Normal Renal Function Research Articles

Clinical characteristics and outcomes of patients presenting with acute coronary syndromes and suspected plaque erosion

Abstract Background Plaque erosion (PE) is the second most common pathology of acute coronary events after plaque rupture. PE is characterized by endothelial denudation and formation of neutrophil extracellular traps. Patients with PE may have a different prognosis as compared to those with plaque rupture. Specific clinical and laboratory predictors were validated to suspect PE among acute coronary syndrome (ACS) patients. Purpose The objectives of this study were to compare both clinical and laboratory findings, and outcomes of ACS patients with high probability of PE and those with less likely PE. Methods Six hundred ninety-six ACS patients were divided into two groups (suspected PE vs less likely PE) based on 5 reported predictors of PE. The predictors were: age <68, anterior ischemia, no diabetes mellitus, hemoglobin >15 g/dL and normal renal function (eGFR> 60 ml/min) as assessed at hospital admission. Patients with 4 or 5 of these 5 predictors were included in the suspected PE group, while patients with 0 or 1 entered less likely PE group. Baseline clinical features and laboratory analyses at hospital admission were compared between the two groups. Major adverse cardiac events (MACE), defined as death from any cause, non-fatal myocardial infarction or unplanned revascularization, were compared between the two groups at 20 months after hospital discharge. Results Among 696 patients, 283 (41%) composed the suspected PE group, while 413 (59%) entered into less likely PE group. The suspected PE group had a higher prevalence of current smokers and had a higher BMI. They showed higher values of both LDL cholesterol and triglycerides, while C-reactive protein and fibrinogen levels were significantly lower. The suspected PE group showed a higher frequency of single vessel disease (Table). The suspected PE group showed a significantly lower rate of MACEs at 20 months (7.4% vs 28.8%, p=0.0001) as well as death from any cause was significantly lower (2.1% vs 24.9%, p=0.0001). The median time from the index ACS episode to recurrent myocardial infarction or unplanned coronary revascularization tended to be longer in the suspected PE group as compared to the less likely PE group (15 months [9-20] vs 9 months [6-13], p=0.062) (Figure). Conclusions In a cohort of ACS population, the suspected PE group showed distinctive clinical characteristics with less coronary plaque burden and low grade of systemic inflammation. The suspected PE group had a better prognosis at 20-month follow-up time with a significantly lower rate of death from any cause, and non-fatal coronary events tended to occur later.Table.Baseline characteristicsFigure.Non fatal coronary events

Clinical Profile And Aetiology of Acute Kidney Injury Developing In Patients Hospitalized Due To Non-Renal Cause With Pre-Existing Normal Renal Function

Background: Acute kidney injury (AKI) is a common complication in patients hospitalized for non-kidney disease and having normal renal function. Early detection of development of deteriorating renal function and assessment of its cause can help to manage the cases effectively and can prevent further kidney damage or progression to end stage renal failure. Methods: This observational study was done on 50 patients selected from the departments of Medicine and Nephrology of Dhaka Medical College (DMCH) and BSMMU, from June 2012 to November 2012. Patients were included in the study who developed clinical features and biochemical findings of acute kidney injury, while being admitted with various non-renal diseases and had previous normal renal function. Results: In this study the cause of deterioration of renal function was Sepsis in 44.0% of the patients, 42.0% had fluid loss, 6.0% had used nephrotoxic drugs, 4.0% had hepatitis, 2.0% patients each had pancreatitis and insect bite respectively. 40% of the patients were above 40 years of age, 54% were male. Vomiting was present in 42% of the patients and diarrhoea in 20% of the patients. 26% patients had DM and 22% had hypertension. Conclusion: Sepsis and hypovolemia were the common causes of developing acute kidney injury in the hospital. In-hospital mortality was 18.0% and 22.0% patients developed CKD after three months follow-up. J Dhaka Med Coll. 2023; 32(1) : 85-91

Obesity, kidney and metabolic bariatric surgery: a surgeon’s narrative review

Excess body weight impacts kidney function in individuals with severe obesity, primarily through metabolic alterations in adipocytes, especially in visceral adipose tissue. The relationship between persistent sterile inflammation associated with obesity and the progression of obesity-related kidney disease to chronic kidney disease (CKD) is an area of growing interest. The beneficial effects of weight loss on the prevention of kidney disease and the improvement of kidney function in individuals with obesity have been well documented. Currently, the most effective weight loss strategy is metabolic bariatric surgery (MBS), which has been proven to not only prevent the progression of CKD but also reverse it. However, awareness and understanding of the impact of obesity on the kidney should also extend to the severely obese population with clinically normal renal function. The purpose of this review is to outline the current knowledge on the pathophysiology of obesity-induced kidney damage, the effects of MBS on renal function in severely obese individuals with or without CKD, and provide the current evidence on perioperative management strategies for CKD patients, including diet and nutrition.

Impaired Renal Function With Higher Remnant Cholesterol Related to Risk of Atherosclerotic Cardiovascular Disease: CGPS.

