tacrolimus and Nephritis

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

Topics: Biopsy; BK Virus; Creatinine; Graft Rejection; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Isoxazoles; JC Virus; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polymerase Chain Reaction; Polyomavirus Infections; Sirolimus; Tacrolimus; Transplantation, Homologous; Viremia

Henoch-Schönlein purpura nephritis has become a significant threat to children's health. Traditional combined therapy of glucocorticoids and cyclophosphamide leads to severe toxicity and complications. Therefore, identifying a feasible and effective strategy with low side-effects for the treatment of Henoch-Schönlein purpura nephritis is of great significance.. A randomized, controlled trial was carried out. A total of 279 children with Henoch-Schönlein purpura nephritis were recruited and randomly divided into three groups: control group (receiving the current standard therapy), TA group (receiving tacrolimus) and TA + tripterygium glycosides group (receiving tacrolimus + tripterygium treatment). The total duration of the trial was 6 months, and the duration of follow-up observation was 9 months.. Various therapies showed similar therapeutic effects in the third and sixth months. The relief of Henoch-Schönlein purpura nephritis symptoms caused by TA + tripterygium glycosides was slower than the TA and control groups. The incidence of adverse reactions in the TA + tripterygium glycosides group was lower in the control and TA groups. The final treatment effect of the experimental groups was better than the control group. The recurrence rate in the TA + tripterygium glycosides group was also significantly lower.. Tacrolimus and tripterygium glycosides combined therapy had better effects and safety for long-term treatment of Henoch-Schönlein purpura nephritis.

Topics: Child; Glycosides; Humans; IgA Vasculitis; Nephritis; Tacrolimus; Tripterygium

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

Topics: Adult; Aged; Antibodies; Atrophy; Calcineurin Inhibitors; Chemokine CXCL9; Early Termination of Clinical Trials; Female; Fibrosis; Graft Rejection; Histocompatibility Testing; HLA-DQ Antigens; Humans; Immunosuppression Therapy; Interferon-gamma; Kidney; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Nephritis; Prospective Studies; Tacrolimus; Withholding Treatment; Young Adult

There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens.. This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL).. Mean TAC concentrations were 6.0 ± 2.4 ng/mL and 5.8 ± 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043-5.267; P = 0.039) were associated with inferior renal function at 24 months.. In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months.

Topics: Adult; Atrophy; Biomarkers; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Drug Substitution; Female; Fibrosis; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Nephritis; Odds Ratio; Proteinuria; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Children with severe Henoch-Schönlein purpura nephritis (HSPN) may progress to end-stage renal disease without appropriate treatment.. This study aimed to investigate the efficacy and safety of tacrolimus combined with glucocorticoids in the treatment of pediatric HSPN.. A total of 87 HSPN patients with urinary protein ≥ 0.75 g/24 h received standard of care, including angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and glucocorticoids. Patients were divided into three groups and additionally received tacrolimus (n = 30), cyclophosphamide (n = 31), or mycophenolate mofetil (MMF) (n = 26). We monitored outcome measures, including proteinuria, hematuria, and renal function and analyzed the efficacy and side effects in each group.. At 2-month follow-up, the overall efficacy was 93.3%, 83.9%, and 61.5% for tacrolimus, cyclophosphamide, and MMF, respectively (P < 0.05). Urinary protein significantly decreased for all groups. Urinary red blood cell counts significantly decreased for patients treated with tacrolimus (P < 0.001) and cyclophosphamide (P < 0.05), whereas no significant decrease was seen for those receiving MMF (P = 0.09). Although urine β2-microglobulin significantly decreased following 2 months of treatment with all medications, efficacy was greater with tacrolimus than with cyclophosphamide and MMF (P < 0.001). Major adverse events were respiratory and urinary infections, with MMF having the highest infection rate. The cyclophosphamide group also experienced additional adverse events, including arrhythmia, hemorrhagic cystitis, leukocytosis, thrombocytopenia, and hyperglycemia.. These results indicate that tacrolimus is more effective at reducing proteinuria and hematuria and improving renal function, with relatively milder side effects, in the treatment of pediatric HSPN.. ChiCTR2200055323, retrospectively registered on January 7, 2022.

