Continuous Renal Replacement Therapy for Liver Disease

Continuous renal replacement therapy (CRRT) is becoming the treatment of choice for critically ill patients with acute renal failure around the world. In particular, CRRT is used for patients with combined liver and acute renal failure, because they are often hemodynamically unstable. The question arises as to whether the use of CRRT should be extended to those patients with acute and chronic liver failure who do not have dialysis-dependent renal failure. CRRT could potentially allow some detoxification by removing water-soluble toxins and also allow regulation of intravascular volume and correction of sodium and other electrolyte and acid–base imbalances. By providing homeostatic control, CCRT could potentially help support patients by bridging to liver transplantation and managing those who eventually recover with hepatic regeneration.     

Digital clubbing as an unusual complication associated with severe secondary hyperparathyroidism: report of two cases

Digital clubbing due to secondary hyperparathyroidism has been described as an unusual complication among patients with chronic kidney disease undergoing maintenance hemodialysis therapy. Although the pathogenesis of digital clubbing is unknown, certain growth factors such as platelet-derived growth factor and hepatocyte growth factor have been associated with this clinical syndrome. Two patients of our renal unit population presented this unique clinical feature bilaterally, among the other clinical findings of severe secondary hyperparathyroidism. Both patients were subjected to parathyroidectomy. Histological examination revealed diffuse hyperplasia of parathyroid glands. Despite the improvement of clinical symptoms and laboratory findings of secondary hyperparathyroism after parathyroidectomy, digital clubbing remained unchanged.     

An exceedingly rare localization of a brown tumor in a hemodialysis patient

Brown tumor, which is seen in the context of hyperparathyroidism, is defined as a uremic bone disease characterized by increased osteoclastic activity and fibroblastic proliferation in the involved bone. In chronic renal failure, there is an excessive parathyroid hormone secretion due to hypocalcemia, hyperphosphatemia, and vitamin D deficiency. Brown tumor of the femur, facial bones, mandible, sternum, ribs, and pelvis are rare, whereas, it rarely involves sacrum. Here, we presented a brown tumor of the sacrum that developed secondary to parathyroid hyperplasia in a patient receiving hemodialysis.     

Variability in calcium, phosphorus, and parathyroid hormone in patients on hemodialysis

Calcium, phosphorus, and parathyroid hormone (PTH) levels are routinely measured in patients undergoing chronic hemodialysis. Medications, diet, and dialytic therapies are modified based upon these lab values to achieve specific goal values in the hope of improving outcomes. However, the variability of these values in patients undergoing chronic hemodialysis has only been rarely studied.
We prospectively investigated the variability of these measures in 35 patients undergoing chronic hemodialysis as well as the impact of this variability on clinical decision-making in a prospective manner over a month. There is significant session-to-session variability in phosphorus and PTH values (mean coefficient of variations [CV] of 0.19 and 0.31, respectively). Calcium variability is much lower (mean CV of 0.05). Not surprisingly, the CV for all values is increased during the long interdialytic interval. The impact of this variability on clinical decision-making was analyzed. The variability in calcium, phosphorus, and PTH values would lead to a different clinical decision in 23.6%, 41.2%, and 39.7% of different session lab values. We also investigated the variability of these lab measures over a year in these patients and found that the session-to-session variability was very similar to the month-to-month variability.
The high degree of variability of these parameters has important implications for clinical decision-making and for implementation of pay-for-performance measures.     

Mysterious PTH values after parathyroidectomy in a patient on maintenance dialysis

A 25-year-old patient with end-stage renal disease on maintenance peritoneal dialysis underwent parathyroidectomy when his secondary hyperparathyroidism did not respond to medical management. However, over the subsequent months he developed extremely raised parathyroid hormone (PTH) levels. When surgical removal of the autotransplant was considered, preoperative work-up revealed a PTH level within the target range. It became apparent that the very high PTH values were due to the location of the blood draw close to the autotransplant, thus measuring a local rather than the systemic PTH value. The multiple causes of varying PTH measurements other than clinical and physiological reasons are reviewed.     

