Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats

Background

Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats.

Methods

Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed.

Results

Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion.

Conclusions

These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23.     

Hemodiafiltration--a new treatment option for hyperphosphatemia in hemodialysis patients.

BACKGROUND: Hemodiafiltration is used to increase the convective transport and thereby the elimination of small and middle molecules, mainly beta2-microglobulin (beta2-M) across the dialysis membranes. There is little information concerning urea, creatinine, beta2-M and principally phosphate kinetics during hemodiafiltration in vivo. In this prospective study, we evaluated the transmembrane solute mass removal (TSR) and clearance (Kd) of urea, creatinine and phosphate as well as serum beta2-M reduction rate (beta2-MRR) and collected beta2-M in dialysate plus ultrafiltrate during high-flux hemodialysis (HD) and post-dilutional hemodiafiltration (HDF). PATIENTS AND METHODS: 16 patients were studied using a polysulfone capillary filter (1.6 m2 surface area, 40 microm fiber internal diameter and 200 microm, wall thickness) during 2 one-week periods: first week HD 1.6 m2 and second week HDF 1.6 m2. Treatment time was 4 hours, blood flow rate 300 ml/min with constant dialysate and ultrafiltration rates for HD and HDF periods. TSR, Kd, beta2-MRR and beta2-M collection were assessed during the mid-week treatment. In a second part of the study, we repeated the same protocol using a second high-flux polysulfone capillary filter (2.4 m2 surface area, 30 microm fiber diameter and 150 microm wall thickness). RESULTS: TSR and Kd of urea and creatinine were not improved by HDF, however, HDF increased TSR and Kd of phosphate. Phosphate clearance rose from 120 (HD 1.6 m2) to 159 (HDF 1.6 m2) (p < 0.005) and from 146 (HD 2.4 m2) to 206 (HDF 2.4 m2) (p < 0.005) ml/min. Beta2-MRR increased from 64.1 +/- 8.6 to 77.7 +/- 8.2% (p < 0.005) and from 75.0 +/- 5.1 to 82.9 +/- 8.5% (p < 0.005) during HDF 1.6 m2 and HDF 2.4 m2, respectively. Collected beta2-M remained unchanged. This discrepancy seems to be due to an enhanced beta2-M adsorption to the polysulfone membrane during HDF. CONCLUSION: Our results provide a strong evidence that HDF has no advantage over HD with respect to urea and creatinine removal in vivo. However, HDF did improve the elimination of phosphate and should be considered as an additional treatment option for hyperphosphatemia in dialysis patients. HDF improves significantly the elimination of beta2-M.     

Evidence-based treatment recommendations for uremic bleeding

Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.     

Pericardiectomy for uremic tamponade.

Pericardial tamponade developed in 29 patients with uremia. The clinical presentation varied, some patients having no symptoms whereas others sustained circulatory collapse. Pericardial friction rub, elevated central venous pressure and a paradoxical pulse were the most common physical findings. Serial chest radiography and echocardiography were most useful procedures in confirming this diagnosis. Two patients were treated conservatively and died despite repeated pericardiocentesis. The remaining 27 patients underwent partial pericardiectomy. One patient died of cardiorespiratory failure and a second from brain damage related to cardiac arrest before pericardiectomy. The other 25 patients reported immediate relief of symptoms and no recurrence of pericarditis. Pericardiectomy is the treatment of choice in uremic pericardial tamponade.     

Parlodel treatment of uremic hypogonadism in men

Parlodel, 2.5 mg daily, was given during 1-3 months to 14 uremic hypogonadal patients (placebo controlled in 6). Except for a decrease in serum prolactin levels on Parlodel (p less than 0.01), no significant changes in hormonal values (gonadotropins and testosterone) were observed either on Parlodel or on placebo. Parlodel treatment improved the potency of 10 patients, eliminated gynecomastia in 2 and normalized spermatogenesis in 6; the best results were obtained in patients on low-protein diet. On placebo, potency improved only in 1 patient; no improvement in spermatogenesis was registered. Thus, Parlodel can improve sexual function and spermatogenesis in hypogonadal uremic males.     

New therapies for uremic secondary hyperparathyroidism.

Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). It affects more than 300,000 end-stage renal disease patients treated by dialysis and probably more than 3 million patients with CKD worldwide. For a long time, traditional therapies for SHPT had consisted of correcting the hypocalcemia using calcium salts and vitamin D derivatives, preventing the hyperphosphatemia by calcium- or aluminum-containing intestinal phosphate binders, and recently by using no metal-containing intestinal phosphate binders; however, these therapies are limited by the occurrence of hypercalcemia, hyperphosphatemia, and the lack of specificity and long-term efficacy. Moreover, surgical parathyroidectomy (PTX), which remains the gold standard therapy, is not exempt from risk. PTX exposes patients to anesthesia risks, presurgical and postsurgical complications, and in many cases a permanent state of hypoparathyroidism. Thus, the medical treatment of SHPT became an ideal target for the development of new therapies and strategies. The purpose of this article is to provide an overview of these new therapies, including vitamin D analogs, intestinal phosphate binders, calcimimetics, parathyroidectomies, tyrosine kinase inhibitors, azydothymidine, anticalcineurins, N-terminal truncated parathyroid hormone fragments, bisphosphonates, calcitonin, osteoprotegerin, and others. The use of these new therapies alone or in combination may help to optimize the future treatment of SHPT in CKD patients.     

Recombinant human erythropoietin treatment improves platelet function in uremic patients.

The effect of recombinant human erythropoietin (rHuEPO) on primary hemostasis was tested in 19 hemodialyzed patients. Bleeding time, platelet aggregation and platelet interaction with vessel subendothelium (SE) under flow conditions were determined before treatment and after patients reached hematocrits greater than or equal to 30%. Two thrombotic events (an acute myocardial infarction and an AV fistula clotting) were recorded during the early stages of treatment. A shortening of average bleeding times (P less than 0.01), an increase in platelet count (P less than 0.01) and an improvement of platelet aggregation (P less than 0.01) and of platelet-SE interaction (P less than 0.01) were observed. A low correlation index was found between hematocrit and bleeding time (r = -0.351, P less than 0.05). To assess a possible effect of rHuEPO on platelet function, the same parameters were evaluated before and after receiving three doses of rHuEPO (40 U/kg i.v. post-hemodialysis) in 14 of the patients. No changes in platelet or erythrocyte counts were observed, the mean bleeding time remained unchanged, but platelet aggregation induced by arachidonic acid (P less than 0.05), ADP (P less than 0.01) and ristocetin (P less than 0.05) improved. Perfusion studies confirmed moderate but significant increases in the parameters that quantify platelet-SE interaction (P less than 0.05). Improvement of ADP-induced aggregation correlated with the increase of platelet adhesion to SE (r = 0.675, P less than 0.05). We conclude that rHuEPO treatment improves primary hemostasis in uremia through an increase of red cell mass but also through a beneficial effect on platelet function, which is independent of the hematocrit rise.     

慢性肾脏病高磷血症所致并发症的机制及防治进展

以往认为,慢性肾脏病(CKD)患者血管钙化是由于体内钙磷代谢失衡、钙磷过饱和所致的钙盐被动沉积于细胞和细胞外基质的一个非细胞介导的过程.近年来,血管钙化的分子机制研究结果表明,细胞介导的主动调节过程在血管钙化的发生过程中占重要地位,其形成过程与骨骼的矿化相似,是一个受多因素调控的、与骨发生类似的主动的可调节过程,其中心环节是血管平滑肌向成骨细胞分化,分泌成骨细胞样基质,最终形成钙化.     

The continuous challenge of cardiovascular and bone and bone disease in uremic patients: clinical consequences of hyperphosphatemia and advanced therapeutic approaches

This review focuses on a series of risk factors involved in the pathogenesis of cardiovascular complications in patients undergoing Regular Dialysis Treatment (RDT). Many of them are not modifiable by any pharmacological strategies or dialysis therapy, others - such as phosphate overload - can be corrected successfully, thus slowing progression of vascular calcification. Another important reason to control serum phosphate is that its accumulation in the body plays a key role in trigger-ing, directly or indirectly, PTH secretion with important metabolic consequences, mainly in the bone. The need to control serum phosphate levels relies mostly on the use of phosphate binders and in this review the pro-con analysis of several P binders (Calcium Salts, Sevelamer, Lanthanum Carbonate) is presented in terms of safety and efficacy.     

