TAFRO syndrome as a cause of glomerular microangiopathy: a case report and literature review.

BACKGROUND: TAFRO syndrome is a systemic inflammatory disorder that manifests as thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Renal dysfunction is frequently complicated with TAFRO syndrome, however, it is challenging to perform kidney biopsy in patients with TAFRO syndrome in the presence of thrombocytopenia. Renal histology in TAFRO syndrome mainly shows membranoproliferative glomerulonephritis (MPGN)-like lesions or thrombotic microangiopathy (TMA)-like glomerulopathy. We review our case and previous reports of TAFRO syndrome with kidney biopsy findings and discuss the renal pathophysiology of TAFRO syndrome. CASE PRESENTATION: We describe a previously healthy 48- year-old woman with TAFRO syndrome. Kidney biopsy performed before the treatment showed diffuse global endocapillary proliferative changes with endothelial cell swelling, double contours of partial capillary walls, and mesangiolysis, consistent with TMA-like glomerulopathy. Glucocorticoid therapy including steroid pulse was ineffective and she developed anasarca, renal dysfunction and oliguria. Hemodialysis was required. However, the anti-Interleukin (IL)-6 receptor antibody (tocilizumab) therapy was very effective. An increase in urinary volume was achieved about 2 weeks after the tocilizumab therapy and hemodialysis was discontinued. To investigate the renal pathophysiology of TAFRO syndrome, we performed immunohistological staining of vascular endothelial growth factor (VEGF)-A, CD34, and D2-40, in our case and a normal control kidney. Glomerular VEGF-A was especially positive in podocytes both, in the control and in the case, with no significant difference and there was a significant increase of VEGF-A staining area in the cortical peritubular capillaries in the case. Both glomerular and renal cortical CD34 expression were significantly decreased in our case. D2-40 expression in cortex was not significantly different. CONCLUSIONS: We reviewed our case and other 10 previous reports about renal biopsy findings in TAFRO syndrome and found that glomerular microangiopathy was a common finding. IL-6-VEGF-axis-induced glomerular microangiopathy may play a crucial role in developing acute kidney injury in TAFRO syndrome and the anti-IL-6 receptor antibody therapy may be useful for TAFRO syndrome refractory to glucocorticoids. About the pathophysiology of VEGF in TAFRO syndrome, VEGF balance in the glomerulus and perhaps in the peritubular capillary system as well may be critical. Further investigation is needed.

IL-6 Trans-Signaling Drives Murine Crescentic GN.

The role of IL-6 signaling in renal diseases remains controversial, with data describing both anti-inflammatory and proinflammatory effects. IL-6 can act via classic signaling, engaging its two membrane receptors gp130 and IL-6 receptor (IL-6R). Alternatively, IL-6 trans-signaling requires soluble IL-6R (sIL-6R) to act on IL-6R-negative cells that express gp130. Here, we characterize the role of both pathways in crescentic nephritis. Patients with crescentic nephritis had significantly elevated levels of IL-6 in both serum and urine. Similarly, nephrotoxic serum-induced nephritis (NTN) in BALB/c mice was associated with elevated serum IL-6 levels. Levels of serum sIL-6R and renal downstream signals of IL-6 (phosphorylated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3) increased over time in this model. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody did not have a significant impact on NTN severity. In contrast, specific inhibition of trans-signaling using recombinant sgp130Fc resulted in milder disease. Vice versa, specific activation of trans-signaling using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated NTN and led to increased systolic BP in NTN mice. This correlated with increased renal mRNA synthesis of the Th17 cell cytokine IL-17A and decreased synthesis of resistin-like alpha (RELMalpha)-encoding mRNA, a surrogate marker of lesion-mitigating M2 macrophage subtypes. Collectively, our data suggest a central role for IL-6 trans-signaling in crescentic nephritis and offer options for more effective and specific therapeutic interventions in the IL-6 system.

New onset of immunoglobulin G4-related disease in a patient with relapsing polychondritis.

Relapsing polychondritis (RP) is a rare systemic autoimmune disorder characterized by the episodic and progressive deterioration of cartilage inflammation. Approximately 30% patients with RP have concurrent disease. However, there have been no previous reports of RP complicated by immunoglobulin G4-related disease (IgG4-RD). Here we report the case of a 67-year-old male who developed IgG4-RD approximately 20 years after RP diagnosis. The association between IgG4-RD and RP remains unclear.

