Mediators of the Impact of Hourly Net Ultrafiltration Rate on Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy.

OBJECTIVES: During continuous renal replacement therapy, a high net ultrafiltration rate has been associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. In this study, we investigated whether the relationship between early (first 48 hr) net ultrafiltration and mortality is mediated by fluid balance, hemodynamic instability, or low potassium or phosphate blood levels using mediation analysis and the primary outcome was hospital mortality. DESIGN: Retrospective, observational study. SETTING: Mixed medical and surgical ICUs at Austin hospital, Melbourne, Australia. PATIENTS: Critically ill patients treated with continuous renal replacement therapy within 14 days of ICU admission who survived greater than 48 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We studied 347 patients (median [interquartile range] age: 64 yr [53-71 yr] and Acute Physiology and Chronic Health Evaluation III score: 73 (54-90)]. After adjustment for confounders, compared with a net ultrafiltration less than 1.01 mL/kg/hr, a net ultrafiltration rate greater than 1.75 mL/kg/hr was associated with significantly greater mortality (adjusted odds ratio, 1.15; 95% CI, 1.03-1.29; p = 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation pathway for this effect by blood pressure, vasopressor therapy, or potassium levels, but identified a possible mediation effect for fluid balance (average causal mediation effect, 0.95; 95% CI, 0.89-1.00; p = 0.060) and percentage of phosphate measurements with hypophosphatemia (average causal mediation effect, 0.96; 95% CI, 0.92-1.00; p = 0.055). However, on multiple mediator analyses, these two variables showed no significant effect. In contrast, a high net ultrafiltration rate had an average direct effect of 1.24 (95% CI, 1.11-1.40; p < 0.001). CONCLUSIONS: An early net ultrafiltration greater than 1.75 mL/kg/hr was independently associated with increased hospital mortality. Its putative effect on mortality was direct and not mediated by a causal pathway that included fluid balance, low blood pressure, vasopressor use, hypokalemia, or hypophosphatemia.

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

BACKGROUND: Female Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before. CASE PRESENTATION: Here we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed that the patient had LMWP, hypercalciuria, hypophosphatemia, delayed bone age, and genital dysplasia. CONCLUSION: The combination of i(X)(q10) and CLCN5 mutation causes the deletion of the wild-type CLCN5 allele that results in Dent-1 and TS. To the best of our knowledge, this is the first case that a female CLCN5 mutation hemizygote is diagnosed with Dent-1 and Turner syndrome due to isochromosome X. Also, our case has indicated that the prevalence of the situation may be largely underestimated because of the mild signs of females with Dent-1.

Relative hypophosphatemia early after transplantation is a predictor of good kidney graft function.

BACKGROUND: Phosphate level is a potent independent risk factor for cardiovascular disease and mortality in patients with chronic kidney disease. The association between hypophosphatemia and kidney function in kidney transplant patients is uncertain. METHODS: In total, 90 kidney transplant recipients were divided into two groups: one group of patients with hypophosphatemia and the other group without hypophosphatemia. The recipients with hypophosphatemia were identified as having less than or equal to the lowest quartile of serum phosphate levels at 1-, 3-, and 12-month post-transplant. The cumulative kidney survival rates were calculated for each group using the Kaplan-Meier method, and the adjusted hazard ratio (HR) was calculated using the Cox regression model. RESULTS: The mean age of patients was 47 years and the median follow-up period was 58 months. During the follow-up period, the following results were demonstrated in 90 transplant patients: graft loss (n = 6), mortality (n = 3). According to the Kaplan-Meier analysis results, the patients with hypophosphatemia demonstrated a significantly lower risk of 30% decline in eGFR compared to those without hypophosphatemia at 1- and 3-month post-transplant, but not at 12-month post-transplant. After adjusting for confounding factors, hypophosphatemia at 1- and 3-month post-transplant was an independent predictor of good kidney survival (HR 0.31, 95% CI 0.10-0.82 and HR 0.31, 95% CI 0.07-0.92, respectively). CONCLUSIONS: Our findings suggest that hypophosphatemia during the first 3 months after kidney transplantation was associated with better kidney survival.

