen (CTx), with suppressed parathormone and calcitriol. Denosumab was administered with a significant response, decreasing ionized calcium and CTx levels. The calcium infusion rate during dialysis procedures, used for citrate anticoagulation compensation, has progressively decreased, suggesting that endogenous calcium was taking part in the citrate chelation. In this report, we highlight the challenges in early diagnosis of immobilization-induced hypercalcemia among patients who are on continuous renal replacement therapy undergoing citrate anticoagulation.

Fluid overload after coronary artery bypass graft in patients on maintenance hemodialysis is associated with prolonged time on mechanical ventilation.

BACKGROUND: Fluid overload is a risk factor for morbidity, mortality, and prolonged ventilation time after surgery. Patients on maintenance hemodialysis might be at higher risk. We hypothesized that fluid accumulation would be directly associated with extended ventilation time in patients on hemodialysis, as compared to patients with chronic kidney disease not on dialysis (CKD3-4) and patients with normal renal function (reference group). METHODS: This is a prospective observational study that included patients submitted to isolated and elective coronary artery bypass surgery, divided in 3 groups according to time on mechanical ventilation: < 24 h, 24-48 h and > 48 h. The same observer followed patients daily from the surgery to the hospital discharge. Cumulative fluid balance was defined as the sum of daily fluid balance over the first 5 days following surgery. RESULTS: Patients requiring more than 48 h of ventilation (5.3%) had a lower estimated glomerular filtration rate, were more likely to be on maintenance dialysis, had longer anesthesia time, needed higher dobutamine and noradrenaline infusion following surgery, and had longer hospitalization stay. Multivariate analysis revealed that the fluid accumulation, scores of sequential organ failure assessment in the day following surgery, and the renal function (normal, chronic kidney disease not on dialysis and maintenance hemodialysis) were independently associated with time in mechanical ventilation. Among patients on hemodialysis, the time from the surgery to the first hemodialysis session also accounted for the time on mechanical ventilation. CONCLUSIONS: Fluid accumulation is an important risk factor for lengthening mechanical ventilation, particularly in patients on hemodialysis. Future studies are warranted to address the ideal timing for initiating dialysis in this scenario in an attempt to reduce fluid accumulation and avoid prolonged ventilation time and hospital stay.

A Randomized Trial of Zoledronic Acid to Prevent Bone Loss in the First Year after Kidney Transplantation.

BACKGROUND: Bone and mineral disorders commonly affect kidney transplant (KTx) recipients and have been associated with a high risk of fracture. Bisphosphonates may prevent or treat bone loss in such patients, but there is concern that these drugs might induce adynamic bone disease (ABD). METHODS: In an open label, randomized trial to assess the safety and efficacy of zoledronate for preventing bone loss in the first year after kidney transplant, we randomized 34 patients before transplant to receive zoledronate or no treatment. We used dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone biopsies to evaluate changes in bone in the 32 evaluable participants between the time of KTx and 12 months post-transplant. RESULTS: Both groups of patients experienced decreased bone turnover after KTx, but zoledronate itself did not affect this outcome. Unlike previous studies, DXA showed no post-transplant bone loss in either group; we instead observed an increase of bone mineral density in both lumbar spine and total hip sites, with a significant positive effect of zoledronate. However, bone biopsies showed post-transplant impairment of trabecular connectivity (and no benefit from zoledronate); HR-pQCT detected trabecular bone loss at the peripheral skeleton, which zoledronate partially attenuated. CONCLUSIONS: Current immunosuppressive regimens do not contribute to post-transplant central skeleton trabecular bone loss, and zoledronate does not induce ABD. Because fractures in transplant recipients are most commonly peripheral fractures, clinicians should consider bisphosphonate use in patients at high fracture risk who have evidence of significantly low bone mass at these sites at the time of KTx.

Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE).

Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (Pi) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent Pi absorption is modulated by dietary Pi. Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary Pi concentration over 2 days would alter hormones involved in Pi metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LPi), normal (Nx/NPi), and high (Nx/HPi). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HPi group than in the Nx/LPi group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LPi group compared with the Nx/HPi group. Modification of Pi concentration in the diet affected the apoptosis of enterocytes, particularly with Pi overload. MEPE expression was higher in the Nx/HPi group than in the Nx/NPi. These data reveal the importance of early control of Pi in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.

Time to rethink the use of bone biopsy to prevent fractures in patients with chronic kidney disease.

