Efficacy of Eculizumab in Gemcitabine-Induced Thrombotic Microangiopathy: Experience of the French Thrombotic Microangiopathies Reference Centre

Abstract Background: Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including hypertension, proteinuria, oedema, acute renal failure and thrombotic microangiopathy (TMA). As opposed to thrombotic thrombocytopenic purpura, gemcitabine-induced TMA generally responds poorly to therapeutic plasma exchange and prognosis is dismal. The usual severe renal involvement and the normal activity of the von Willebrand factor-cleaving protease ADAMTS13 relate gemcitabine-induced TMA to atypical haemolytic syndrome, in which complement blockage is remarkably efficient. In this regard, this study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA. Methods: We conducted an observational, retrospective, multicentric study including all patients with gemcitabine-induced TMA treated by eculizumab in 4 French centres, between 2011 and 2014. Patients with a TMA considered to be directly attributed to an uncontrolled cancer were excluded. Results: 8 patients with a gemcitabine-induced TMA treated by eculizumab were included (6 women, 2 men). Gemcitabine was prescribed for pancreatic (n=3, 37.5%), ovarian (n=3, 37.5%) and pulmonary (n=2, 25%) cancer. TMA occurred after a median of 5.5 months (range 1.7-13) and a median cumulative dose of 22.8g (range 9.0-48.0). The main characteristics were microangiopathic hemolytic anemia (100%), thrombocytopenia (87.5%), normal ADAMTS13 activity (100%), acute renal failure (100%, including 62% stage 3 acute kidney injury (AKI) and 25% renal replacement therapy), hypertension (75%) and diffuse oedema (62.5%). Eculizumab was started after a median of 19.5 days (range 6-44) following TMA diagnosis. A median of 4.5 injections of eculizumab was performed (range 3-22). Complete haematological remission was achieved in 6 patients (75%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 2 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, p=.015). Two patients recovered completely renal function (25%), and 4 achieved a partial remission (50%), with a median estimated glomerular filtration rate (GFR) improvement of 15 ml/min/1.73m2 (range 7-16). Five patients (62.5%) died during follow-up, from a septic and hemorrhagic shock on early stage (1 case), and from cancer evolution after a median of 6 months (range 2-13) following eculizumab initiation (4 cases). Conclusion: These encouraging results suggest that eculizumab is efficient on hemolysis and reduces transfusion requirement in gemcitabine-induced TMA. Moreover, eculizumab may improve renal function. Prospective trials are now required to further investigate this issue. Disclosures No relevant conflicts of interest to declare.

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Successful Treatment of aHUS Recurrence and Arrest of Plasma Exchange Resistant TMA Post-Renal Transplantation with the Terminal Complement Inhibitor Eculizumab.

Blood ◽

10.1182/blood.v114.22.2421.2421 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2421-2421 ◽

Cited By ~ 10

Author(s):

