Difference In Fractional Excretion Research Articles

#5525 NEPHROTOXICITY OF CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T) THERAPY: ACUTE KIDNEY INJURY AND ELECTROLYTE DISORDERS

Abstract Background and Aims Chimeric antigen receptor T cell therapy (CAR-T) has improved the prognosis of patients with refractory hematologic malignancies. The most important toxicities are the cytokine release syndrome (CRS), where interleukin 6 (IL-6) plays a major role, and the immune effector cell-associated neurotoxicity syndrome (ICANS). A low incidence of acute kidney injury (AKI) with a high frequency of electrolyte imbalance has been described with CAR-T therapy. The aim of our study is to describe the nephrotoxicity of CAR-T therapy and to focus on AKI and the physiopathology of hypophosphatemia. Method A prospective single-center case series was performed which included all patients undergoing CAR-T therapy between 2020 and 2022. Clinical data included medical history, previous chemotherapy treatments, concomitant treatments, and clinical evolution. Daily monitoring of renal function, electrolytes and IL-6 was obtained after infusion of CAR-T. A urine sample was obtained on days 0, +7 and +14 with parathyroid hormone (PTH) and 25-OH vitamin D. AKI was classified according to the KDIGO criteria. Results 40 patients received CAR-T therapy during the follow-up period. The median age was 62 years. The same number of men as women were included. The most frequent comorbidities were hypertension (27.5%), followed by diabetes (12.5%) and chronic kidney disease (12.5%). 12 patients presented AKI. Baseline serum creatinine (SCr) in patients with AKI was 0.9 mg/dL (0.68-1.04) with a SCr peak of 1.27 mg/dL (1.1-1.7). The time from CAR-T therapy infusion to SCr peak was 6.5 days (4-10). Of these 12 patients, 8 presented stage 1, 3 stage 2, and 1 stage 3 AKI. There were no differences between the AKI and non-AKI group in baseline characteristics, inflammatory markers, CRS, ICANS or hospital length stay. Hypophosphatemia was the most frequent electrolyte imbalance, occurring in 36 patients (90 %), 22 (61 %) patients experienced moderate hypophosphatemia (phosphorus < 2 mg/dL) while 14 (39 %) patients experienced mild hypophosphatemia. 29 patients (72 %) presented hypokalemia and 25 patients (62.5 %) hyponatremia. Patients with moderate hypophosphatemia had a significantly higher elevation of IL-6 but there were no differences in PTH or vitamin D (Table 1). Although there were no significant differences in fractional excretion of filtered phosphate (FEPO4), patients with moderate hypophosphatemia trend to have higher FEPO4 values. Conclusion Electrolyte disturbances are common in CAR-T therapy, with hypophosphatemia being the most frequent. There is probably a mechanism for renal phosphorus loss related to systemic inflammation. AKI is less frequent and has mild characteristics in these patients.

Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

Backgroundphosphate homeostasis is mediated through complex counter regulatory feed-back balance between parathyroid hormone, FGF-23 and 1,25(OH)2D. Both parathyroid hormone and FGF-23 regulate proximal tubular phosphate excretion through signaling on sodium- phosphate cotransporters IIa and IIc. However, the interaction between these hormones on phosphate excretion is not clearly understood. We performed the present study to evaluate whether the existence of sufficient parathyroid hormone is necessary for full phosphaturic function of FGF-23 or not.MethodsIn this case-control study, 19 patients with hypoparathyroidism and their age- and gender-matched normal population were enrolled. Serum calcium, phosphate, alkaline phosphatase,parathyroid hormone, FGF-23, 25(OH)D, 1,25(OH)2D and Fractional excretion of phosphorous were assessed and compared between the two groups, using SPSS software.ResultsThe mean serum calcium and parathyroid hormone level was significantly lower in hypoparathyroid patients in comparison with the control group (P < 0.001 and P < 0.001, respectively). We found high serum level of phosphate and FGF-23 in hypoparathyroid patients compared to the control group (P < 0.001 and P < 0.001, respectively). However, there was no significant difference in Fractional excretion of phosphorous or 1,25OH2D level between the two groups. There was a positive correlation between serum FGF-23 and Fractional excretion of phosphorous just in the normal individuals (P < 0.001, r = 0.79).ConclusionsAlthough the FGF-23 is a main regulator of urinary phosphate excretion but the existence of sufficient parathyroid hormone is necessary for the full phosphaturic effect of FGF-23.