Chronic kidney disease confers a high risk of atherosclerotic cardiovascular disease (ASCVD), partly due to hyperlipidemia. Although statins reduce the risk of ASCVD in chronic kidney disease, residual risk persists. We investigated whether higher remnant cholesterol is associated with an increased risk of ASCVD in statin users and nonusers with impaired renal function. We included 107 925 individuals from CGPS (Copenhagen General Population Study) initiated in 2003 to 2015, of whom 10 427 had impaired renal function (estimated glomerular filtration rate, <60 mL/min per 1.73 m2). Remnant cholesterol was calculated from a standard lipid profile. ASCVD was myocardial infarction, coronary heart disease death, ischemic stroke, coronary artery bypass graft, or percutaneous coronary intervention extracted from Danish nationwide health registries from baseline through 2018; individuals with events before the start of follow-up were excluded from relevant analysis. In individuals with impaired renal function during up to 15 years of follow-up, 597 were diagnosed with myocardial infarction, 618 with ischemic stroke, and 1182 with ASCVD. In these individuals, a 1-mmol/L (39 mg/dL) higher remnant cholesterol level was associated with multivariable-adjusted hazard ratios of 1.21 (95% CI, 1.03-1.43) for myocardial infarction, 1.12 (95% CI, 0.93-1.34) for ischemic stroke, and 1.19 (95% CI, 1.05-1.35) for ASCVD. Corresponding hazard ratios for ASCVD were 1.36 (95% CI, 1.01-1.81) in statin users and 1.16 (95% CI, 1.01-1.33) in nonusers. Of the 1.36-fold excess risk of ASCVD in impaired versus normal renal function, elevated remnant cholesterol and elevated LDL (low-density lipoprotein) cholesterol explained 25% (95% CI, 2.5%-47%) and 0% in statin users and 8.3% (95% CI, 2.4%-14%) and 14% (95% CI, 6.4%-22%) in nonusers, respectively. Our results suggest that higher remnant cholesterol is a good marker of increased risk of ASCVD in individuals with impaired renal function, while higher LDL cholesterol may not be. Patients with chronic kidney disease who have high levels of remnant cholesterol are identifiable through higher non-HDL (high-density lipoprotein) cholesterol or apoB levels.

β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis

Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.

Plasma protein binding of arsenic species in acute promyelocytic leukemia patients and their relationships with hepatic and renal function

ABSTRACT Objectives Percentage protein binding (%PB) of arsenic species in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide remains unclear. It can be different depending on the status of hepatic or renal function. Methods This study obtained steady-state blood samples from normal APL patients and those with hepatic or renal impairment. %PB of inorganic arsenic (iAs), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) was determined by analyzing free and total plasma concentrations using ultrafiltration method by HPLC-HG-AFS. Results There is a linear relationship between free and total plasma concentrations for iAs (r2 = 0.952), MMAV (r2 = 0.603), and DMAV (r2 = 0.945). For patients with normal hepatic and renal function, mean %PB was as follows: iAs at 26.7 ± 14.3%, MMAV at 53.3 ± 11.9%, and DMAV at 24.7 ± 7.8%. %PB decreased in patients with renal impairment, with MMAV and DMAV showing statistically significant differences (p < 0.05 for MMAV, p < 0.01 for DMAV). No significant differences in %PB between normal and hepatic impairment group were observed. Conclusion Free arsenic species fraction can be estimated by total concentration. DMAV and iAs present low %PB, while MMAV exhibits a relatively high %PB in plasma. Level of %PB is more likely to be affected by renal function and age.

Pharmacokinetics of Vancomycin in Healthy Korean Volunteers and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients with Normal Renal Function.

Background/Objectives: To date, population pharmacokinetic (PK) studies of vancomycin on healthy Korean adults have not been conducted. This study aimed to investigate the PK properties of vancomycin in healthy volunteers and to identify optimal dosing regimens based on the area under the concentration-time curve (AUC) in adult patients with normal renal function. Methods: We conducted a prospective clinical study, analysing PK samples from 12 healthy participants using noncompartmental analysis and non-linear mixed-effects modelling. The population PK parameters derived were employed in Monte Carlo simulations to evaluate the adequacy of the current dosing regimen and to formulate dosing recommendations. Results: The PK profiles were optimally described by a two-compartment model, with body weight and age as significant covariates affecting total clearance. The simulations indicated that to achieve a therapeutic target-defined as an AUC at steady-state over 24 h of 400-600 mg·h/L-daily doses ranging from 60 to 70 mg/kg are necessary in adults with normal renal function. Conclusions: This study underscores the need to actively adjust dosage and administration based on a vancomycin PK model that adequately reflects the demographic characteristics of patients to meet both safety and efficacy standards.

Population Pharmacokinetic Simulations for Dose Optimization of Tenofovir Disoproxil Fumarate in HIV-Infected Patients with Moderate-to-Severe Renal Impairment.

