Functional Magnetic Resonance Imaging to Monitor Disease Progression: a prospective study in Patients with Primary Membranoproliferative Glomerulonephritis.

INTRODUCTION: Primary membranoproliferative glomerulonephritis (MPGN) is a rare kidney disease with poor prognosis and no specific therapies. The disease heterogeneity and the difficulty of performing repeated kidney biopsies poses big challenges. This study investigates the correlation between non-contrast enhanced magnetic resonance imaging (MRI) and histologic and clinical findings in patients with primary MPGN. METHODS: Patients with primary MPGN underwent baseline and 1-year kidney MRI in addition to biopsy and laboratory testing as part of a prospective MRI subproject of a clinical trial (ClinicalTrials.gov identifier NCT03723512). Diffusion-weighted and phase-contrast MRI were used to investigate kidney diffusivity and perfusion. Peritubular interstitial volume and fibrosis were quantified on kidney biopsies. RESULTS: Seven patients with primary MPGN (18[17-21] years, 43% females) were included. Kidney biopsies showed variable degree of global and segmental glomerular sclerosis ([5-30]% and [10-60]%), mild interstitial fibrosis (<10%), and increased peritubular interstitial volume ([19-40]%). MRI and laboratory parameters changed very differently from patient to patient over 1 year. Peritubular interstitial volume and glomerular sclerosis negatively associated with renal blood flow (RBF)(rho = -0.81 and -0.77), and positively with renal vascular resistance (RVR)(rho = 0.65 and 0.73). Urinary albumin to creatinine ratio (uACR) negatively associated with RBF and filtration fraction (FF)(rho = -0.86 and -0.6), while positively with RVR (rho = 0.88). uACR decrease was associated with kidney diffusivity increase (rho = -0.5). Measured glomerular filtration rate (GFR) positively associated with kidney diffusivity, RBF, and FF (rho = 0.87, 0.85 and 0.59), while negatively with RVR (rho = -0.89); GFR increase was associated with kidney diffusivity, RBF, and FF increase (rho = 0.77, 0.7, and 0.7) and RVR decrease (rho = -0.7). DISCUSSION/CONCLUSION: The strong correlation found between MRI and histologic and clinical findings, despite the rather limited number of patients, highlights MRI potential to monitor disease progression in patients with rare kidney disease.

Preimplantation Histological Score Associates with 6-Month GFR in Recipients of Perfused, Older Kidney Grafts: Results from a Pilot Study.

BACKGROUND: Biopsy-guided selection of older kidneys safely expands the organ pool, and pretransplant perfusion improves the preservation of these fragile organs. Herein, we studied morphofunctional variables associated with graft outcomes in perfused, histologically evaluated older kidneys. METHODS: This single-center prospective cohort pilot study evaluated the relationships between preimplantation histologic scores and renal perfusion parameters during hypothermic, pulsatile, machine perfusion (MP) and assessed whether these morphofunctional parameters associated with GFR (iohexol plasma clearance) at 6 months after transplantation in 20 consecutive consenting recipients of a biopsy-guided single or dual kidney transplant from >60-year-old deceased donors. RESULTS: The donor and recipient age was 70.4 ± 6.5 and 63.6 ± 7.9 years (p = 0.005), respectively. The kidney donor profile index (KDPI) was 93.3 ± 8.4% (>80% in 19 cases), histologic score 4.4 ± 1.4, and median (IQR) cold ischemia time 19.8 (17.8-22.8 h; >24 h in 5 cases). The 6-month GFR was 41.2 (34.9-55.7) mL/min. Vascular resistances positively correlated with global histologic score (p = 0.018) at MP start and then decreased from 0.88 ± 0.43 to 0.36 ± 0.13 mm Hg/mL/min (p < 0.001) in parallel with a three-fold renal flow increase from 24.0 ± 14.7 to 74.7 ± 31.8 mL/min (p < 0.001). Consistently, vascular resistance reductions positively correlated with global histologic score (p = 0.009, r = -0.429). Unlike KDPI or vascular resistances, histologic score was independently associated with 6-month GFR (beta standardized coefficient: -0.894, p = 0.005). CONCLUSIONS: MP safely improves graft perfusion, particularly in kidneys with severe histologic changes that would not be considered for transplantation because of high KDPI. The preimplantation histologic score associates with the functional recovery of older kidneys even in the context of a standardized program of pulsatile perfusion.

Functional Magnetic Resonance Imaging Versus Kidney Biopsy to Assess Response to Therapy in Nephrotic Syndrome: A Case Report.

In recent years, kidney functional magnetic resonance imaging (MRI) has seen great advances, with several cross-sectional studies demonstrating correlations between MRI biomarkers and glomerular filtration rate. However, the potential of MRI to monitor response to therapy in kidney disease remains undescribed. In this case report, a man in his 40s with drug-resistant membranous nephropathy was addressed to ofatumumab therapy. He underwent kidney biopsy before and 2 years after treatment and repeat non-contrast-enhanced MRI of the kidney every 6 months. An age- and sex-matched healthy volunteer was included as a normal control. The patient showed a striking positive immunologic response to therapy. Repeat MRI of the kidney documented progressive kidney functional recovery, with a significant widespread increase in kidney diffusivity, assessed using diffusion-weighted imaging, paralleling the increase in glomerular filtration rate and regression of albuminuria. Renal blood flow and ultrafiltration coefficient, assessed using phase-contrast MRI, significantly increased, suggesting an increase in filtration fraction. This case report provides the first clinical evidence in support of MRI of the kidney as a tool to noninvasively monitor pathophysiologic changes occurring in response to treatment. Although kidney biopsy remains critical for diagnosis, functional MRI of the kidney has promise for monitoring disease progression and response to therapy.

