Use of 3‐hour daily hemodialysis and paricalcitol in patients with severe secondary hyperparathyroidism: A case series

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3‐hour daily hemodialysis (3 hours × 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321–1983]–472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium × phosphorus product (80.3 ± 26.8–48.9 ± 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 ± 2.34–4.75 ± 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 ± 2.04–9.62 ± 0.93 mg/dL, P<0.01). Three‐hour daily hemodialysis with the use of high‐dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.     

Efficacy and safety of Cinacalcet on secondary hyperparathyroidism in Chinese chronic kidney disease patients receiving hemodialysis

Introduction Secondary hyperparathyroidism (SHPT) develops in patients with chronic renal failure. Cinacalcet hydrochloride has been used successfully in U.S., Europe, and Japan in the treatment of SHPT, while maintaining serum levels of calcium and phosphorus. The efficacy and safety profile of Cinacalcet treatment vs. conventional treatments has been of great interest in clinical practice. In this recent phase III study conducted in China, efficacy and safety of a calcimimetic agent, Cinacalcet (Kyowa Hakko Kirin Co., Ltd.), were assessed for SHPT treatment in stable chronic renal disease patients on hemodialysis. Methods In this double‐blind, multicenter, placebo‐controlled, randomized phase III study, 238 subjects were enrolled in 12 centers and randomly divided into a Cinacalcet group and a placebo group. The percentage of patients achieving a serum parathyroid hormone (PTH) level ≤250 pg/mL was the primary efficacy end point. Serum calcium and phosphorus levels were measured. Adverse events and serious adverse events were recorded, and causal analysis performed. Findings In primary analysis, 25.4% of the Cinacalcet group and 3.5% of the placebo group achieved the primary end point (PTH ≤250 pg/mL). Calcium and phosphorus levels and calcium–phosphorus product were lower in the Cinacalcet group compared with the placebo group. Eleven serious adverse events were reported and considered to be not related to study drugs. Mild to moderate hypocalcemia and reduced calcium levels were reported and considered to be Cinacalcet related. Discussion This phase III study demonstrated that Cinacalcet is effective and well tolerated in treating SHPT in Chinese chronic kidney disease patients on hemodialysis, and in a patient population with much higher baseline PTH levels.     

Cervical tumoral calcinosis with secondary hyperparathyroidism in a chronic hemodialysis patient

Tumoral calcinosis is an uncommon and severe complication of chronic renal failure. It is generally associated with the presence of a high‐serum calcium‐and‐phosphorus product. We report here a case of a patient on maintenance hemodialysis who presented with progressively increasing, solitary, tumor‐like swelling over the nape of the neck. A 50‐year‐old female on thrice weekly maintenance hemodialysis for the last 3 years presented with a small swelling over the nape of the neck that had been progressively increasing over the last 1 year to cricket ball size. The patient was investigated and diagnosed as having tumoral calcinosis. The metastatic calcification occurring in the patient was most likely related to high calcium × phosphate product with coexistent secondary hyperparathyroidism possibly aggravated by vitamin D therapy. The patient was treated with withdrawal of vitamin D therapy, strict control of serum phosphate levels with noncalcemic phosphate binders, and subtotal parathyroidectomy. The neck swelling started decreasing in size after 2 months of parathyroidectomy and there was marked clinical improvement with drop in serum parathormone levels, over a period of 6 months. After 2 years of parathyroidectomy, the neck swelling again started increasing in size with increase in serum parathormone levels. The patient was treated with cinacalcet and the neck swelling gradually decreased in size along with control of serum parathormone and phosphate levels.     

Hyponatremia in patients with chronic kidney disease

Hyponatremia is a common condition encountered in clinical practice. A number of studies have associated low serum sodium levels with increased mortality in various patient populations, such as hospitalized patients and patients with various comorbid conditions; recent studies have shown that individuals with chronic kidney disease also are afflicted by hyponatremia. However, few studies have focused on patients with hemodialysis. Evidence supporting the incidence and prevalence of hyponatremia, clinical characteristics and the association with patient outcomes with hemodialysis is limited. In the present review, we examined the physiology and pathophysiology of water and sodium balance with a special emphasis on changes occurring during end‐stage renal disease. The outcomes in patients undergoing hemodialysis were associated with low serum sodium. We evaluated the associations between hyponatremia and mineral bone abnormalities and discussed the elevated incidence and prevalence of difficult clinical outcomes associated with hyponatremia. We also provided specific recommendations for hemodialysis treatment in hyponatremic patients.     

