Understudied Hyperphosphatemia (Chronic Kidney Disease) Treatment Targets and New Biological Approaches.

Hyperphosphatemia is a secondary disorder of chronic kidney disease that causes vascular calcifications and bone-mineral disorders. As per the US Centers for Disease Control and Prevention, renal damage requires first-priority medical attention for patients with COVID-19; according to a Johns Hopkins Medicine report, SARS-CoV-2 can cause renal damage. Therefore, addressing the research inputs required to manage hyperphosphatemia is currently in great demand. This review highlights research inputs, such as defects in the diagnosis of hyperphosphatemia, flaws in understanding the mechanisms associated with understudied tertiary toxicities, less cited adverse effects of phosphate binders that question their use in the market, socioeconomic challenges of renal treatment and public awareness regarding the management of a phosphate-controlled diet, novel biological approaches (synbiotics) to prevent hyperphosphatemia as safer strategies with potential additional health benefits, and future functional food formulations to enhance the quality of life. We have not only introduced our contributions to emphasise the hidden aspects and research gaps in comprehending hyperphosphatemia but also suggested new research areas to strengthen approaches to prevent hyperphosphatemia in the near future.

Esophageal Mucosal Calcinosis: A Rare Site of Calcium Deposition in End-Stage Renal Disease

Introduction: Calciphylaxis, otherwise known as calcium uremic arteriolopathy, is defined as calcium deposition around blood vessels in skin and fat tissue which occurs in 1-4% of patients with end-stage renal disease (ESRD). Calcium deposition in the esophagus is extremely rare;to date, there have been only 4 cases reported worldwide. We report the fifth case of esophageal mucosal calcinosis occurring in a young male with ESRD. Case Description/Methods: A 37-year-old Thai man with ESRD on peritoneal dialysis since 2005 presented with generalized weakness and odynophagia due to oral ulcers, resulting in poor PO intake. He denied drinking alcohol, illicit drug use, or smoking. On exam his abdomen was soft, non-distended, non-tender, without any guarding. Past medical history included hypertension and COVID-19 in January 2022. Laboratory tests revealed neutropenia and pancytopenia, hyperphosphatemia, and hypocalcemia. EGD revealed distal esophageal esophagitis and hemorrhagic erosive gastropathy. Biopsy showed ulcerative esophagitis with dystrophic calcification, consistent with esophageal mucosal calcinosis .No intestinal metaplasia was noted. Immunohistochemistry was negative for CMV, HSV1, and HSV2. The patient was treated with pantoprazole 40mg IV every 12 hours, Magic Mouthwash 5ml qid, and Carafate 10mg qid. He was transferred to a cancer center where he had a bone marrow biopsy formed which was negative. His symptoms resolved and the patient was discharged to home (Figure). Discussion(s): Esophageal mucosal calcinosis is extremely rare. It is due to a combination of factors involving acidosis and the phenotypic differentiation (and apoptosis) of vascular smooth muscle cells (VSMC) into chondrocytes or osteoblast-like cells. These changes, along with the passive accumulation of calcium and phosphate, induce calcification. Acidosis is well-known to promote inflammation of the arterial walls, releasing cytokines that induce vascular calcification. The benefits of treatment with sodium thiosulfate remain unclear. An ample collection of cases should help devise standardized treatment options and establish management guidelines for this condition.

Is there any link between Hyperphosphatemia, Hypoalbuminemia, and Hypocalcemia with Hospital Outcomes in COVID-19 Patients?

Background: Disturbed biochemical factors have been observed in viral infections including SARS, Ebola virus, and now COVID-19. This study aimed to evaluate the association between Calcium axis' derangements and hospital duration, ICU admission, mechanical ventilation, and death in patients with COVID-19. Methods: 428 hospitalized patients with COVID-19 were included in this study. On the first day of admission, the patients were extensively evaluated for biochemical and hormonal factors and followed up until discharge/death. The association between hyperphosphatemia, hypoalbuminemia, and hypocalcemia and major outcomes, including hospital duration, ICU admission, mechanical ventilation, and death, was investigated by logistic regression analysis. Results: Hyperphosphatemia and hypoalbuminemia were present in 27 (6.3%) and 59 (13.8%) cases, respectively in the study population. The results of the present study reveal the relation of these factors with worse outcomes in COVID-19 patients; such as hospital duration, ICU admission, mechanical ventilation, and death. On the other hand, high frequency of hypocalcemia (59.1%, 253 subject) has no significant influence on the mentioned outcomes (All P values were greater than 0.05). Conclusions: Poor outcomes were associated with hyperphosphatemia and hypoalbuminemia. It seems that we should evaluate the patients for derangements of phosphate, albumin, and calcium and try to treat them for all COVID-19 patients.