Topics: Child; Cyclophosphamide; Glucocorticoids; Hematuria; Humans; IgA Vasculitis; Immunosuppressive Agents; Mycophenolic Acid; Nephritis; Proteinuria; Tacrolimus

Topics: Adolescent; Diagnosis, Differential; Drug Therapy, Combination; Glucocorticoids; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Nephritis; Prednisolone; Ribonucleosides; Tacrolimus

The Nephrology Quiz and Questionnaire remains an extremely popular session for attendees of the Annual Kidney Week Meeting of the American Society of Nephrology. Once again, the conference hall was overflowing with audience members and eager quiz participants. Topics covered by the expert discussants included electrolyte and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases representing each of these categories along with single best answer questions were prepared and submitted by the panel of experts. Before the meeting, program directors of United States nephrology training programs and nephrology fellows answered the questions through an internet-based questionnaire. During the live session, members of the audience tested their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They compared their answers in real time using audience response devices with the answers of the nephrology fellows and training program directors. The correct and incorrect answers were then discussed after the audience responses and the results of the questionnaire were displayed. As always, the audience, lecturers, and moderators enjoyed this educational session. This article recapitulates the session and reproduces its educational value for the readers of CJASN. Enjoy the clinical cases and expert discussions.

Topics: Anemia; Calcineurin Inhibitors; Female; Humans; Hypertension, Renal; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nephritis; Nephrology; Neuroimaging; Parvoviridae Infections; Parvovirus B19, Human; Posterior Leukoencephalopathy Syndrome; Radiography; Surveys and Questionnaires; Tacrolimus

The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are key drugs in current immunosuppressive regimes for solid organ transplantation. However, they are nephrotoxic and promote death and profibrotic responses in tubular cells. Moreover, renal inflammation is observed in CNI nephrotoxicity but the mechanisms are poorly understood. We have now studied molecular pathways leading to inflammation elicited by the CNIs in cultured and kidney tubular cells. Both CsA and tacrolimus elicited a proinflammatory response in tubular cells as evidenced by a transcriptomics approach. Transcriptomics also suggested several potential pathways leading to expression of proinflammatory genes. Validation and functional studies disclosed that in tubular cells, CNIs activated protein kinases such as the JAK2/STAT3 and TAK1/JNK/AP-1 pathways, TLR4/Myd88/IRAK signaling and the Unfolded Protein Response (UPR) to promote NF-κB activation and proinflammatory gene expression. CNIs also activated an Nrf2/HO-1-dependent compensatory response and the Nrf2 activator sulforaphane inhibited JAK2 and JNK activation and inflammation. A murine model of CsA nephrotoxicity corroborated activation of the proinflammatory pathways identified in cell cultures. Human CNIs nephrotoxicity was also associated with NF-κB, STAT3 and IRE1α activation. In conclusion, CNIs recruit several intracellular pathways leading to previously non-described proinflammatory actions in renal tubular cells. Identification of these pathways provides novel clues for therapeutic intervention to limit CNIs nephrotoxicity.

Topics: Adult; Aged; Animals; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Humans; Inflammation Mediators; Janus Kinase 2; Kidney Tubules; Male; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Middle Aged; Nephritis; NF-kappa B; Signal Transduction; Tacrolimus; Toll-Like Receptor 4; Unfolded Protein Response

BK viremia can lead to nephritis, which can progress to irreversible kidney transplant failure. Our prospective study provides management and outcome of BK viremia in renal transplant recipients.. Two hundred forty de novo kidney-only recipients were enrolled from July 2007 to July 2010 and followed for 1 year. Standard immunosuppression with Thymoglobulin/interleukin 2 receptor blocker and mycophenolate mofetil/tacrolimus (Tac)/prednisone was employed. Quantitative BK virus (BKV) DNA surveillance in plasma/urine was performed at 1, 3, 6, 12, and 24 months after transplantation. Patients with significant viremia (defined as ≥10,000 viral copies/mL) underwent renal biopsy and treated with 30% to 50% reduction in doses of both mycophenolate mofetil and Tac without antiviral therapy. The target 12-hr Tac trough levels were lowered to 4 to 6 ng/mL in the significant viremia group, whereas the target levels remained unchanged at 5 to 8 ng/mL for all other groups.. Sixty-five patients (27%) developed BK viremia; 28 (12%) of whom had significant viremia. A total of five (21%) of the 23 (of 28) patients who underwent biopsy presented with subclinical BKV nephritis. The mean plasma BKV DNA declined by 98% (range, 76%-100%) at 1 year after peak viremia. Acute cellular rejection seen in four (14%) of 28 patients, responded to bolus steroids. There was no decline in estimated glomerular filtration rate over time from 1 month after transplantation to 1 year after peak viremia (P=0.57).. Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of renal function and prevention of clinical BKV nephritis and graft loss.