An introduction to phosphate binders for the treatment of hyperphosphatemia in patients with chronic kidney disease

Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperphosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperphosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of phosphate binders to absorb excess ingested phosphate, can help to maintain serum phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based binders pioneered in the 1970s to calcium-based binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer--a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperphosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well.     

尿毒症继发甲状旁腺功能亢进的特点及外科治疗

继发性甲状旁腺功能亢进（SHPT）是慢性肾功能衰竭的重要并发症,SHPT患者甲状旁腺呈非对称性增大并伴有结节形成,甲状旁腺组织中Ca^2＋敏感受体基因、维生素D受体基因有异常表达.SHPT可致患者出现骨痛、骨骼畸形、甲状旁腺激素和碱性磷酸酶水平增高、骨纤维囊性变、弥漫性脱钙等表现,严重者可出现胸骨畸形、压缩性骨折、心脏瓣膜钙化等。对于存在甲状旁腺激素显著增高、甲状旁腺增大、纤维性骨炎或高度骨代谢运转以及内科治疗无效等情况者杠般建议行外科治疗。甲状旁腺全切前臂自体移植对晚期肾性SHPT是非常有效的治疗方法。手术的关键是要切除所有的甲状旁腺,使用质地柔软的弥漫性增生的组织进行移植。切除的甲状旁腺数一般为2-4枚,若有多余腺体,应在初次手术时切除。术后应进行钙替代治疗。甲状旁腺切除前臂自体移植可显著改善SHPT患者的临床症状和生化参数。持续性和复发性HPT的发生率一般为0-10％。持续性HPT的主要原因为纵隔甲状旁腺,复发的原因常为前臂自体移植物增生、多余腺体、剩余增生腺体、周围组织中旁腺组织的种植、旁腺癌的转移等。为防止术后发生持续性或复发性HPT．在初次手术时要切除所有的腺体以及胸腺舌,手术后应定期随访。根据患者血甲状旁腺激素水平、核素及影像学检查可诊断移植物依赖性复发。     

A case of refractory uremic pleuropericarditis--successful corticosteroid treatment

We report the case of a patient with uremic pleuropericarditis who showed a marked improvement following corticosteroid therapy. A 66-year-old man who had been on hemodialysis therapy for 13 years was admitted to our hospital presenting with increases in bilateral pleural effusions and pericardial effusion. Repeated thoracentesis showed hemorrhagic and exudative findings. Pleural and pericardial fluid cytologic examination, bacterial culture and acid-fast staining showed negative findings. Despite the administration of antibiotics and antituberculosis drugs, low-grade fever continued and C-reactive protein level remained high. A pleural biopsy revealed fibrinous pleuritis without infectious disease or malignancy. He was diagnosed as having uremic pleuropericarditis on the basis of the clinicopathological features, but had been unresponsive to conventional treatments including repeated thoracentesis and the continuance of hemodiafiltration using nafamostat mesylate. Ultimately, both pleural and pericardial effusions were controlled after the treatment with prednisolone at an initial dose of 50 mg per day. In conclusion, corticosteroid therapy seems to be useful for treating patients with conventional therapy-resistant uremic pleuropericarditis.     

组合型人工肾治疗尿毒症患者皮肤瘙痒的效果观察

目的探讨组合型人工肾治疗尿毒症患者皮肤瘙痒的效果及护理方法。方法选择50例尿毒症伴皮肤瘙痒的维持性血液透析患者,随机分成对照组与观察组各25例,分别采用组合型人工肾治疗与常规血液透析8周。治疗前后检测甲状旁腺素水平,观察皮肤瘙痒改善情况。结果观察组治疗后甲状旁腺素水平显著低于对照组,皮肤瘙痒改善情况显著优于对照组(P0.05,P0.01)。结论组合型人工肾能有效地清除甲状旁腺素等大中分子毒素,改善患者的皮肤瘙痒症状;透析中防止感染、凝血,正确回血等是其护理要点。     

