Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort.

AIMS: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). METHODS: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. RESULTS: G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m-2 . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. CONCLUSION: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.

Immunoadsorption and Plasma Exchange are Comparable in Anti-Neutrophil Cytoplasmic Antibodies or Anti-Glomerular Basement Membrane Removal Kinetics.

Introduction: Apheresis allows the fast removal of autoantibodies in anti-glomerular basement membrane (anti-GBM) disease, and in severe antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. The CINEVAS study tested whether immunoadsorption (IA) allowed a faster removal of ANCA and/or anti-GBM antibodies than plasma exchanges (PEx). Methods: CINEVAS was a prospective multicenter study comparing IA to PEx in consecutive patients with ANCA and/or anti-GBM vasculitides. The primary objective was the reduction rate in autoantibody titers between the beginning of the first and the end of the seventh apheresis session. Secondary objectives were number of sessions needed to obtain desired reduction rates; reduction rates of total Ig levels; tolerance of sessions; and patients' outcome. Results: The results of 38 patients (16 treated with IA and 22 with PEx), and 43 autoantibodies, were analyzed. There was no difference in the reduction rates in autoantibody titers between IA and PEx over 7 sessions (respectively 98% vs. 96%, P = 0.39). The numbers of sessions needed to obtain undetectable autoantibodies, or 50%, 75%, or 90% reductions, did not differ between techniques. Greater reduction rates of autoantibodies were observed when plasma was separated by filtration compared to centrifugation, with IA and PEx. IA allowed a greater reduction in total IgG levels, and better preservation of total IgA and IgM levels than PEx. PEx sessions required higher volumes of plasma, IA sessions higher volumes of citrate; IA sessions were longer. Conclusions: IA and PEx were comparable in ANCA or anti-GBM removal kinetics, despite a faster reduction in total IgG with IA.

Thrombocytopenia is not mandatory to diagnose haemolytic and uremic syndrome.

BACKGROUND: Hemolytic and uremic syndrome (HUS) diagnosis involves association of non immune hemolytic anemia, thrombocytopenia, and renal failure. HUS without thrombocytopenia has been observed, we call it partial HUS. Its real frequency and outcome are unknown. The aim of this study was to determine the prevalence of patients with normal platelets count in two HUS cohorts and to compare their outcome to patients with thrombocytopenia. METHODS: We retrospectively identified HUS diagnosis in two different cohorts. The first cohort was from a single center and consisted of all cases of HUS whatever the aetiology, the second was multicentric and consisted of atypical HUS patients. These cohorts were divided into two groups depending on the presence or absence of thrombocytopenia. Clinical and biological data were compared between thrombopenic and non thrombopenic group. RESULTS: We identified 13% (20/150) of patients with normal platelets count: 10 episodes (18%) of HUS in six patients (14%) in the monocentric cohort and 14 patients (13%) with 17 episodes (12%) in the multicentric cohort of atypical HUS. Groups differed in platelets count and LDH level. In both cohorts, renal outcome was similar to patient presenting with thrombocytopenia. CONCLUSION: HUS with normal platelets count is not infrequent. Relative to classical clinical presentation of HUS, partial HUS has similar characteristics and identical poor renal outcome and so must be treated in the same way.

Short- and long-term renal outcomes following severe rhabdomyolysis: a French multicenter retrospective study of 387 patients.

BACKGROUND: Rhabdomyolysis is a life-threatening disease that can lead to severe hyperkalemia, acute kidney injury (AKI) and hypovolemic shock. The predictive factors of AKI and acute to chronic kidney disease (CKD) transition remain poorly described. METHODS: This multicenter retrospective study enrolled 387 patients with severe rhabdomyolysis (CPK > 5000 U/L). Primary end-point was the development of severe AKI, defined as stage 2 or 3 of KDIGO classification. Secondary end-points included the incidence of AKI to CKD transition. RESULTS: Among the 387 patients, 315 (81.4%) developed AKI, including 171 (44.1%) with stage 3 AKI and 103 (26.6%) requiring RRT. Stage 2-3 AKI was strongly correlated with serum phosphate, potassium and bicarbonate at admission, as well as myoglobin over 8000 U/L and the need for mechanical ventilation. 42 patients (10.8%) died before day 28. In the 80 patients with available eGFR values both before and 3 months after the rhabdomyolysis, the decrease in eGFR (greater than 20 mL/min/1.73 m2 in 23 patients; 28.8%) was correlated to the severity of the AKI and serum myoglobin levels > 8000 U/L at admission. CONCLUSIONS: Severe rhabdomyolysis leads to AKI in most patients admitted to an ICU. Mechanical ventilation and severity of the rhabdomyolysis, including myoglobin level, are associated with the risk of stage 2-3 AKI. The long-term renal decline is correlated to serum myoglobin at admission.

