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BMC Nephrology Dec 2018Post-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic...
BACKGROUND
Post-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic nephropathy (DN) occurrence in transplanted kidneys is poorly investigated. Current knowledge describes DN recurrence in graft 5.9 years from kidney transplantation however there is little data about PTDM and DN. Here, we report a clinical case peculiar for an early appearance of advanced glomerular diabetic lesions, after kidney transplantation.
CASE PRESENTATION
A 45-year-old Caucasian male affected by autosomal polycystic kidney disease was transplanted with a cadaveric-kidney-donor from 58-year-old male. Induction immunosuppressive therapy included basiliximab and steroids while the maintenance treatment included, tacrolimus, mofetil micophenolate and methylprednisolone. One month after transplantation the patient developed diabetes requiring treatment with repaglinide quickly replaced with insulin to obtain an acceptable glycemic control (HbA1c 52 mmol/mol). Glycosuria was detected persistently during the first six months after transplantation. To achieve further improvement in glycemic control, a shift from tacrolimus to cyclosporine (CyA) was made and steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors toxicity, which was revealed in the 1-year-protocol-biopsy, everolimus was introduced thereby lowering CyA through levels. Moderate hypertension was well controlled with doxazosin. Thirty months after transplantation a second graft biopsy was performed owing to renal function decline and microalbuminuria appearance. Histological analysis surprisingly showed mesangiolysis and microaneurysms; glomerular sclero-hyalinosis and basal membrane thickness and typical nodular glomerulosclerosis. C4d staining was negative and no evidence of immune deposits were detected. Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative. Retrospective analysis on donor history didn't show diabetes or insulin resistance and no diabetic lesions were found in kidney pre-implant biopsy.
CONCLUSIONS
In our knowledge, this is the first report describing a very early onset of advanced diabetic glomerular lesions in a graft biopsy after PTDM. We hypothesize that additional factors such as everolimus and hypertension, may have contribute to kidney damage.
Topics: Diabetes Mellitus; Everolimus; Glomerulonephritis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications
PubMed: 30526503
DOI: 10.1186/s12882-018-1141-9 -
Journal of Diabetes and Its... Jan 2019Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue...
Previous studies demonstrated that global deficiency of eNOS in diabetic mice exacerbated renal lesions and that overexpression of eNOS may protect against tissue injury. Our study revealed for the first time overexpression of eNOS leads to disease progression rather than protection. Transgenic mice selectively expressing eNOS in endothelial cells (eNOSTg) were cross bred with Ins2Akita type-1 (AK) diabetic mice to generate eNOS overexpressing eNOSTg/AK mice. Wild type, eNOSTg, AK and eNOSTg/AK mice were assessed for kidney function and blood glucose levels. Remarkably, overexpressing eNOSTg mice showed evidence of unpredicted glomerular injury with segmental mesangiolysis and occasional microaneurysms. Notably, in eNOSTg/AK mice overexpression of eNOS led to increased glomerular/endothelial injury that was associated with increased superoxide levels and renal dysfunction. Results indicate for the first time that overexpressing eNOS in endothelial cells cannot ameliorate diabetic lesions, but paradoxically leads to progression of nephropathy likely due to eNOS uncoupling and superoxide upsurge. This novel finding has a significant impact on current therapeutic strategies to improve endothelial function and prevent progression of diabetic renal disease. Further, the eNOSTg/AK model developed in this study has significant translational potentials for elucidating the underlying mechanism implicated in the deflected function of eNOS in diabetic nephropathy.
Topics: Animals; Diabetic Nephropathies; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Insulin; Kidney Glomerulus; Mice; Mice, Inbred Strains; Mice, Transgenic; Microscopy, Electron; Nitric Oxide Synthase Type III
PubMed: 30424931
DOI: 10.1016/j.jdiacomp.2018.10.003 -
Kidney Research and Clinical Practice Jun 2018The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early... (Review)
Review
The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early and critical step in the development of diabetic nephropathy, and analysis of structural lesions within the mesangium such as mesangiolysis implicate the loss of podocytes as a key mediating event. The BTBR / mouse has proved a useful tool to demonstrate that restoration of podocyte density, once thought to be an absolute barrier to glomerular repair, can be achieved with replacement of the hormone leptin that is constitutively absent in these mice. Restoration of podocyte density is associated with reversal of the structural lesions of morphologically advanced diabetic glomerular injury in this model. This finding, in conjunction with the demonstration in human diabetic patients with morphologically advanced diabetic nephropathy and with long-standing functioning pancreatic transplants of ten years duration that their diabetic nephropathy can be reversed, suggests that restoration of podocyte number and density is an appropriate target for the development of new therapeutics for diabetic nephropathy.