Daniel J Legault ◽

Mark R Boelkins

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Renal Transplantation ◽

Serum Creatinine ◽

Renal Biopsy ◽

Thrombotic Microangiopathy ◽

Complement Inhibitor ◽

Post Transplant ◽

Terminal Complement

Abstract Abstract 2421 Poster Board II-398 Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and acute renal failure (ARF). The prognosis for aHUS is poor as 25% of patients die during acute phases of the disease and 50% progress to end stage renal disease (ESRD). A high percentage of patients with aHUS experience recurrence and graft failure following renal transplantation. This report summarizes the successful use of a terminal complement inhibitor as a treatment for aHUS following renal transplant with demonstration of both clinical and pathological resolution of aHUS in a patient who was resistant to plasma therapy. A 34-year-old female with ESRD due to aHUS underwent living related renal transplantation. Approximately one month after renal transplantation, she presented with acute renal failure (ARF), with creatinine (Cr) increasing from 1.2 to 2.2 mg/dl. The renal biopsy showed thrombotic microangiopathy (TMA). ADAMTS-13 activity was normal. Tacrolimus was discontinued and corticosteroids were initiated. She responded to 14 sessions of every-other-day plasma exchange (PLEX), with stabilization of her creatinine at 1.5mg/dl. At month 5, she again presented with ARF with a renal biopsy showing TMA. PLEX was initiated once again (3 times per week) but her serum creatinine did not improve significantly during PLEX from month 5 to month 9 and ranged from 1.9 to 2.3 mg/dL with urine protein:creatinine ratio of 1.7 to 3.0. Elevations of Cr (2.34 to 3.65mg/dLl), modest elevations in LDH (209 to 380 IU/L) and ∼20% decrease in platelets (227 to 185 × 109/L) were observed when PLEX was interrupted. Diagnostic renal biopsy during this period of PLEX dependency displayed ongoing TMA. With ongoing persistent TMA despite maximal PLEX, at month 9, treatment with eculizumab, a humanized monoclonal antibody that blocks the cleavage of the terminal complement molecule C5 and generation of pro-inflammatory C5a and C5b-9, was initiated. The patient was dosed with eculizumab 900mg weekly for 4 weeks followed by 1200mg at week 5 and 1200mg every 2 weeks thereafter. After 4 weeks of induction therapy with eculizumab and no PLEX sessions, her serum creatinine stabilized at 4.0 to 4.3 mg/dL. At month 10 post transplant, and 7 weeks after the switch from PLEX to eculizumab, renal biopsy now showed no TMA and moderate residual interstitial fibrosis. Fifteen (15) months post transplant and 6 months of eculizumab treatment, the patient continues on eculizumab maintenance therapy with no requirement for PLEX. She is experiencing her best stable renal function to date, with Cr=2.7 mg/dL, a urine protein:creatinine ratio of 2.29 as well as normal platelet counts and slightly elevated LDH (∼350 IU/L) with normal haptoglobin. These results demonstrate that PLEX following recurrent aHUS post transplant did not stabilize renal function and biopsy-proven TMA persisted despite intensive PLEX therapy post transplant. In contrast, switch of PLEX to chronic terminal complement inhibitor treatment with eculizumab resolved the TMA process, stabilized and improved the transplanted kidney function, and eliminated the need for PLEX for this patient with recurrent aHUS post transplant. Clinical trials to further investigate and confirm the efficacy of eculizumab in the treatment of aHUS are ongoing. Disclosures: Legault: Alexion Pharmaceuticals: Research Funding. Off Label Use: Eculizumab, a terminal complement inhibitor, used to treat aHUS.

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Acute renal failure and the MELAS syndrome, a mitochondrial encephalomyopathy.

Journal of the American Society of Nephrology ◽

10.1681/asn.v75647 ◽

1996 ◽

Vol 7 (5) ◽

pp. 647-652

Author(s):

F Hsieh ◽

R Gohh ◽

L Dworkin

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Lactic Acidosis ◽

Renal Involvement ◽

Mitochondrial Encephalomyopathy ◽

Melas Syndrome ◽

Mitochondrial Encephalomyopathies ◽

Hypoxic Injury ◽

Tubular Necrosis

Melas (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) is one of a group of heterogeneous yet clinically distinct syndromes ascribed to a defect in mitochondrial function. Here, the case of a patient diagnosed with the MELAS syndrome who subsequently developed acute renal failure is reported. Although no clear renal insult was evident at the time, the clinical picture was consistent with the diagnosis of acute tubular necrosis. The patient's renal function subsequently returned to baseline. This article reviews the literature concerning renal involvement in the mitochondrial encephalomyopathies, including MELAS, and proposes a mechanism by which patients suffering from mitochondrial disorders may be more susceptible to renal hypoxic injury and acute renal failure.

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Plasma D Dimer: A Useful Marker of Fibrin Breakdown in Renal Failure

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646627 ◽

1989 ◽

Vol 61 (03) ◽

pp. 522-525 ◽

Cited By ~ 32

Author(s):

M P Gordge ◽

R W Faint ◽

P B Rylance ◽

H Ireland ◽

D A Lane ◽

...

