Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo.

Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient's endogenous MDSCs.

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts.

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.

Recurrence of FSGS after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.

Phospholipase A2 receptor-associated membranous nephropathy in a patient with IgG4-related disease: A case report.

RATIONALE: IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN) is the most common renal manifestation of IgG4-RD, but membranous nephropathy (MN) has also been described and often occurs in the context of concurrent TIN. Patients with IgG4-related MN have been characteristically negative for autoantibodies to the phospholipase A2 receptor (PLA2R). PATIENT CONCERNS: A 45-year-old man presented with abdominal pain and lower extremity edema. DIAGNOSIS: Histopathological evaluation of pancreas and liver biopsies established a diagnosis of IgG4-RD. Renal biopsy confirmed a diagnosis of PLA2R-associated MN without evidence of concurrent TIN. INTERVENTIONS: The patient was treated with rituximab, a short course of low-dose, oral cyclophosphamide, and a rapid glucocorticoid taper. OUTCOMES: The patient achieved remission of MN after 8 months of therapy and maintained remission of IgG4-RD. LESSONS: PLA2R-associated MN may be a rare manifestation of IgG4-RD. Systematic evaluation of larger cohorts of IgG4-RD patients for the presence of PLA2R autoantibodies and the investigation of PLA2R-associated MN cohorts for evidence of IgG4-RD would facilitate the understanding of the nature of the relationship between these observations.

Combination Therapy With Rituximab and Cyclophosphamide for Remission Induction in ANCA Vasculitis.

INTRODUCTION: Remission induction in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis may be complicated by slow response to treatment and toxicity from glucocorticoids. We describe outcomes with a novel remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper. METHODS: Patients were included in this retrospective study if they had newly diagnosed or relapsing ANCA vasculitis with a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS-WG) ≥3 and received a standardized remission induction regimen. The primary outcome was complete remission, defined as a BVAS-WG of 0 and a prednisone dose of ≤7.5 mg/d. RESULTS: We identified 129 patients who met the inclusion criteria, 31% of whom also received plasma exchange (PLEX) for rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage. Seventy percent of patients had myeloperoxidase (MPO)-ANCA and 9% had relapsing disease. Median time to complete remission was 4 months (interquartile range [IQR] 3.9-4.4), and by 5 months 84% of patients were in complete remission. Prednisone was tapered to discontinuation as tolerated, such that the median prednisone dose at 8 months was 0 mg/d (IQR 0-2.5). In patients with RPGN, proteinase 3-ANCA was associated with a greater increase in eGFR at 6 months compared with MPO-ANCA (16 vs. 5.6 ml/min per 1.73m2; P = 0.028). During the year following remission, 1 major relapse occurred over 122 patient-years. Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Four deaths occurred, 3 of which were associated with serious infections. CONCLUSION: Combination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.

Diagnosis and treatment of hypernatremia.

Hypernatremia is defined as a serum sodium level above 145 mmol/L. It is a frequently encountered electrolyte disturbance in the hospital setting, with an unappreciated high mortality. Understanding hypernatremia requires a comprehension of body fluid compartments, as well as concepts of the preservation of normal body water balance. The human body maintains a normal osmolality between 280 and 295 mOsm/kg via Arginine Vasopressin (AVP), thirst, and the renal response to AVP; dysfunction of all three of these factors can cause hypernatremia. We review new developments in the pathophysiology of hypernatremia, in addition to the differential diagnosis and management of this important electrolyte disorder.

TGF-ß signaling in the kidney: profibrotic and protective effects.

Transforming growth factor-ß (TGF-ß) is generally considered as a central mediator of fibrotic diseases. Indeed, much focus has been placed on inhibiting TGF-ß and its downstream targets as ideal therapeutic strategies. However, pharmacological blockade of TGF-ß has not yet translated into successful therapy for humans, which may be due to pleiotropic effects of TGF-ß signaling. Equally, TGF-ß signaling as a protective response in kidney injury has been relatively underexplored. An emerging body of evidence from experimental kidney disease models indicates multifunctionality of TGF-ß capable of inducing profibrotic and protective effects. This review discusses recent advances highlighting the diverse roles of TGF-ß in promoting not only renal fibrosis but also protective responses of TGF-ß signaling. We review, in particular, growing evidence that supports protective effects of TGF-ß by mechanisms which include inhibiting inflammation and induction of autophagy. Additional detailed studies are required to fully understand the diverse mechanisms of TGF-ß actions in renal fibrosis and inflammation that will likely direct toward effective antifibrotic therapies.

Night Sweats as a Prominent Symptom of a Patient Presenting with Pulmonary Embolism.