PubMed: 29971205
DOI: 10.23876/j.krcp.2018.37.2.106 -
CEN Case Reports Nov 2018TAFRO syndrome represents a characteristic constellation of symptoms comprising Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, and Organomegaly, and is...
TAFRO syndrome represents a characteristic constellation of symptoms comprising Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, and Organomegaly, and is considered to be a clinicopathologic variant of idiopathic multicentric Castleman disease. A 51-year-old woman was admitted to the hospital complaining of abdominal distension. Findings on physical examination were indicative of anasarca. Computed tomography revealed mild splenomegaly, pericardial effusion, pleural effusion, ascites, and paraaortic lymphadenopathy. Blood tests showed thrombocytopenia, and urinalysis demonstrated hematuria, proteinuria, and worsening renal function. Kidney biopsy was performed and revealed thrombotic microangiopathy-like lesions with global sclerosis of 1 of the 16 glomeruli on light microscopy. The remaining glomeruli had a distinct lobular pattern, with mesangiolysis, double contours of the glomerular basement membranes, and marked endothelial swelling. Immunofluorescence studies for IgG, IgM, IgA, C1q, C3, C4, κ-light chains, and λ-light chains were indeterminate. Electron microscopy showed marked endothelial swelling. We made a diagnosis of TAFRO syndrome and started steroid treatment, following which her symptoms gradually improved. There are few reports describing renal pathology in a patient with TAFRO syndrome.
Topics: Castleman Disease; Edema; Female; Glomerular Mesangium; Glucocorticoids; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Methylprednisolone; Middle Aged; Sclerosis; Syndrome; Thrombotic Microangiopathies; Treatment Outcome
PubMed: 29766467
DOI: 10.1007/s13730-018-0338-x -
Human Pathology Dec 2018An 84-year-old Japanese man was admitted due to anasarca, thrombocytopenia, systemic inflammation, and progressive renal insufficiency, resistance to diuretics,...
An 84-year-old Japanese man was admitted due to anasarca, thrombocytopenia, systemic inflammation, and progressive renal insufficiency, resistance to diuretics, glucocorticoid therapy, and plasma exchange. Renal biopsy showed diffuse endocapillary proliferation and mesangiolysis without any immune deposits. Tocilizumab suppressed systemic inflammation, resulting in improvement of anasarca and renal dysfunction, but thrombocytopenia persisted and platelet-associated IgG antibody was elevated. Although romiplostim was effective for thrombocytopenia, the patient died of aspiration pneumonia after cerebral hemorrhage. Autopsy showed hyaline vascular-type Castleman disease-like lymphadenopathy and reticulin myelofibrosis with an increase of megakaryocytes. Renal finding showed that endocapillary injury improved, and collapsed glomeruli were noted. This patient fitted the criteria for TAFRO (thrombocytopenia [T], anasarca [A], fever [F], reticulin myelofibrosis [R], and organomegaly [O]) syndrome. The clinical course suggests that 2 factors, including overproduction of interleukin 6 and autoimmune-mediated thrombocytopenia via thrombopoietin receptor, may have contributed to the pathogenesis of TAFRO syndrome in this patient.
Topics: Aged, 80 and over; Autopsy; Biopsy; Castleman Disease; Disease Progression; Fatal Outcome; Humans; Immunosuppressive Agents; Kidney; Male; Microscopy, Electron; Renal Dialysis; Renal Insufficiency; Treatment Outcome
PubMed: 29626596
DOI: 10.1016/j.humpath.2018.03.021 -
PloS One 2018The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and...
BACKGROUND AND OBJECTIVES
The impact of the newly proposed pathological classification by the Japan Renal Pathology Society (JRPS) on renal outcome is unclear. So we evaluated that impact and created a new pathological scoring to predict outcome using this classification.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
A multicenter cohort of 493 biopsy-proven Japanese patients with diabetic nephropathy (DN) were analyzed. The association between each pathological factor-Tervaert' and JRPS classifications-and renal outcome (dialysis initiation or 50% eGFR decline) was estimated by adjusted Cox regression. The overall pathological risk score (J-score) was calculated, whereupon its predictive ability for 10-year risk of renal outcome was evaluated.