Refractoriness of Hyperkalemia and Hyperphosphatemia in Dialysis-Dependent AKI Associated with COVID-19.

Background: Persistent hyperkalemia (hyperK) and hyperphosphatemia (hyperP) despite renal replacement therapy (RRT) was anecdotally reported in COVID-19 and acute kidney injury (AKI) requiring RRT (CoV-AKI-RRT). However, observation bias could have accounted for the reports. Thus, we systematically examined the rate and severity of hyperK and hyperP in patients with CoV-AKI-RRT in comparison with the pre-COVID-19 era. Methods: We identified patients with CoV-AKI-RRT treated with sustained low-efficiency dialysis (SLED) for ≥2 days in March-April 2020. As pre-COVID-19 control, we included patients with AKI treated with SLED in December 2019. We examined the rates of hyperK (serum potassium [sK] ≥5.5 mEq/L), severe hyperK (sK ≥6.5 mEq/L), hyperP (serum phosphate [sP] ≥4.5 mg/dl), and moderate or severe hyperP (sP ≥7-10 and >10 mg/dl, respectively) as %SLED-days with an event. Results: Along the duration of SLED, the incidence of hyperK was greater in CoV-AKI-RRT (n=64; mean 19%±2% versus 14%±3% SLED-days, P=0.002) compared with control (n=60). The proportion of patients with one or more event of severe hyperK was greater in CoV-AKI (33% versus 7%, P<0.001). The incidence of hyperP was similar between groups (mean 56%±4% versus 53%±5% SLED-days, P=0.49). However, the proportion of patients with one or more event of moderate and severe hyperP was greater in CoV-AKI-RRT (86% versus 60%, P=0.001, and 50% versus 18%, P<0.001, respectively). Among those with CoV-AKI-RRT, sK and sP correlated with lactate dehydrogenase (LDH; r=0.31, P=0.04, and r=0.31, P=0.04, respectively), whereas hyperP also correlated with shorter SLED runs (hours/run; r=-0.27, P=0.05). Conclusions: Refractory hyperK and hyperP were more frequent in CoV-AKI-RRT compared with the pre-COVID-19 era. Because of the correlation of sK and sP with higher LDH and sP with shorter SLED runs, intracellular ion release from cell injury due to cytokine storm and RRT interruptions may account for the findings.