Risk factors for severity of COVID-19 in chronic dialysis patients from a multicentre French cohort.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease, related to severe acute respiratory syndrome coronavirus 2 infection. Few data are available in patients with end-stage renal disease (ESRD). METHODS: We conducted an observational cohort study of COVID-19 patients at 11 dialysis centres in two distinct districts of France to examine the epidemiological and clinical characteristics of COVID-19 in this population, and to determine risk factors of disease severity (defined as a composite outcome including intensive care unit admission or death) and mortality. RESULTS: Among the 2336 patients enrolled, 5.5% had confirmed COVID-19 diagnosis. Of the 122 patients with a follow-up superior to 28 days, 37% reached the composite outcome and 28% died. Multivariate analysis showed that oxygen therapy on diagnosis and a decrease in lymphocyte count were independent risk factors associated with disease severity and with mortality. Chronic use of angiotensin II receptor blockers (ARBs) (18% of patients) was associated with a protective effect on mortality. Treatment with azithromycin and hydroxychloroquine (AZT/HCQ) (46% of patients) were not associated with the composite outcome and with death in univariate and multivariate analyses. CONCLUSIONS: COVID-19 is a severe disease with poor prognosis in patients with ESRD. Usual treatment with ARBs seems to be protective of critical evolution and mortality. There is no evidence of clinical benefit with the combination of AZT/HCQ.

Metformin-related lactic acidosis with acute kidney injury: results of a French observational multicenter study.

Background: Metformin-associated lactic acidosis (MALA) and metformin-induced lactic acidosis (MILA) remain controversial entities. Metformin toxic effect depends on accumulation to lead to lactic acidosis (LA), particularly during an episode of acute kidney injury (AKI). In MILA, no other condition contributing to LA is found. The aims of this study were to describe the characteristics and prognosis of AKI associated with LA in metformin users and to clarify the role of this drug in the different types of LA.Methods: We performed a French multicenter retrospective study in diabetic patients treated by metformin presenting with LA in a context of AKI in 2015. 126 nephrology units (NU) and 23 intensive care units (ICU) were contacted. We individualized MILA and MALA patients in order to illustrate the role of metformin.Results: We included 173 patients (109 MILA, 64 MALA). 103 patients presented without hemodynamic instability (82 MILA and 21 MALA) whereas 70 patients were shocked including 27 MILA. The shock was associated with death with an odds ratio (OR) of 12.92 (p < .001). Digestive disorders (DD) were strongly associated with MILA (p = .0001). MALA was significantly associated with shock (p < .0001). The mortality rate was higher in MALA (26%) when compared with MILA (7%). Dialysis performed in 133 patients was significantly associated with shock, kalemia, lactate and serum creatinine levels. In multivariate analysis, metformin level was independently associated with pH or lactate level only in MILA patients.Conclusions: MILA is associated with DD and death is due to severe refractory acidosis leading to cardiovascular collapse attributed to metformin accumulation mainly via AKI. MALA patients are more frequently shocked and death is related to their underlying condition, metformin accumulation increasing LA.

Apheresis to treat systemic vasculitis.

Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for over 40 years. The aim is to rapidly remove autoantibodies or circulating immune complexes from the plasma. The two main indications at present are vasculitis associated with Antineutrophil Cytoplasmic Antibodies (ANCAs) manifesting as severe renal involvement and/or intraalveolar hemorrhage and antiglomerular basement membrane disease (Goodpasture syndrome). The ongoing PEXIVAS randomized controlled trial is assessing plasmapheresis to treat ANCA-associated vasculitis with or without severe renal involvement or intraalveolar hemorrhage. The two main apheresis techniques used to treat systemic vasculitis are plasmapheresis (by filtration, centrifugation, or double filtration) and immunoadsorption. The advantages and drawbacks of each technique are discussed here. Whether one technique is superior over the other in the current indications has not been proven.