RESULTS
The J-scores of diffuse lesion classes 2 or 3, GBM doubling class 3, presence of mesangiolysis, polar vasculosis, and arteriolar hyalinosis were, respectively, 1, 2, 4, 1, and 2. The scores of IFTA classes 1, 2, and 3 were, respectively, 3, 4, and 4, and those of interstitial inflammation classes 1, 2, and 3 were 5, 5, and 4 (J-score range, 0-19). Renal survival curves, when dividing into four J-score grades (0-5, 6-10, 11-15, and 16-19), were significantly different from each other (p<0.01, log-rank test). After adjusting clinical factors, the J-score was a significant predictor of renal outcome. Ability to predict 10-year renal outcome was improved when the J-score was added to the basic model: c-statistics from 0.661 to 0.685; category-free net reclassification improvement, 0.154 (-0.040, 0.349, p = 0.12); and integrated discrimination improvement, 0.015 (0.003, 0.028, p = 0.02).
CONCLUSIONS
Mesangiolysis, polar vasculosis, and doubling of GBM-features of the JRPS system-were significantly associated with renal outcome. Prediction of DN patients' renal outcome was better with the J-score than without it.
Topics: Aged; Diabetic Nephropathies; Female; Humans; Japan; Male; Middle Aged
PubMed: 29408865
DOI: 10.1371/journal.pone.0190923 -
CEN Case Reports May 2018Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease. Neurological disorders and visual disturbance are...
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease. Neurological disorders and visual disturbance are highlighted as manifestations of RVCL; however, there are few reports focused on nephropathy. Herein, we describe detailed renal histopathological findings in a daughter and father with RVCL, proven by TREX1 genetic analysis. A kidney biopsy of the daughter, 35-year-old with asymptomatic proteinuria, revealed unique and various glomerular changes. Atypical double contour (not tram track-like) of the capillary wall was widely found, an apparent characteristic finding. Glomerular findings were varied due to a combination of new and old segmental mesangial proliferative changes, mesangiolysis, and segmental glomerulosclerosis-like lesions; these changes may be related to endothelial cell damage. Collapsed tufts were also found and thought to be the result of ischemia due to arterial changes. Glomerular findings in a kidney biopsy of the father revealed similarity to the daughter's glomerulus at a relatively advanced stage, but the degree of variety in the glomerular findings was much less. Kidney biopsy findings suggesting endothelial cell damage of unknown etiology need to be considered for possible RVCL.
PubMed: 29322432
DOI: 10.1007/s13730-017-0300-3 -
Autophagy 2018Autophagy is a lysosomal degradation system by which cytosolic materials and damaged organelles are broken down into basic components. To explore the physiological role...
Autophagy is a lysosomal degradation system by which cytosolic materials and damaged organelles are broken down into basic components. To explore the physiological role of autophagy in glomerular endothelial cells (GEnCs), we compared the autophagic flux among cells in the kidney under starvation. Inhibition of autophagy by chloroquine administration significantly increased the number of autophagosomes or autolysosomes in GEnCs and proximal tubular cells, but not in podocytes, suggesting that the GEnCs exhibit substantial autophagic activity. Next, we analyzed endothelial and hematopoietic cell-specific atg5-deficient mice (atg5-conditional KO [cKO] mice). Glomeruli of 4-wk-old atg5-cKO mice exhibited slightly distended capillary loops accompanied by an accumulation of reactive oxygen species (ROS). Glomeruli of 8-wk-old atg5-cKO mice showed a lobular pattern with thickening of the capillary loops and mesangial matrix expansion; however, the vasculature of other organs was preserved. The atg5-cKO mice died by 12 wk of age, presumably due to pancytopenia resulting from the defect in their hematopoietic lineages. Therefore, we subjected 4-wk atg5-cKO mice to irradiation followed by bone marrow transplantation from normal littermates. Transplanted mice recapitulated the glomerular phenotypes of the atg5-cKO mice with no obvious histological changes in other organs. Twelve-mo-old transplanted mice developed mesangiolysis and glomerulosclerosis with significant deterioration of kidney function. Administration of N-acetyl-l-cysteine, a ROS scavenger, to atg5-cKO mice rescued the glomerular phenotypes. These data suggest that endothelial autophagy protects glomeruli from oxidative stress and maintains the integrity of glomerular capillaries. Enhancing endothelial autophagy may provide a novel therapeutic approach to minimizing glomerular diseases.