Pulmonary embolism is a common, potentially fatal disease. Making the correct diagnosis early can significantly reduce mortality and morbidity. We report the first case of drenching night sweats as one of the presenting symptoms of submassive pulmonary embolism. One week after undergoing laparotomic sigmoidectomy for diverticulitis, our patient started to experience drenching night sweats and pleuritic back pain. CT identified bilateral main stem pulmonary artery emboli, and treatment was initiated with subcutaneous enoxaparin injections. Imaging and laboratory workup failed to reveal any other explanation for the night sweats. Patient was discharged on rivaroxaban, and he reported complete resolution of symptoms upon the 3-month follow-up visit and 9-month follow-up call. Based on our case we propose night sweats to be a potential presenting symptom of pulmonary embolism. Our observation can help make an earlier diagnosis of pulmonary embolism.

Epidemiology, Clinical Features and Outcome of Liver Abscess: A single Reference Center Experience in Qatar.

OBJECTIVE: To describe the etiology, clinical presentation, management and outcome of liver abscess in adult patients admitted at Hamad general hospital, Qatar. METHODS: A cross sectional study was conducted to involve all adult patients who sequentially encountered episodes of liver abscess during the period from January 1, 2009, to December 31, 2010. Blood cultures were drawn from all patients in the first 24 hours after admission. In addition, all patients had stool examinations and indirect Hemagglutination test for Entameba histolytica. Aspiration of abscess was done under CT guidance and aspirated pus was sent for gram stain and culture. RESULTS: In total, 67 patients were admitted with liver abscess; 56 patients with pyogenic liver abscess and 11 with amebic liver abscess. There were 61 (91%) males and six (9%) females and their mean age was 47.4 ± 18.5 years. Fever, abdominal pain and vomiting were the commonest presenting features. Of the 56 pyogenic liver abscess patients, four discharged against medical advice and seven refused all invasive procedures and were treated with antibiotics for six weeks. The remaining 44 (79%) patients were treated with antibiotics and one or more invasive procedures, while one patient was treated surgically. The commonest organism isolated was Klebseilla pneumonia found in 21 patients (38%). The mean duration of hospitalization was 13.6 ± 8.1 days; the mean duration of antibiotic therapy was 34.7 ± 40.6 days, and one patient died. In contrast, all amebic liver abscess patients underwent ultrasound guided aspiration and showed good response to metronidazole treatment. Their mean duration of hospitalization was 7.7 ± 4.1 days, mean duration of therapy was 11.8 ± 2.1 days, and all patients were cured. CONCLUSION: Pyogenic liver abscess was more common than amebic liver abscess with Klebseilla pneumonia being the commonest organism. With good medical measures and early drainage of liver abscess, surgical intervention was unnecessary in almost all the cases.

Toxicokinetic and mechanistic basis for the safety and tolerability of liposomal amphotericin B.

INTRODUCTION: Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone®). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome®). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L-AmB. AREAS COVERED: This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB. EXPERT OPINION: L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB.

Impact of multi-approach strategy on acid suppressive medication use in a teaching hospital in Qatar.

OBJECTIVE: To evaluate the impact of a multi-approach strategy to improve the appropriate usage of acid suppressive medication (ASM) in medical inpatients and compare it with the baseline data from 2007. SETTING: Five general medicine wards in a 600-bed teaching hospital in Doha, Qatar. METHOD: A prospective evaluation of the usage of ASM 1 year after a multi-approach strategy. This consisted of four main interventions: audit and feedback method (including awareness lectures to all medical and pharmacy staff), implementation of a usage guideline for medical inpatients, circulating a logarithmic chart on the proper usage of ASM for medical inpatients from admission through to discharge and participation of clinical pharmacists in the multidisciplinary rounds. All medical patients admitted from May through June 2009 were evaluated. Data about the usage of ASM were collected upon and during admission, at discharge and at the next follow-up visit. Justified indications for its usage were based on the approved product information and on evidence-based literature recommendations. Data were compared with the findings of the baseline clinical audit done 2 years earlier. MAIN OUTCOME MEASURE: The usage of ASM in justified and non-justified indications upon and during admission, at discharge and at the next follow up visit. RESULTS: A total of 414 patients were admitted during the study period, 208 patients (50%) received ASM compared to 53% in 2007 (206 patients out of 389). Seventy-four patients (36%) were using ASM upon admission compared to 48 patients (23%) in the 2007 clinical audit. Inappropriate ASM use decreased with 51% during admission (66 to 32%, P < 0.0001), 62% at discharge (34 to 13%, P < 0.0001) and 67% at the next follow up visit (15 to 5%, P = 0.0008). CONCLUSION: Despite the higher number of patients receiving ASM upon admission, the multi-approach strategy used in our institution resulted in a significant improvement in the appropriate usage of ASM in medical inpatients.