Prognostic implications of clinical practice guidelines among hemodialysis patients

Although the National Kidney Foundation (NKF) has published clinical practice guidelines for the management of risk factors for cardiovascular disease, these guidelines have not been tested rigorously for their effectiveness. We conducted an observational study among patients with end-stage kidney disease to examine the prognostic impact of threshold levels recommended by the NKF for blood pressure, hemoglobin, calcium-phosphate product, parathyroid hormone, low-density lipoprotein, and glycosylated hemoglobin. The study population (N = 197) was assembled from a previously completed randomized trial examining arteriovenous graft thrombosis. Cox proportional hazard analysis was used to calculate hazard ratios for the association of levels outside guideline recommended targets and death, adjusting for age, comorbidity, race, and albumin. The proportion of patients outside guideline targets ranged from 33% to 81%, and the impact of levels outside guideline targets on mortality varied substantially. Elevated calcium-phosphate product and glycosylated hemoglobin had harmful effects, with adjusted hazard ratios of 1.58 (95% CI 1.00-2.50; p = 0.050) and 2.21 (95% CI 0.99-4.97; p = 0.054), respectively. Nontarget levels for blood pressure, hemoglobin, and parathyroid hormone had little effect, with adjusted hazard ratios of 1.15 (95% CI 0.74-1.78; p = 0.542), 1.04 (95% CI 0.65-1.68; p = 0.866), and 0.90 (95% CI 0.50-1.61; p = 0.722), respectively. Elevated low-density lipoprotein had a paradoxically beneficial effect, with an adjusted hazard ratio of 0.48 (95% CI 0.23-1.00; p = 0.049). These results suggest that the prognostic impact of current threshold levels recommended by select NKF guidelines on mortality is variable. Accordingly, the development and implementation of clinical practice guidelines should be accompanied by corresponding efforts to confirm their impact on patient outcomes. Such efforts are essential for the improvement of guidelines and to inform health policy optimally.     

Hyperparathyroidism caused by distant pulmonary lesions and parathyromatosis after ethanol injection/parathyroidectomy for secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) treatment includes parathyroidectomy and percutaneous ethanol injection therapy (PEIT), which are invasive procedures. The condition in which benign hyperfunctioning parathyroid tissue is distributed throughout the neck and mediastinum is termed parathyromatosis. Here, we present the case of a 51‐year‐old woman who began hemodialysis in 1986 due to chronic kidney disease of unknown etiology and developed SHPT in 1999. She underwent 6 rounds of PEIT followed by total a parathyroidectomy with partial forearm autotransplantation. Between 2011 and 2013, surgeons removed several nodules from her pulmonary and cervical regions and the transplanted masses from her forearm; all showed hyperplasia but exhibited no histological evidence of malignancy. Damage to the parathyroid capsule after repeated PEITs may cause local cervical recurrence and pulmonary lesions, although distant lesions are extremely rare in SHPT. This case is of interest due to the possible association between PEIT and parathyromatosis and distal lesions.     

Primary hyperoxaluria in an adult presenting with end-stage renal failure together with hypercalcemia and hypothyroidism