Prevalence of 25(OH) vitamin D insufficiency and deficiency in chronic kidney disease stage 5 patients on hemodialysis

Little is known about the magnitude of vitamin D deficiency in patients with stage 5 chronic kidney disease (CKD-5) on hemodialysis (HD). In the present study, we examined the prevalence of vitamin D deficiency in patients with CKD-5 undergoing HD, evaluating the relationship between calcidiol levels with other parameters of mineral metabolism, nutrition/inflammation, functional capacity (FC), and sunlight exposure. Serum 25(OH) vitamin D levels were evaluated in 84 stable patients on chronic HD not receiving vitamin D supplements, with a mean age 58.9+/-16.6 years, during the month of September (end of winter in the southern hemisphere). 25(OH) vitamin D serum levels, intact PTH (iPTH), as well as serum albumin, calcium, phosphorus, and alkaline phosphatase were analyzed in fasting samples. Similarly, protein catabolic rate (PCR) and body mass index (BMI) were determined as nutritional parameters. Functional capacity according to the Karnofsky index, and sunlight exposure were also analyzed. In this study, we considered adequate vitamin D levels those above 30 ng/mL (U.S.A. National Kidney Foundation DOQI Guidelines), vitamin D insufficiency when levels were between 15 and 30 ng/mL, and vitamin D deficiency when levels were below 15 ng/mL. The mean 25(OH) D levels were significantly higher in men than in women (28.6 vs. 18.9 ng/mL; p=0.001). Vitamin D insufficiency was found in 53.5% of the patients (n=45) and vitamin D deficiency in 22.6% (n=19). In the univariate analysis, there were no correlations between 25(OH) D levels with age, iPTH, calcium, or phosphorus. There were positive correlations between serum 25(OH) D levels and degrees of sunlight exposure (R=0.55; p<0.0001), serum creatinine (r=0.38; p<0.001), serum albumin (r=0.22; p=0.04), and a negative correlation with BMI (r=-0.26; p=0.01). In the multiple regression analysis, only sunlight exposure (B=0.361), BMI (B=-0.23), and gender (B=-0.27) were significantly associated with 25(OH) D levels. Patients with FC 1 to FC 2 (n: 70%, 83.3%) had significantly higher 25(OH) D serum levels compared with FC 3 to FC 4 patients (n: 14%, 16.6%): 25.9 vs. 17.1 ng/mL (p=0.03). These results indicate that vitamin D insufficiency/deficiency is highly prevalent (76.1%) at the end of winter, in stage 5 CKD patients on HD, and lower values seem to be related to decreased sunlight exposure, female gender, increased BMI, and worse functional class.     

Severe Cortical and Trabecular Osteopenia in Secondary Hyperparathyroidism

Background: Peripheral quantitative computed tomography (pQCT) provides real volumetric bone density values, not only of the total, but also of trabecular and cortical bone, separately. In addition, it provides data on bone geometry that can be related to the risk of fracture. Methods: Total, cortical, and trabecular volumetric bone mineral densities (BMD), as well as the main geometric parameters (cross‐sectional area, cortical area, trabecular area, and cortical thickness) were assessed by pQCT at the distal radius in 24 hemodialysis patients affected by severe secondary hyperparathyroidism (PTH, mean ± SD: 1444 ± 695 pg/mL). The strength‐strain index (SSI), a biomechanical parameter describing bone fragility, was also determined. Results: Compared with a control group of 64 healthy age‐matched subjects, volumetric BMD (mg/cm³) was significantly reduced in all patients (total BMD: 243 ± 87 vs. 405 ± 138, cortical BMD: 605 ± 218 vs. 856 ± 204, trabecular BMD: 95 ± 51 vs. 182 ± 75). Cortical area and cortical thickness showed significant modifications, while cross‐sectional area did not. SSI was significantly reduced (547 ± 125 vs. 927 ± 306 mm³). PTH levels showed a significant inverse correlation with cortical BMD (r = ?0.56), cortical thickness (r = ?0.46), cortical area (r = ?0.61), and SSI (r = ?0.54). Quantitative analysis of bone demonstrated cortical porosity. Conclusions: In dialysis patients with severe secondary hyperparathyroidism, pQCT showed a significant cortical osteopenia, associated with geometric and mechanical bone impairment. Interestingly, we also found a comparable deficit of trabecular bone, which may be related to the very high PTH levels. Generalized cortical thinning, intracortical porosity and cortical‐endosteal resorption (“trabecularization” of the cortical bone) are major determinants of reduced bone strength, which may be quantitated by pQCT.     

