Simplified regional citrate anticoagulation protocol for CVVH, CVVHDF and SLED focused on the prevention of KRT-related hypophosphatemia while optimizing acid-base balance.

BACKGROUND: Hypophosphatemia is a common electrolyte disorder in critically ill patients undergoing prolonged kidney replacement therapy (KRT). We evaluated the efficacy and safety of a simplified regional citrate anticoagulation (RCA) protocol for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) and sustained low-efficiency dialysis filtration (SLED-f). We aimed at preventing KRT-related hypophosphatemia while optimizing acid-base equilibrium. METHODS: KRT was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 filters (ST 150, 1.5 m2, Baxter), combining a 18 mmol/L pre-dilution citrate solution (Regiocit 18/0, Baxter) with a phosphate-containing solution (HPO42- 1.0 mmol/L, HCO3- 22.0 mmol/L; Biphozyl, Baxter). When needed, phosphate loss was replaced with sodium glycerophosphate pentahydrate (Glycophos™ 20 mmol/20 mL, Fresenius Kabi Norge AS, Halden, Norway). Serum citrate measurements were scheduled during each treatment. We analyzed data from three consecutive daily 8-h SLED-f sessions, as well as single 72-h CVVH or 72-h CVVHDF sessions. We used analysis of variance (ANOVA) for repeated measures to evaluate differences in variables means (i.e. serum phosphate, citrate). Because some patients received phosphate supplementation, we performed analysis of covariance (ANCOVA) for repeated measures modelling phosphate supplementation as a covariate. RESULTS: Forty-seven patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) requiring KRT were included [11 CVVH, 11 CVVHDF and 25 SLED-f sessions; mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score 25 ± 7.0]. Interruptions for irreversible filter clotting were negligible. The overall incidence of hypophosphatemia (s-P levels <2.5 mg/dL) was 6.6%, and s-P levels were kept in the normality range irrespective of baseline values and the KRT modality. The acid-base balance was preserved, with no episode of citrate accumulation. CONCLUSIONS: Our data obtained with a new simplified RCA protocol suggest that it is effective and safe for CVVH, CVVHDF and SLED, allowing to prevent KRT-related hypophosphatemia and maintain the acid-base balance without citrate accumulation. TRIAL REGISTRATION: NCT03976440 (registered 6 June 2019).

The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis.

BACKGROUND & AIMS: Heavy alcohol consumption is a common cause of acute pancreatitis; however, alcohol abuse does not always result in clinical pancreatitis. As a consequence, the factors responsible for alcohol-induced pancreatitis are not well understood. In experimental animals, it has been difficult to produce pancreatitis with alcohol. Clinically, alcohol use predisposes to hypophosphatemia, and hypophosphatemia has been observed in some patients with acute pancreatitis. Because of abundant protein synthesis, the pancreas has high metabolic demands, and reduced mitochondrial function leads to organelle dysfunction and pancreatitis. We proposed, therefore, that phosphate deficiency might limit adenosine triphosphate synthesis and thereby contribute to alcohol-induced pancreatitis. METHODS: Mice were fed a low-phosphate diet (LPD) before orogastric administration of ethanol. Direct effects of phosphate and ethanol were evaluated in vitro in isolated mouse pancreatic acini. RESULTS: LPD reduced serum phosphate levels. Intragastric administration of ethanol to animals maintained on an LPD caused severe pancreatitis that was ameliorated by phosphate repletion. In pancreatic acinar cells, low-phosphate conditions increased susceptibility to ethanol-induced cellular dysfunction through decreased bioenergetic stores, specifically affecting total cellular adenosine triphosphate and mitochondrial function. Phosphate supplementation prevented ethanol-associated cellular injury. CONCLUSIONS: Phosphate status plays a critical role in predisposition to and protection from alcohol-induced acinar cell dysfunction and the development of acute alcohol-induced pancreatitis. This finding may explain why pancreatitis develops in only some individuals with heavy alcohol use and suggests a potential novel therapeutic approach to pancreatitis. Finally, an LPD plus ethanol provides a new model for studying alcohol-associated pancreatic injury.

[Hypophosphatemia after iron infusion†: can we still ignore it†?] / Hypophosphatémie après perfusion de fer†: pouvons-nous encore l'ignorer†?