Primary hyperoxaluria (PH) is a rare genetic disorder characterized by overproduction of oxalate due to specific enzyme deficiencies in glyoxylate metabolism. The primary clinical presentation is in the form of recurrent urolithiasis, progressive nephrocalcinosis, end-stage renal disease, and systemic oxalosis. Herein, we present a case of PH who was diagnosed at 47 years of age after 6 years on hemodialysis. He presented with fatigue, anorexia, weight loss, and was found to have cachexia, diffuse edema, hepatomegaly, ascites, hypercalcemia, hyperphosphatemia, hypoalbuminemia, low parathyroid hormone levels, lytic and resorptive areas in the vertebrae, diffusely increased echogenity of the liver, multiple renal stones, and bilateral nephrocalcinosis. Bone marrow biopsy showed calcium oxalate crystals and crystal granulomas. The liver biopsy could not be performed. The absence of an identifiable reason for secondary forms, the severity of the clinical presentation, and pathological findings led to the diagnosis of PH2. He died while waiting for a potential liver and kidney donor. The presented case is consistent with the literature as he had renal stone disease in the third decade and end-stage renal disease in the fifth decade. Hypercalcemia was thought to be due to osteoclast-stimulating activity of macrophages constituting the granuloma. Erythropoietin-resistant anemia and hypothyroidism were thought to be due to accumulation of oxalate in the bone marrow and thyroid gland, respectively. It is very important to keep in mind the possibility of PH when faced with a patient with nephrocalcinosis and oxalate stone disease.     

Looking at calcimimetics impact on hypercalcemia of immobilization: hypotheses and a case study

For the treatment of secondary hyperparathyroidism (HPTH-II) in dialysis patients and hypercalcemia in patients with parathyroid carcinoma. Calcimimetics are a new class of drugs approved in the European Community and the United States by the Food and Drug Administration that were designed to suppress parathyroid hormone (PTH) levels with a simultaneous reduction in serum calcium and phosphorus levels, and calcium phosphorus product (Ca x P). Hypocalcemia is a frequent finding during the correction phase of the HPTH-II with calcimimetics. By contrast, the appearance of a hypercalcemia has yet to be described. In this paper, we report a case of severe hypercalcemia of immobilization in a 40-year-old hemodialyzed woman treated by cinacalcet HCl for a severe HPTH-II (PTH>1,000 pg/mL). A kidney transplantation recipient 1983 to 1995, she was diagnosed with Charcot-Marie Tooth disease in 1991. She had multiple orthopedic interventions for kidney-related osteoarticular problems probably favored by the kidney graft and the immunosuppressive treatment. While she was receiving the maximum dose of 180 mg/day of cinacalcet HCl and PTH at 443 pg/mL, she needed to be hospitalized for a right hip prothesis. Two weeks after the intervention she developed a symptomatic hypercalcemia of 3.57 mmol/L which was resistant to several measures including lowering the calcium concentration in the dialysate, withdrawing all vitamin D and calcium supplementation and the administration of calcitonin. Her serum calcium level was finally stabilized in the 2.37-2.95 mmol/L by administration of a single intravenous dose of pamidronate. This observation illustrates that the pharmacological activation of the parathyroid CaR and other putative CaR on bone cells by calcimimetics did not protect against the occurrence of hypercalcemia of immobilization favored by a severe HPTH-II in a hemodialysis patient.     

Teriparatide Therapy as an Adjuvant for Tissue Engineering and Integration of Biomaterials

Critically sized large bone defects commonly result from trauma, radical tumor resections or infections. Currently, massive allografting remain as the clinical standard to treat these critical defects. Unfortunately, allograft healing is limited by the lack of osteogenesis and bio-integration of the graft to the host bone. Based on its widely studied anabolic effects on the bone, we have proposed that teriparatide [recombinant parathyroid hormone (PTH(1-34))] could be an effective adjuvant for massive allograft healing. In support of this theory, here we review studies that have demonstrated that intermittent PTH(1-34) treatment enhances and accelerates the skeletal repair process via a number of mechanisms including: effects on mesenchymal stem cells (MSC), angiogenesis, chondrogenesis, bone formation and remodeling. We also review the current literature on the effects of PTH(1-34) therapy on bone healing, and discuss this drug's long term potential as an adjuvant for endogenous tissue engineering.     