Morphofunctional Effects of C5 Convertase Blockade in Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Report of Two Cases with Evidence of Terminal Complement Activation.

A membranoproliferative pattern of glomerular injury is frequently observed in patients with complement-mediated disorders, such as C3 glomerulopathies (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). The outcomes of C3G and -IC-MPGN are poor, independently of immunosuppressive therapy. However, two 48-week treatment periods with the anti-C5 monoclonal antibody eculizumab, divided by a -12-week washout period, achieved remission of proteinuria and stabilization/improvement of the glomerular filtration rate (GFR), measured through iohexol plasma clearance, in 3 of 10 patients with biopsy-proven MPGN, nephrotic syndrome and terminal complement complex sC5b-9 plasma levels >1,000 mg/mL, at inclusion. Baseline and end-of-study kidney biopsies were available for 2 patients with IC-MPGN, and their baseline characteristics were similar. However, in 1 patient proteinuria and GFR did not improve during the study, whereas in the other proteinuria decreased from 4.84 to 2.12 g/24-h and GFR increased from 91.5 to 142.7 mL/min/1.73 m2. Glomerular inflammation improved and median (interquartile range) glomerular staining for C5b-9 decreased in both cases: from 23.6 to 18.2% (p = 0.021) in the patient who achieved remission and from 15.8 to 10.7% (p = 0.019) in the patient with persistent proteinuria. Chronic glomerular lesions progressed and C3 glomerular staining and electron-dense deposits did not change appreciably in either case. However, in the patient who achieved remission, ultrastructural evaluation revealed features of glomerular microangiopathy at inclusion, which fully recovered posttreatment. Podocyte foot process effacement was observed in both patients at inclusion, but recovered only in the patient with microangiopathy. Thus, in 2 patients with -IC-MPGN, chronic glomerular changes progressed despite eculizumab-induced amelioration of glomerular inflammation and inhibition of sC5b-9 deposition, and independently of treatment effects on proteinuria and podocytes. The finding that the regression of microangiopathic changes was associated with improved clinical outcomes suggests that C5 blockade might have a therapeutic role in patients with IC-MPGN displaying microangiopathic endothelial injury.

Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation.

BACKGROUND: In donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells. METHODS: We evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8-deficient donors. RESULTS: Cold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8-deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses. CONCLUSIONS: IL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.

Histological Examination of the Diabetic Kidney.

The increasing prevalence of diabetes worldwide has led to a concomitant rise in diabetic kidney disease (DKD) as a major cause of end-stage renal disease. Glomerular lesions constitute the most striking and consistent features identified in biopsies from patients with DKD, although tubulointerstitial injury has an important and often under-recognized role in the progression to overt nephropathy. In advanced stages of the disease, podocyte detachment is a pivotal event in the loss of glomerular filtration barrier integrity and may explain, at least in part, the inability of current therapies to halt renal function decline. This chapter details the systematic method that can be used to study renal tissue samples from diabetic patients, and the specific role of different imaging techniques, such as light microscopy, immunofluorescence microscopy, and transmission and scanning electron microscopy in detecting histologic lesions specific to DKD.

Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation.

BACKGROUND: Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation. METHODS: To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion. RESULTS: Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival. CONCLUSIONS: These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.

Acute Kidney Injury and Hemolytic Anemia Secondary to Mycoplasma pneumoniae Infection.

Glomerulonephritis as well as kidney injury secondary to fulminant intravascular hemolysis are rare extrapulmonary manifestations of Mycoplasma pneumoniae infection. We describe a 50-year-old female diagnosed with M. pneumoniae infection-associated hemolytic anemia, characterized by negative cold agglutinin tests but with laboratory evidence of complement alternative pathway activation. The patient presented both with anemia and severe kidney failure and she was treated with steroids and red blood cell transfusions along with plasmapheresis. She also received a short course of antibiotics. Renal biopsy showed combined features of resolving postinfectious glomerulonephritis and hemolysis-associated extensive acute tubular injury characterized by renal hemosiderosis and intratubular hemoglobin casts. Electron microscopy revealed features of glomerular microangiopathic injury. The treatment led to complete disease remission and a favorable renal outcome at the first year follow-up.

BRAF Signaling Pathway Inhibition, Podocyte Injury, and Nephrotic Syndrome.

Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury. Kidney function and glomerular ultrastructural changes recovered fully after drug withdrawal. In vitro, BRAF inhibition decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte-vascular endothelial growth factor (VEGF) system. In addition to implications for nephrotic syndrome pathophysiology, we suggest that patients given dabrafenib and trametinib be monitored closely for potential glomerular damage.

Necrotizing and crescentic glomerulonephritis with membranous nephropathy in a patient exposed to levamisole-adulterated cocaine.

Levamisole is an antihelminthic agent widely used as an adulterant of illicit cocaine recently implicated as a cause of antineutrophil cytoplasmic antibody (ANCA)-associated microscopic polyangiitis in cocaine abusers. An isolated case of membranous nephropathy (MN) associated with levamisole exposure has also been reported. We report the first case, to our knowledge, of a patient with both microscopic polyangiitis manifest as a pauci-immune necrotizing and crescentic glomerulonephritis and concurrent MN in the setting of chronic cocaine abuse and presumed levamisole exposure, raising the hypothesis that levamisole was the causative agent in the development of this rare dual glomerulopathy.