[Uro- and nephrotoxic effects of drugs of abuse: Literature review and pharmaco-epidemiological survey in France and in the Marseille area]. / Effets uro-néphrologiques des produits utilisés par les usagers de drogues : revue de la littérature et enquête pharmaco-épidémiologique en France et dans la région de Marseille.

A great diversification of drugs of abuse has been observed in recent years, both in the populations using them and in the types of drugs. Although dependency and psychiatric disorders associated with the abuse of these substances is well known, somatic complications, uro-nephrotoxicity in particular, are less recognized. We propose here an overview of the products used by drugs abusers in France, through the analysis of the national pharmaco-epidemiological study Observation des produits psychotropes illicites ou détournés de leur utilisation médicamenteuse (OPPIDUM). Among the 5003 patients who participated in this survey, 84% were on prescribed psychoactive substances, with indicators of abuse in 28% of cases; more than half of these patients had also been using drugs of abuse (mainly cannabis) in the previous week. We then describe the main urological and renal toxicities of these drugs, in particular of heroin, cocaine, cannabis, ecstasy, LSD, amphetamine, new designer drugs, ketamine and opiate substitution treatment. We finally present a pharmaco-epidemiological survey of patients hospitalized for drugs complications in nephrology at the university hospital of Marseille. Between 2000 and 2015, 22 patients aged 18 to 57 years were hospitalized for renal adverse effects of drugs of abuse, such as glomerulonephritides, focal segmental glomerulosclerosis, acute kidney injury or chronic kidney disease. The somatic complications of drugs participate in their dangerousness and should be a red flag. They should be systematically reported to the addictovigilance national network to allow the improvement of information given to the patients and the medical community, and to adapt the prevention and risk reduction policies.

[Beware, polyarteritis nodosa still exists in nephrology!] / Attention, la périartérite noueuse existe encore en néphrologie !

Renal involvement of systemic vasculitides is an emergency in nephrology. Although it has become very rare, the diagnosis of polyarteritis nodosa must be considered in some patients. A 70-year-old patient, previously healthy, presented with acute renal failure and malignant hypertension and abundant albuminuria. Subcutaneous nodule, orchitis and mononeuritis appeared subsequently. The search for auto-immunity or viral infection was negative. Markers of thrombotic microangiopathy, present initially, resolved after blood pressure control. After a renal computed tomography with contrast medium injection was considered normal, without any micro-aneurysm, a renal biopsy was performed. It showed vascular lesions and glomerular ischemia. It was complicated by hemorragic shock after 36hours. The diagnosis of periarteritis nodosa was finally made after arterial angiography showed millimetric renal micro-aneurysms. In case of systemic vasculitis with renal involvement, periarteritis nodosa must be part of differential diagnosis, especially in case of malignant hypertension, subcutaneous nodosa and orchitis, and despite albuminuria. This implies the search for micro-aneurysms with arterial angiography, and the contraindication of renal biopsy, associated with a high risk of severe hemorrhage. Periarteritis nodosa still exists in nephrology, even without hepatitis B infection. The association of acute renal failure with medium vessel vasculitis, with negative ANCA, must alert the nephrologist and lead to arterial angiography not to renal biopsy.

A pilot study comparing furosemide and hydrochlorothiazide in patients with hypertension and stage 4 or 5 chronic kidney disease.

Furosemide is the diuretic of choice for the treatment of hypertension in chronic kidney disease but the adaptative changes in the distal nephron may decrease its efficacy. Hydrochlorothiazide is not believed to be efficient in this setting. In a randomized, double-blind, cross-over trial, 23 patients with hypertension and stage 4 or 5 chronic kidney disease received long-acting furosemide (60 mg) and hydrochlorothiazide (25 mg) for 3 months and then both diuretics for 3 months. Sodium and chloride fractional excretions were measured after 3 months of each diuretic and then after their association. A trend towards an increase in the fractional excretion of sodium and chloride was observed with furosemide and hydrochlorothiazide (P=not significant). The association of the two diuretics increased the fractional excretions of sodium and chloride from 3.4±1.8 to 4.9±2.8 and from 3.8±2.0 to 6.0±3.1, respectively (P<.05). Furosemide and hydrochlorothiazide decreased mean blood pressure by the same extent. The association of the two diuretics was more efficient on blood pressure. There were no differences between furosemide and hydrochlorothiazide with respect to natriuresis and blood pressure control in patients with hypertension and chronic kidney disease.