PURPOSE OF REVIEW: The purpose of this review is to provide evidence to justify the use of bone biopsy data to guide decisions regarding fracture prevention in patients with chronic kidney disease (CKD). To date, no data can support the use of bone biopsy for this purpose. However, we believe that bone turnover, mineralization and volume (TMV) data might help decide, which therapy to use. RECENT FINDINGS: Previous bone biopsy-based prospective and intervention studies have used bone turnover as an outcome measure. Recent data have shown that bone volume (trabecular and cortical) and mineralization should also be evaluated. Moreover, crystal quality and osteocytic protein expression can be analyzed using bone fragments. Noninvasive analysis of bone volume and bone turnover markers can be performed during patient follow-up. SUMMARY: Only bone biopsy can provide information on the TMV parameters. Case reports and retrospective studies suggest that bone histomorphometric analysis can guide better therapeutic decisions to prevent fractures in patients with CKD. However, prospective data are still lacking.

Analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as inflammatory biomarkers in chronic kidney disease: impact of parathyroidectomy.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) is one of the causes for inflammation in CKD. We assessed the impact of parathyroidectomy (PTX) on neutrophil-to-lymphocyte (N/L) and platelet-to-lymphocyte (P/L) ratios in SHPT patients. METHODS: A total of 118 patients [hemodialysis (HD, n = 81), and transplant recipients (TX, n = 37)] undergoing PTX between 2015 and 2021 were analyzed. RESULTS: There was a significant reduction in calcium and PTH levels in both groups, in addition to an increase in vitamin D. In the HD group, PTX did not alter N/L and P/L ratios. In the TX group, there was a reduction in N/L and P/L ratios followed by a significant increase in total lymphocyte count. CONCLUSION: N/L and P/L ratios are not reliable biomarkers of inflammation in SHPT patients undergoing PTX. Uremia, which induces a state of chronic inflammation in dialysis patients, and the use of immunosuppression in kidney transplant recipients are some of the confounding factors that prevent the use of this tool in clinical practice.

Parathyroidectomy: still the best choice for the management of severe secondary hyperparathyroidism.

INTRODUCTION: Management of secondary hyperparathyroidism (SHPT) is a challenging endeavor with several factors contruibuting to treatment failure. Calcimimetic therapy has revolutionized the management of SHPT, leading to changes in indications and appropriate timing of parathyroidectomy (PTX) around the world. METHODS: We compared response rates to clinical vs. surgical approaches to SHPT in patients on maintenance dialysis (CKD 5D) and in kidney transplant patients (Ktx). A retrospective analysis of the one-year follow-up findings was carried out. CKD 5D patients were divided into 3 groups according to treatment strategy: parathyroidectomy, clinical management without cinacalcet (named standard - STD) and with cinacalcet (STD + CIN). Ktx patients were divided into 3 groups: PTX, CIN (cinacalcet use), and observation (OBS). RESULTS: In CKD 5D we found a significant parathormone (PTH) decrease in all groups. Despite all groups had a higher PTH at baseline, we identified a more pronounced reduction in the PTX group. Regarding severe SHPT, the difference among groups was evidently wider: 31%, 14% and 80% of STD, STD + CIN, and PTX groups reached adequate PTH levels, respectively (p<0.0001). Concerning the Ktx population, although the difference was not so impressive, a higher rate of success in the PTX group was also observed. CONCLUSION: PTX still seems to be the best treatment choice for SHPT, especially in patients with prolonged diseases in unresourceful scenarios.

Parathyroidectomy reduces the costs of medication in patients with secondary hyperparathyroidism.

INTRODUCTION: Subtotal Parathyroidectomy (S-PTx) and total Parathyroidectomy with immediate Autograft (PTx-AG) are well-established techniques for the treatment of refractory Secondary Hyperparathyroidism (SHPT), with comparable improvements in patients' quality of life and survival. However, the long-term costs after these operations may impact the choice of surgical technique. The objective of the study is to analyze the impact of surgical treatment on medication costs and whether there is any difference between medication use after each procedure, considering impacts on the health system. MATERIAL AND METHODS: Prospective and randomized study in patients with severe SHPT undergoing S-PTx and PTx-AG. Analysis of prescribed medication costs in the month before the postoperative period at 1-, 3-, 6-, 12-, and 18 months. Costs were estimated according to government payment system values. The medications of 65 patients after PTx-AG were compared with those of 24 patients after S-PTx. A comparison of the total costs of the period between 38 men and 51 women was also made. RESULTS: There were 89 evaluable cases. Surgery reduced medication costs after 12 months. The median of total drug costs in the analyzed period was R$ 8,375.00 per patient. There was no difference in costs per patient in the S-PTx group compared to the PTx-AG group. The median total costs were R$ 11,063.0 for men and R$ 7,651.0 for women (p = 0.0078). CONCLUSIONS: The type of parathyroidectomy did not impact costs after surgery. In the first year after surgery, the use of calcium and calcitriol was more significant than the use of other medications. In the following months, the use of sevelamer is responsible for the highest costs. Men have higher costs in outpatient follow-up after surgery.