The occurrence of hypophosphatemia after iron infusion has been known for a long time but has only recently led to clinical concerns. It was considered to be of low clinical importance. The elucidation of the physiological mechanisms responsible for this effect, involving FGF23 and the ever-increasing number of cases with regard to the potentially very serious consequences on bone metabolism have recently raised probably justified concerns. In this article, we summarize the mechanisms of phosphate homeostasis, how intravenous iron can induce a phosphate deficiency and what precautions and treatments needs to be undertaken to prevent it.

La survenue d'une hypophosphatémie après une perfusion de fer est connue de longue date mais n'a que depuis peu suscité des inquiétudes cliniques. L'élucidation des mécanismes physiologiques à l'origine de cet effet indésirable, impliquant le facteur de croissance des fibroblastes 23 (FGF23), et les rapports de cas toujours plus nombreux quant aux conséquences potentiellement graves sur le métabolisme osseux ont récemment soulevé des préoccupations probablement justifiées. Dans cet article, nous résumons les mécanismes de régulation du phosphate et la manière dont le fer par voie intraveineuse peut induire un déficit en phosphate, ainsi que les précautions et traitements à mettre en œuvre pour le prévenir.

Iron Infusion and Induced Hypophosphatemia: The Role of Fibroblast Growth Factor-23.

The mechanism of action of fibroblast growth factor-23 (FGF23) is becoming increasingly clearer as a result of studies that have defined its structure and pleiotropic effects. Furthermore, data are emerging on the effects exerted on this hormone by iron administration. Ten main iron formulations are recognized (with clear differences in composition and possible reactions of intolerance and anaphylaxis), which are indicated for iron deficiency anemia, including nephropathic subjects, as suggested by medical guidelines. With some types of iron formulation (especially iron carboxymaltose) a particular side effect has been observed: hypophosphatemia, mediated by FGF23. This review aims to draw attention to this correlation and the contradiction represented by the presence of both positive and negative modulation by FGF23, with the effects induced by its increase even after long-term treatment with iron formulation. However, more evidence is needed to understand the reasons for this differential stimulation.

Management of mineral and bone disorders in renal transplant recipients.

The management of post-transplantation bone disease is a complex problem that remains under-appreciated in clinical practice. In these patients, pre-existing metabolic bone disorder is further impacted by the use of immunosuppressive medications (glucocorticoids and calcineurin-inhibitors), variable post-transplantation renal allograft function and post-transplantation diabetes mellitus. The treatment of post-transplantation bone loss should begin pre-transplantation. All patients active on transplant waiting lists should be screened for bone disease. Patients should also be encouraged to take preventative measures against osteoporosis such as regular weight-bearing exercise, smoking cessation and reducing alcohol consumption. Biochemical abnormalities of disordered mineral metabolism should be corrected prior to transplantation wherever possible, and because these abnormalities commonly persist, post transplant hypophosphatemia, persistent hyperparathyroidism and low vitamin D levels should be regularly monitored and treated. Bone loss is greatest in the first 6-12 months post-transplantation, during which period any intervention is likely to be of greatest benefit. There is strong evidence that bisphosphonates prevent post-transplantation bone loss; however, data are lacking that this clearly extends to a reduction in fracture incidence. Denosumab is a potential alternative to vitamin D receptor agonists and bisphosphonates in reducing post-transplantation bone loss; however, further studies are needed to demonstrate its safety in patients with a significantly reduced estimated glomerular filtration rate. Clinical judgement remains the cornerstone of this complex clinical problem, providing a strong rationale for the formation of combined endocrinology and nephrology clinics to treat patients with Chronic Kidney Disease-Mineral and Bone Disorder, before and after transplantation.

Preventing Continuous Renal Replacement Therapy-Induced Hypophosphatemia: An Extended Clinical Experience with a Phosphate-Containing Solution in the Setting of Regional Citrate Anticoagulation.