Are We Aware that Hyperphosphatemia Affects Mortality and Morbidity as much as Hypophosphatemia in Pediatric Intensive Care Patients?

OBJECTIVE: Hypophosphatemia was previously shown to affect the duration of admission, mechanical ventilator requirements, mortality and morbidity during pediatric intensive care. Different from previous studies, our study was planned with the aim of showing whether hyperphosphatemia affects morbidity and mortality in pediatric intensive care patients as much as hypophosphatemia. METHOD: Patients' ages, genders, reason for admission, underlying diseases, phosphorus levels examined on admission and on the 1-4th and 5-10th-days, duration on mechanical ventilation, duration of admission, final status and PRISM and PELOD scores calculated in the first 24 hours of admission were recorded. RESULTS: Mortality was distinctly higher for those who were hypophosphatemic and hyperphosphatemic compared to those who were normophosphatemic. The highest mortality was identified in those who were hyperphosphatemic on the 5-10th-days. PELOD scores were only significantly different according to admission phosphorus levels (p:0.04). CONCLUSION: In our study, we identified that hyperphosphatemia is a serious problem as hypophosphatemia for patients who admitted to the PICU. Patients identified to be hyperphosphatemic on admission had a significantly higher PELOD score. The significant difference of hyperphosphatemia in terms of PELOD score is one of the important points shown in our study. It should not be forgotten that like hypophosphatemia, hyperphosphatemia may cause serious problems in pediatric intensive care patients.

FGF23 and Associated Disorders of Phosphate Wasting.

Fibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option.

[Diagnosis and treatment of hypophosphatemia]. / Que faire de l'hypophosphatémie†?

Phosphate is widely spread in the human body, filling many roles across various tissues, both in the intra- and extracellular space. Serum phosphorus makes up only a slight fraction of the total body stocks but acts as an exchange between the different compartments. Hypophosphatemia is commonly found among hospitalized patients, especially those in an intensive care unit. Clinical manifestations associated with hypophosphatemia are mainly respiratory, neuromuscular, cardiac and hematologic, all of which are more common in the presence of severe hypophosphatemia. Interventional evidence on the benefit of correcting hypophosphatemia is lacking. Currently available recommendations vary and are based on weak evidence.

Le phosphate a un rôle physiologique essentiel dans l'organisme humain, il est ubiquitaire, tant en intracellulaire qu'en extracellulaire. La phosphatémie ne représente qu'une faible proportion du contenu corporel total de phosphate, mais joue un rôle important dans les échanges entre les différents compartiments de l'organisme. L'hypophosphatémie est fréquente chez les patients hospitalisés, en particulier aux soins intensifs. Des manifestations respiratoires, cardiologiques, neuromusculaires et hématologiques peuvent y être associées, pouvant même être à l'origine d'une surmortalité si elle est sévère. A ce jour, il n'existe pas d'évidence du bénéfice de corriger l'hypophosphatémie. Les recommandations pour la correction d'une hypophosphatémie varient et sont basées sur des évidences faibles.

Refeeding syndrome: relevance for the critically ill patient.

PURPOSE OF REVIEW: To provide an overview of recent findings concerning refeeding syndrome (RFS) among critically ill patients and recommendations for daily practice. RECENT FINDINGS: Recent literature shows that RFS is common among critically ill ventilated patients. Usual risk factors for non-ICU patients addressed on ICU admission do not identify patients developing RFS. A marked drop of phosphate levels (>0.16 mmol/l) from normal levels within 72 h of commencement of feeding, selects patients that benefit from hypocaloric or restricted caloric intake for at least 48 h resulting in lower long-term mortality. SUMMARY: RFS is a potentially life-threatening condition induced by initiation of feeding after a period of starvation. Although a uniform definition is lacking, most definitions comprise a complex constellation of laboratory markers (i.e. hypophosphatemia, hypokalemia, hypomagnesemia) or clinical symptoms, including cardiac and pulmonary failure. Recent studies show that low caloric intake results in lower mortality rates in critically ill RFS patients compared with RFS patients on full nutritional support. Therefore, standard monitoring of RFS-markers (especially serum phosphate) and caloric restriction when RFS is diagnosed should be considered. Furthermore, standard therapy with thiamin and electrolyte supplementation is essential.

