Rituximab Responsive Relapsing-Remitting IgG4 Anticontactin 1 Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated With Membranous Nephropathy: A Case Description and Brief Review.

ABSTRACT: Nodal/paranodal IgG4-related chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) rarely involves anticontactin (CNTN1) subtype and exceptionally complicates with nephrotic syndrome. A 65-year-old man developed weakness, facial palsy, and balance impairment; after spontaneous recovery, he severely relapsed 1 month later. Electroneuromyography confirmed CIDP. Proteinorachy (462 mg/dL; N < 45), proteinuria (3.5 g/g creatine), and biopsy-proven membranous nephropathy were identified. Intravenous immunoglobulins, corticosteroids, and plasmaphereses did not allow recovery. Anti-CNTN1 immunoglobulin G4 (IgG4) assay was positive. Rituximab (375 mg/m2/week, 4 weeks) provided obvious improvement. Relapsing-remitting anti-CNTN1-CIDP co-occurring with nephrotic syndrome is exceptional, and its identification is essential because efficient therapies such as rituximab are available for this severe condition.

Donor-Derived Myeloid Heme Oxygenase-1 Controls the Development of Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) remains a major clinical drawback of allogeneic hematopoietic stem cell transplantation (HSCT). Here, we investigated how the stress responsive heme catabolizing enzyme heme oxygenase-1 (HO-1, encoded by HMOX1) regulates GVHD in response to allogeneic hematopoietic stem cell transplantation in mice and humans. We found that deletion of the Hmox1 allele, specifically in the myeloid compartment of mouse donor bone marrow, promotes the development of aggressive GVHD after allogeneic transplantation. The mechanism driving GVHD in mice transplanted with allogeneic bone marrow lacking HO-1 expression in the myeloid compartment involves enhanced T cell alloreactivity. The clinical relevance of these observations was validated in two independent cohorts of HSCT patients. Individuals transplanted with hematopoietic stem cells from donors carrying a long homozygous (GT)n repeat polymorphism (L/L) in the HMOX1 promoter, which is associated with lower HO-1 expression, were at higher risk of developing severe acute GVHD as compared to donors carrying a short (GT)n repeat (S/L or S/S) polymorphism associated with higher HO-1 expression. In this study, we showed the unique importance of donor-derived myeloid HO-1 in the prevention of lethal experimental GVHD and we corroborated this observation by demonstrating the association between human HMOX1 (GT)n microsatellite polymorphisms and the incidence of severe acute GVHD in two independent HSCT patient cohorts. Donor-derived myeloid HO-1 constitutes a potential therapeutic target for HSCT patients and large-scale prospective studies in HSCT patients are necessary to validate the HO-1 L/L genotype as an independent risk factor for developing severe acute GVHD.

Mental Health Outcomes in Healthcare Workers in COVID-19 and Non-COVID-19 Care Units: A Cross-Sectional Survey in Belgium.

BACKGROUND: The literature shows the negative psychological impact of the coronavirus disease 2019 (COVID-19) outbreak on frontline healthcare workers. However, few are known about the mental health of physicians and nurses working in general hospitals during the outbreak, caring for patients with COVID-19 or not. OBJECTIVES: This survey assessed differences in mental health in physicians and nurses working in COVID-19 or non-COVID-19 medical care units. DESIGN: A cross-sectional mixed-mode survey was used to assess burnout, insomnia, depression, anxiety, and stress. SETTING: A total of 1,244 physicians and nurses from five general hospitals in Belgium, working in COVID-19 care units (CCU), non-COVID-19 care units (NCCU), or both (CCU + NCCU) were informed of the study. PARTICIPANTS: Six hundred forty-seven healthcare workers participated in the survey (response rate = 52%). MEASUREMENTS: Validated instruments were used to assess the outcomes: the PFI (burnout/professional fulfillment), the ISI (insomnia), and the DASS-21 (depression, anxiety, and stress). RESULTS: Results showed high prevalence of burnout, insomnia, depression, and anxiety among participants. After adjusting for confounders, multivariate analysis of variance showed no differences between CCU, NCCU, and CCU + NCCU workers. Univariate general linear models showed higher level of burnout, insomnia, and anxiety among nurses in comparison to physicians. Being a nurse, young, isolated, with an increased workload were risk factors for worse mental health outcomes. LIMITATIONS: The mental health of the tested sample, before the outbreak, is unknown. Moreover, this cross-sectional design provides no information on the evolution of the mental health outcomes over time. CONCLUSION: Directly caring for patients with COVID-19 is not associated with worse mental health outcomes among healthcare workers in general hospitals. High prevalence of burnout, insomnia, depression, and anxiety among physicians and nurses requires special attention, and specific interventions need to be implemented. PROTOCOL REGISTRATION: ClinicalTrials.gov, identifier NCT04344145.

HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk.

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). IRI-induced AKI releases proinflammatory cytokines (e.g. IL-1ß, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in proinflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur. Acute lung injury (ALI) is a major remote organ dysfunction associated with AKI. Hence, kidney-lung cross-talk remains a clinical challenge, especially in critically ill population. The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against renal IRI and may be preventively induced using hemin prior to renal insult. However, the use of hemin-induced HO-1 to prevent AKI-induced ALI remains poorly investigated. Mice received an intraperitoneal injection of hemin or sterile saline 1 day prior to surgery. Twenty-four hours later, mice underwent bilateral renal IRI for 26 min or sham surgery. After 4 or 24 h of reperfusion, mice were sacrificed. Hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation, and oxidative stress). This protective effect was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, mitigated lung inflammation was found in hemin-treated mice (i.e. neutrophils influx and lung KC). The present study demonstrates that hemin-induced HO-1 controls the magnitude of renal IRI and the subsequent AKI-induced ALI. Therefore, targeting HO-1 represents a promising approach to prevent the impact of renal IRI on distant organs, such as lung.

Prevalence of asymptomatic bacteriuria among kidney transplant recipients beyond two months post-transplant: A multicenter, prospective, cross-sectional study.

BACKGROUND: During routine post-kidney transplant care, most European transplant physicians screen patients for asymptomatic bacteriuria. The usefulness of this strategy is debated. To make screening cost-effective, asymptomatic bacteriuria should be prevalent enough to justify the expense, and antibiotics should improve patient outcomes significantly if asymptomatic bacteriuria is detected. Regrettably, the prevalence of asymptomatic bacteriuria among kidney transplant recipients is not well defined. METHODS: To determine the prevalence of asymptomatic bacteriuria among kidney transplant recipients, we did a cross-sectional study among kidney transplant recipients undergoing routine surveillance in three outpatient transplant clinics in Belgium and France. We excluded patients who were in the first two months post-transplantation and/or had a urinary catheter. Asymptomatic participants who had a urine culture with one organism isolated at ≥ 105 CFU/mL were asked to provide a confirmatory urine specimen. Asymptomatic bacteriuria was defined per Infectious Diseases Society of America guidelines. RESULTS: We screened 500 consecutive kidney transplant recipients. Overall, the prevalence of asymptomatic bacteriuria was 3.4% (17/500 patients). It was similarly low among kidney transplant recipients who were between 2 and 12 months after transplantation (1.3%, 1/76 patients) and those who were farther after transplantation (3.8%, 16/424 patients: p = 0.49). Asymptomatic bacteriuria was significantly associated with female gender (risk ratio 3.7, 95% CI 1.3-10.3, p = 0.007) and older age (mean age: 61 ± 12 years [bacteriuric participants], versus 53 ± 15 years [non-bacteriuric participants], p = 0.03). One participant's colistin-resistant Escherichia coli isolate carried the globally disseminated mcr-1 gene. CONCLUSIONS: Among kidney transplant recipients who are beyond the second month post-transplant, the prevalence of asymptomatic bacteriuria is low. Further studies are needed to ascertain the cost-effectiveness of a screen-and-treat strategy for asymptomatic bacteriuria in this population.

Dual effect of hemin on renal ischemia-reperfusion injury.

Acute kidney injury (AKI) is a major public health concern, which is contributing to serious hospital complications, chronic kidney disease (CKD) and even death. Renal ischemia-reperfusion injury (IRI) remains a leading cause of AKI. The stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against renal IRI and may be preventively induced using hemin prior to renal insult. This HO-1 induction pathway called hemin preconditioning is largely known to be effective. Therefore, HO-1 might be an interesting therapeutic target in case of predictable AKI (e.g. partial nephrectomy or renal transplantation). However, the use of hemin to mitigate established AKI remains poorly characterized. Mice underwent bilateral renal IRI for 26 min or sham surgery. After surgical procedure, animals were injected either with hemin (5 mg/kg) or vehicle. Twenty-four hours later, mice were sacrificed. Despite strong HO-1 induction, hemin-treated mice exhibited significant renal damage and oxidative stress as compared to vehicle-treated mice. Interestingly, higher dose of hemin is associated with more severe IRI-induced AKI in a dose-dependent relation. To determine whether hemin preconditioning remains efficient to dampen postoperative hemin-amplified IRI-induced AKI, we pretreated mice either with hemin (5 mg/kg) or vehicle 24 h prior to surgical procedure. Then, all mice (hemin- and vehicle-pretreated) received postoperative injection of hemin (5 mg/kg) to amplify IRI-induced AKI. In comparison to vehicle, prior administration of hemin to renal IRI mitigated hemin-amplified IRI-induced AKI as attested by fewer renal damage, inflammation and oxidative stress. In conclusion, hemin may have a dual effect on renal IRI, protective or deleterious, depending on the timing of its administration.