Tenofovir disoproxil fumarate (TDF) requires dosage adjustments from the standard 300 mg once daily to every 48-96 h for moderate-to-severe renal impairment to avoid excessive exposure. However, this extended interval can lead to variable drug exposure and inconvenience. This study aimed to utilize the population pharmacokinetic (PPK) models to optimize TDF dosing regimens for HIV-infected patients with renal impairment. A systematic literature search was conducted across PubMed, Cochrane Library, and Scopus databases to identify relevant PPK studies of TDF in HIV-infected patients. From the included studies, the PPK models and associated parameters were extracted. Monte Carlo simulations (n = 2000) were performed to generate concentration-time profiles and derive PK parameters compared against reference ranges. For moderate renal impairment, the TDF 150 mg once-daily regimen achieved cumulative exposure comparable to the approved 300 mg every-other-day regimen. In severe renal impairment, TDF 75-100 mg administered once daily provided similar cumulative exposure as 300 mg every 72-96 h regimen while maintaining daily exposure comparable to the standard dose in patients with normal renal function. The approved extended dosing intervals of 72-96 h exhibited high drug exposure variability, initially resulting in supratherapeutic levels followed by suboptimal levels preceding the subsequent dose administration. In conclusion, administering smaller once-daily doses of TDF maintains consistent daily drug exposure comparable to the standard dose in patients with normal renal function while reducing variability in drug exposure, potentially mitigating the risk of nephrotoxicity. However, additional clinical studies are required to confirm these findings.

Impact of renal impairment on the pharmacokinetic profile of intravenous difelikefalin, a kappa opioid receptor agonist for the treatment of pruritus

BackgroundDifelikefalin is a selective kappa opioid receptor agonist that is approved for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis (HD). In this study, we assessed the pharmacokinetics (PK) of intravenous (IV) difelikefalin in healthy subjects, in non–dialysis-dependent (NDD) subjects with varying stages of kidney disease, and in subjects with end-stage renal disease (ESRD) undergoing HD.MethodsThe PK and safety of single IV doses of difelikefalin (3.0 mcg/kg) were initially evaluated in NDD subjects with mild, moderate, or severe renal impairment compared with matched healthy subjects. Based on those data, the PK and safety of 3 dose levels of IV difelikefalin (0.5, 1.0, or 2.5 mcg/kg) were compared with matched placebo in subjects undergoing HD with each dose administered following dialysis, 3 times over a 1-week treatment period).ResultsSingle IV dosing of difelikefalin in NDD subjects (N = 36) with mild renal impairment demonstrated comparable exposure to healthy subjects with normal renal function, while subjects with moderate or severe renal impairment had higher total exposure. NDD subjects with severe renal impairment had higher total exposure compared with those with moderate renal impairment (i.e., exposure in severe NDD > moderate NDD > mild NDD ≈ healthy subjects). Clearance of difelikefalin correspondingly decreased with increasing renal impairment. In the multiple-dose study in subjects with ESRD undergoing HD (N = 19), IV difelikefalin demonstrated dose proportionality and was shown to be mostly cleared by dialysis; steady state was achieved with the second dose on day 3. Safety findings for all subjects were consistent with the known profile of IV difelikefalin.ConclusionsIV difelikefalin was well tolerated. Similar exposure was observed in NDD subjects with mild renal impairment compared with healthy subjects with normal renal function, with reduced clearance and higher exposure in NDD subjects with moderate or severe renal impairment. Dose proportionality was demonstrated in subjects with ESRD undergoing HD administered IV difelikefalin 3 times per week following dialysis and was shown to be mostly cleared by dialysis.Trial registrationSingle-dose study: NA; multiple-dose study: ClinicalTrials.gov registration number NCT02229929, first registration 03/09/2014.

Severe Combined Kidney Injury in an Hiv-Infected Patient Receiving Antiretroviral Therapy (Clinical Observation)

Kidney injury in patients infected with the human immunodeficiency virus (HIV) has a diverse spectrum. Some antiretroviral therapy (ART) drugs have nephrotoxic effects. We present a clinical case of severe combined kidney injury — chronic kidney disease (CKD) and acute kidney disease (AKD) — in a patient with HIV infection. She was on long-term treatment with a fixed-dose combination of rilpivirine, tenofovir, and emtricitabine and had normal pre-treatment renal function (estimated glomerular filtration rate 69 mL/min/1.73m2 ). There was gradual increase in blood creatinine, but the patient did not visit a nephrologist and the ART was not changed. The patient was admitted to the nephrology department two years later because she had arterial hypertension and hyperazotemia (blood creatinine 718 μmol/l). Diagnosis: chronic tubulointerstitial nephritis, CKD G5 taking into account the gradual increase in blood creatinine during long-term ART. The patient was treated with peritoneal dialysis. There was persistent decrease and stabilization of blood creatinine (210-190 μmol/l was) which indicated in AKD. The presented observation demonstrates that ART in an HIVinfected patient can lead to the development of severe combined chronic and acute kidney injury. HIV-infected patients receiving ART require regular monitoring of renal function and follow-up by a nephrologist.