Iron-induced hypophosphatemia: an emerging complication.

PURPOSE OF REVIEW: Iron-induced hypophosphatemia is a well documented side-effect but associated complications are largely neglected, because the results from single dosing studies suggest that transient decreases in plasma phosphate concentrations are asymptomatic and fully reversible. However, an increasing number of case reports and case series suggest that some patients develop severe and symptomatic hypophosphatemia. Long-term complications from hypophosphatemia include osteomalacia and bone fractures, which can result from repeated intravenous administration of certain high-dose iron preparations. RECENT FINDINGS: Results from clinical trials suggest that the highest risk for the development of hypophosphatemia is associated with ferric carboxymaltose, iron polymaltose, and saccharated iron oxide. Clinical studies show that renal phosphate wasting mediated by increased fibroblast growth factor 23 causes hypophosphatemia after iron therapy. Impaired renal function therefore protects from hypophosphatemia, whereas the highest incidences and most severe manifestations have been reported in patients in whom the underlying cause of iron deficiency cannot be corrected. SUMMARY: Diagnosis of iron-induced hypophosphatemia requires clinical suspicion. Treatment is guided by the severity of hypophosphatemia, and most patients will require oral or intravenous phosphate substitution. Future treatment options could involve therapeutic anti-FGF23 antibody (KRN23). Prevention and correction of vitamin D deficiency represents a supportive treatment option.

Hyperparathyroidism and increased fractional excretion of phosphate predict allograft loss in long-term kidney transplant recipients.

BACKGROUND: After kidney transplantation, fibroblast growth factor-23 (FGF-23) normally returns to baseline within 1 year whereas hyperparathyroidism persists in most kidney transplant (KT) recipients. As a result, serum phosphate remains relatively low in association with increased serum calcium and urinary phosphate excretion when compared to chronic kidney disease patients. The relationship between mineral metabolism and outcomes in long-term KT recipients has not been extensively studied. This study investigated whether the alteration in mineral metabolism influenced graft survival in long-term KT recipients. METHODS: This study included 273 KT recipients after 1 year of transplantation. Mineral parameters were obtained at the time of enrolment and patients were followed prospectively for an average of 71 months. RESULTS: Graft loss (death-censored) occurred in 41 (15%) patients. In univariate analysis, deceased donor transplantation, decreased serum albumin and estimated glomerular filtration rate, increased serum phosphate, parathyroid hormone (PTH), FGF-23 and fractional excretion of phosphate (FePi) predicted future allograft loss. After adjustments for cardiovascular disease risk factors, donor type, dialysis vintage, serum albumin and allograft function, only increased PTH and FePi remained associated with the outcome. Relationships between increased serum phosphate and FGF-23 with graft survival were lost after adjustments. Adjusted survival curves revealed the association between PTH > 90 pg/mL and FePi > 20% with worse graft survival. CONCLUSIONS: Hyperparathyroidism and increased FePi predicted allograft loss in long-term KT recipients.

The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

[Refeeding syndrome during alcohol detoxification]. / Refeedingsyndroom bij alcoholdetoxificatie.

Refeeding syndrome (RS) can occur when malnourished patients are reintroduced to carbohydrates. The symptoms are caused by a combination of electrolyte shifts and fluid retention. Symptoms are wide-ranging; some patients may suffer from harmless muscle cramps, others from more severe neurological and cardiological symptoms that can even lead to death. Although alcohol dependence is a risk factor for the development of RS, little attention is being given to this problem in addiction treatment. In this article we report a case of RS that occurred during alcohol detoxification. We also present the results of a pilot study on the incidence of RS during the alcohol detoxification of 12 patients.

Using phosphate supplementation to reverse hypophosphatemia and phosphate depletion in neurological disease and disturbance.