AIMS: To evaluate the efficacy and safety of a commercially available phosphate-containing solution for continuous renal replacement therapy (CRRT) in preventing CRRT-related hypophosphatemia. METHODS: In heart surgery patients undergoing continuous veno-venous haemodiafiltration (CVVHDF) with regional citrate anticoagulation (RCA), we combined an 18 mmol/l citrate solution with a phosphate-containing (1.2 mmol/l) dialysate/replacement fluid evaluating the incidence of hypophosphatemia and the need for parenteral phosphorus supplementation. RESULTS: In 75 patients on RCA-CVVHDF, the mean filter life was 53.9 ± 33.6 h. Regardless of baseline levels, phosphoremia was progressively corrected and maintained in a narrow normality range throughout RCA-CRRT days (after 72 h: 1.14 ± 0.25 mmol/l). Considering the whole CRRT period, 45 out of 975 (4.6%) serum phosphorus determinations met the criteria for mild (<0.81 mmol/l) or moderate (<0.61 mmol/l) hypophosphatemia; severe hypophosphatemia (<0.32 mmol/l) never occurred. After 72 h 88% of the patients were normophosphatemic, 9% hyperphosphatemic and 3% hypophosphatemic. CONCLUSIONS: RCA-CVVHDF with a phosphate-containing solution enabled the maintenance of phosphorus levels within normophosphatemic range in most of the patients, minimizing the occurrence of CRRT-related hypophosphatemia.

Serum phosphate and magnesium in children recovering from severe acute undernutrition in Ethiopia: an observational study.

BACKGROUND: Children with severe acute malnutrition (SAM) have increased requirements for phosphorus and magnesium during recovery. If requirements are not met, the children may develop refeeding hypophosphatemia and hypomagnesemia. However, little is known about the effect of current therapeutic diets (F-75 and F-100) on serum phosphate (S-phosphate) and magnesium (S-magnesium) in children with SAM. METHODS: Prospective observational study, with measurements of S-phosphate and S-magnesium at admission, prior to rehabilitation phase and at discharge in children aged 6-59 months admitted with SAM to Jimma Hospital, Ethiopia. Due to shortage of F-75, 25 (35 %) children were stabilized with diluted F-100 (75 kcal/100 ml). RESULTS: Of 72 children enrolled, the mean age was 32 ± 14 months, and edema was present in 50 (69 %). At admission, mean S-phosphate was 0.92 ± 0.34 mmol/L, which was low compared to normal values, but increased to 1.38 ± 0.28 mmol/L at discharge, after on average 16 days. Mean S-magnesium, at admission, was 0.95 ± 0.23 mmol/L, and increased to 1.13 ± 0.17 mmol/L at discharge. At discharge, 18 (51 %) children had S-phosphate below the normal range, and 3 (9 %) had S-phosphate above. Most children (83 %) had S-magnesium above normal range for children. Both S-phosphate and S-magnesium at admission were positively associated with serum albumin (S-albumin), but not with anthropometric characteristics or co-diagnoses. Using diluted F-100 for stabilization was not associated with lower S-phosphate or S-magnesium. CONCLUSION: Hypophosphatemia was common among children with SAM at admission, and still subnormal in about half of the children at discharge. This could be problematic for further recovery as phosphorus is needed for catch-up growth and local diets are likely to be low in bioavailable phosphorus. The high S-magnesium levels at discharge does not support that magnesium should be a limiting nutrient for growth in the F-100 diet. Although diluted F-100 (75 kcal/100 mL) is not designed for stabilizing children with SAM, it did not seem to cause lower S-phosphate than in children fed F-75.

Continuous veno-venous hemofiltration using a phosphate-containing replacement fluid in the setting of regional citrate anticoagulation.