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Monoclonal Antibodies ◽

Diabetic Nephropathy ◽

Renal Disease ◽

Plasma Concentrations ◽

Significant Negative Correlation ◽

Healthy Controls ◽

D Dimer

SummaryD dimer and other large fragments produced during the breakdown of crosslinked fibrin may be measured by enzyme immunoassay using monoclonal antibodies. In 91 patients with renal disease and varying degrees of renal dysfunction, plasma D dimer showed no correlation with renal function, whereas FgE antigen, a fibrinogen derivative which is known to be cleared in part by the kidney, showed a significant negative correlation with creatinine clearance. Plasma concentrations of D dimer were, however, increased in patients with chronic renal failure (244 ± 3l ng/ml) (mean ± SEM) and diabetic nephropathy (308 ± 74 ng/ml), when compared with healthy controls (96 ± 13 ng/ml), and grossly elevated in patients with acute renal failure (2,451 ± 1,007 ng/ml). The results indicate an increase in fibrin formation and lysis, and not simply reduced elimination of D dimer by the kidneys, and are further evidence of activated coagulation in renal disease. D dimer appears to be a useful marker of fibrin breakdown in renal failure.

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Effect of Curcuma longa and Galega orientalis on renal function in rats with experimental diabetes mellitus and acute renal failure

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2019.04.88-95 ◽

2019 ◽

pp. 88-95

Author(s):

Р.И. Айзман ◽

А.П. Козлова ◽

Е.И. Гордеева ◽

М.С. Головин ◽

Г.А. Корощенко ◽

...

Keyword(s):

Diabetes Mellitus ◽

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Experimental Diabetes ◽

Curcuma Longa ◽

Diabetic Rats ◽

Standard Diet ◽

Experimental Diabetes Mellitus ◽

Galega Orientalis

Цель - исследование влияния куркумы длинной и галеги восточной на осмо- и ионорегулирующую функции почек крыс при аллоксан-индуцированном сахарном диабете и острой почечной недостаточности в эксперименте. Методика. Эксперименты выполнены на самцах крыс Wistar (n=70) с моделью сахарного диабета (1-я серия) и острой почечной недостаточности (2-я серия). В обеих сериях животные были поделены на 3 группы: крыс 1-й группы содержали на стандартном корме, крысам остальных групп в корм добавляли куркуму (2-я группа) или галегу (3-я группа) (2% от массы корма). На 7-е сут эксперимента проводили исследование диуретической и ионоуретической функций почек натощак и после 5% водной нагрузки. Концентрацию ионов в моче и плазме определяли методом пламенной фотометрии; осмотическую концентрацию биологических жидкостей - методом криоскопии; биохимические показатели крови - колориметрическим методом. Результаты. У животных с сахарным диабетом фоновый диурез, а также экскреция натрия и калия были статистически значимо выше, чем у контрольных животных. При острой почечной недостаточности наблюдался более низкий уровень диуреза и ионоуреза, особенно после водной нагрузки. Прием куркумы и галеги вызывал улучшение осмо- и ионорегулирующей функции почек у крыс с сахарным диабетом, и практически не влиял на эти функции почек при острой почечной недостаточности. Заключение. При сахарном диабете оба фитопрепарата вызывали понижение концентрации глюкозы, креатинина, мочевины и улучшение ионно-осмотических показателей плазмы крови, при этом эффект куркумы был выражен отчетливее. При острой почечной недостаточности эти фитопрепараты не давали описанного эффекта. Aim. To study effects of the phytomedicines, Curcuma longa and Galega orientalis, on osmosis- and ion-regulating renal functions in rats with experimental diabetes mellitus (DM) and acute renal failure (ARF). Methods. Experiments were performed in two series on Wistar male rats (n=70) with modeled diabetes mellitus (series 1) and acute renal failure (series 2). In each series, the animals were divided into 3 groups, 1) rats of group 1 receiving a standard diet; 2) rats of groups 2 and 3 receiving a standard diet supplemented with turmeric or galega (2% of food weight), respectively. On the 7th day of the experiment, the diuretic and ionuretic renal function was studied in fasting state and after 5% water loading. Concentrations of ions in urine and plasma were determined by flame photometry; osmotic concentrations of biological fluids were measured by cryoscopy; blood biochemical parameters were measured by colorimetry. Results. In diabetic rats, background diuresis and sodium and potassium excretion were significantly higher than in the control animals. In rats with acute renal failure, diuresis and ionuresis were significantly lower, particularly after the water loading. Turmeric and galega supplementation improved the osmotic and ion-regulating renal function in diabetic rats and left practically unchanged these functions in rats with acute renal failure. Conclusion. In rats with diabetes mellitus, both herbal remedies reduced concentrations of glucose, creatinine, and urea and improved ion-osmotic parameters of blood plasma with a more pronounced effect of turmeric. In acute renal failure, these phytomedicines did not produce the described effects.