Impact of the new risk stratification in the 2011 Japanese Society of Nephrology clinical guidelines for IgA nephropathy on incidence of early clinical remission with tonsillectomy plus steroid pulse therapy.

BACKGROUND: In 2011, the Japanese Society of Nephrology (JSN) published new clinical guidelines for IgA nephropathy (IgAN) with a new risk stratification based on clinical and histological severity. For classification, patients are divided into four groups (low, medium, high, and very high risk). However, differences in responsiveness to each treatment among different groups remain unclear. We evaluate the responsiveness of tonsillectomy plus steroid pulse (TSP) therapy using the new risk stratification. METHODS: We retrospectively reviewed 111 IgAN patients with TSP therapy between January 2003 and January 2013. Study patients were divided into three groups [low- (n = 40), medium- (n = 43) and high-/very high-risk group (n = 28)]. The primary outcome was clinical remission (CR). The observation period was 1 year following tonsillectomy. RESULTS: 57 out of 111 patients (51.4 %) reached CR. The CR incidence was 70.0, 41.9 and 39.3 % (the low-, the medium- and the high-/very high-risk group, respectively). The incidence of CR was significantly higher in the low-risk group (P = 0.013). In a multivariate logistic regression analysis, both the medium- and the high-/very high-risk group showed significantly lower incidence of inducing CR than the low-risk group [(odds ratio 0.324; 95 % confidence interval 0.106-0.939, P = 0.041) (odds ratio 0.239; 95 % confidence interval 0.058-0.910, P = 0.040), respectively]. CONCLUSIONS: The new risk stratification in the 2011 JSN clinical guidelines for IgAN had a positive impact on early CR of TSP therapy.

Gp130-dependent signaling in the podocyte.

Renal inflammation, in particular glomerular, is often characterized by increased IL-6 levels. The in vivo relevance of IL-6 signaling in glomerular podocytes, which play central roles in most glomerular diseases, is unknown. Here, we show that in normal mice, podocytes express gp130, the common signal-transducing receptor subunit of the IL-6 family of cytokines. Following systemic IL-6 or LPS injection in mice, podocyte IL-6 signaling was evidenced by downstream STAT3 phosphorylation. Next, we generated mice deficient for gp130 in podocytes. Expectedly, these mice exhibited abrogated IL-6 downstream signaling in podocytes. At the age of 40 wk, they did not show spontaneous renal pathology or abnormal renal function. The mice were then challenged using two LPS injury models as well as nephrotoxic serum to induce crescentic nephritis. Under all conditions, circulating IL-6 levels increased markedly and the mice developed the pathological hallmarks of the corresponding injury models such as proteinuria and development of glomerular crescents, respectively. However, despite the capacity of normal podocytes to transduce IL-6 family signals downstream, there were no significant differences between mice bearing the podocyte-specific gp130 deletion and their control littermates in any of these models. In conclusion, under the different conditions tested, gp130 signaling was not a critical component of the (patho-)biology of the podocyte in vivo.

Tubulointerstitial nephritis with IgG4-positive plasma cell infiltration and tertiary lymphoid tissue in a patient with cryoglobulinemic vasculitis: a case report.

Tertiary lymphoid tissue (TLT) develops at sites of chronic immune stimulation, including infection, autoimmune disease, transplant rejection, and cancer. Recently, TLT has been focused on an indicator for poor renal prognosis in various kidney diseases. In cryoglobulinemic vasculitis (CV), specific glomerular and vascular lesions are seen; however, tubulointerstitial lesions are usually nonspecific. We herein report the case of a 74-year-old man with idiopathic CV with rare tubulointerstitial lesions, such as tubulointerstitial nephritis (TIN) with IgG4-positive plasma cell infiltration and TLT. To our knowledge, this is the first report identifying TLT in the kidney biopsy in a patient with CV. Glucocorticoid improved the renal outcome. The association between CV and TIN with TLT remains unknown.

Growth arrest-specific protein 1 is a novel endogenous inhibitor of glomerular cell activation and proliferation.