PURPOSE: The need for prolonged anticoagulation and the occurrence of hypophosphatemia are well known drawbacks of continuous renal replacement therapies (CRRT). The aim was to evaluate the effects on acid-base status and serum phosphate of a regional citrate anticoagulation (RCA) protocol for continuous veno-venous hemofiltration (CVVH) combining the use of citrate with a phosphate-containing replacement fluid. METHODS: In a small cohort of heart surgery patients undergoing CRRT for acute kidney injury, we adopted an RCA-CVVH protocol based on a commercially available citrate solution (18 mmol/l) combined with a recently introduced phosphate-containing replacement fluid (HCO3 -30 mmol/l, phosphate 1.2), aimed at preventing phosphate depletion. RESULTS: In 10 high bleeding-risk patients, the RCA-CVVH protocol provided an adequate circuit lifetime (46.8 ± 30.3 h) despite the adoption of a low citrate dose and a higher than usual target circuit Ca2+ (≤0.5 mmol/l). Acid-base status was adequately maintained without the need for additional interventions on RCA-CVVH parameters and without indirect sign of citrate accumulation [(pH 7.43 (7.41-7.47), bicarbonate 24.4 mmol/l (23.2-25.6), BE 0 (-1.5 to 1.1), calcium ratio 1.97 (1.82-2.01); median (IQR)]. Serum phosphate was steadily maintained in a narrow range throughout RCA-CVVH days [1.1 mmol/l (0.9-1.4)]. A low amount of phosphorus supplementation (0.9 ± 2 g/day) was required in only 30% of patients. CONCLUSIONS: Although needing further evaluation, the proposed RCA-CVVH protocol ensured a safe and effective RCA without electrolyte and/or acid-base derangements. CRRT-induced hypophosphatemia was prevented in most of the patients by the adoption of a phosphate-containing replacement solution, minimizing phosphate supplementation needs.

Continuous venovenous hemodiafiltration with a low citrate dose regional anticoagulation protocol and a phosphate-containing solution: effects on acid-base status and phosphate supplementation needs.

BACKGROUND: Recent guidelines suggest the adoption of regional citrate anticoagulation (RCA) as first choice CRRT anticoagulation modality in patients without contraindications for citrate. Regardless of the anticoagulation protocol, hypophosphatemia represents a potential drawback of CRRT which could be prevented by the adoption of phosphate-containing CRRT solutions. The aim was to evaluate the effects on acid-base status and phosphate supplementation needs of a new RCA protocol for Continuous Venovenous Hemodiafiltration (CVVHDF) combining the use of citrate with a phosphate-containing CRRT solution. METHODS: To refine our routine RCA-CVVH protocol (12 mmol/l citrate, HCO3- 32 mmol/l replacement fluid) (protocol A) and to prevent CRRT-related hypophosphatemia, we introduced a new RCA-CVVHDF protocol (protocol B) combining an 18 mmol/l citrate solution with a phosphate-containing dialysate/replacement fluid (HCO3- 30 mmol/l, Phosphate 1.2). A low citrate dose (2.5-3 mmol/l) and a higher than usual target circuit-Ca(2+) (≤ 0.5 mmol/l) have been adopted. RESULTS: Two historical groups of heart surgery patients (n = 40) underwent RCA-CRRT with protocol A (n = 20, 102 circuits, total running time 5283 hours) or protocol B (n = 20, 138 circuits, total running time 7308 hours). Despite higher circuit-Ca(2+) in protocol B (0.37 vs 0.42 mmol/l, p < 0.001), circuit life was comparable (51.8 ± 36.5 vs 53 ± 32.6 hours). Protocol A required additional bicarbonate supplementation (6 ± 6.4 mmol/h) in 90% of patients while protocol B ensured appropriate acid-base balance without additional interventions: pH 7.43 (7.40-7.46), Bicarbonate 25.3 (23.8-26.6) mmol/l, BE 0.9 (-0.8 to +2.4); median (IQR). No episodes of clinically relevant metabolic alkalosis, requiring modifications of RCA-CRRT settings, were observed. Phosphate supplementation was needed in all group A patients (3.4 ± 2.4 g/day) and in only 30% of group B patients (0.5 ± 1.5 g/day). Hypophosphatemia developed in 75% and 30% of group A and group B patients, respectively. Serum phosphate was significantly higher in protocol B patients (P < 0.001) and, differently to protocol A, appeared to be steadily maintained in near normal range (0.97-1.45 mmol/l, IQR). CONCLUSIONS: The proposed RCA-CVVHDF protocol ensured appropriate acid-base balance without additional interventions, providing prolonged filter life despite adoption of a higher target circuit-Ca(2+). The introduction of a phosphate-containing solution, in the setting of RCA, significantly reduced CRRT-related phosphate depletion.