Hypophosphatemia (HP) with or without intracellular depletion of inorganic phosphate (Pi) and adenosine triphosphate has been associated with central and peripheral nervous system complications and can be observed in various diseases and conditions related to respiratory alkalosis, alcoholism (alcohol withdrawal), diabetic ketoacidosis, malnutrition, obesity, and parenteral and enteral nutrition. In addition, HP may explain serious muscular, neurological, and haematological disorders and may cause peripheral neuropathy with paresthesias and metabolic encephalopathy, resulting in confusion and seizures. The neuropathy may be improved quickly after proper phosphate replacement. Phosphate depletion has been corrected using potassium-phosphate infusion, a treatment that can restore consciousness. In severe ataxia and tetra paresis, complete recovery can occur after adequate replacement of phosphate. Patients with multiple risk factors, often with a chronic disease and severe HP that contribute to phosphate depletion, are at risk for neurologic alterations. To predict both risk and optimal phosphate replenishment requires assessing the nutritional status and risk for re-feeding hypophosphatemia. The strategy for correcting HP depends on the severity of the underlying disease and the goal for re-establishing a phosphate balance to limit the consequences of phosphate depletion.

[Refeeding syndrome]. / Realimentacní syndrom.

Despite being known more than 60 years, refeeding syndrome (RS) still bears many uncertainties. For example, its definition is not clear and definite, and the attitude to it varies from the complete neglect to over-prevention.The term "refeeding syndrome" refers to electrolyte and metabolic changes occurring in malnourished patients after the readministration of nutrition. These changes concern especially to phosphates and ions. Potassium, magnesium, naturism and fluids balance are involved. The changes lead to cell energetic metabolism and electric potential disturbances, with related clinical symptoms.Fully developed refeeding syndrome is quite rare; nevertheless it can be fatal for the patient. However, even its development can lead to many complications increasing the patient's morbidity and the length of stay in the hospital. Yet the refeeding syndrome is more or less predictable and if kept in mind also preventable.The aim of this article is to get the reader to know more about this metabolic phenomenon and possible attitudes towards it.

[Pathogenesis of hypophosphatemia].

Chronic hypophosphatemia is seriously involved in several disorders of musculoskeletal system. Symptoms of patients are usually non-specific, such as pain with or without muscle weakness on lower extremities and are often hard to be correctly diagnosed. It is clinically important for physicians to understand pathogenesis and clinical features of hypophosphatemia and its related diseases.

Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature.

AIM: Central and extrapontine myelinolysis are collectively known as osmotic demyelination syndrome. This encephalopathic illness has been well documented in the adult literature, occurring most commonly in the context of chronic alcoholism, correction of hyponatraemia and liver transplantation. Aetiology and outcome in the paediatric population are less well understood. METHODS: Two cases of osmotic demyelination syndrome occurring in children with transient severe hypophosphataemia during the course of their illness are presented. Both had very different neurological outcomes, but the changes of central and extrapontine myelinolysis were apparent on neuroimaging. Sixty-one cases in the paediatric literature were then reviewed. RESULTS: We summarize aetiology and outcome in paediatric cases of osmotic demyelination syndrome and postulate a role for hypophosphataemia as a contributing factor in the development of these sometimes devastating conditions. CONCLUSION: Hypophosphataemia may contribute to the risk of developing osmotic demyelination syndrome in at-risk paediatric patients and further study of this association should be undertaken.

Approach to treatment of hypophosphatemia.

Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole.

Refeeding syndrome in children in developing countries who have celiac disease.