Growth arrest-specific protein-1 (GAS1) is a GPI-anchored protein which is highly expressed in embryonic mouse fibroblasts and inhibits their proliferation. Glomerular mesangial cells release soluble GAS1 protein into the supernatant in vitro. Growth arrest led to GAS1 overexpression and increased release. Secretion involved disintegrin and metalloproteinase 10 and 17 as signified by inhibition experiments. Recombinant soluble GAS1 protein inhibited the proliferation of mesangial cells. Conversely, the induction of mesangial cell proliferation by PDGF-BB or -DD led to downregulation of GAS1 mRNA. Specific ligands of the PDGF α-receptor, PDGF-AA and -CC, had no effect. The GAS1 protein was localized in podocytes in kidneys from healthy rats. During the time course of mesangioproliferative glomerulonephritis in anti-Thy1.1-treated rats, glomerular GAS1 expression decreased prior to the onset of mesangial cell proliferation and increased at later stages during glomerular recovery. Finally, a plasmid expressing soluble GAS1 fused to an Fc fragment was systemically overexpressed in rats with mesangioproliferative glomerulonephritis. This ameliorated renal damage was indicated by decreased albuminuria and serum creatinine. Gas1/Fc-transfected rats also exhibited a reduction of the glomerular mesangial cell activation and proliferation. Thus, GAS1 is a novel endogenous inhibitor of glomerular mesangial cell proliferation and may be a novel therapeutic target in mesangioproliferative glomerular diseases.

Cytokine nephropathy in a patient with fatal Epstein-Barr virus-associated hemophagocytic syndrome.

Occasionally, patients with acute Epstein-Barr virus (EBV) infection develop hemophagocytic syndrome (HPS). Acute kidney injury (AKI) is considered a strong prognostic factor, but very few data are available about the biopsy-proven renal involvement of EBV-HPS. Here we describe a previously healthy 17-year-old girl with EBV-HPS. Combination therapy failed and renal necropsy was performed. The renal histology showed that intact glomeruli, remarkable interstitial edema and some cellular infiltration, and protein casts. These findings were compatible with cytokine nephropathy as recently advocated. We suggest that hypercytokinemia may play an important role in the pathophysiology in AKI of EBV-HPS.

Streptococcal Infection-related Glomerulonephritis in an Elderly Diabetic Patient Complicated by Hemophagocytic Syndrome and Cytomegalovirus Nephritis.

There has been a significant shift in epidemiology and renal outcomes of infection-related glomerulonephritis (IRGN) in recent years. The renal prognosis of IRGN is often poor in adults, especially in the elderly and diabetics. We herein report an elderly diabetic patient with IRGN due to streptococcal infection complicated by hemophagocytic syndrome and cytomegalovirus nephritis, which is uncommon among non-transplant patients. Infection control and steroids did not recover the patient's renal function. For elderly IRGN patients with diabetes, a further investigation of the most effective treatment for related renal outcomes is needed.

Renoprotective effects of paramylon, a ß-1,3-D-Glucan isolated from Euglena gracilis Z in a rodent model of chronic kidney disease.

Paramylon is a novel ß-glucan that is stored by Euglena gracilis Z, which is a unicellular photosynthesizing green alga with characteristics of both animals and plants. Recent studies have indicated that paramylon functions as an immunomodulator or a dietary fiber. Currently, chronic kidney disease (CKD) is a global health problem, and there is no effective preventive treatment for CKD progression. However, paramylon may suppress the progression of CKD via the elimination of uremic toxins or modulation of gut microbiota, leading to the alleviation of inflammation. The aim of this study was to evaluate the effect of paramylon in CKD rat model. Eight-week-old male Wistar rats with a 5/6 nephrectomy were given either a normal diet or a diet containing 5% paramylon for 8 weeks. Proteinuria was measured intermittently. Serum and kidney tissues were harvested after sacrifice. We performed a renal molecular and histopathological investigation, serum metabolome analysis, and gut microbiome analysis. The results showed that paramylon attenuated renal function, glomerulosclerosis, tubulointerstitial injury, and podocyte injury in the CKD rat model. Renal fibrosis, tubulointerstitial inflammatory cell infiltration, and proinflammatory cytokine gene expression levels tended to be suppressed with paramylon treatment. Further, paramylon inhibited the accumulation of uremic toxins, including tricarboxylic acid (TCA) cycle-related metabolites and modulated a part of CKD-related gut microbiota in the CKD rat model. In conclusion, we suggest that paramylon mainly inhibited the absorption of non-microbiota-derived uremic solutes, leading to protect renal injury via anti-inflammatory and anti-fibrotic effects. Paramylon may be a novel compound that can act against CKD progression.