Evolution of secondary hyperparathyroidism after kidney transplantation in patients receiving cinacalcet on dialysis.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a relevant problem in patients undergoing dialysis, and cinacalcet hydrochloride seems to be the best option for controlling it. After kidney transplantation (KTx), moderate to severe SHPT may persist and cause hypercalcemia and hypophosphatemia, among other deleterious effects. The number of patients receiving cinacalcet before KTx is increasing. OBJECTIVE: To evaluate the evolution of calcemia, phosphatemia, and intact parathyroid hormone (iPTH) after KTx in patients with SHPT receiving cinacalcet on dialysis. PATIENTS AND METHODS: The study included 19 patients (15 men and 4 women; mean [SD] age, 52 [13] years) undergoing dialysis and receiving cinacalcet before KTx. Mean duration of dialysis before KTx was 33 (25) months, and cinacalcet dose was 45 (15) mg/d. Creatinine, calcium, phosphorus, alkaline phosphatase, and iPTH concentrations were evaluated at baseline (day of surgery), at 15 days after surgery, and then monthly for 6 months. In all patients, cinacalcet therapy was discontinued on the day of surgery. RESULTS: After the first month post-KTx, mean (SD) serum creatinine concentration was 1.6 (0.4) mg/dL and remained stable during follow-up. Calcium and phosphorus concentrations were normal in 13 patients after KTx; however, in 6 patients, hypercalcemia (calcium concentration, 11 [1.3] mg/dL) or hypophosphatemia (phosphorus concentration, 1.7 [0.6] mg/dL) developed, with iPTH concentration of 557 (400) pg/mL and alkaline phosphatase concentration of 307 (114) IU/mL. Treatment with cinacalcet resulted in correction of calcium and phosphorus concentrations (10.1 [0.4] mg/dL and 1.7 [0.7] mg/dL, respectively). Patients in whom hypercalcemia or hypophosphatemia developed were receiving cinacalcet, 60 mg/d or more, during dialysis therapy. Patients who received cinacalcet, 30 mg/d, before KTx did not exhibit hypercalcemia or hypophosphatemia after KTx. CONCLUSION: In patients with HPT undergoing dialysis and receiving cinacalcet, 60 mg/d or more, this drug therapy should be continued after KTx to avert development of hypercalcemia or hypophosphatemia.

Refeeding syndrome: an important aspect of supportive oncology.

Refeeding syndrome (RFS) is an underappreciated, yet common and potentially dangerous, constellation of metabolic derangements that can occur upon reinstitution of any type of nutritional intervention. The typical patient who experiences RFS has been malnourished for days to weeks and develops hypophosphatemia and, occasionally, hypokalemia and hypomagnesemia when administered a carbohydrate load in the form of glucose-containing fluids, total parenteral nutrition (TPN), tube feedings, or an oral diet. The pathophysiology of RFS is complex but mainly results from an acute intracellular shift in electrolytes, increased phosphate demand during tissue anabolism, and formation of high-energy phosphate bonds. Potential complications of RFS include fatal cardiac arrhythmia, systolic heart failure, respiratory insufficiency, and hematologic derangements. Because supportive care of the cancer patient often involves nutritional and metabolic support, any clinician involved with providing acute or palliative oncologic care should be familiar with the risks, manifestations, and treatment of RFS.

Refeeding syndrome in cancer patients.

BACKGROUND: Refeeding syndrome (RFS) is a common, yet underappreciated, constellation of electrolyte derangements that typically occurs in acutely ill, malnourished hospitalised patients who are administered glucose solutions or other forms of intravenous or enteral nutrition. DISCUSSION: The hallmark of RFS is hypophosphataemia, but hypokalaemia and hypomagnesaemia are also common. Patients with various types of malignancies are at-risk for RFS, but very little exists in the oncologic literature about this disorder. CONCLUSIONS: As RFS can have many adverse metabolic, cardiovascular, haematologic and neurologic complications, practicing oncologist needs to be aware of the pathophysiology, risk factors and clinical manifestations to promptly recognise this important, and potentially fatal, metabolic disorder.

Hypophosphatemia in postoperative patients with total parenteral nutrition: influence of nutritional support teams.