Brown tumors in dialyzed patients with secondary hyperparathyroidism: Report of 16 cases

Brown tumors (BTs) are relatively uncommon but they are serious complications of renal osteodystrophy. The objective of this study was to analyze the clinical, biological, and radiological characteristics of 16 patients with BTs provoked by secondary hyperparathyroidism (sHPT) and its response to the decrease in parathyroid hormone levels after parathyroidectomy (PTX). The management of that uncommon condition was also reviewed. We conducted a retrospective study including 16 end‐stage renal disease patients who underwent subtotal PTX between 1997 and 2007 for severe sHPT with BTs. Our study included 10 men and 6 women, whose average age was 34 years. All patients were on dialysis. Ten of them were on dialysis for more than 5 years. The median duration on dialysis was 84 months. Patients included suffered from swellings associated with functional limitations. BTs had multiple locations in 7 patients. Jaw was the most frequent location (62%). Radiography and tomodensitometry demonstrated a mixed radio lucent and radio‐opaque lesions with an expansion of the cortical bone. Bone scan demonstrated an increased uptake of lesions. Chirurgical treatment was indicated in all cases because of severe refractory sHPT with functional limitations and/or disfiguring deformities. In all cases, BTs stopped its progression and even decreased in size. However, it was insufficient in four cases, which required a surgical resection. PTX remains an efficacious approach in resistant cases of sHPT with persistent BTs.     

Acute renal failure and chronic kidney disease following liver transplantation

Acute renal failure (ARF) and chronic kidney disease (CKD) are common complications after liver transplantation (LTx). The incidence of ARF post-LTx varies between 48% and 94%; 8% to 17% of patients require renal replacement therapy (RRT). The most common cause of ARF early after LTx is ischemic acute tubular necrosis, followed later by cyclosporine toxicity and sepsis. Preoperative serum creatinine >1.5 mg/dL and early hepatic allograft dysfunction are risk factors for the occurrence of postoperative ARF. Of patients with ARF due to the hepatorenal syndrome, approximately two-thirds will recover, although recovery may be delayed 3 months or longer after LTx. Mortality after LTx is affected modestly by the presence of ARF pretransplant (<2-fold increase), but increases markedly (up to 8-fold) in the face of ARF posttransplant. Mortality does not appear to be influenced by the mode of RRT used. The risk of CKD after LTx is approximately 18% at 5 years and increases to approximately 25% by 10 years after transplantation. Calcineurin inhibitor toxicity is the most common cause. Specific prognosticators for predicting CKD after LTx are presently lacking. The occurrence of CKD after LTx markedly impairs long-term survival.     

Treating mineral metabolism disorders in patients undergoing long hemodialysis: A search for an optimal strategy

In hemodialysis (HD) patients, mineral metabolism (MM) disorders have been associated with an increased mortality rate. We report the evolution of MM parameters in a stable HD population undergoing long hemodialysis by performing an annual cross-sectional analysis for every year from 1994 to 2008. The therapeutic strategy has changed: the dialysate calcium concentration has decreased from a mean of 1.7 ± 0.1 to 1.5 ± 0.07 mmol/L and has been adapted to parathyroid hormone serum levels (from 1 to 1.75 mmol/L). The use of calcium-based and aluminum-based phosphate binders has decreased and they have been replaced by sevelamer; alfacalcidol has partly been replaced by native vitamin D. The percentage of patients with a parathyroid hormone serum level between 150 and 300 pg/mL has increased from 9% to 67% (P<0.001); the percentage of patients with phosphataemia between 1.15 and 1.78 mmol/L has increased from 39% to 84% (P<0.001). The percentage of those with albumin-corrected calcemia between 2.1 and 2.37 mmol/L has increased from 29% to 61% (P<0.001), and that of patients with a calcium-phosphorous product (Ca × P) level >4.4 mmol/L decreased from 8.8% to 2% (P=0.02). Although patients undergo long and intensive HD treatment, MM disorders are common. However, an appropriate strategy, mostly consisting of native vitamin D supplementation, progressive replacement of calcium-based phosphate binders with non–calcium-based ones, and individualization of dialysis session duration and dialysate calcium concentration, would result in a drastic improvement.     