AS SEEN ON TV: A CAUTIONARY TALE OF VITAMIN D SUPPLEMENTATION FOR COVID-19 PREVENTION

CASE: An 80-year-old woman with untreated osteoporosis and suspected primary hyperparathyroidism presents to establish care. Review of systems and physical examination are normal. She has mild hypercalcemia (11.2), and normal albumin and phosphorous. Parathyroid hormone (PTH) is elevated (71). Bone density testing demonstrates osteoporosis at the hip and spine (Tscore -2.9 and -3.0). She reports self-medicating with 12,000 IU of vitamin D daily to prevent COVID-19 infection, which she learned about from a popular news source;she is unvaccinated for COVID-19. Her vitamin D 25-OH level is 172 (normal 30-100). The patient was instructed to stop vitamin D supplementation. Additional work up for hyperparathyroidism was initiated, including 24-hour urine collection for calcium, and she was referred for a parathyroidectomy. IMPACT/DISCUSSION: Adequate vitamin D supplementation has been postulated to reduce the risk and severity of the COVID-19 infection through its immunomodulatory effects that augment the immune cell response, decrease inflammation, and prevent RAAS system dysregulation, which is associated with more severe coronavirus infection. However, trials and metaanalyses have yielded inconclusive data, with most reporting no associations between adequate or high-dose vitamin D supplementation and COVID-19 morbidity and mortality. Nonetheless, popular news sources and social media have called for high-dose vitamin D supplementation, which can result in hypervitaminosis D through patient self-medication. Both hypervitaminosis D and primary hyperparathyroidism present with signs and symptoms of hypercalcemia, including nephrolithiasis, osteoporosis, bone pain, weakness, and neuropsychiatric changes. Hypervitaminosis D is caused by ingestion of too much exogenous vitamin D (normally more than 10,000 IU/day), dysregulation of the vitamin D pathway, or overproduction of vitamin D. Primary hyperparathyroidism is caused by parathyroid adenomas, hyperplasia, and carcinomas. Distinguishing between the two conditions involves a thorough history and physical, laboratory measurements, and occasionally imaging. Hypervitaminosis D patients have suppressed PTH levels, serum 25(OH)D > 150ng/mL, and hyperphosphatemia while primary hyperparathyroidism patients have normal/elevated PTH levels, low/normal 25(OH)D levels, and hypophosphatemia. Primary hyperparathyroidism is the most common cause of hypercalcemia, but this case highlights the importance of screening for and identifying other etiologies of hypercalcemia. This patient's vitamin D toxicity can be treated by stopping vitamin D supplementation. Her primary hyperparathyroidism meets criteria for a parathyroidectomy due to the presence of osteoporosis. CONCLUSION: 1. High dose vitamin D supplementation is ineffective as prophylaxis against the COVID-19 infection. 2. Hypercalcemia secondary to vitamin D toxicity is distinguished from primary hyperparathyroidism by PTH, 25(OH)D, and phosphorus levels.

Hypo- and Hyperphosphatemia at Admission as Independent Factors of Mortality of COVID-19 Patients: Findings from a Retrospective Cohort Study.

Background: Electrolyte imbalances are common in COVID-19 infection and are associated with poor outcomes in hospitalized patients. Objectives: This study examined whether serum phosphate imbalances at admission are associated with mortality in hospitalized COVID-19 patients. Methods: In this registry-based single-center retrospective cohort study, 1349 inpatients with COVID-19 were included from March 2020 to March 2021 in an academic hospital in Ilam (southwest Iran). The Cox proportional hazard (PH) regression model was applied to the data set of COVID-19. Results: The in-hospital median survival time for patients with low, normal, and high serum phosphate levels was 14, 25, and 8 days, respectively. In a multivariate model, adjusted for the other variables, patients with hypophosphatemia (adjusted hazard ratio [HR], 2.53; 95% CI, 1.15 - 5.58; P = 0.02) and hyperphosphatemia (adjusted HR, 1.77; 95% CI, 1.00 - 3.14; P = 0.05) had an increased mortality hazard compared with those who had normal levels of serum phosphate. Conclusions: Our results demonstrate associations of hypophosphatemia and hyperphosphatemia with increased in-hospital mortality in COVID-19 patients. Intensive medical care and more attention must be paid to COVID-19 patients with serum phosphate imbalances at admission.