OBJECTIVES: The clinical presentations of celiac crisis and refeeding syndrome in celiac disease are almost similar, but information about refeeding syndrome is scarce. We are reporting for the first time 5 cases of refeeding syndrome in children with celiac disease that could have otherwise been labeled as celiac crisis. METHODS: From January to December 2010, a chart review of hospital records of all celiac disease cases was performed, and refeeding syndrome was ascribed in those celiac patients who deteriorated clinically after initiation of a gluten-free diet and had biochemical parameters suggestive of refeeding syndrome such as hypophosphatemia, hypokalemia, hypocalcemia, and hypoalbuminemia. RESULTS: Of the total 35 celiac disease patients, 5 (median age 6.5 [range 2.2-10] years, 3 boys) were identified as having refeeding syndrome. All 5 children were severely malnourished (body mass index <14 kg/m) and all of them had anemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and hypocalcemia, meaning that they had the perfect setting for developing refeeding syndrome. At the same time, their clinical features fulfilled the criteria for celiac crisis except that their symptoms have worsened after the introduction of a gluten-free diet. Nevertheless, instead of using steroids, they were managed as refeeding syndrome in terms of correction of electrolytes and gradual feeding, and that led to a successful outcome in all of them. CONCLUSIONS: Severely malnourished patients with celiac disease are at risk of developing potentially life-threatening refeeding syndrome, which may mimic celiac crisis, especially in developing countries. Early recognition and appropriate treatment are the keys to a successful outcome.

Severe anorexia nervosa: outcomes from a medical stabilization unit.

OBJECTIVE: We report data from the medical stabilization and refeeding of patients with severe anorexia nervosa admitted over a 15-month period. METHOD: Through chart review and computerized data collection, we evaluated demographic and clinical data from 25 consecutive patients admitted to our medical stabilization unit from October 2008 to January 2010. RESULTS: In this adult-patient population with a median body mass index (BMI) of 13.1 kg/m(2) (interquartile range, 11.0-14.4), 44% developed hypoglycemia, 76% had abnormal liver function, 83% had abnormal bone density, 45% developed refeeding hypophosphatemia, and 92% were hypothermic. Severe liver function abnormality predicted the development of hypoglycemia (p = 0.02, OR 9.78, CI: 1.55-61.65). No clinical features predicted hypophosphatemia, including admission BMI (p = 0.19), serum glucose level (p = 0.21), elevated liver function tests (p = 0.39 for AST), or initial amount of kilocalories consumed (p = 0.06). DISCUSSION: Patients with the most severe cases of anorexia nervosa have a high prevalence of serious medical complications during initial refeeding.

Changes in serum phosphate during treatment of diabetic ketoacidosis: predictive significance of severity of acidosis on presentation.

Changes in serum phosphate during diabetic ketoacidosis (DKA) treatment are not well characterised, although it is known that serum phosphate falls with treatment. We sought to define the nature of these changes and whether the severity of acidosis on admission influenced the severity of subsequent hypophosphataemia. We retrospectively reviewed data on all patients with confirmed DKA presenting to our unit between 2007 and 2010 inclusive. Forty-three patients with 64 episodes of DKA were evaluated. At presentation, 62.5% of patient episodes were hyperphosphataemic. Initial serum phosphate in all patient episodes correlated significantly with the initial serum creatinine (r = 0.694, P < 0.01) and the initial blood glucose (r = 0.593, P < 0.01). Serum phosphate fell during the course of treatment in all episodes (mean absolute fall 1.28 ± 0.77 (SEM) mmol/L). The mean nadir phosphate was 0.58 ± 0.19 mmol/L. Ninety per cent of nadir phosphate levels were hypophosphataemic (<0.8 mmol/L), and 11% were severely hypophosphataemic (<0.32 mmol/L). Mean initial bicarbonate differed significantly between those with nadir phosphates <0.5 mmol/L (9.26 ± 4.55) and those with nadir phosphates >0.5 mmol/L (13.0 ± 4.59, P = 0.0031). Similar significant bicarbonate differences were noted between those with nadir phosphates less than and more than 0.32 mmol/L respectively (7.42 ± 2.44 and 12.2 ± 4.87, P < 0.01). The initial hyperphosphataemia is reflective of intravascular volume depletion and pre-renal renal impairment. The severity of subsequent hypophosphataemia can be predicted by the degree of metabolic acidosis on presentation. As profound hypophosphataemia can be associated with serious complications, clinicians should recognise the likelihood of this biochemical derangement in those DKA patients presenting with profound acidosis.

Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO.

FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P(i)). When TgHMW mice were fed a high P(i) diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na(+)/P(i) co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P(i) wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P(i) homeostatic axis.