Status epilepticus induced by putrid salted gray mullet fish intoxication in patients with chronic kidney disease

Neurological and psychiatric symptoms are common presentations, but are often ignored in fresh salted gray Mullet fish intoxication. We report 2 patients with chronic renal failure at a predialyzed stage who developed refractory status epilepticus after ingestion of putrid salted gray Mullet. We warn consultant neurologists that fresh salted gray Mullet fish intoxication must be considered when patients with chronic kidney disease present with seizures or other unexplained neurological or psychiatric symptoms.     

Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high‐dose cinacalcet exposure

We are reporting on a series of two patients with end‐stage renal disease on hemodialysis, presented for surgical parathyroidectomy secondary refractory hyperparathyroidism. Both patients had failed maximized medical managements, including higher‐than‐usual doses of the calcimimetic cinacalcet (270 and 180 mg/day, respectively). On physical exam, both patients had marked symmetrical craniofacial hypertrophy with coarse distortion of facial features, similar in appearance to past reports of Sagliker syndrome. On X‐ray and computed tomographic exam, they had peculiar areas of bone absorption on the skull, imitating the radiologic appearance of multiple myeloma. Bone biopsy of the maxilla, however, did not show the expected brown tumor, but rather described only fibrosis and reactive bone formations. This phenotype developed while being on cinacalcet, progressed despite escalation of therapy, and improved only after parathyroidectomy. Both patients developed massive “hungry bone syndrome” after parathyroidectomy necessitating prolonged IV calcium infusion. This pattern of severe facial distortion likely represented an adverse consequence of severe tertiary hyperparathyroidism, along with supraphysiologic dose of cinacalcet administration and 25‐hydroxy vitamin D deficiency in sensitive individuals. The genetic base of this observation remained unexplained.     

Association between depression and inflammatory/anti‐inflammatory cytokines in chronic kidney disease and end‐stage renal disease patients: A review of literature

Depression is a common psychiatric disorder in patients with advanced chronic kidney diseases (CKDs). Strong correlation has been reported between depression and patients' morbidity and mortality among dialysis patients. On the contrary, chronic inflammation may be a major contributor to morbidity and mortality in these patients. Elevated plasma levels of proinflammatory cytokines, especially C‐reactive protein and interleukin (IL)‐6, have been correlated with cardiovascular events, hospitalization, and all‐cause and cardiovascular‐associated mortality in dialysis patients. Studies suggested that inflammation‐mediated atherosclerotic cardiovascular diseases are the possible reasons for depression‐induced mortality among patients without renal diseases. Several studies found significant elevations in circulating levels of proinflammatory cytokines, particularly IL‐6 and tumor necrosis factor‐α, in patients with major depression. Furthermore, depressive mood and behaviors, including sadness and suicidal ideation, were observed in patients who received repeated injections of recombinant cytokines. A thorough literature review indicates that while depressive symptoms and elevated inflammatory cytokine levels coexist in CKD and dialysis patients, their association is uncertain. Depression seems to be more associated with elevated serum levels of IL‐6 than other cytokines in these patients. Further studies are needed to clarify the possibility of a causal relationship between inflammation and depressive symptoms in CKD and dialysis patients.     