Portal vein thrombosis in adult-onset Still's disease: a case report and literature review.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease in which a variety of thrombotic events may occur. However, to our knowledge, portal vein thrombosis (PVT), a potential cause of gastrointestinal bleeding, has not been described in the English literature. A previously well 47-year-old man diagnosed with AOSD showed a transient increase in serum transaminase level. A careful observation led to a prompt discovery of a re-increase in serum transaminase level and PVT that involved an entire left portal vein plus parts of supramesenteric vein. PVT resolved completely in 6 months, and the patient remained well for at least 1 year receiving anticoagulants plus an immunosuppressant that selectively inhibits guanosine monophosphate synthesis in the purine metabolism pathway. Thrombotic events, if not lethal, deteriorate the quality of life in AOSD patients. This report illustrates the spectrum of AOSD and underlines the need to include PVT in differential diagnosis if serum liver enzyme levels fluctuate.

[Infective endocarditis successfully treated by early medical therapy in a patient with Henoch-Schönlein purpura nephritis under oral steroid therapy].

A 29-year-old man was admitted to our hospital because of high fever and dyspnea. About two months before this admission the patient was diagnosed as Henoch-Schönlein purpura nephritis who was treated with 40 mg/day of prednisolone(PSL). When the dose of PSL was decreased to 32.5 mag/day, his temperature was 40 degrees C, the pulse was 120 beats per minute and the blood pressure was 71/36 mmHg. In the peripheral blood study, the white blood cell count was 23,800/microL and C-reactive protein was 6.1 mg/dL. He was diagnosed as bilateral lower lung pneumonia by chest-computed tomography findings, non-segmental and high-density consolidation of the bilateral lower lungs. Streptococcus pneumoniae was detected from blood culture. Therefore it was concluded that sepsis was caused by severe pneumonia. Thereafter infective endocarditis was diagnosed from the findings of vegetation of both the tricuspid and mitral valves detected by ultrasonic cardiography. Infective endocarditis resulted from septicemia caused by Streptococcus pneumoniae. The infection related endocarditis was completely healed by early treatment including an adequate quantity of penicillin G with high sensitivity. There have been few case reports of infective endocarditis in patients with nephritis under steroid therapy. Steroid therapy is widely used in patients with various types of nephritis including IgA nephropathy and focal segmental glomerular sclerosis in addition to Henoch-Shönlein purpura. Infective endocarditis should be recognized as a complication of steroid treatment of these patients.

Comparison of Renal Outcome among Japanese Patients with or without Microangiopathic Hemolysis in Malignant Phase Hypertension: A Single-Center Retrospective Study.

BACKGROUND/AIMS: Although microangiopathic hemolysis (MAH) is a well-known complication of malignant phase hypertension (MPH), only less data on whether MAH in MPH predicts renal outcome exist. Therefore, we evaluated whether MAH was associated with the renal outcome in patients with MPH. METHODS: We conducted a single-center, retrospective, cohort study. Data from 35 patients diagnosed with MPH between October 1998 and January 2015 were analyzed. MPH was defined as the presence of a diastolic blood pressure of ≥120 mm Hg and grades III/IV hypertensive retinopathy according to the Keith-Wagener-Barker classification. MAH was defined as the presence of a low platelet count (<150 × 109/L) together with either an elevated level of lactate dehydrogenase (LDH; >220 U/L), or the presence of schistocytes, or both and the normalization of platelet and LDH level or schistocyte levels after adequate blood pressure control was achieved. The primary outcome was dialysis induction. RESULTS: Fifteen patients had MAH. Those with MAH had significantly severe renal dysfunction at the onset of MPH. The length of follow-up (median, interquartile range) of patients with MAH and those without MAH were 30 (16-94) and 48 (25-115) months, respectively. Dialysis was induced in 9 of 15 patients with MAH and in 6 of 20 patients without MAH. Renal survival in patients with MAH was worse than that in those without, but this was not statistically significant (p = 0.08). By multivariate Cox regression analysis, MAH was not shown to contribute to dialysis induction. CONCLUSION: MAH did not predict renal outcome in MPH.

