Renal Impairment Associated with the Pre-Operative Administration of Recombinant Interleukin-2

1. The T-cell-derived cytokine interleukin-2 may be used to reverse the immune suppression associated with major surgery. However, both major surgical procedures and recombinant interleukin-2 therapy are known to induce renal dysfunction. 2. Eighteen patients were randomized to receive either recombinant interleukin-2 (18 × 106 i.u./day) or placebo, given subcutaneously for 3 days before undergoing curative colorectal cancer surgery. Indices of renal function were determined pre-operatively and for 21 days after surgery. 3. Pre-operative recombinant interleukin-2 was found to significantly increase, compared with placebo controls, N-acetyl-β-D-glucosaminidase [peak levels 28 (SEM 2) versus 11 (SEM 3) i.u./mmol of Cr] and γ-glutamyltransferase [peak levels 5.3 (SEM 0.6) versus 2.4 (SEM 0.2) i.u./mmol/l] and decrease urinary fractional excretion of sodium [peak difference 0.32 (SEM 0.06) versus 0.76 (SEM 0.08)] (all P < 0.05). Significantly increased urinary excretions of creatinine, N-acetyl-β-D-glucosaminidase and γ-glutamyltransferase were also identified after surgery. All variables returned to pretreatment limits by the seventh day post-operatively, except N-acetyl-β-D-glucosaminidase, which was still significantly elevated 21 days after surgery. No differences in the serum concentrations of sodium, creatinine or urea were observed before or after surgery in either group. 4. Recombinant interleukin-2, when given in the preoperative period, was associated with significant renal dysfunction. However, routine monitoring of serum indices (i.e. sodium, urea, creatinine and albumin) failed to detect such renal damage. These results suggest that, with the use of recombinant interleukin-2 to enhance natural cytotoxicity in the peri-operative period, such therapy may potentiate the renal impairment occurring after surgery.

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Modulation of the cytokine and acute-phase response to major surgery by recombinant interleukin-2

British Journal of Surgery ◽

10.1002/bjs.1800820130 ◽

1995 ◽

Vol 82 (1) ◽

pp. 86-90 ◽

Cited By ~ 10

Author(s):

D. J. Deehan ◽

S. D. Heys ◽

W. Simpson ◽

J. Broom ◽

D. N. McMillan ◽

...

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

Interleukin 2 ◽

Phase Response ◽

Major Surgery ◽

Recombinant Interleukin 2

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Modulation of the cytokine and acute-phase response to major surgery by recombinant interleukin 2

British Journal of Surgery ◽

10.1002/bjs.1800820956 ◽

1995 ◽

Vol 82 (9) ◽

pp. 1289-1290 ◽

Cited By ~ 2

Author(s):

S. J. Wigmore ◽

J. A. Ross ◽

K. C. H. Fearon ◽

D. J. Deehan

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

Interleukin 2 ◽

Phase Response ◽

Major Surgery ◽

Recombinant Interleukin 2

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Empagliflozin in Heart Failure

Circulation ◽

10.1161/circulationaha.120.045691 ◽

2020 ◽

Vol 142 (11) ◽

pp. 1028-1039 ◽

Cited By ~ 22

Author(s):

Matthew Griffin ◽

Veena S. Rao ◽

Juan Ivey-Miranda ◽

James Fleming ◽

Devin Mahoney ◽

...

Keyword(s):

Heart Failure ◽

Renal Dysfunction ◽

Blood Volume ◽

Serum Magnesium ◽

Fractional Excretion ◽

Interquartile Range ◽

Neurohormonal Activation ◽

Sodium Glucose Cotransporter ◽

Fractional Excretion Of Sodium ◽

Urinary Glucose

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure–related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations. Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated. Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours ( P <0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (−208 mL [interquartile range, −536 to 153 mL] versus −14 mL [interquartile range, −282 to 335 mL]; P =0.035) and plasma volume (−138 mL, interquartile range, −379 to 154±453 mL; P =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior ( P =0.02) and all other neurohormones were similar ( P <0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting ( P =0.20) or renal dysfunction ( P >0.11 for all biomarkers), whereas both serum magnesium ( P <0.001) and uric acid levels ( P =0.008) improved. Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03027960.

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Differential central nervous system responses folloqing single and multiple recombinant interleukin-2 infusions

Journal of Neuroimmunology ◽

10.1016/0165-5728(90)90018-i ◽

1990 ◽

Vol 28 (3) ◽

pp. 249-260 ◽

Cited By ~ 36

Author(s):

Mary D. Ellison ◽

Richard J. Krieg ◽

John T. Povlishock

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Interleukin 2 ◽

Recombinant Interleukin 2

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Low molecular weight B-cell growth factor and recombinant interleukin-2 are together able to generate cytotoxic T lymphocytes with LAK activity from the bone marrow cells of children with acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v74.4.1355.1355 ◽

1989 ◽

Vol 74 (4) ◽

pp. 1355-1359 ◽

Cited By ~ 1

Author(s):