A randomized trial with steroids and antithymocyte globulins comparing cyclosporine/azathioprine versus tacrolimus/mycophenolate mofetil (CATM2) in renal transplantation.

BACKGROUND: The best immunosuppressive regimen in benefit-risk ratio in renal transplantation is debated. Nowadays, tacrolimus (Tac) and mycophenolate mofetil (MMF) are considered more efficient than cyclosporine A (CsA) and MMF, but recent studies have challenged this assumption. METHODS: We conducted a monocentric, prospective, open-labeled, randomized, and controlled trial comparing CsA/azathioprine (Aza) versus Tac/MMF in 289 kidney transplant recipients treated with antithymocyte globulins and prednisone. Primary outcome was the number of patients with clinically suspected acute rejection at 1 year. Secondary outcomes were the number of patients with biopsy-proven acute rejection (BPAR), estimated glomerular filtration rate (eGFR), patient and graft survivals, and adverse events at 1 and 3 years. RESULTS: During the first year, 21 patients had clinically suspected acute rejection with CsA/Aza (14.4%) vs. 11 (7.7%) with Tac/MMF (P=0.07). BPAR, including borderline, was more frequent in the CsA/Aza group (14.4%) than in the Tac/MMF group (5.6%; P=0.013). At 1 year, patient and graft survivals were not different, and eGFR was 48±1 in the CsA/Aza group and 53±1 mL/min/1.73 m in the Tac/MMF group (P=0.007). There was no significant difference in diabetes after transplantation (16.8% and 18.8%, respectively). CONCLUSIONS: With antithymocyte globulins and steroids, clinically suspected acute rejections did not differ between CsA/Aza and Tac/MMF arms. Analysis of secondary endpoints showed a lower rate of BPAR, including border line, and a higher eGFR in the Tac/MMF group. CsA/Aza allowed a low acute rejection rate, but Tac/MMF seemed as a better regimen regarding severe secondary outcomes.

A randomized trial of furosemide vs hydrochlorothiazide in patients with chronic renal failure and hypertension.

BACKGROUND: Loop diuretics are the drugs of choice for the treatment of hypertension in chronic renal failure patients. However, the adaptive changes in the distal nephron and the short half-life of these drugs may decrease their long-term efficacy. Thiazides are not believed to be efficient in advanced renal failure, but this is debated. METHODS: We compared the efficacy of long-acting furosemide (60 mg/day) and hydrochlorothiazide (25 mg/day) in a double-blind, randomized crossover trial in seven patients with severe renal failure and hypertension (seven men, 54+/-10 years old). The primary end-points were sodium and chloride fractional excretions after 1 month of each diuretic and then after their combination. During the trial, other treatments and the diet were controlled. RESULTS: A trend towards an increase in the fractional excretion of sodium and of chloride was observed with furosemide, but the difference did not reach the level of statistical significance (P = NS). Hydrochlorothiazide significantly increased fractional excretion of sodium and chloride from 3.7+/-0.9 to 5.5+/-0.3 and from 3.9+/-0.19 to 6.5+/-0.3, respectively (P<0.05). The combination of the two diuretics had no additional effect on the increase in sodium and chloride fractional excretion. Furosemide, hydrochlorothiazide and the combination of the two diuretics decreased mean arterial blood pressure by the same extent from 112 to 97, 99 and 97 mmHg, respectively (P<0.05). CONCLUSIONS: Hydrochlorothiazide increased the fractional excretion of sodium and chloride more than furosemide did in hypertensive severe renal failure patients. Mean arterial blood pressure decreased by the same amount with both diuretics. Combining furosemide and hydrochlorothiazide did not increase the efficacy of hydrochlorothiazide.