Continent urinary diversion and management of pouch calculi as a late complication: A case series

Objective: Following cystectomy, there are several reconstructive options. A continent cutaneous urinary diversion (CUD) avoids an ileal conduit if patients are unsuitable for an orthotopic neobladder. Reservoir stone formation is common, and management is challenging. Our data present incidence and management of calculi following Indiana pouch reconstruction after radical cystectomy. Patients and Methods: Prospective database review identified 30 patients with Indiana pouch CUD in our series of 450 open cystectomies. Paper, electronic medical records, and radiological imaging were reviewed. Results: Six (20%) patients with up to 15 years follow-up were identified with stones. At cystectomy, all patients were stone free with normal renal function and electrolytes. Time to first stone formation was 29–60 months. Eighty percent became recurrent stone formers. Management involved a combination of endoscopic LASER litholapaxy, percutaneous and open access. All patients had a functioning CUD following stone treatment. Time to stone recurrence improved with assessment for metabolic abnormalities, timed pouch emptying, pouch irrigation and treatment of urine infections. Conclusion: The risk of stone formation and requirement for rigorous post-operative prevention protocols should be discussed with patients. Follow-up for this group should be lifelong to include imaging and metabolic monitoring. Management requires a multimodal, multi-disciplinary approach. Level of evidence: Not applicable

12375 Rhabdomyolysis As A Cause Of PTH-independent Hypocalcemia In A Child With Acute Influenza Infection

Abstract Disclosure: S. Bhattarai: None. K. Halpin: None. Introduction: Hypocalcemia is characterized by low blood calcium level. Normal range for calcium for ages 12- 19-year is 8.5-10.6 mg/dli . Severe hypocalcemia is considered as serum calcium level of &amp;lt;7 mg/dl. Hypoparathyroidism, pseudohypoparathyroidism and Vitamin D deficiency are some of the most common causes encountered by pediatrician endocrinologists. Rhabdomyolysis with hypocalcemia and elevated PTH is a rare presentation that should be considered, particularly for children presenting with acute viral illness. We present a rare case of rhabdomyolysis associated with hypocalcemia not related to hypoparathyroidism. Case: A 12-year-old female presented to the ED with body ache, poor oral intake and vomiting. She was found to be influenza positive. Labs showed hypocalcemia (4.8 mg/dl). She had an undetectable 25-OH vitamin D level (&amp;lt;5 ng/ml) and elevated iPTH level (609 pg/ml). We discussed the possibility of her etiology of hypocalcemia as Vitamin D deficiency although her presentation was atypical at an older age with negative imaging for rickets, hyperphosphatemia (6.0 mg/dl), and normal ALP (334 unit/L). She did not have any phenotypic features of Albright’s hereditary osteodystrophy with normal renal function. She had elevated CK (4829 U/L) supporting rhabdomyolysis secondary to acute influenza as a cause of her hypocalcemia. Rhabdomyolysis, a known complication of influenza infection, causes cell membrane destruction which impairs the normal function of Na-K-ATPase channel leading to increase in intracellular sodium activating Na/Ca exchanger. This in turn causes influx of calcium intracellularly causing hypocalcemia. Additionally, any injury leads to high phosphorus release from cells due to its lysis. High phosphorus is also caused by reduced oxidative metabolism in muscles impairing phosphate use. This excess of phosphate then combines with calcium and causes calcium-phosphate complex in soft tissues. Hyperphosphatemia additionally inhibits 1 alpha hydroxylase limiting formation of calcitriol leading to hypocalcemia. iiConclusion: Our patient had severe hypocalcemia due to influenza-related rhabdomyolysis. Rhabdomyolysis is an important cause of hypocalcemia in children, especially with acute viral illness. Accordingly, it is also important to obtain serum electrolytes in patients presenting with rhabdomyolysis as hypocalcemia may lead to complications like seizures and cardiac arrhythmia. Endnotes:i Roizen, Jeffrey &amp; Shah, Vipul &amp; Levine, Michael &amp; Carlow, Dean. (2013). Determination of Reference Intervals for Serum Total Calcium in the Vitamin D-Replete Pediatric Population. The Journal of clinical endocrinology and metabolism. 98. 10.1210/jc.2013-3105.ii Ding LN, Wang Y, Tian J, Ye LF, Chen S, Wu SM, Shang WB. Primary hypoparathyroidism accompanied by rhabdomyolysis induced by infection: A case report. World J Clin Cases. 2019 Oct 6;7(19) Presentation: 6/2/2024