UNLABELLED: PURPOSE, SETTING AND SUBJECTS: We conducted a prospective, descriptive study of postoperative patients under total parenteral nutrition controlled by a Multidisciplinary Nutritional Support Team in a tertiary care hospital. Between january 2002 and november 2003. Data of nutritional status, nutritional support, hypophosphatemia, electrolyte and metabolic complications were reviewed. RESULTS: 215 postoperative patients (63.3% male, 68 +/- 13.9 years old, 47.4% neoplasia). were included. Nutritional support according nutritional needs was made during fasting 14.2 +/- 18.4 days. Mild-moderate initial malnutrition was present in 58% of patients. 18.1% developed postoperative hypophosphatemia 96 hours after starting total parenteral nutrition containing phosphate. 37.7% patients showed moderated and 6.5% severe hypophosphatemia. Nutritional intervention corrected hypophosphatemia (p < 0.001). Factors related to hypophosphatemia were hypokalemia, hypomagnesemia, hypercalcemia, female sex, neoplasia, 96-hour postoperative period and duration of nutrition. CONCLUSIONS: Prevalence of hypophosphatemia in postoperative patients with total parenteral nutrition is high and needs timely monitoring. The intervention of Multidisciplinary Nutritional Support Team is effective detecting and correcting postoperative hypophosphatemia.

Enteral supplementation of phosphate does not prevent hypophosphatemia during refeeding of cachectic patients.

Hypophosphatemia due to parenteral nutrition has been described frequently. It was attributed to the lack of phosphorus content in parenteral nutrition solutions. With modern parenteral nutrition regimens containing phosphorus, this problem has been virtually eliminated. Enteral nutrition solutions contain adequate phosphate for patients with normal phosphate stores. Hypophosphatemia has therefore rarely been reported in enteral nutrition. We describe two patients with protein-energy malnutrition who developed severe hypophosphatemia during tube feeding with phosphorus-containing formula diets. Chronic alcoholism and vitamin D deficiency due to malabsorption because of Crohn's disease were additional risk factors in these two patients. Patients with depleted phosphate stores and high metabolic demand have a higher daily requirement for phosphorus than is available in routine isotonic enteral formulas. This case report emphasizes the importance of monitoring serum phosphate concentration daily during the first week of refeeding.

Hipocalcemia, hipomagnesemia e hipofosfatemia en pacientes pediátricos críticamente enfermos

Las alteraciones en las concentraciones séricas de iones como el calcio, el magnesio y el fósforo han sido estudiadas extensamente en los últimos años en pacientes críticamente enfermos y han sido asociadas con aumento de la mortalidad. En los reportes de Broner, de valores de electrolitos en pacientes pediátricos, al ingreso en una unidad de cuidado intensivo (1), la alteración electrolítica más frecuente fue alteración en la concentración de magnesio sérico (43.4 por ciento) de los pacientes, estando 25.6 por ciento de éstos por debajo y 17.8 por ciento por encima de los valores considerados como normales (0.74 - 0.95 mmol/dl) y encontrándose además una rata significativamente diferente de mortalidad (38 por ciento) en los pacientes hipermagnesémicos. Se encontró además 16.5 por ciento de alteración en los valores de calcio ionizado y una correlación estadísticamente significativa entre la presencia de hipocalcemia ionizada y mayor mortalidad. Los valores de calcio total no se correlacionaron con los valores de calcio iónico. Otro estudio realizado por Cárdenas-Rivero y cols (2), reporta una incidencia de hipocalcemia ionizada de 18 por ciento entre pacientes pediátricos que ingresan a una UCIP, correlacionando además la presencia de hipocalcemia ionizada con una mayor severidad de la enfermedad y una mayor mortalidad. El reporte de Reinhart y Desbiens (3) muestra una incidencia de 20 por ciento de hipomagnesemia y de 9 por ciento de hipermagnesemia en adultos que ingresan a una UCI médica. Se ha reportado una importante incidencia de hipofosfatemia en pacientes adultos que ingresan a unidades de cuidado intensivo por trauma como en el estudio de Daily (4), que sugiere la administración rutinaria de infusión de fosfato a estos pacientes para evitar la presencia de hipofosfatemia. Se conoce además la importancia de la fosfatemia como causante de muchas de las manifestaciones que presentan pacientes desnutridos a los que se les administra una dieta hipercalórica. Todos los anteriores datos nos llevan a revisar la fisiopatología de estas alteraciones, para poder detectar y tratar oportunamente sus manifestaciones.