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Faculty Opinions recommendation of Predictors of postoperative acute renal failure after noncardiac surgery in patients with previously normal renal function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1099139.555351 ◽

2008 ◽

Author(s):

Lee Fleisher ◽

Michael Banks

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Normal Renal Function ◽

Noncardiac Surgery

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Predictors of Postoperative Acute Renal Failure after Noncardiac Surgery in Patients with Previously Normal Renal Function

Anesthesiology ◽

10.1097/01.anes.0000290588.29668.38 ◽

2007 ◽

Vol 107 (6) ◽

pp. 892-902 ◽

Cited By ~ 323

Author(s):

Sachin Kheterpal ◽

Kevin K. Tremper ◽

Michael J. Englesbe ◽

Michael O’Reilly ◽

Amy M. Shanks ◽

...

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Creatinine Clearance ◽

Normal Renal Function ◽

Noncardiac Surgery ◽

Intraoperative Management ◽

All Cause Mortality ◽

Calculated Creatinine Clearance ◽

Preoperative Predictors

Background The authors investigated the incidence and risk factors for postoperative acute renal failure after major noncardiac surgery among patients with previously normal renal function. Methods Adult patients undergoing major noncardiac surgery with a preoperative calculated creatinine clearance of 80 ml/min or greater were included in a prospective, observational study at a single tertiary care university hospital. Patients were followed for the development of acute renal failure (defined as a calculated creatinine clearance of 50 ml/min or less) within the first 7 postoperative days. Patient preoperative characteristics and intraoperative anesthetic management were evaluated for associations with acute renal failure. Thirty-day, 60-day, and 1-yr all-cause mortality was also evaluated. Results A total of 65,043 cases between 2003 and 2006 were reviewed. Of these, 15,102 patients met the inclusion criteria; 121 patients developed acute renal failure (0.8%), and 14 required renal replacement therapy (0.1%). Seven independent preoperative predictors were identified (P < 0.05): age, emergent surgery, liver disease, body mass index, high-risk surgery, peripheral vascular occlusive disease, and chronic obstructive pulmonary disease necessitating chronic bronchodilator therapy. Several intraoperative management variables were independent predictors of acute renal failure: total vasopressor dose administered, use of a vasopressor infusion, and diuretic administration. Acute renal failure was associated with increased 30-day, 60-day, and 1-yr all-cause mortality. Conclusions Several preoperative predictors previously reported to be associated with acute renal failure after cardiac surgery were also found to be associated with acute renal failure after noncardiac surgery. The use of vasopressor and diuretics is also associated with acute renal failure.

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Renal function following acute renal failure in childhood: A long term follow-up study

Kidney International ◽

10.1038/ki.1989.11 ◽

1989 ◽

Vol 35 (1) ◽

pp. 84-89 ◽

Cited By ~ 23

Author(s):

Helen N. Georgaki-Angelaki ◽

David B. Steed ◽

Cyril Chantler ◽

George B. Haycock

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Follow Up Study ◽

Long Term Follow Up

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Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction

Clinical Science ◽

10.1042/cs103s434s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 434S-437S ◽

Cited By ~ 27

Author(s):

Masanori TAKAOKA ◽

Mikihiro YUBA ◽

Toshihide FUJII ◽

Mamoru OHKITA ◽

Yasuo MATSUMURA

Keyword(s):

Renal Failure ◽

Renal Function ◽

Acute Renal Failure ◽

Renal Dysfunction ◽

Tissue Injury ◽

Male Rats ◽

Left Renal Artery ◽

Protective Effects ◽

Endothelin 1 ◽

Ischaemia Reperfusion

We investigated whether the treatment with 17β-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17β-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17β-oestradiol (20 or 100µg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17β-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17β-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.

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