CD4+ and CD8+ T Cells Exert Regulatory Properties During Experimental Acute Aristolochic Acid Nephropathy.

Experimental aristolochic acid nephropathy is characterized by transient acute proximal tubule necrosis and inflammatory cell infiltrates followed by interstitial fibrosis and tubular atrophy. The respective role of T-cell subpopulations has never been studied in the acute phase of the mouse model, and was heretofore exclusively investigated by the use of several depletion protocols. As compared to mice injected with aristolochic acids alone, more severe acute kidney injury was observed after CD4+ or CD8+ T-cells depletion. TNF-alpha and MCP-1 mRNA renal expressions were also increased. In contrast, regulatory T-cells depletion did not modify the severity of the aristolochic acids induced acute kidney injury, suggesting an independent mechanism. Aristolochic acids nephropathy was also associated with an increased proportion of myeloid CD11bhighF4/80mid and a decreased proportion of their counterpart CD11blowF4/80high population. After CD4+ T-cell depletion the increase in the CD11bhighF4/80mid population was even higher whereas the decrease in the CD11blowF4/80high population was more marked after CD8+ T cells depletion. Our results suggest that CD4+ and CD8+ T-cells provide protection against AA-induced acute tubular necrosis. Interestingly, T-cell depletion was associated with an imbalance of the CD11bhighF4/80mid and CD11blowF4/80high populations.

An exceptional cause of hemoptysis in the elderly patient : IgA vasculitis.

We describe here the case of a 73-year-old woman who presented a recurrent macular rash, acute respiratory distress, and hemoptysis. Chest CT scan showed diffuse ground-glass opacities that were suggestive of alveolar hemorrhage. With the development of severe acute kidney injury and nephrotic-range proteinuria (creatininemia 2.6 from 1.9 mg/dL with overt proteinuria 34 from 2.1 g/g creat), a kidney-lung syndrome was evoked. Skin biopsy revealed leukocytoclastic vasculitis with IgA deposits. Blood tests showed an increased IgA level. Those findings were consistent with a rare form of IgA vasculitis (formerly Henoch-Schönlein syndrome), the originality of the case lying in the occurrence of a kidney-lung syndrome in an elderly patient.

Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury.

Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1M-KO), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b+ F4/80lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1+ CD11b+ F4/80lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.

Acute Kidney Injury After Subarachnoid Hemorrhage.

BACKGROUND: Acute kidney injury (AKI) is common in critically ill patients and may contribute to poor outcome. Few data are available on the incidence and impact of AKI in patients suffering from nontraumatic subarachnoid hemorrhage (SAH). METHODS: We reviewed all patients admitted to our Department of Intensive Care with SAH over a 3-year period. Exclusion criteria were time from SAH symptoms to intensive care unit (ICU) admission >96 hours and ICU stay <48 hours. AKI was defined as sustained oligoanuria (urine output <0.5 mL/kg/h for 24 h) or an increase in plasma creatinine (≥0.3 mg/dL or a 1.5-fold increase from baseline level within 48 h). Neurological status was assessed at day 28 using the Glasgow Outcome Scale (GOS) (from 1=death to 5=good recovery; favorable outcome=GOS 4 to 5). RESULTS: Of 243 patients admitted for SAH during the study period, 202 met the inclusion/exclusion criteria (median age 56 y, 78 male). Twenty-five patients (12%) developed AKI, a median of 8 (4 to 10) days after admission. Independent predictors of AKI were development of clinical vasospasm, and treatment with vancomycin. AKI was more frequent in ICU nonsurvivors than in survivors (11/50 vs. 14/152, P=0.03), and in patients with an unfavorable neurological outcome than in other patients (17/93 vs. 8/109, P=0.03). Nevertheless, in multivariable regression analysis, AKI was not an independent predictor of outcome. CONCLUSIONS: AKI occurred in >10% of patients after SAH. These patients had more severe neurological impairment and needed more aggressive ICU therapy; AKI did not significantly influence outcome.