Hemoglobin Kansas as a Rare Cause of Cyanosis: A Case Report and Review of the Literature.

Hemoglobin (Hb) Kansas is an inherited Hb variant with a low oxygen affinity that is associated with low oxygen saturation on pulse oximetry (SpO2). It leads to asymptomatic cyanosis. Patients with Hb Kansas do not require any specific treatment and the prognosis is good. In patients with unexplained cyanosis, we should thus consider Hb variants, including Hb Kansas and avoid unnecessary investigations and managements. We herein report the case of 65-year-old woman with Hb Kansas and review five other cases (three lineages) that have been reported in Japan.

Absence of mesangial C1q deposition is associated with resolution of proteinuria and hematuria after tonsillectomy plus steroid pulse therapy for immunoglobulin a nephropathy.

INTRODUCTION AND AIMS: Deposition of C1q occurs in 0 to 45% of patients with IgAN. In order to identify whether mesangial C1q deposition in IgAN is a novel marker for the response to tonsillectomy plus steroid pulse therapy (TSP), we studied the association between mesangial C1q deposition in IgAN and the remission rate after TSP therapy for IgAN. METHODS: We conducted a retrospective cohort study at a single Japanese center. We analyzed data on 110 patients diagnosed with IgA nephropathy who received TSP between January 2003 and December 2012. Positive C1q findings were defined as diffuse mesangial C1q deposition. The study outcome was the resolution of abnormal urinary findings and was defined as negative proteinuria and negative occult blood 1 year after steroid pulse therapy. RESULTS: In all enrolled cases, 69 patients (62.7%) went into remission. Ten out of 24 (41.7%) C1q-positive patients experienced remission, and 59 out of 86 (68.6%) C1q-negative patients experienced remission. Multiple logistic regression model analysis showed that the absence of C1q deposition increased the odds ratio for remission (odds ratio 4.41; 95% confidence interval 1.33-15.75, p = 0.017). CONCLUSIONS: These results suggest that the absence of diffuse C1q deposition in the mesangial area of the glomerulus in patients with IgA nephropathy is a positive predictive sign for a response to TSP and is associated with the resolution of urinary abnormalities 1 year after TSP.

Liver abscessation and multiple septic pulmonary emboli associated with Lemierre's syndrome: a case report.

BACKGROUND: In Lemierre's syndrome, patients first exhibit pharyngitis and peritonsillar abscessation, followed by the development of anaerobic bacterial (usually Fusobacterium necrophorum) septicemia and metastatic infections throughout the body. However, these infections rarely affect the liver. We describe a case of Lemierre's syndrome, in which the first disease manifestation was liver abscess, for drawing attention of emergency physicians to this rare but fatal disease. CASE PRESENTATION: A 28-year-old Asian ethnicity Filipino male, who was previously healthy, entered the emergency department presenting with fever and pharyngeal pain that had persisted for 5 days. Contrast-enhanced abdominal computed tomography revealed a 3-cm area of low density in segment 6 of the liver, consistent with an abscess. Chest computed tomography also revealed that multiple nodes in both lungs were enlarged, and septic emboli were suspected. The patient was hospitalized and antibiotic treatment was initiated. On hospital day 6, blood culture results confirmed Fusobacterium necrophorum septicemia. The patient was diagnosed with Lemierre's syndrome, as pharyngitis developed into bacteremia associated with hepatic and pulmonary lesions. The patient's condition improved with antibiotics and he was discharged following three weeks of treatment in the hospital. CONCLUSION: With the widespread use of antibiotics, Lemierre's syndrome is rarely encountered anymore, but it can be fatal if not properly diagnosed. It is a crucial differential diagnosis in young patients exhibiting septicemia or multiple metastatic infection of unknown origin.