ATYPICAL HAEMOLYTIC UREMIC SYNDROME ASSOCIATED WITH COVID-19: CASE REPORT

BACKGROUND AND AIMS: Renal manifestations are common in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report here the case of a patient with confirmed SARS-CoV-2 infection with the clinical picture of atypical haemolytic uremic syndrome (aHUS). METHOD: Case report RESULTS: Our case is a 31-year-old man with a nasopharyngeal swab with real-time reverse-transcriptase polymerase chain reaction (RT-PCR) for SARS-CoV-2 positive, who was hospitalized in the Clinic of Infectious Diseases. His medical history had a respiratory illness of 7-day evolution characterized by cough, fever, dyspnoea, muscle pain, nausea, vomiting and non-bloody diarrhoea, and decreased urine output with dark colour urine. The chest computed tomography (CT) scan showed few rounded ground-glass opacities. Laboratory tests at admission revealed the following: (i) acute kidney injury stage 3 with a serum creatinine of 3.85 mg/dL (basal value 0.9 mg/dL);serum urea 221 mg/dL. His urinary volume in the first 24 h of hospitalization was 800 mL. (ii) Severe haemolytic anaemia with haemoglobin (Hgb) level of 3.7 g/dL, and peripheral smear showing large number of schistocytes, haptoglobin <10 mg/dL and indirect bilirubin 9.7 mg/dL, direct coombs testing was negative;reticulocyte count 8.9%. (iii) Severe thrombocytopaenia with platelet count of 25 000/μL, prothrombin time 45%, international normalized ratio 1.7, D-dimer 1082 ng/dL and fibrinogen 880 mg/dL. Increased blood levels of enzymes and inflammatory markers were present: lactate dehydrogenase 1867 U/L and protein C reactive 9.1 mg/dL. Electrolyte disturbances characterized by hyperkalaemia, hyperphosphatemia, hypocalcaemia and severe metabolic acidosis. Dynamic changes of laboratory data are presented in Table 1. The usual liver panel tests, alkaline phosphatase, γ -glutamyl transferase and albuminemia were normal. Toxic hepatitis was excluded. Hepatobiliary and spleen imaging (ultrasonography) was normal. ELISA serologic tests for HIV, hepatitis B, hepatitis C virus and cytomegalovirus were negative. Serological and virological tests for hepatitis A, B, C, HIV and CMV were negative. Stool was negative for Shiga toxin-producing Escherichia coli (STEC). The results of antinuclear antibodies and anti-smooth-muscle antibodies were negative, C3 serum level was mildly depressed (82 mg/dL;normal range 88- 201 mg/dL) and C4 serum level was normal (20 mg/dL;normal range 10-44 mg/dL). ADAMTS13 activity was 90% on day 10. He was treated with broad spectrum antibiotics, intravenous dexamethasone and supportive therapy. One week from admission, renal function recovered, and 1 week after intravascular haemolysis and thrombocytopaenia recovered. The patient was hospitalized for 21 days. CONCLUSION: Close monitoring and early intervention can help for a better outcome of SARS-CoV-2 patients complicated with aHUS.

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Evaluation of Pattern and Impact of Electrolytes Abnormalities in Critically Ill Covid-19 Patients

OBJECTIVE: To evaluate the pattern of serum electrolytes abnormalities and their impact on ICU admitted Covid-19 patient outcomes. METHODOLOGY: This retrospective study was carried out at OMI hospital and Dr. Ziauddin Hospital, Karachi, Pakistan, between August to December 2020. Total 102 PCR positive, ICU admitted with severe Covid-19 patients as per WHO criteria were included. The patient's demographic characteristics, clinical features including co-morbidities, electrolytes reports at the time of admission, length of ICU and/or hospital stay, and outcome (expired/survived) were evaluated. RESULTS: Biochemical testing found abnormal electrolyte levels in 90.2% ICU admitted Covid-19 patients. Electrolytes abnormalities including hyponatremia 45.1%, hypermagnesemia 40.2%, hypocalcemia 31.4%, hyperchloremia23.5% and hyperphosphatemia in 20.6% patients. Out of the total, 28.4% of patients needed invasive respiratory support, and 37.3% could not survive. A higher incidence of mortality (39.1% vs. 20%) was seen in patients with electrolytes abnormalities compared to those presented with normal values. CONCLUSION: Electrolyte abnormalities were found in 90% of the ICU Admitted Covid-19 patients. The most common abnormalities found among the patients were hyponatremia, hypermagnesemia, and Hypocalcemia. The findings revealed that several electrolyte imbalances harm patients' in-hospital outcomes. Electrolyte assessment of Covid-19 patients at the time of admission would be helpful in risk stratification for adverse outcomes.

POS-531 MONOCLONAL GAMMOPATHY PRESENTING AS ACUTE PSEUDOHYPERPHOSPHATEMIA IN A MAINTENANCE HEMODIALYSIS PATIENT: A RARE PRESENTATION