高致敏尿毒症患者肾移植术前的脱敏治疗及效果

目的 探讨高致敏尿毒症患者肾移植术前脱敏治疗的可行性和效果.方法 等待肾移植的群体反应性抗体(PRA,抗HLA Ⅰ类抗体)＞50%的尿毒症患者35例,27例的T淋巴细胞和(或)B淋巴细胞毒交叉配合试验阳性,8例T淋巴细胞和B淋巴细胞毒交叉配合试验为阴性.移植前接受血浆置换(PP)联合静脉注射小剂量免疫球蛋白(IVIG)进行脱敏治疗.采用美国One Lambda公司抗原板检测PRA,并用相应电脑软件分析抗HLA抗体特异性.当淋巴细胞毒交叉配合试验为阴性时接受肾移植.结果 淋巴细胞毒交叉配合试验阳性的27例中,25例(92.6%,25/27)在PP+IVIG治疗(6.2±2.1)次后转为阴性,其抗HLA Ⅰ类抗体从治疗前的(77±14)%下降至(36±17)%(P＜0.01),抗HLA Ⅱ类抗体从治疗前的(52±33)%降至(37±30)%(P＜0.01),最终接受了肾移植;另2例因淋巴细胞毒交叉配合试验持续阳性而放弃肾移植.接受肾移植的25例中,有8例(32.0%,8/25)发生急性排斥反应,其中5例(62.5%,5/8)为急性体液性排斥反应(AHR),均经治疗后逆转.随访(52±26)个月,受者术后1年和2年时的血肌酐分别为(112±18)μmol/L和(130±38)μmol/L.移植肾1年和3年存活率分别为96.0%和80.0%.结论 肾移植前采用PP+IVIG能有效地对高致敏患者进行脱敏治疗,但术后AHR发生率较高,其近期效果可以接受,远期效果还有待观察.

Abstract：

Objective To explore the feasibility and efficacy of desensitization protocol for highly sensitized renal transplant patients (HSP). Methods Thirty-five HSPs ( HLA class-Ⅰ panel reactive antibody ＞50 %), including 27 patients with a positive T and/or B cell cytotoxicity crossmatch (XM) and 8 patients with a negative T and B cell XM, received plasmapheresis plus intravenous immunoglobulin (PP-IVIG)treatment. Results The positive XM was rendered negative by PP-IVIG treatment in 25 of 27 (92.6 %)HSPs, and subsequent transplantation was performed. Two patients did not receive renal transplants due to persistent positive XM. In 25 patients receiving renal transplants, no hyperacute rejection occurred. There were 8 cases of acute rejection, including 5 cases of acute humoral rejection (AHR). All rejection episodes were reversed. During a follow-up period of 52 ± 26 months, the serum creatinine levels at 12th and 24th month were 112± 18 and 130 ± 38 mol/L respectively. The 1- and 3-year graft survival rate was 96. 0 %and 80. 0 % respectively. Conclusion The desensitization therapy by PP-IVIG is effective for HSP. High rate of AHR is the major defect of this protocol. The short-term graft survival rate after this protocol is acceptable but the long-term survival rate needs to be defined.     

The clinical management of hyperphosphatemia

As renal function declines in patients with end-stage renal disease (ESRD), excess dietary phosphorus accumulates in the bloodstream. Routine dialysis removes up to 70% of absorbed phosphorus; therefore, hyperphosphatemia is found in the majority of patients with ESRD. The consequences of this imbalance include secondary hyperparathyroidism and osteodystrophy. Recent studies have also documented that hyperphosphatemia can lead to soft-tissue and vascular calcification; the latter is strongly associated with cardiovascular disease and, thus, increased mortality and morbidity. The reduction of phosphorus levels is, therefore, an important therapeutic target in this patient group. Management of hyperphosphatemia using conventional phosphate binders is not always successful. However, emerging therapies aim to reduce the incidence of hyperparathyroidism, bone disease, and calcification in this patient population. In this article, the consequences of hyperphosphatemia are reviewed, and recent developments in the treatment of the condition are discussed.