Survival to discharge among patients treated with continuous renal replacement therapy

Continuous renal replacement therapy (CRRT) is widely used in critically ill patients with acute renal failure (ARF). The survival of patients who require CRRT and the factors predicting their outcomes are not well defined. We sought to identify clinical features to predict survival in patients treated with CRRT. We reviewed the charts of all patients who received CRRT at the Toronto General Hospital during the year 2002. Our cohort (n=85) represented 97% of patients treated with this modality in 3 critical care units. We identified demographic variables, underlying diagnoses, transplantation status, location (medical-surgical, coronary, or cardiovascular surgery intensive care units), CRRT duration, baseline estimated glomerular filtration rate (eGFR), and presence of oliguria (<400 mL/day) on the day of CRRT initiation. The principal outcome was survival to hospital discharge. Among those alive at discharge, we assessed whether there was an ongoing need for renal replacement therapy. Greater than one-third (38%, 32/85) of patients survived to hospital discharge. Three (9%) survivors remained dialysis-dependent at the time of discharge. Survivors were younger than nonsurvivors (mean age 56 vs. 60 years), were on CRRT for a shorter duration (7 vs. 13 days), and had a higher baseline eGFR (74 vs. 62 mL/min/m(2)). Patient survival varied among different critical care units (medical surgical 33%, coronary 38%, and cardiovascular surgery 45%). Multivariable logistic regression revealed that shorter duration of CRRT, nonoliguria, and baseline eGFR >60 mL/min/m(2) were independently associated with survival to hospital discharge (p<0.05). Critically ill patients with ARF who require CRRT continue to have high in-hospital mortality. A shorter period of CRRT dependence, nonoliguria and higher baseline renal function may predict a more favorable prognosis. The majority of CRRT patients who survive their critical illness are independent of dialysis at the time of hospital discharge.     

Development and utility of a multi‐dimensional grid to assess individual mineral metabolism control in hemodialysis patients: A potential aid for therapeutic decision making?

A grid was developed to evaluate control of serum calcium, phosphate, and parathyroid hormone levels in hemodialysis patients, based on guideline recommendations (National Kidney Foundation Kidney Disease Outcomes Quality Initiative and Canadian Society of Nephrology), and its face validity was examined in a representative sample of Canadian patients. A retrospective chart review was undertaken in hemodialysis patients from 7 Canadian units. Patients >18 years, on hemodialysis for ≥12 months, and ≥3 parathyroid hormone levels measured ≥1 month apart were included. The grid classified mineral metabolism control as optimal, suboptimal, or poor (mean of 3 measurements). Medication use, hospitalization, and Emergency Department visits were evaluated in relation to grid occupancy. A second comparative analysis of grid occupancy was undertaken on prevalent hemodialysis cases in British Columbia in 2008. Data from 268 patients (mean age 62.3 years) were analyzed. Using National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines, 17.5%, 28.8%, and 53.7% of patients had optimal, suboptimal, and poor control, respectively, of all 3 parameters (calcium, phosphate, and parathyroid hormone). Using Canadian Society of Nephrology criteria, optimal, suboptimal, and poor control rates were 6.3%, 4.2%, and 89.5%, respectively. Poor control was a possible or a probable cause of hospitalization or Emergency Department attendance in 8 patients. Data from British Columbia in 2008 (n=1858) show optimal, suboptimal, and poor control rates of 15.8%, 24.5%, and 59.7%, respectively. Poor mineral metabolism control among Canadian hemodialysis patients is not showing improvement. The therapeutic grid is a valid tool and may help guide therapeutic decisions, quality control initiatives, and patient counseling. http://www.ukidney.com/bone‐and‐mineral‐metabolism‐resource .     