Growth in children with chronic kidney disease and associated risk factors for short stature.

INTRODUCTION: Growth failure in chronic kidney disease is related to high morbidity and mortality. Growth retardation in this disease is multifactorial. Knowing the modifiable factors and establishing strategies to improve care for affected children is paramount. OBJECTIVES: To describe growth patterns in children with chronic kidney disease and the risk factors associated with short stature. METHODS: We retrospectively analyzed anthropometric and epidemiological data, birth weight, prematurity, and bicarbonate, hemoglobin, calcium, phosphate, alkaline phosphatase, and parathormone levels of children with stages 3-5 CKD not on dialysis, followed for at least one year. RESULTS: We included 43 children, the majority of which were boys (65%). The mean height/length /age z-score of the children at the beginning and follow-up was -1.89 ± 1.84 and -2.4 ± 1.67, respectively (p = 0.011). Fifty-one percent of the children had short stature, and these children were younger than those with adequate stature (p = 0.027). PTH levels at the beginning of the follow-up correlated with height/length/age z-score. A sub-analysis with children under five (n = 17) showed that 10 (58.8%) of them failed to thrive and had a lower weight/age z-score (0.031) and lower BMI/age z-score (p = 0.047). CONCLUSION: Children, particularly younger ones, with chronic kidney disease who were not on dialysis had a high prevalence of short stature. PTH levels were correlated with height z-score, and growth failure was associated with worse nutritional status. Therefore, it is essential to monitor the growth of these children, control hyperparathyroidism, and provide nutritional support.

A feasibility study of avoiding positive calcium balance and parathyroid hormone increase in patients on peritoneal dialysis.

Background: The effect of the dialysate calcium concentration (D[Ca]) on mineral and bone metabolism in patients on peritoneal dialysis (PD) is overlooked. D[Ca] of 1.75 mmol/L is still prescribed to many patients on PD around the world. Previous studies on the effects of reducing D[Ca] have been carried out before the incorporation of calcimimetics in clinical practice. We hypothesized that a reduction in D[Ca] is safe and without the risk of a rise in serum parathyroid hormone (PTH). Methods: In this non-randomized clinical trial, the D[Ca] was reduced from 1.75 mmol/L to 1.25 mmol/L for one year in prevalent patients on PD. Demographic, clinical, and CKD-MBD-related biomarkers were evaluated at baseline, 3, 6, and 12 months of follow-up. Results: 20 patients completed 1-year follow-up (56 ± 16 years, 50 % male, 25 % diabetic, 55 % with baseline parathyroid hormone - PTH >300 pg/mL). Over time, there was no significant change in calcium, phosphate, total alkaline phosphatase, 25(OH)-vitamin D or PTH, although adjustments in calcitriol and sevelamer prescription were required. After 1 year, absolute and percentual change in PTH levels were 36 (-58, 139) pg/mL, and 20 % (-28, 45) respectively. The proportion of patients with PTH > 300 pg/mL did not change during the follow-up (p = 0.173). Conclusion: Knowing the risk of a positive calcium balance in patients on PD, reducing the D[Ca] concentration is a safe and valuable option, although medication adjustments are needed to detain PTH rising.

Effect of parathyroidectomy on bone tissue biomarkers and body composition in patients with chronic kidney disease and secondary hyperparathyroidism.

BACKGROUND/OBJECTIVE: Loss of renal function may induce secondary hyperparathyroidism (s-HPT), which triggers several complications leading to an extreme decline in quality of life and increased mortality in affected patients. We evaluated whether parathyroidectomy (PTx), as surgical treatment for s-HPT, modifies body composition, and hormones involved in the protein-energy metabolism of affected patients. SUBJECTS/METHODS: Overall, 30 s-HPT patients were evaluated at two times, before PTx (pre PTx) and 6 months after PTx (post PTx). Patients were evaluated by biochemistry analysis, anthropometry, electrical bioimpedance (BIA), food intake diary, handgrip strength, and modified global subjective nutritional assessment (SGA). RESULTS: After PTx, patients showed decreased serum levels of total and ionic calcium, as well as decreased alkaline phosphatase and PTH, and increased 25 (OH) vitamin D. These results demonstrate that PTx was efficient to correct part of the mineral disorder. We also observed an increase in caloric intake, body weight, body mass index (BMI), phase angle, handgrip strength, SGA score, and a decreasing in the percentage of weight loss. The osteocalcin concentration of both carboxylated (cOC) and undercarboxylated form was diminished post PTx. The cOC correlated with bone metabolism markers and SGA score. CONCLUSIONS: PTx modified body composition improving nutritional status and preventing the progression of weight loss with increased of energy intake, BMI, handgrip strength, phase angle of BIA, and SGA score. The present study also suggests an association of cOC with bone markers and SGA score. Further studies are needed to better clarify these associations with larger sample size.