7289 An interesting case of Diabetes Mellitus Type 1 induced Renal Tubal Acidosis Type 1

Abstract Disclosure: R. Ripa: None. A. Itani: None. S.K. Patel: None. Introduction: Renal Tubular Acidosis (RTA) are a group of disorders that involve dysfunctional transporters and channels in the renal system. These disorders can be acquired (idiopathic, medication side effects, and medical disorders) or inherited. The most common type worldwide is type 4 RTA, the main cause is diabetic nephropathy leading to hypoaldosteronism. The association of type 1 RTA with diabetes has rarely been reported in studies. Here, we report the presentation, diagnosis and management of a rare case of type 1 RTA in a patient with a history of diabetes mellitus type 1. Case: A male in his 50s with a 30-year history of uncontrolled type 1 diabetes mellitus on insulin pump and coronary artery disease presented to his cardiologist with worsening chest pain, fatigue, polyuria, weight loss of 15 lbs, and recent insulin pump change. Blood tests revealed serum bicarbonate of 10 mmol/L and he was sent to the hospital. On examination, he was hypotensive and bradycardic with dry mouth and decreased skin turgor. His blood tests were consistent with type 1 RTA, he was treated with intravenous fluids containing bicarbonate plus potassium and transitioned to oral potassium citrate on discharge. He underwent renal biopsy as work up was unrevealing for a cause of type 1 RTA. Biopsy revealed normal glomeruli with negative immunofluorescence and Congo red stain. The biopsy, however, did show mild patchy chronic interstitial fibrosis with lymphocytes and mild tubular atrophy. At one year follow up, he remained on oral potassium citrate with resulting serum bicarbonate of 26 mmol/L and a normal renal function. Discussion: Diabetes mellitus can lead to a variety of renal pathologies, specifically metabolic acidosis that can be either seen as diabetic ketoacidosis or hyporeninemic hypoaldosteronism (Type 4 RTA). In our patient, despite being a diabetic, he did not present with either elevated anion gap, ketonuria or hyperkalemic hyperchloremic acidosis typical of type 4 RTA. He was noted to have hypokalemic hyperchloremic acidosis, with a positive urine anion gap, and an alkaline urine, all characteristic of type 1 RTA. Acquired distal RTA occurs more commonly due to certain medications or autoimmune diseases as in Sjögren’s syndrome. The relationship between distal RTA and Sjögren’s syndrome has already been established, unlike the relationship with type 1 diabetes. There have been few case reports of distal RTA in association with type 1 diabetes mellitus, implying a possible autoimmune pathology. Prior case reports also not only had patients who were insulin dependent, but diabetes was present for more than a decade at least suggesting chronicity of disease is needed. Traditional management consists of alkaline therapy and treatment of the underlying disease, or removal of offending medication. In this case, we hope to highlight distal RTA in a diabetic who doesn’t meet criteria for DKA or type 4 RTA. Presentation: 6/1/2024

6588 Insulin Autoimmune Syndrome Presenting with Severe Insulin Resistance and Recurrent Diabetic Ketoacidosis

Abstract Disclosure: E. Looi: None. R. Rosenberg: None. S. Sugar: None. H. Stone: None. A.W. Michels: None. D. Saxon: None. Background: Insulin autoimmune syndrome (IAS) is a rare cause of severe insulin resistance and is typically associated with intermittent hypoglycemia due to insulin antibodies (IA) with high binding capacity and low insulin affinity. However, consideration should be given for atypical presentation of IAS or co-presentation of IAS with type B insulin resistance syndrome (TBIRS) in the absence of hypoglycemia, as described in this case. Case: A 78-year-old African American female (BMI 21 kg/m2) with poorly controlled type 2 diabetes (A1c 11%) experienced recurrent episodes of diabetic ketoacidosis (DKA) despite adherence to escalating insulin doses (310 units daily, 5 u/kg/day). She was referred to endocrinology and continuous glucose monitoring revealed consistently elevated glucose levels (300-400 mg/dL) without hypoglycemia. She had normal renal function, hepatic function, and lipid panel. During a subsequent hospitalization, she required insulin drip rates of 50-70 u/hr. Insulin resistance workup revealed significantly elevated IA level (8.346, normal ≤ 0.010) measured using a fluid-phase radiobinding assay with high insulin binding capacity (1040 U insulin-binding/L blood) and low insulin binding affinity (1.9x107 M), which supported the diagnosis of IAS. Rheumatologic workup for other autoimmune diseases was negative. Due to recurrent DKA episodes, severe insulin resistance without obvious alternative cause, and lack of hypoglycemic events despite low IA binding affinity, co-morbid TBIRS was considered. As there are no commercially available insulin receptor antibody (IRAb) assays, diagnosis could not be confirmed before her condition worsened, and she was admitted for another episode of DKA within a week of being discharged. Due to clinical deterioration and high suspicion for IAS ± TBIRS, treatment with a combination of immunosuppressive agents was initiated in accordance with an NIH protocol (Klubo-Gwiezdzinska J, et al. 2018). Intravenous immune globulin (0.5g/kg/day) was administered over 2 days which resulted in a brief reprieve and followed by significant relapse. Two doses of rituximab (750 mg/m2) and 2 steroid pulses (dexamethasone 40 mg PO daily for 4 days) were then administered 2 weeks apart. Cyclophosphamide 100 mg daily was also started. Her hyperglycemia and insulin requirements subsequently improved, and she was eventually discharged with good glycemic control on a total daily dose of 40 units of insulin (0.5 u/kg/day), an 87.1% reduction in daily insulin requirement. Conclusion: This case demonstrates that IAS - although classically associated with hypoglycemic episodes - may also present with severe insulin resistance and recurrent DKA without hypoglycemia. Whether characterized by high IA binding capacity and affinity or coexisting with IRAb, a combination of immunosuppressants proved effective in treating both TBIRS and IAS in this instance. Presentation: 6/3/2024