Bucindolol Prevents Atrial Flutter via the Beta-1 389 Arg/Gly Adrenergic Receptor Polymorphism

Background: Loop diuretics are the mainstay of treatment for volume overload in heart failure. Data is limited as to which loop diuretic is the preferred agent. Studies in animal models suggest that torsemide may have a positive anti-aldosterone effect, through receptor antagonism and inhibition of aldosterone secretion. However, the clinical significance of these effects in human heart failure is unknown. Hypothesis: If the anti-aldosterone effects of torsemide are clinically meaningful, potassium losses from torsemide should be reduced compared to other loop diuretics lacking anti-aldosterone effects. Methods: We studied 75 hospitalized heart failure patients treated with loop diuretics. Within this sample, 51 patients received bumetanide, 25 torsemide, and 12 furosemide with 13 patients receiving both bumetanide and torsemide on different days. A spot urine was collected prior to diuretic administration and then a timed 6-hour urine collection was performed after diuretic administration to determine total potassium excretion. Values reported represent median (quartile 1 quartile 4). Results: The doses of bumetanide, torsemide, and furosemide received were 3 mg (2-4 mg), 40 mg (20-70 mg) and 40 mg (25-80 mg), respectively. There was no significant difference in total potassium excretion and the potassium to sodium excretion ratio between the patients on torsemide, bumetanide and furosemide (Table 1). There was also no significant difference in fractional excretion of potassium (FEK) or change in FEK between patients on different diuretics (Table 1). In the subgroup of patients that received both bumetanide and torsemide on different days (n513) total potassium excretion (p50.30), potassium to sodium excretion ratio (p50.58), FEK (p50.41), and change in FEK (p50.74) were similar across diuretics. Conclusion: Torsemide did not produce a detectable change in total potassium excretion or potassium handling compared to furosemide or bumetanide. Acute anti-aldosterone effects of torsemide do not appear to be clinically significant in heart failure patients receiving high dose loop diuretics.

The Anti-aldosterone Effects of Torsemide Do Not Lead to Detectable Improvement in Potassium Losses in Patients Treated for Decompensated Heart Failure

Background: Loop diuretics are the mainstay of treatment for volume overload in heart failure. Data is limited as to which loop diuretic is the preferred agent. Studies in animal models suggest that torsemide may have a positive anti-aldosterone effect, through receptor antagonism and inhibition of aldosterone secretion. However, the clinical significance of these effects in human heart failure is unknown. Hypothesis: If the anti-aldosterone effects of torsemide are clinically meaningful, potassium losses from torsemide should be reduced compared to other loop diuretics lacking anti-aldosterone effects. Methods: We studied 75 hospitalized heart failure patients treated with loop diuretics. Within this sample, 51 patients received bumetanide, 25 torsemide, and 12 furosemide with 13 patients receiving both bumetanide and torsemide on different days. A spot urine was collected prior to diuretic administration and then a timed 6-hour urine collection was performed after diuretic administration to determine total potassium excretion. Values reported represent median (quartile 1 quartile 4). Results: The doses of bumetanide, torsemide, and furosemide received were 3 mg (2-4 mg), 40 mg (20-70 mg) and 40 mg (25-80 mg), respectively. There was no significant difference in total potassium excretion and the potassium to sodium excretion ratio between the patients on torsemide, bumetanide and furosemide (Table 1). There was also no significant difference in fractional excretion of potassium (FEK) or change in FEK between patients on different diuretics (Table 1). In the subgroup of patients that received both bumetanide and torsemide on different days (n513) total potassium excretion (p50.30), potassium to sodium excretion ratio (p50.58), FEK (p50.41), and change in FEK (p50.74) were similar across diuretics. Conclusion: Torsemide did not produce a detectable change in total potassium excretion or potassium handling compared to furosemide or bumetanide. Acute anti-aldosterone effects of torsemide do not appear to be clinically significant in heart failure patients receiving high dose loop diuretics.