Topics: Adult; Aged; Biopsy; BK Virus; Female; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nephritis; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Tacrolimus; Treatment Outcome; Tumor Virus Infections; Viral Load; Viremia

Proximal tubular cholesterol levels rise within 18 hours of diverse forms of acute renal tubular injury (eg, myoglobinuria, ischemia/reperfusion, urinary tract obstruction). These increments serve to protect against further bouts of tubular attack (so-called "acquired cytoresistance"). Whether these cholesterol increments are merely transitory, or persist into the maintenance phase of acute renal failure (ARF), has not been previously defined. Furthermore, whether subacute/insidious tubular injury [eg, cyclosporine A (CSA), tacrolimus toxicity], nontubular injury (eg, acute glomerulonephritis), or physiological stress (eg, mild dehydration) impact renal cholesterol homeostasis have not been addressed. This study sought to resolve these issues. Male CD-1 mice were subjected to glycerol-induced ARF. Renal cortical-free cholesterol (FC) and cholesterol ester (CE) levels were determined 3, 5, 7, or 14 days later, and the values contrasted to prevailing blood-urea nitrogen concentrations. The impact of 40 minutes of unilateral renal ischemia plus reflow (3 to 6 days) on mouse cortical FC/CE content was also assessed. Additionally, FC/CE levels were measured in rat renal cortex either 10 days after CSA or tacrolimus therapy, or 48 hours after induction of nephrotoxic serum nephritis. Finally, the impact of overnight dehydration on mouse renal cortical/medullary FC/CE profiles was determined. Compared to sham-treated animals, glycerol, CSA, tacrolimus, ischemia-reperfusion, and nephrotoxic serum each induced dramatic CE +/- FC elevations, rising as much as 10x control values. In the glycerol model, striking correlations (r

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Cholesterol; Cholesterol Esters; Cyclosporine; Dehydration; Glomerulonephritis; Glycerol; Ischemia; Kidney; Kidney Cortex; Kidney Medulla; Kidney Tubules; Male; Mice; Nephritis; Rats; Rats, Sprague-Dawley; Reperfusion; Tacrolimus

Recent studies have correlated renal allograft function with individual histologic lesions defined in the Banff schema of kidney transplantation pathology. The clinical significance of severe tubulitis (Banff 97 grade t3) has not been specifically examined. We compared the clinical course and response to antirejection therapy in 36 patients with t3 tubulitis, and 137 patients with milder grades of tubulitis and varying grades of intimal arteritis. Rejection associated with severe tubulitis (grade t3) was associated with graft outcome that was worse than mild to moderate tubulitis (grades t1 or t2) and approached that seen in grade v1 intimal arteritis. Rejection characterized by grade v2 or v3 intimal arteritis had worse prognosis than v1 intimal arteritis and all grades of tubulitis without coexisting intimal arteritis. These observations validate the Banff 97 recommendation that the severity of both tubulitis and intimal arteritis needs to be graded in renal allograft biopsies. In addition, grade t3 tubulitis is identified as a lesion which should be a cause for clinical concern.

Topics: Acute Disease; Adult; Arteritis; Creatinine; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Muromonab-CD3; Nephritis; Tacrolimus; Tunica Intima

The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-positive cells and intercellular adhesion molecule-1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.

Topics: Animals; Antibodies, Heterophile; Basement Membrane; Complement C3; Immunoglobulin G; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Leukocytes; Lymphocyte Activation; Lymphocyte Function-Associated Antigen-1; Male; Nephritis; Proteinuria; Rats; Rats, Sprague-Dawley; Receptors, Interleukin-2; Tacrolimus

FK506 is a new drug which has potent immunosuppressive activity. We studied its immunosuppressive effects on active Heymann's nephritis and the autologous phase of Masugi nephritis. The induction of active Heymann's nephritis was completely suppressed by FK506 injected simultaneously with the antigen (day 1) and then daily for 14 days at a dose of 0.64 mg/kg per day or more. With a lower dosage of this agent, antibody production and immune deposits in the glomerular basement membrane occurred despite the suppression of proteinuria. Similar results were obtained in rats on other treatment schedules (1-7 days or day 8-14 days duration). Rats that were prevented from developing Heymann's nephritis or the autologous phase of nephrotoxic antiserum nephritis by FK506 treatment exhibited a suppressed immune response to a second immunization of the same antigen even 4 weeks after cessation of drug administration: however, they developed antibodies when inoculated with other antigens. Rat peripheral leucocyte counts and serum creatinin were not remarkably influenced by the administration of FK506. These results indicate that FK506 has potent immunosuppressive activity, and it is suggested that it is able to induce an antigen-specific immunotolerance.

Topics: Animals; Anti-Bacterial Agents; Basement Membrane; Creatinine; Dose-Response Relationship, Drug; Female; Immune Tolerance; Immunoglobulin G; Immunosuppressive Agents; Kidney; Leukocyte Count; Nephritis; Proteinuria; Rats; Rats, Inbred WKY; Tacrolimus; Time Factors