Introduction: Phosphorus is an essential component of many macromolecules found in bone, lipid membranes, and DNA. It circulates in serum as phosphate. Phosphate level is mainly determined by kidney function. Other factors such as 1, 25 vitamin D3, thyroid hormone and low phosphorous intake can increase renal absorption of phosphate. Hyperphosphatemia presents when serum phosphate is above 4.5 mg/dl (1.45 mmol/L). The phosphate target for hemodialysis (HD) patients is 5.5 mg/dl (1.77 mmol/L) or less. Serum phosphate is commonly measured through the colorimetric method and can also be measured isotopically. Depending on the method used to measure the serum phosphate, many factors have been reported to produce falsely elevated levels. Methods: 52-year-old female with past medical history of end stage renal disease on HD, heart failure with severely reduced ejection fraction secondary to ischemic cardiomyopathy status post left ventricular assist device (LVAD), type 2 diabetes, hypertension, upper gastrointestinal bleeding, anemia, was admitted at a rehabilitation center after a hospital stay due to COVID-19 infection and E. faecium bacteremia secondary to a drive-line infection of the LVAD which was treated with daptomycin. On admission, the patient was found to have a phosphorus level of 6.3 mg/dl, PTH 265 pg/mL, corrected calcium 10 mg/dl, and hemoglobin 9.1 g/dL. Results: Patient was started on oral Sevelamer tablets 800 mg every 8 hours and underwent regular full HD sessions. However, the hyperphosphatemia persisted. Sevelamer was increased to 1600 mg every 8 hours, and she was maintained on a strict low phosphorous renal diet. Four days later while on the new regimen, the phosphorous increased to 12.2 mg/dl. She remained asymptomatic. Hemolysis and hyperbilirubinemia were excluded. A serum protein electrophoresis revealed a monoclonal spike in the gamma region with gamma % of 38.5 (normal range 11-20), gamma globulin 3.0 g/dL (normal range 0.6 – 1.6 g/dL), and quantification of the abnormal protein of 0.41 g/dL (5.3% total). Serum immunofixation showed a probable IgG Lambda monoclonal band. A serum free light chain assay demonstrated a Kappa light chain free serum of 548.9 mg/L (normal range 3.3 – 19.4 mg/L) and Lambda light chain free serum 549.7 mg/L (normal range 5.7 – 26.3 mg/L). Patient was diagnosed with a monoclonal gammopathy, and the elevated phosphorus deemed to be pseudohyperphosphatemia secondary to paraproteinemia. Conclusions: Colorimetric assay with phosphomolybdate ultraviolet (UV) is commonly used for measurement of serum phosphate. The ammonium molybdate reacts with the phosphate to form a cloudy complex, UV absorbance is measured at a specific wavelength. Several factors have been reported to cause falsely high phosphate such as hyperlipidemia, hyperbilirubinemia, hemolysis, liposomal amphotericin B, recombinant tissue plasminogen activator, heparin sulfate, and gammopathies. The paraproteinemia present in monoclonal gammopathies creates a cloudier sample which increases the absorbance of UV light leading to spurious elevation of serum phosphate. Although hyperphosphatemia is a common finding in dialysis patients, the presence of persisting or worsening hyperphosphatemia in a compliant patient taking phosphorous binders and adhering to a low phosphorus diet should raise concern for pseudohyperphosphatemia. No conflict of interest

A Novel Case of Hypoparathyroidism Secondary to SARS-CoV-2 Infection.

Hypoparathyroidism is usually caused by postsurgical or autoimmune damage to the parathyroid gland. We present the case of a 46-year-old Hispanic male with no significant past medical history who was admitted to the hospital with hypoxic respiratory failure due to coronavirus disease 2019 (COVID-19) infection and had a prolonged hospital course. He was incidentally found to have hyperphosphatemia and low parathyroid hormone (PTH) levels. During the second month of hospitalization, his phosphorus levels rose to 6.9 mg/dL (normal range: 2.4-4.7 mg/dl). His PTH levels were found to be at 8 pg/mL. Vitamin D levels obtained were also low (7 ng/dL), phosphorus was at 5.8 mg/dL with albumin of 2.9 g/dL, and calcium level was normal at 9.2 mg/dl. Parathyroid hormone-related peptide (PTHrP) level was low at 10. Malignancy and genetic causes were ruled out. The patient was started on 50,000 units of ergocalciferol once a week. He was also started on calcium acetate 1,334 mg three times a day for hyperphosphatemia. Phosphorus levels remained elevated, and sevelamer was added on discharge after he was weaned off oxygen and cleared by physical therapy. No explanation for persistent hyperphosphatemia and hypoparathyroidism was found. To date, there have been some reports linking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to widespread tissue injury; however, there have been no reports so far on the effect of the parathyroid gland. Further studies are necessary to elaborate and to confirm the causative relationship between SARS-CoV-2 and hyperphosphatemia.