8016 Resolution of Refractory Hypoglycemia Following Pancreatic Solitary Fibrous Tumor Resection

Abstract Disclosure: M.E. Horowitz: None. S. Stefan: None. Introduction: Solitary fibrous tumors (SFT) are exceptionally rare mesenchymal tumors, accounting for only 3.7% of all cases of soft-tissue sarcoma with an incidence of 0.35 cases per 100,000 persons per year. SFT may arise in various anatomical locations, approximately 30% occuring in the abdomen. SFT can manifest with paraneoplastic syndromes, with the most commonly described being non-islet cell hypoglycemia. We present a case of refractory hypoglycemia which resolved following the resection of a large pancreatic SFT. Clinical Case: A 75-year-old male with a history of hypertension presented from oncology clinic with hypoglycemia. Two weeks prior, a 26cm mass of the pancreatic head was identified after he presented to the hospital for one month of abdominal pain and distention, and biopsy of the mass confirmed an SFT. The patient complained of nighttime weakness, confusion, nausea, vomiting, and urinary incontinence for two nights prior to arrival. During this time, the patient had multiple fingersticks showing hypoglycemia below 70 mg/dL, the lowest at 37 mg/dL. On arrival, fingerstick glucose was 38 mg/dL and serum glucose was 27 mg/dL, with a c-peptide level of 0.28 ng/mL (1.00-4.00 ng/mL). Despite hypoglycemia, he was asymptomatic at the time of presentation, indicating hypoglycemia unawareness. Investigation into the cause of hypoglycemia included normal morning cortisol levels, normal thyroid function tests, and normal liver and renal function tests. Further assessment for paraneoplastic disease was conducted, revealing an IGF1 level of 36 ng/dL (5-34 ng/dL) and IGF2 241 ng/dL (267-616 ng/dL), with a ratio of IGF2:IGF1 of 6.7:1. He underwent surgical removal of the large abdominal mass with distal gastrectomy and Billroth-I reconstruction. Pathology was consistent with a 34cm retroperitoneal SFT, STAT6 positivity, and negative margins. Following surgery, the patient did not experience any further hypoglycemia or related symptoms, and glucose ranged 78-135 mg/dL through discharge. Clinical Lessons: Refractory hypoglycemia resulting from a tumor's production of IGF2 is a rare paraneoplastic syndrome known as Doege-Potter Syndrome. This syndrome is observed in fewer than 5% of patients with SFT. The first documented case of hypoglycemia in a patient with "fibrous sarcoma" dates back to 1930. To establish a diagnosis, a ratio of IGF2:IGF1 exceeding 3:1 is suggestive of tumor-mediated production, while a ratio exceeding 10:1 is considered diagnostic. A positive immunohistochemical stain for STAT6 confirms the diagnosis. Patients with these tumors should be routinely monitored for hypoglycemia and related symptoms. Presentation: 6/3/2024

8243 Euglycemic Diabetic Ketoacidosis Unveiled: Delayed Presentation and Complications of SGLT-2 Inhibitor Therapy in a Multimorbid Patient - A Case Report