Preemptive reduction of immunosuppression upon high urinary polyomavirus loads improves patient survival without affecting kidney graft function.

BACKGROUND: Polyomavirus (PV) is a major cause of kidney graft disease. Monitoring by polymerase chain reaction (PCR) on blood is currently recommended. In order to avoid irreversible lesions, we investigated the clinical impact of preemptive reduction of immunosuppression (IS) in kidney transplant recipients (KTR) upon detection of high urinary PV (Upv) load, including BK virus and JC virus. MATERIAL AND METHODS: From 2000 to 2011, in our single center, 789 consecutive KTR were distributed into 4 groups, according to the maximal Upv levels (by PCR) during the first year and the therapeutic option: (A) Upv <104 copies (cp)/mL (n=573), (B) ≥104 Upv <107 cp/mL (n=100), and (C) Upv ≥107 cp/mL (n=116); in group C, the IS drug doses were reduced in subgroup Ca (n=102) only, as 14 patients (subgroup Cb) were at risk for graft rejection. RESULTS: The preemptive reduction of IS (group Ca) increased patient survival as compared with all other groups (P<.05), did not modify graft function, and increased graft survival vs group A (risk ratio: 5.7, confidence interval: 1.8-18.1, P=.003). Differences for risk factors are as follows (groups Ca vs A): incidence of human leukocyte antigen (HLA) immunization (>5% panel reactive antibodies): 3% vs 8% (P=.05), number of HLA mismatches: 2.7 vs 2.5 (P=.049), and incidence of acute rejection: 9.8% vs 24.2% (P=.005). PV-associated nephropathy occurred only in group Ca (2% of total grafts) without effect on patient or graft outcome. CONCLUSION: The reduction of IS in patients with high Upv loads is beneficial for patient survival and does not affect graft survival or graft function.

Chronic kidney disease as major determinant of the renal risk related to on-pump cardiac surgery: a single-center cohort study.

BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication and is associated with the poorest outcomes. Therefore, early prediction of CSA-AKI remains a major issue. Severity scores such as the STS score could estimate the risk of AKI preoperatively. The main objective of this study was to evaluate the risk factors of on-pump CSA-AKI and to assess the performance of the STS score in order to predict CSA-AKI. PATIENTS: We identified 252 patients with on-pump cardiac surgery, and the STS score was defined retrospectively. RESULTS: AKI occurred in 14.6% (n = 37/252) of patients and renal replacement therapy was required in 21.6% of AKI (n = 8/37). CSA-AKI was associated with 35.1% in-hospital mortality (vs. 1.4%) and nearly doubled length of stay (14.5 vs. 8.0 d). The risk of CSA-AKI was mainly determined by preoperative morbidities such as chronic kidney disease, peripheral vascular disease, and severe congestive heart failure. Long cardio-pulmonary bypass time was also a determinant. CSA-AKI + patients exhibited higher STS renal risk (5.6% vs. 2.0%; p < 0.0001), resulting in a good discrimination between AKI + and AKI - patients (area under curve [AUC] 0.80). Interestingly, a basal renal function ≤55 ml/min/1.73m2 was as good as the STS score to predict CSA-AKI (AUC 0.75; P 0.26). CONCLUSIONS: On-pump CSA-AKI was observed in nearly 15% of cases and was associated with poorer outcomes. Interestingly, the risk of CSA-AKI could be estimated preoperatively, thanks to the basal renal function, which exhibited an equal performance to the STS score.

Acute Kidney Injury in Elderly Patients With Chronic Kidney Disease: Do Angiotensin-Converting Enzyme Inhibitors Carry a Risk?

In contrast to angiotensin receptor blockers (ARBs), mainly excreted by the liver, the dosage of angiotensin-converting enzyme (ACE) inhibitors, cleared by the kidney, must be adapted to account for renal clearance in patients with chronic kidney disease (CKD) to avoid acute kidney injury (AKI). Community-acquired AKI and the use of ACE inhibitors or ARBs in the emergency department were retrospectively assessed in 324 patients with baseline stage 3 or higher CKD. After stepwise regression analysis, the use of ACE inhibitors (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.1; P=.02) and the presence of dehydration (OR, 30.8; 95% CI, 3.9-239.1) were associated with AKI. A total of 45% of patients using ACE inhibitors experienced overdosing, which causes most of the excess risk of AKI. These results suggest that dosage adjustment of ACE inhibitors to renal function or substitution of ACE inhibitors with ARBs could reduce the incidence of AKI. Moreover, ACE inhibitors and ARBs should be stopped in cases of dehydration.