Glomerular and tubular function in young adults treated with stem-cell transplantation in childhood

We evaluated renal function at a median follow-up of 18 (range 10.3-22.1) years after total body irradiation in 18 patients treated with stem-cell transplantation (SCT) (autologous SCT in 15 and allogeneic SCT in three) for hematologic malignancies and compared them with 18 healthy controls. No patient had chronic graft-versus-host disease. We found no difference in glomerular filtration rate estimated from cystatin C (105 vs 111 ml/min/1.73 m(2), p = 0.28). Patients had higher albumin excretion (0.8 vs 0.4 mg/mmol, p = 0.001), but no patient had overt albuminuria (>200 mg/L). Patients had higher diastolic blood pressure (74 vs 67 mmHg, p = 0.003). Two patients (11%) had hypertension. Patients had lower tubular reabsorption of phosphate (0.78 vs 0.91 mmol/L, p = 0.014) and higher excretion of alpha-1-microglobulin (AMG/urine creatinine, 0.4 vs 0.25 mg/mmol, p = 0.038), which correlated with time after SCT (r = 0.6, p = 0.01). We found no difference in fractional excretion (FE) of other electrolytes, amino acid excretion, or urine osmolality. We conclude that renal function was relatively well preserved at a median follow-up of 18 years after childhood SCT. The higher albumin excretion in our patients is of concern, as is the association between excretion of AMG and time after SCT, suggesting that both glomerular and tubular function may deteriorate further.

Renal function in children with sickle cell anemia.

Patients with sickle cell anemia have various forms of renal dysfunction. The purpose of this study is to demonstrate the abnormalities of HbSS patients' renal function in childhood. Renal function studies were performed in 55 patients with homozygote sickle cell anemia and compared with 13 healthy children. The blood and timed urine samples were obtained for hematological and biochemical determinations. Mean serum creatinine, sodium, phosphorus and calcium levels were not statistically different between patients and controls. Mean serum potassium and uric acid levels were significantly higher in patients than in controls. Mean tubular phosphate reabsorption (p < 0.001) and fractional excretion of potassium (p < 0.05) were lower in patients than in the control. There were no significant differences in fractional excretion of sodium and uric acid between patients and controls. Patients had significantly higher urine pH and significantly lower specific gravity and osmolality than controls. Also, there were no significant differences in urinary protein/ creatinine, urinary N-acetyl-beta-D-glucosaminidase/creatinine and urinary malondialdehyde/creatinine between patients and controls. Thus, significant proximal tubular dysfunction is not a common feature but distal tubular abnormality is the most consistent renal functional derangement of patients with SCA in childhood.

MRNA Expression of Renal Urea Transporters in Normal and Brattleboro Rats: Effect of Dietary Protein Intake

Differences in dietary protein level induce differences in fractional excretion of urea, in arginine vasopressin (AVP) plasma level, and in urine concentrating activity (in which intervene the renal urea transporters (UT)). The abundance of mRNA for UT-A1 (of the inner medullary collecting duct, IMCD) UT-A2 (of the descending thin limb) and UT-B1 (of descending vasa recta) was determined by Northern analysis of total RNA extracted from medullary subregions of Sprague-Dawley rats fed for 1 week, a low, normal, or high protein diet. The implication of AVP was then examined by studying AVP-deprived (Brattleboro) rats. Our results show that none of these transporters is affected by the level of protein intake, except UT-A1 that is reduced in terminal IMCD by low protein diet in the absence of AVP (Brattleboro rats). These data suggest that (1) the previously reported effect of kidney medulla hypertonicity on UT-A2 and UT-B1 mRNA expression is somehow obliterated by protein intake deficiency or excess, and (2) AVP influences the mRNA abundance of the UT-A1 of the terminal IMCD during protein deficiency.

Vitamin D receptor gene polymorphism is associated with urinary calcium excretion but not with bone mineral density in postmenopausal women.