Abstract Disclosure: T. Amin: None. A.K. Bala: None. M.A. Jones: None. M.S. Akula: None. K. Chalasani: None. M. Patel: None. J. Cheng: None. Introduction: Normal serum glucose levels (&amp;lt;200 mg/dL) in euglycemic diabetic ketoacidosis (EDKA) can complicate the typical clinical presentation of diabetic ketoacidosis (DKA), posing a diagnostic challenge. SGLT-2 inhibitors, a class of antihyperglycemic drugs, have been rarely but significantly associated with EDKA. These inhibitors enhance renal glucose clearance by preventing glucose reabsorption via sodium-glucose cotransport. The increased renal clearance may contribute to the euglycemic picture, potentially leading to an underestimation of required insulin dosage, thereby precipitating ketoacidosis in EDKA. Although the mechanisms of EDKA are not fully understood, the association with SGLT-2 inhibitors is becoming increasingly evident. Case A 53-year-old male with a medical history of type 2 Diabetes Mellitus, coronary artery disease, chronic kidney disease, hyperlipidemia, was admitted to the trauma bay after a fall. Medications included empagliflozin, metformin, aspirin, amlodipine, spironolactone, and carvedilol. Upon presentation, he had a brief loss of consciousness, complained of headache and chest pain, and was found to have an epidural hematoma with regional brain compression on the CT head. Admission labs showed a blood glucose level of 172, an unremarkable anion gap, and normal renal and liver function tests. Due to traumatic brain injury, he was admitted to the ICU for neurological monitoring. Despite remaining neurologically stable, he developed hypoxia, necessitating intubation. After successful extubation, he exhibited worsening metabolic acidosis on the fourth day, with an elevated anion gap of 22 and a blood glucose level of 174. Arterial blood gas analysis revealed a pH of 7.3 (and elevated beta-hydroxybutyrate (&amp;gt;4), while lactic acid levels remained normal. Urine analysis showed elevated blood glucose (&amp;gt;1000) and ketones (&amp;gt;40). Home medications, metformin, and empagliflozin were appropriately withheld, but euglycemic DKA attributed to empagliflozin was diagnosed. Treatment included intravenous fluid resuscitation and insulin infusion, leading to resolution of acidosis and improved mentation within 24 hours. Conclusion: EDKA is a diagnosis of exclusion often overlooked in ICU patients due to diverse causes of high-anion gap metabolic acidosis. Typical cases occur while the patient is using the drug, often associated with triggers like illness, alcohol use, surgery, or starvation. SGLT2 inhibitors, such as empagliflozin, with a half-life of 12.4 hours, are expected to clear the bloodstream in about 48 hours, yet this case suggests an association with EDKA both during use and after drug cessation. This delayed presentation highlights additional risk considerations associated with SGLT2 inhibitors, guiding future clinical diagnoses of EDKA even several days post discontinuation. Presentation: 6/3/2024

6874 A Rare Case Of Hereditary 1,25 (OH)2D Resistant Rickets

Abstract Disclosure: G. Umarji: None. F. Thelmo: None. S.A. Jabbour: None. Vitamin D-dependent rickets type 2A (VDDR2A) also known as hereditary 1,25 (OH)2D resistant rickets is due to biallelic loss-of-function mutations in the gene encoding vitamin D receptor on chromosome 12q13.11, thus, it represents a true form of tissue resistance to vitamin D. It is a scarce form of rickets with approximately only 120 cases reported. A 37-year-old male was referred to endocrinology by neurosurgery for evaluation of metabolic bone disease. Seven years ago, he was in a car accident which resulted in a lumbar spine injury causing radiculopathy and severe low back pain leading to lumbar spine decompression/fusion. However, he suffered from nonunion of bones and had to undergo another surgery a year later with recurrent postoperative nonunion of bones. During the operation, the surgeon noticed that his spine seemed demineralized. He had a history of multiple minor fractures in childhood, decreased hearing in left ear for two years, fragile teeth for many years, and some hair loss since age 30. Physical exam showed a height of 1.82 m, weight 89.3 kg with body mass index of 26 kg/m2, broken teeth, no leg bowing and normal stance. Laboratory results showed normal renal function, thyroid function tests and testosterone level, corrected calcium 8.3 mg/dL (8.7-10.2), 25-OH-vitamin D 54 ng/mL (30-100), phosphorus 2.8 mg/dL (2.8-4.1), intact parathyroid hormone 65 pg/mL (15-65), bone-specific alkaline phosphatase 21 mcg/L (4-27), 24-hour urine calcium 156 mg/day (100-300), 24-hour urine phosphorus 1,752 mg/day (390-1,425), FGF-23: 93 RU/mL (44-215) and 1,25 (OH)2D 92 pg/mL (24-81.5). Dual absorptiometry of the lumbar spine and hip showed osteopenia with Z scores of -2.2 and -1.2 respectively. Genetic testing for metabolic bone disease panel showed heterozygous mutation in VDR gene at nucleotide position c.146+9dup associated with autosomal recessive VDDR2A. We present a very rare form of vitamin D resistant rickets. As many patients with VDDR2A are unable to respond to any form of vitamin D, it is suggested that VDDR2 be more appropriately described as hereditary 1,25 (OH)2D resistant rickets (HVDRR), hereditary resistance to 1,25 (OH)2D, or even pseudovitamin D-deficiency type IIA (PDDR IIA). Clinical features include severe rickets, bone pain, hypotonia, dental caries and alopecia. Biochemical features include hypocalcemia, hypophosphatemia, normal to elevated alkaline phosphatase, normal 25(OH)D and importantly, elevated 1,25-(OH)2D levels. Management is with high doses of calcium and vitamin D therapy. While rare, this disease highlights the need for a comprehensive evaluation of metabolic bone diseases and a thorough understanding of calcium and vitamin D metabolism. Presentation: 6/2/2024