Therapeutic drug monitoring of enteric-coated mycophenolate sodium by limited sampling strategies is associated with a high rate of failure.

BACKGROUND: Therapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients. METHODS: Sixty-two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3-4 months of transplantation. RESULTS: EC-MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8-78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (<30 mg h/L) in comparison with tacrolimus [55% (n = 11/20) and 10% (n = 9/88), respectively; RR 5.4 (95% CI 2.6-11.2); P < 0.0001]. CONCLUSIONS: The risk of therapeutic drug monitoring failure with EC-MPS is >30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with MMF.

Delayed Graft Function in Kidney Transplants: Time Evolution, Role of Acute Rejection, Risk Factors, and Impact on Patient and Graft Outcome.

Background. Although numerous risk factors for delayed graft function (DGF) have been identified, the role of ischemia-reperfusion injury and acute rejection episodes (ARE) occurring during the DGF period is ill-defined and DGF impact on patient and graft outcome remains controversial. Methods. From 1983 to 2014, 1784 kidney-only transplantations from deceased donors were studied. Classical risk factors for DGF along with two novel ones, recipient's perioperative saline loading and residual diuresis, were analyzed by logistic regression and receiver operating characteristic (ROC) curves. Results. Along with other risk factors, absence of perioperative saline loading increases acute rejection incidence (OR = 1.9 [1.2-2.9]). Moreover, we observed two novel risk factors for DGF: patient's residual diuresis ≤500 mL/d (OR = 2.3 [1.6-3.5]) and absence of perioperative saline loading (OR = 3.3 [2.0-5.4]). Area under the curve of the ROC curve (0.77 [0.74-0.81]) shows an excellent discriminant power of our model, irrespective of rejection. DGF does not influence patient survival (P = 0.54). However, graft survival is decreased only when rejection was associated with DGF (P < 0.001). Conclusions. Perioperative saline loading efficiently prevents ischemia-reperfusion injury, which is the predominant factor inducing DGF. DGF per se has no influence on patient and graft outcome. Its incidence is currently close to 5% in our centre.

Sodium bicarbonate to prevent cardiac surgery-associated kidney injury: the end of a dream?

The rationale of urine alkalinization through intravenous sodium bicarbonate to prevent cardiac surgery-associated acute kidney injury relies on several pathophysiological arguments. Urine alkalinization is easily feasible in the ICU setting and is often considered to be associated with few side effects. In a previous issue of Critical Care, a retrospective study evaluates the effect of routine intravenous bicarbonate use to prevent cardiac surgery-associated acute kidney injury with cardiopulmonary bypass. This commentary discusses recent data on the use of bicarbonate to prevent cardiac surgery-associated acute kidney injury.

The once-daily formulation of tacrolimus: a step forward in kidney transplantation?

Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf. Here, we discuss the possible reasons for this observation and how it could affect the expected benefits of Advagraf, and we comment on the fact that a similar lack of bioequivalence might prevail with generic immunosuppressive drugs.

Conversion from Prograf to Advagraf among kidney transplant recipients results in sustained decrease in tacrolimus exposure.

BACKGROUND: Advagraf is a slow release form of tacrolimus with once-daily formulation. The potential advantages of Advagraf are better adherence and a safer profile by avoiding toxic peak concentrations. In this study, we evaluated the required daily doses of tacrolimus and subsequent blood levels on conversion from Prograf to Advagraf among kidney transplant recipients. METHODS: We retrospectively reviewed data from 55 patients for whom a switch from Prograf to Advagraf was identified. Tacrolimus daily doses and concomitant blood levels were analyzed at several time points ranging from 3 months before to 6 months after conversion. RESULTS: We observed a significant increase in tacrolimus daily doses, starting with a dose of 0.063 mg/kg of Prograf, increasing up to 0.081 mg/kg of Advagraf at 6 months (P<0.0001). After conversion, we observed a quick and sustained decrease in trough tacrolimus levels, decreasing from 8.05 ng/mL at day 0 to 6.30 ng/mL at day 180 (P=0.0009). At 6 months, 35% of patients experienced a decrease in trough levels of more than 30%. Creatinine values remained stable over time, and no patient experienced an acute rejection episode. CONCLUSIONS: Contrary to the manufacturer instructions, we found a significant decrease in tacrolimus exposure after switching to Advagraf. Therefore, the switch from Prograf to Advagraf should be performed under close medical supervision.