Treatment of vitamin D deficiency/insufficiency with ergocalciferol is associated with reduced vascular access dysfunction in chronic hemodialysis patients

Vitamin D deficiency or insufficiency is highly prevalent among patients with chronic kidney disease (CKD). This study aims to determine the relationship between vitamin D and frequency of vascular access dysfunction (VAD) in hemodialysis (HD) patients. We reviewed medical records of all HD patients who had serum 25‐hydroxyvitamin D (25OHD) levels at 4 outpatient dialysis facilities between January 2011 and January 2012. Patients were included if they were ≥18 years of age, had been on maintenance dialysis for ≥3 months, and had native arteriovenous fistula or synthetic polytetrafluoroethylene grafts for dialysis access. Patients with catheters were excluded. 25‐Hydroxyvitamin D levels <30 ng/mL were documented in 183 patients (86%). Median and interquartile range [Q1, Q3] of 25OHD level was 16 [11, 25] ng/mL. Among 213 dialysis patients, 102 had VAD. Median 25OHD level was significantly lower in patients who had VAD than in those without VAD (14.5 [10, 22] vs. 19 [12, 27.5] ng/mL; P = 0.003). There was significant association between VAD and the lowest quartile relative to the highest quartile of 25OHD level. A 25OHD level <12 ng/mL was associated with more than doubling of risk for VAD (OR 2.56; 95% CI [1.05–6.23], P < 0.05). Of 213 patients, 140 were treated with ergocalciferol and 73 were not treated. Treatment was associated with significant reduction in VAD (OR = 0.36; 95% CI [0.19–0.68], P = 0.002). Vitamin D deficiency or insufficiency is an independent risk factor for VAD in HD patients; its treatment with ergocalciferol is associated with decreased VAD.     

Physical function was related to mortality in patients with chronic kidney disease and dialysis

Previous studies have shown that exercise improves aerobic capacity, muscular functioning, cardiovascular function, walking capacity, and health‐related quality of life (QOL) in patients with chronic kidney disease (CKD) and dialysis. Recently, additional studies have shown that higher physical activity contributes to survival and decreased mortality as well as physical function and QOL in patients with CKD and dialysis. Herein, we review the evidence that physical function and physical activity play an important role in mortality for patients with CKD and dialysis. During November 2016, Medline and Web of Science databases were searched for published English medical reports (without a time limit) using the terms “CKD” or “dialysis” and “mortality” in conjunction with “exercise capacity,” “muscle strength,” “activities of daily living (ADL),” “physical activity,” and “exercise.” Numerous studies suggest that higher exercise capacity, muscle strength, ADL, and physical activity contribute to lower mortality in patients with CKD and dialysis. Physical function is associated with mortality in patients with CKD and dialysis. Increasing physical function may decrease the mortality rate of patients with CKD and dialysis. Physicians and medical staff should recognize the importance of physical function in CKD and dialysis. In addition, exercise is associated with reduced mortality among patients with CKD and dialysis.     

The relationship of insulin resistance and body fat in chronic kidney disease patients.

Background:  Insulin resistance has been associated with type 2 diabetes, hypertension, central obesity, and dyslipidemia, all of which are important risk factors for progression of chronic kidney disease (CKD). A greater degree of insulin resistance may predispose to renal injury by worsening renal hemodynamics through the elevation of glomerular filtration fraction. However, there are sparse data on the relationship between insulin resistance, glomerular filtration rate (GFR), and total body fat or phase angle in CKD without diabetes. Methods:  We examined 84 non‐diabetes CKD patients according to the K/DOQI definitions; only 79 patients were enrolled into the study (GFR between 15 and 90 ml/min/1.73 m²). The value of insulin resistance was obtained by homeostasis model assessment (HOMA). Bioelectrical impedance analysis was performed to determine the percentage of total body fat or phase angle. GFR was calculated by the average of creatinine and urea clearances. Results:  The correlation analysis showed that HOMA‐insulin resistance was positively correlated with phase angle (r = 0.35, P < 0.01), percentage of total body fat (r = 0.27, P < 0.01), body mass index (r = 0.48, P < 0.01) and serum triglyceride levels (r = 0.32, P < 0.01), but not significantly correlated with gender (r = −0.07, P > 0.05), age (r = 0.05, P > 0.05), GFR (r = −0.006, P > 0.05), and mean arterial blood pressure (r = 0.11, P > 0.05). Conclusion:  In non‐diabetic chronic kidney disease patients, the major risk factor for insulin resistance is the amount of total body fat. The insulin level is not dependent on the GFR in these patients.