6574 Pheochromocytoma In A Patient With ESRD; Clinical Challenges And Lessons From A Successful Evaluation

Abstract Disclosure: S. Younes: None. A. Sayed: None. K. Selk: None. L.A. Willard: None. Introduction: Pheochromocytomas are rare tumors that arise from the chromaffin cells in the adrenal medulla, that secrete norepinephrine, epinephrine and dopamine. Common presentations include resistant hypertension (HTN) and adrenergic spells with headaches, sweating and tachycardia. The literature has few cases of pheochromocytoma in the setting of end stage renal disease (ESRD). Case: A 46-year-old male with a history of resistant HTN on amlodipine, lisinopril, and labetalol, complicated by ESRD on hemodialysis (HD) and secondary hyperparathyroidism initially presented with gross hematuria. The patient reported sporadic, intermittent headaches associated with palpitations and sweating. A renal ultrasound revealed a left-sided complex renal cystic mass. CT abdomen/pelvis demonstrated an enhancing left adrenal lesion and MRI abdomen/pelvis confirmed an enhancing 4.6 x 2.8 cm adrenal mass. Laboratory studies revealed elevated normetanephrine of 1186 pg/mL (ref &amp;lt;149 pg/mL), elevated metanephrine at 139 pg/mL (ref &amp;lt;57 pg/mL) and elevated epinephrine at 128 pg/mL (ref &amp;lt;95 pg/mL). Given the laboratory and imaging findings in conjunction with clinical presentation, an excision of the adrenal mass was set. Two weeks prior to the surgery, alpha blockade was started with doxazosin 1mg daily with a goal blood pressure &amp;lt;130/80. He was admitted to the hospital with a goal to keep him 1-1.5kg above his dry weight. His dry weight was 81.5kg close to admission weight, so he was started on gentle IV hydration. He had a left robotic assisted adrenalectomy and was given stress dose steroids and a steroid taper given no preoperative Cushing’s screen was completed. No postoperative complications reported, and doxazosin was discontinued. 2 weeks later, he reported his adrenergic spells had resolved. Surgical pathology confirmed pheochromocytoma and he was referred for genetic consultation. Conclusion: Although there is little in the literature regarding management of a pheochromocytoma in patients with ESRD, similar principles of management in patients with normal renal function apply, including blood pressure control, alpha blockade, and establishment of euvolemia with recommendation of a high-sodium diet and 1-2 liters of saline the day prior to the procedure. This case highlights successful perioperative management with traditional use of alpha blockade but also incorporated maintaining the patient 1-1.5 kg above their dry weight for surgery to limit postoperative hypotension. Presentation: 6/3/2024

Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement membrane nephropathy

The glomerular basement membrane (GBM) is a critical component of the glomerular filtration barrier (GFB), with its thickness directly influencing renal function. While a uniformly thinned GBM can cause hematuria while preserving normal renal function, this condition is typically diagnosed as thin basement membrane nephropathy (TBMN). However, the pathogenesis and potential progression to renal insufficiency of TBMN are not fully understood. In this study, we analyzed clinical cohorts presenting with microscopic hematuria who underwent genetic testing and identified five novel pathogenic FN1 mutations. Through bioinformatics analysis of these variants, expression localization analysis of GBM-related molecules in renal biopsies, and functional studies of the mutants, we found that these variants exhibited gain-of-function characteristics. This led to the excessive deposition of aberrant serum-derived FN1 variants on glomerular endothelial cells rather than cell-type-specific variants. The deposition competitively binds FN1 variants to Integrin β1, disrupting the interaction with Laminin α5β2γ1 and subsequently reducing the expression of key GBM components, resulting in TBMN. This study elucidated, for the first time, the genetic pathogenesis of TBMN caused by FN1 variants. It provides a crucial foundation for understanding the progression of renal dysfunction associated with simple hematuria, highlights the potential for targeted therapeutic strategies, and differentiates TBMN from early-stage Alport syndrome.

Population pharmacokinetics of nirmatrelvir/ritonavir in critically ill Chinese COVID-19 patients and recommendations for medication use: a two-center retrospective study

ABSTRACT Background This study aimed to establish population pharmacokinetics (PPK) models of nirmatrelvir/ritonavir in critically ill Chinese patients with the coronavirus disease 2019 (COVID-19) infection, explore factors affecting the pharmacokinetics (PK) of nirmatrelvir/ritonavir. Methods A total of 285 serum samples and clinical data were collected from 152 patients. The PPK models of nirmatrelvir/ritonavir were analyzed using nonlinear mixed-effect modeling (NONMEM) approach. The optimal dosing regimen for patients with different renal function was determined using Monte Carlo simulations. Results The population typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) of nirmatrelvir were 2.26 L/h and 15.3 L, respectively. Notably, creatinine clearance (CrCL) significantly influenced the PK variation of nirmatrelvir. Monte Carlo simulations suggested that patients with mild-to-moderate renal impairment experienced a 22.0–59.9% increase in the area under the curve (AUC) when they were administered a standard dose of nirmatrelvir compared to those with normal renal function. The AUC in patients with severe renal impairment after administration of 150 mg q12h nirmatrelvir was similar to that in patients with normal renal function after administration of 300 mg q12h nirmatrelvir. Conclusions PPK modeling and simulation provided a reference for the rational clinical application of nirmatrelvir/ritonavir in critically ill Chinese patients.