The Protein-Independent Role of Phosphate in the Progression of Chronic Kidney Disease.

Several factors contribute to renal-function decline in CKD patients, and the role of phosphate content in the diet is still a matter of debate. This study aims to analyze the mechanism by which phosphate, independent of protein, is associated with the progression of CKD. Adult Munich-Wistar rats were submitted to 5/6 nephrectomy (Nx), fed with a low-protein diet, and divided into two groups. Only phosphate content (low phosphate, LoP, 0.2%; high phosphate, HiP, 0.95%) differentiated diets. After sixty days, biochemical parameters and kidney histology were analyzed. The HiP group presented worse renal function, with higher levels of PTH, FGF-23, and fractional excretion of phosphate. In the histological analysis of the kidney tissue, they also showed a higher percentage of interstitial fibrosis, expression of α-actin, PCNA, and renal infiltration by macrophages. The LoP group presented higher expression of beclin-1 in renal tubule cells, a marker of autophagic flux, when compared to the HiP group. Our findings highlight the action of phosphate in the induction of kidney interstitial inflammation and fibrosis, contributing to the progression of renal disease. A possible effect of phosphate on the dysregulation of the renal cell autophagy mechanism needs further investigation with clinical studies.

Parathyroid hormone levels after parathyroidectomy for secondary hyperparathyroidism.

OBJECTIVE: The parathormone level after parathyroidectomy in dialysis patients are of interest. Low levels may require cryopreserved tissue implantation; however, the resection is necessary in case of recurrence. We analyzed post parathyroidectomy parathormone levels in renal hyperparathyroidism. METHODS: Prospective observation of postoperative parathormone levels over defined periods in a cohort of dialysis patients that underwent total parathyroidectomy and immediate forearm autograft from 2008 to 2010, at a single tertiary care hospital. RESULTS: Of 33 patients, parathormone levels until 36 months could be divided into four patterns. Patients with stable function (Pattern 1) show relatively constant levels after two months (67% of the cases). Early function and later failure (Pattern 2) were an initial function with marked parathormone reduction before one year (18%). Graft recurrence (Pattern 3) showed a progressive increase of parathormone in four cases (12%). Complete graft failure (Pattern 4) was a nonfunctioning implant at any period, which was observed in one patient (3%). Parathormone levels of Pattern 3 became statistically different of Pattern 1 at 36 months. CONCLUSIONS: Patients that underwent the total parathyroidectomy and autograft present four different graft function patterns with a possible varied therapeutic management.

Effects of bone remodelling on calcium mass transfer during haemodialysis.

BACKGROUND: During haemodialysis, calcium balance can affect, or be affected by, mineral metabolism. However, when dialysate calcium concentration (d[Ca]) is chosen or kinetic models are employed to calculate calcium balance, bone remodelling is rarely considered. In this study, we examined whether bone remodelling affects calcium mass transfer during haemodialysis. METHODS: We dialysed 23 patients using a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L. Calcium mass transfer was measured and associated with remodelling bone factors. RESULTS: Calcium balance varied widely depending on the d[Ca]. Calcium removal was -578 +/- 389, -468 +/- 563, +46 +/- 400 and +405 +/- 413 mg when a d[Ca] of 1.0, 1.25, 1.5 or 1.75 mmol/L was used, respectively (1.0 and 1.25 vs 1.5 and 1.75 mmol/L, P < 0.001; 1.5 vs 1.75 mmol/L, P < 0.05). Univariate analysis showed that calcium balance correlated with calcium gradient, parathyroid hormone (PTH), osteocalcin and dialysis vintage. Multivariate analysis revealed that calcium balance was dependent on calcium gradient, PTH and osteocalcin. CONCLUSIONS: These results suggest that bone remodelling could affect calcium mass transfer during haemodialysis.

Chronic kidney disease is a main confounding factor for 25-vitamin D measurement.