Sternal instability in a hemodialysis patient with secondary hyperparathyroidism

A 77‐year‐old man, 11 years under chronic hemodialysis treatment for chronic renal failure of unknown origin, presented with anterior chest pain, dyspnea with paradoxical breathing, and sternal instability after a simple fall from a standing height. Patient underwent three‐vessel coronary artery bypass grafting 31 months ago. Computed tomography with three‐dimensional volume rendering showed sternal nonunion with a great gap between the two halves of the sternum and at least one fracture in the left half of the sternum. A successful surgical repair followed. Patient suffered from severe secondary hyperparathyroidism for many years. Despite treatment with sevelamer, paricalcitol and cinacalcet, intact parathyroid hormone was 1682 pg/mL. During the last 5 years, serum intact parathyroid hormone remained steadily above 1000 pg/mL. Patient refused parathyroidectomy in the past. We assume that long‐lasting severe hyperparathyroidism contributed to this rare and life‐threatening complication of median sternotomy in our patient, due to the detrimental effect of hyperparathyroidism on bone metabolism and its association with increased incidence of bone fractures and defect in bone fracture healing.     

Self-reported symptoms in patients on hemodialysis with moderate to severe secondary hyperparathyroidism receiving combined therapy with cinacalcet and low-dose vitamin D sterols

Patients with secondary hyperparathyroidism experience a variety of clinical symptoms which may adversely affect physical and mental function. As part of a multicenter, open-label clinical trial, subjects completed a questionnaire that included the Medical Outcomes Study Short Form-36 and 14 kidney disease-related symptoms at multiple time points during the study. Out of the 567 subjects who received at least one dose of cinacalcet, 528 to 535 (93.8-94.4%) completed all or portions of the questionnaire at baseline. The median bioactive parathyroid hormone (PTH) was 294 pg/mL (10%, 90% range, 172-655 pg/mL). Following treatment with cinacalcet and low-dose vitamin D sterols, subjects reported significant improvement in the frequency of pain in muscles, joints and bones, stiff joints, dry skin, itchy skin, excessive thirst, and trouble with memory. At end of the efficacy assessment phase (Weeks 16 to 22), the magnitude of improvement was the greatest in joint pain, bone pain, dry skin, and excessive thirst (>5 on a 0-100 scale; P < 0.001). There were no clinically or statistically significant changes in any of the Short Form-36 subscales or in the physical or mental health composite scores. Among patients on hemodialysis with moderate to severe secondary hyperparathyroidism, treatment with cinacalcet and low-dose vitamin D sterols results in significant improvement in pain in the muscles, joints and bones, joint stiffness, dry and itchy skin, excessive thirst, and trouble with memory.     

Intradialytic changes of serum magnesium and their relation to hypotensive episodes in hemodialysis patients on different dialysates

Magnesium is a crucial mineral, involved in many important physiological processes. Magnesium plays a role of maintaining myocardial electrical stability in hemodialysis patients. Intradialytic hypotension is a common complication of dialysis and it is more common with acetate dialysate. The significance of the intradialytic changes of magnesium and their relation to parathyroid hormone (PTH) level and calcium changes during dialysis, and their relation to hypotensive episodes during dialysis are interesting. The aim of this work is to investigate the intradialytic changes of serum magnesium in chronic hemodialysis patients with different hemodialysis modalities and the relation to other electrolytes and to PTH, and also the relation to intradialytic hypotension. The present study was conducted on 20 chronic renal failure patients. All patients were on regular hemodialysis thrice weekly 4 hr each using acetate dialysate (group I). To study the effect of an acetate-based dialysate vs. a bicarbonate-based dialysate on acute changes of magnesium, calcium, phosphorus, and PTH during a hemodialysis session, the same patients were shifted to bicarbonate dialysis (group II). All patients were subjected to full history and clinical examination, predialysis laboratory assessment of blood urea nitrogen (BUN), serum creatinine, albumin, and hemoglobin, serial assessment of magnesium, calcium, phosphorus, and parathyroid hormone at the start of the hemodialysis session, 2 hr later, and at the end of the session, blood pH, and electrocardiogram (ECG) presession and postsession. All patients were urged to fix their dry weight, diet, and current medications. None of the patients had diabetes, neoplasia, liver disease, or cachexia, nor had they been recently on magnesium-containing drugs or previously parathyroidectomized. Hemodialysis sessions were performed by volumetric dialysis machines using the same electrolyte composition. Magnesium level significantly increased in the bicarbonate group at the end of dialysis (0 hr: 2.73+/-0.87, 2 hr: 3.21+/-1.1, and at 4 hr: 5.73+/-1.45 mg/dL, p value <0.01), while it significantly decreased in the acetate group (0 hr: 3.00+/-0.58, 2 hr: 2.26+/-0.39, 4 hr: 1.97+/-0.33 mg/dL, p value <0.01). Calcium level significantly increased in the bicarbonate group (p=0.024) but not in the acetate group. Phosphorus level significantly decreased in both acetate and bicarbonate groups. PTH level did not significantly change in either group, p value > or =0.05. Blood pH significantly increased, changing from acidic to alkaline pH, with both modalities of hemodialysis. ECG showed no significant changes during sessions with either type of dialysate. Hypotension was significantly higher in group I compared with group II (p=0.01), and this hypotension was positively correlated with a decrease in serum magnesium level in group I. Intradialytic changes in serum magnesium have no correlation with intradialytic changes in serum calcium or with PTH level. However, it was significantly correlated with hypotension during the dialysis session, especially with acetate dialysate. Further investigations are needed to determine whether or not this is true in patients using bicarbonate dialysis.     