Polymorphism of vitamin D receptor (VDR) gene has been found to be associated with serum osteocalcin (OC) levels and bone mineral density (BMD) in Caucasian identical twins and unrelated postmenopausal women. Being ethnically different and living in a geographic area with adequate vitamin D status due to abundant sunshine exposure, it is unclear whether VDR gene polymorphism will affect bone mass in Thai population. In the present study, we investigated the association between VDR gene polymorphism and bone metabolism in Thai postmenopausal women. Subjects consisted of 84 postmenopausal women. Bsm I, Taq I and Apa I polymorphisms of VDR gene were determined by PCR-RFLP. B, T and A represent the absence of the corresponding restriction sites while b, t and a indicate the presence of the restriction sites. Data were expressed as mean +/- SE. Sixty-six subjects (78.6%) had bb genotype while 18 (21.4%) had Bb genotype. None of the subjects was found to have BB genotype. Taq I restriction site was in linkage disequilibrium to the Bsm I site. For Apa I polymorphism, 33 (39.3%), 42 (50.0%) and 9 (10.7%) of the subjects had aa, Aa and AA genotypes, respectively. There was no significant difference in serum intact OC levels and BMD at various skeletal sites among subjects with different genotypes. Despite the lack of difference in BMD and intact OC levels, subjects with bb genotype had higher 24-hour urinary calcium excretion than those with Bb genotype (bb, 6.1 +/- 0.3 mmol/day; Bb, 4.4 +/- 0.6 mmol/day; p < 0.05). The effect of Bsm I VDR genotype was still significant (p < 0.05) after dietary calcium intake was controlled using analysis of covariance. Despite the difference in urinary calcium levels, there was no significant difference in fractional excretion of calcium among subjects with different Bsm I-related genotypes, suggesting that the effect of the VDR gene polymorphism on urinary calcium excretion is more likely due to the effect on intestinal calcium absorption rather than renal tubular calcium reabsorption. We conclude that VDR genotype distributions in Thai postmenopausal women are different from those reported in Caucasians. VDR gene polymorphism does not appear to be associated with BMD or bone turnover in Thai postmenopausal women. However, Bsm I VDR polymorphism may have physiologic role in calcium homeostatasis by modulating intestinal calcium absorption.

Effect of cisplatin on proximal straight tubule transport of divalent cations in the rabbit.

Clearance and in vitro microperfusion studies were performed in rabbits to determine the effect of cisplatin on proximal straight tubule transport of calcium and magnesium. Rabbits were injected with cisplatin (2.5 mg/kg i.p. once weekly) for 3 weeks, whereas control rabbits received normal saline solution which served as a diluent for cisplatin. In 5 rabbits, 24-hour clearance studies were performed with the aid of a metabolic cage. Following cisplatin treatment, fractional excretion of magnesium rose significantly (73.3 +/- 11.5 vs. 111.4 +/- 17.5%). Glomerular filtration rate fell with cisplatin treatment (4.05 +/- 0.76 vs. 2.81 +/- 28 ml/min). There was no difference in fractional excretion of calcium (26.3 +/- 9.5 vs. 22.7 +/- 3.2%). The cortical and juxtamedullary proximal straight tubules were perfused in vitro. Net volume absorption was the same in the control and cisplatin-treated rabbits. However, there was a significant reduction in JCa (cortical 0.57 +/- 0.10 vs. -0.10 +/- 0.12 pmol/min/mm; juxtamedullary 0.96 +/- 0.17 vs. 0.31 +/- 0.37 pmol/min/mm) and JMg (cortical 0.43 +/- 0.08 vs. -0.15 +/- 0.07 pmol/min/mm; juxtamedullary 0.40 +/- 0.27 vs. -0.30 +/- 0.28 pmol/min/mm). In contrast to chronic administration, acute addition of cisplatin into the bath had no effect on JCa and JMg in the cortical and juxtamedullary proximal straight tubules. These data indicate that chronic but not acute cisplatin treatment depresses the transport of calcium and magnesium in the cortical and juxtamedullary nephrons of the proximal straight tubule of the rabbit.