BACKGROUND: Current guidelines recommend assessment of 25-vitamin D status in patients with chronic kidney disease (CKD). Although significant differences among assays have been described, the impact of CKD on this variability has never been tested. METHODS: We tested the variability between two 25-vitamin D assays in patients with CKD (eGFR < 60 mL/min/1.73m2) who had consecutive 25-vitamin D measurements in 2015 (Assay 1 - Diasorin LIASON 25 TOTAL - D assay®) and 2016 (Assay 2 - Beckman Coulter Unicel Xl 800®). The cohort consisted of 791 adult patients (122 with normal renal function and 669 with CKD - 33, 30, and 37% in stages 3, 4, and 5 on dialysis, respectively). RESULTS: Levels of 25-vitamin D were lower and the prevalence of hypovitaminosis D using assay 1 was higher than using assay 2 in patients with CKD, regardless of similar levels of calcium, phosphate, and parathyroid hormone. As kidney function decreased, the percentage of disagreement between the assays increased. CONCLUSION: There is a noteworthy variability between assays in patients with CKD such that the diagnosis of hypovitaminosis D is modified. The mechanism behind this result is still unclear and might be due to a possible interference in the analytical process. However, the clinical significance is unquestionable, as the supplementation of vitamin D can be erroneously prescribed to these patients.

Flow Cytometry of CD14, VDR, Cyp27 and Cyp24 and TLR4 in U937 Cells.

Chronic Kidney Disease (CKD) patients present a micro inflammation state due to failure renal function. The calcitriol has been described as an anti-inflammatory factor that might modulates the inflammatory response in CKD patients. However, these patients have deficiency of Calcitriol due to failure renal function. But, synthesis of this vitamin has been reported in extra renal production, as in monocytes. In this context, it has been reported that the supplementation with 25 vitamin D (calcidiol or inactive form of vitamin D) induces monocytes to downregulate inflammation, due to the intracellular 1α-hidroxilase that converts calcidiol to calcitriol in these cells. Besides some reports used RT-qPCR, Western Blot or immunofluorescence techniques to investigate the expression of inflammatory and vitamin D machinery biomarkers in several disease, in the present study we used flow cytometry technique to evaluate the effect of 25 vitamin D on CD14, Toll-like receptor 4 (TLR4), vitamin D receptor (VDR), 1-α hydroxylase (CYP27), 24 hydroxylase (CYP24) in monocytes lineage (U937). The U937 culture was incubated with healthy or CKD serum and treatment with/without 25-vitamin D (50 ng/ml for 24 h) to evaluate CD14, TRL4, VDR, CYP27 and CYP24 expression. This protocol showed the advantage to investigate the effect of treatment with 25 vitamin D on the intracellular and cell membrane biomarkers expression quickly and simultaneously. In addition, this technique is not laborious, but easy to perform and to interpret compared to RT-qPCR, western blot or immunofluorescence.

25-vitamin D reduces inflammation in uremic environment.

Chronic kidney disease (CKD) is characterized by loss of renal function and a consequent increase of serum uremic toxins, which contribute to inflammation status. Deficiency of 25-vitamin D, often found in patients with CKD, has been included as an inflammatory factor since it might modulate the immune system. The aim of this study was to investigate the role of 25-vitamin D on inflammatory pathways in healthy and uremic environment. Toll-like receptor 4 (TLR4), oxidative stress (ROS), vitamin D receptor (VDR), 1-α hydroxylase (CYP27), 24 hydroxylase, cathelicidin, and MCP-1 were evaluated in monocytes exposed to a uremic serum pool compared with healthy pool. The human monocytes lineage (U937) was incubated with or without 25-vitamin D (50 ng/ml for 24 hours). TRL4, VDR, CYP27, CYP24, and ROS were evaluated by flow cytometry. We used ELISA to measure IL-6, TNF-α, IL-10, cathelicidin, and MCP-1 in the cell culture supernatant. We observed a higher expression of TRL-4, IL-6, TNF-α, IL-10, cathelicidin and MCP-1 in monocytes incubated with uremic serum when compared with serum from healthy individuals. Supplementation of 25-vitamin D was able to reduce the expression of TRL4, cathelicidin, and MCP-1 in the uremic environment. There was no difference in the expression of VDR, CYP27 and CYP24 intracellular enzymes. This in vitro study showed that the uremic pool activates inflammatory response in monocytes, which was reversed by 25-vitamin D supplementation; this finding suggests that 25-vitamin D has an anti-inflammatory role in the uremic environment.