Switch from calcitriol to paricalcitol in secondary hyperparathyroidism of hemodialysis patients: Responsiveness is related to parathyroid gland size

Paricalcitol is more effective than calcitriol in hemodialysis patients (HD) with secondary hyperparathyroidism (SHPT), but it is not effective in some of them. We have investigated the relationship between paricalcitol responsiveness and parathyroid gland (PTG) size. Thirty HD with SHPT treated previously with calcitriol for at least 6 months were switched to paricalcitol (1:4 conversion ratio). Parathyroid gland number and size (maximum longitudinal diameter [MLD] of largest PTG) was measured by ultrasonography. Patients were divided into 2 groups: group A (MLD ≤9.0 mm [17 HD]); and group B (MLD >9.0 mm [13 HD]). They were defined responder if both the last 2 monthly determinations of inhibit parathyroid hormone (iPTH) were within the target (<300 pg/mL) according to National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommendations. Twenty‐six and 20 HD completed 6‐month and 12‐month paricalcitol therapy, respectively. After 6 months of paricalcitol treatment, 23.5% HD of group A and 7.7% of group B were responders. At 12 months, 41.2 % of group A and 7.7% of group B were responders. Throughout paricalcitol therapy, serum calcium and phosphorus concentrations slightly increased in all HD but more significantly in group B. The baseline iPTH and MLD of the largest PTG were significantly correlated with final iPTH levels. Paricalcitol is more effective than calcitriol in SHPT, but the responsiveness to paricalcitol and hypercalcemia are related to PTG size. The measurement of MLD by ultrasonography may be useful for predicting responsiveness to paricalcitol, avoiding an unnecessary and expensive therapy.     

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.     

Percutaneous ethanol injection treatment of severe hyperparathyroidism in maintenance dialysis: Risks and benefits

Renal hyperparathyroidism is one of the main and serious complications that occur in chronic kidney disease and particularly during long‐term maintenance dialysis. Several recent trials indicate that a high calcium phosphorus product is correlated with high cardiovascular morbidity and mortality and poor outcome. Thus, it is important to improve the control of hyperparathyroidism in chronic renal failure patients. Several methods have been reported for treating severe hyperparathyroidism resistant to medical therapy. Total parathyroidectomy and transplantation or excision of tumor is considered as the treatment of choice. More recently, interventional methods with percutaneous ethanol or calcitriol injection have been developed. These latter techniques have been reported as an alternative to surgical treatment for patients with high perioperative risk. We report the occurrence of laryngeal recurrent nerve palsy, vocal fold paralysis, and hemiplegia after a successful injection of ethanol in a left parathyroid adenoma in a maintenance hemodialysis patient and discuss the restrictions of the procedure and alternative treatments in view of the available studies.