MX Zhou ◽

HW Jr Findley ◽

AH Ragab

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Growth Factor ◽

Cytotoxic T Lymphocytes ◽

Lymphoblastic Leukemia ◽

Interleukin 2 ◽

Leukemic Cells ◽

Recombinant Interleukin 2 ◽

B Cell Growth Factor ◽

Lak Activity

Abstract We are reporting here that low-mol wt B-cell growth factor (LMW-BCGF) and recombinant interleukin-2 (rIL-2) are together able to induce CD3+ cytotoxic T lymphocytes (CTL) with lymphokine-activated killer cell (LAK) activity from the bone marrow (BM) cells of children with acute lymphoblastic leukemia (ALL). Ficoll-Hypaque (FH)-separated BM cells were obtained from patients with active disease (at diagnosis N = 13, in relapse N = 15) and in complete remission (CR; N = 12). CD3+ cells were removed by Leu-4 antibody and immunobeads. Cells were cultured (10(5) cells/mL) in semisolid media with rIL-2 (100 mu/mL), LMW-BCGF (0.1 mu/mL), and the combination of rIL-2 plus LMW-BCGF, respectively, for seven to ten days. Pooled colonies were harvested for phenotyping. LMW-BCGF plus rIL-2 induced large numbers of CD3+ colonies from CD3- precursors. rIL-2 alone did not induce colony formation. In addition, cells were cultured in liquid media with LMW-BCGF, rIL-2, and the combination of LMW-BCGF plus rIL-2, respectively, for seven to 21 days. They were harvested for phenotyping, and cytotoxicity assays were performed v K562, Raji, and autologous leukemic cells. LMW-BCGF plus rIL-2 induced significant expansion of CD3+ cells from CD3- precursors, and these cells were activated to kill autologous leukemic cells in addition to Raji and K562 cell lines. LMW-BCGF or rIL-2 alone did not induce significant expansion or activation of cytotoxic CD3- cells. Our hypothesis is that LMW-BCGF plus rIL-2 stimulates the proliferation and activation of CD3- precursors from the BM cells of children with acute leukemia to become CD3+ cells that have LAK activity. This finding may have therapeutic implications.

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Antagonistic effect of theophylline on the adenosine-induced decreased in renin release

AJP Renal Physiology ◽

10.1152/ajprenal.1984.247.2.f246 ◽

1984 ◽

Vol 247 (2) ◽

pp. F246-F251 ◽

Cited By ~ 5

Author(s):

W. S. Spielman

Keyword(s):

Angiotensin Ii ◽

Sodium Excretion ◽

Renal Cortex ◽

Fractional Excretion ◽

Antagonistic Effect ◽

Renin Release ◽

Detectable Effect ◽

Fractional Sodium Excretion ◽

Fractional Excretion Of Sodium ◽

Anesthetized Dogs

The action of theophylline on the adenosine-induced decrease in renin release was studied in anesthetized dogs. Adenosine inhibited renin release, decreased GFR and fractional sodium excretion, and decreased the concentration of angiotensin II in the renal lymph. Theophylline (5 mumol/min intrarenally) had no significant effect on GFR or RBF yet produced a significant increase in the release of renin and the fractional excretion of sodium. The intrarenal infusion of adenosine (3 X 10(-7) mol/min) during theophylline infusion produced no effect on GFR or RBF, but fractional sodium excretion and renin release were significantly decreased. Adenosine was infused at a lower dose (3 X 10(-8) mol/min) during theophylline (5 X 10(-6) mol/min) infusion in a second group of dogs. With the exception of fractional sodium excretion, all effects of adenosine were effectively antagonized by theophylline. Theophylline at 5 X 10(-6) mol/min, which stimulates renin release and effectively antagonizes the renal effects of adenosine, had no detectable effect on cAMP measured in renal cortex. Furthermore, no change in cortical cAMP was observed until theophylline was increased 50-fold over the dose effective in antagonizing adenosine. These findings demonstrate that theophylline, at concentrations having no effect on cortical cAMP, antagonizes the effect of adenosine on renin release. The results are also consistent with the view that theophylline stimulates renin release by a mechanism other than its action on cAMP.

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Nephrocalcinosis, Renal Dysfunction, and Calculi in Patients With Primary Hypoparathyroidism on Long-Term Conventional Therapy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz319 ◽

2020 ◽

Vol 105 (4) ◽

pp. e1215-e1224 ◽

Cited By ~ 2

Author(s):

Soma Saha ◽

Devasenathipathy Kandasamy ◽

Raju Sharma ◽

Chandrasekhar Bal ◽

Vishnubhatla Sreenivas ◽

...

Keyword(s):

Renal Dysfunction ◽

Conventional Therapy ◽

Care Center ◽

Tertiary Care ◽

Fractional Excretion ◽

Renal Calculi ◽

Serum Total Calcium ◽

Calcium Phosphorus

Abstract Context There are concerns about the long-term safety of conventional therapy on renal health in patients with hypoparathyroidism. Careful audit of these would help comparisons with upcoming parathyroid hormone therapy. Objective We investigated nephrocalcinosis, renal dysfunction, and calculi, their predictors and progression over long-term follow-up in patients with primary hypoparathyroidism (PH). Design and Setting An observational study at a tertiary care center was conducted. Participants and Methods A total of 165 PH patients receiving conventional therapy were evaluated by radiographs, ultrasonography, and computed tomography. Their glomerular filtration rate (GFR) was measured by Tc-99m-diethylenetriamine penta-acetic acid clearance. Clinical characteristics, serum total calcium, phosphorus, creatinine, hypercalciuria, and fractional excretion of phosphorus (FEPh) at presentation and during follow-up were analyzed as possible predictors of renal complications. Controls were 165 apparently healthy individuals. Results Nephrocalcinosis was present in 6.7% of PH patients but not in controls. Patients younger than 15 years at presentation and with higher serum calcium-phosphorus product were at higher risk. Nephrocalcinosis showed no significant association with cataract and intracranial calcification. Prevalence of renal calculi was comparable between hypoparathyroid patients and controls (5% vs 3.6%, P = .58). Fourteen percent of patients had a GFR less than 60 mL/min/1.73 m2. Increased FEPh during follow-up was the significant predictor of low GFR. Nephrocalcinosis developed in 9% of patients over 10 years of conventional therapy. Conclusion A total of 6.7% of PH patients had nephrocalcinosis, and 14% showed renal dysfunction. Prevalence of renal calculi was similar in patients and controls. Nine percent of patients developed nephrocalcinosis over 10 years of conventional therapy.

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