Topics: Animals; Antioxidants; Autophagy; Autophagy-Related Protein 5; Capillaries; Cells, Cultured; Chloroquine; Endothelial Cells; Humans; Kidney Diseases; Kidney Glomerulus; Mice; Mice, Knockout; Oxidative Stress; Reactive Oxygen Species
PubMed: 29130363
DOI: 10.1080/15548627.2017.1391428 -
The Journal of Histochemistry and... Jan 2018The homeostatic chemokine receptor CCR7 serves as key molecule in lymphocyte homing into secondary lymphoid tissues. Previous experiments from our group identified CCR7...
The homeostatic chemokine receptor CCR7 serves as key molecule in lymphocyte homing into secondary lymphoid tissues. Previous experiments from our group identified CCR7 also to be expressed by human mesangial cells. Exposing cultured human mesangial cells to the receptor ligand CCL21 revealed a positive effect on these cells regarding proliferation, migration, and survival. In the present study, we localized CCR7 and CCL21 during murine nephrogenesis. Analyzing wild-type and CCR7 deficient (CCR7) mice, we observed a retarded glomerulogenesis during renal development and a significantly decreased mesangial cellularity in adult CCR7 mice, as a consequence of less mesangial cell proliferation between embryonic day E17.5 and week 5 postpartum. Cell proliferation assays and cell-wounding experiments confirmed reduced proliferative and migratory properties of mesangial cells cultured from CCR7 kidneys. To further emphasize the role of CCR7 as important factor for mesangial biology, we examined the chemokine receptor expression in rats after induction of a mesangioproliferative glomerulonephritis. Here, we demonstrated for the first time that extra- and intraglomerular mesangial cells that were CCR7-negative in control rats exhibited a strong CCR7 expression during the phase of mesangial repopulation and proliferation.
Topics: Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Gene Deletion; Gene Expression Regulation, Developmental; Glomerular Mesangium; Glomerulonephritis; Kidney; Male; Mice, Inbred C57BL; Rats, Wistar; Receptors, CCR7
PubMed: 29077526
DOI: 10.1369/0022155417737975 -
Medicine Oct 2017TAFRO syndrome is a systemic inflammatory disease characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, MyeloFibrosis, Renal dysfunction, and... (Review)
Review
RATIONALE
TAFRO syndrome is a systemic inflammatory disease characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, MyeloFibrosis, Renal dysfunction, and Organomegaly. Progressive renal insufficiency is a predominant symptom; however, the mechanism of acute kidney injury (AKI) remains unclear, probably because severe thrombocytopenia prevents kidney biopsy. We report a rare case of TAFRO syndrome with histologically confirmed renal involvement.
PATIENTS CONCERNS
A 70-year-old man developed fever, anasarca, AKI, thrombocytopenia, and hepatosplenomegaly.
DIAGNOSES
Plasma vascular endothelial growth factor and serum interleukin-6 levels were significantly elevated. The diagnosis of TAFRO syndrome was made based on his clinical and laboratory findings. Kidney biopsy was performed for the evaluation of AKI and provided a diagnosis of membranoproliferative glomerulonephritis-like lesions due to endothelial injury. Glomerular capillary lumens were extremely narrowed or occluded by endothelial swelling, and marked widening of the subendothelial space by electron-lucent material resulted in mesangiolysis and a double-contoured glomerular basement membrane with no immune complex deposits.
INTERVENTIONS AND OUTCOMES
The patient required temporary hemodialysis due to oliguric AKI, but steroid therapy rapidly improved renal function.
LESSONS
Typically, patients with progressive renal involvement in TAFRO syndrome rapidly develop oliguric or anuric AKI. This report suggests that the reduction of glomerular perfusion by glomerular endothelial injury might be a primary factor in the progressive AKI of TAFRO syndrome. Our case and the literature review indicate that steroid and/or biological therapies result in highly favorable renal outcomes in patients with progressive AKI in TAFRO syndrome.
Topics: Acute Kidney Injury; Aged; Disease Progression; Edema; Humans; Hypertrophy; Interleukin-6; Kidney; Kidney Diseases; Male; Primary Myelofibrosis; Syndrome; Thrombocytopenia; Vascular Endothelial Growth Factor A
PubMed: 28984775
DOI: 10.1097/MD.0000000000008216