Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming.

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

Increased intrarenal post-glomerular blood flow is a key condition for the development of calcineurin inhibitor-induced renal tubular acidosis in kidney transplant recipients.

BACKGROUND: Hyperchloremic metabolic acidosis (HCMA) from renal tubular acidosis (RTA) is common in kidney transplant (KT) recipients. Calcineurin inhibitors (CNIs) are a potential cause of RTA, and whether HCMA is a determinant of poor graft prognosis is controversial. METHODS: The subjects were living-donor KT recipients (LDKTRs, n = 47) and matched donors (n = 43). All cases of rejection, extrarenal causes, and respiratory disorders were excluded. HCMA was defined as having a [Na+]-[Cl- ] value of ≤34 or starting alkalization. We determined the potential causes of HCMA in LDKTRs at 3 months (m) and 1 year (y) post-KT. We examined renal hemodynamic parameters in 26 LDKTRs at 1 y post-KT: namely, glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction (FF; GFR/RPF) and pre-/post-glomerular vascular resistance (pre-/postVR). RESULTS: The HCMA incidence in the 3-m post-KT LDKTR group was higher than that of the donors (51.0% vs. 6.9%, p < 0.001, adjusted odds ratio: 6.7-15.7). Among adjusted factors, the most dominant HCMA contributor was low hemoglobin concentration (Hb ≤ 12 g/dl). Compared to non-HCMA cases, HCMA patients had low FF and low post-VR (p = 0.008, 0.003, respectively) suggesting increased intrarenal post-glomerular blood flow. The high pathological score of alternative arteriolar hyalinosis (aah) ≥2 was a significant HCMA risk. The tacrolimus trough level was not high in HCMA but was significantly high in HCMA in the low post-VR setting (p = 0.002). CONCLUSION: Among LDKTRs, low hemoglobin level is an important contributor to the manifestation of HCMA in the induction period, and increased intrarenal post-glomerular blood flow is a key condition for the development of CNI-induced RTA.

Epidemiology and temporal changes in the prognosis of rapidly progressive glomerulonephritis in Japan: a nationwide 1989-2015 survey.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) can progress to end-stage kidney disease within a short period. This study is a continuation of the chronological nationwide survey conducted by the Japan-RPGN working group. METHODS: We examined a total of 2793 RPGN cases registered during four periods (1989-1998, 1999-2001, 2002-2008, 2009-2011) plus 1386 cases in 2012-2015. As potential prognostic determinants, we investigated the onset period, the clinical severity (CS) grade [classified according to age, serum creatinine (sCr) and C-reactive protein levels, and presence/absence of lung lesions], and causative disease. RESULTS: The cumulative overall RPGN patient survival at 24 months kept improving over the five periods (72.0%, 72.9%, 77.7%, 83.0%, 84.9%, p < 0.001 for trend). The cumulative renal survival also improved in the latest period (68.7%, 75.4%, 76.7%, 73.4%, 78.2%, p < 0.001 for trend). The CS grade was well stratified to predict both life and renal prognoses. Anti-glomerular basement membrane disease (aGBMD)-RPGN had a poorer renal prognosis than other diseases. In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV-RPGN, accounting for > 70% of the overall RPGN), the prognostic results were similar to that for overall RPGN. There was a much better renal prognosis for the latest period under the condition of sCr < 3 mg/dL (the 24-month cumulative renal survival: 97.9%), but not for sCr ≥ 3 mg/dL (61.5%). CONCLUSIONS: In overall RPGN as well as AAV-RPGN, both life and renal prognoses tended to improve, but the favorable renal result was substantially limited to mild cases. There was no improvement of the renal prognosis in aGBMD-RPGN.

Literature review of allograft adenovirus nephritis and a case presenting as mass lesions in a transplanted kidney without symptoms of urinary tract infection or acute kidney injury.

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52-year-old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post-KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast-enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT-guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis-like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis.

Unusual ischemic kidney injury presenting as slowly declining graft function and successful use of oral desmopressin in a kidney transplant recipient with subclinical central diabetes insipidus.

Polyuria in post-kidney transplant (KT) patients is a common condition generally attributed to delayed tubular function, fluid administration, and solute diuresis. Since excessive water intake post-KT physiologically suppresses arginine vasopressin (AVP) secretion, central diabetes insipidus (CDI) caused by deficient primary AVP release can be overlooked. Although DDAVP (desmopressin) - a selective AVP V2 receptor agonist - has been used to treat massive polyuria, CDI rarely progresses to kidney injury due to the preservation of fluid balance by thirst-dependent osmoregulation. Administration of DDAVP in post-KT recipients with mild polyuria and subclinical CDI is difficult to assess, and whether long-term use of DDAVP is beneficial for the transplanted kidney has not been established. We present the case of a 36-year-old Japanese female who was diagnosed with subclinical/partial CDI post KT. CDI was caused by a sequela of suprasellar germinoma. Graft function gradually declined without evidence of hypovolemia or hypernatremia, and a kidney biopsy revealed advanced ischemic kidney injury. Although daily oral DDAVP administration did not increase extracellular fluid volume, treatment resulted in a gradual improvement of graft function, and a follow-up transplanted kidney biopsy indicated substantial recovery.

Ratio of serum creatinine to cystatin C is related to leg strength in predialysis CKD patients.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) patients have lower levels of physical function. Especially, leg strength is important for daily living and preventing falls. However, physical function screenings are difficult to perform at clinical sites. To find clinically useful method to evaluate physical function in predialysis CKD patients, we tried to evaluate the relationship between the ratio of serum creatinine to serum cystatin C (Cre/CysC), and knee extensor muscle strength/body weight (KEMS) which reflects their leg strength. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We recruited 147 outpatients with CKD (87 men; mean age, 61.6 ± 9.8 years; mean eGFRcreat, 40.7 ± 12.9 mL/min/1.73m2) in this cross-sectional study. KEMS was assessed using a wire strain gauge dynamometer. Skeletal muscle mass and body fat mass were assessed by bioelectrical impedance analysis. RESULTS: The mean value of Cre/CysC was 1.01 ± 0.18. The mean value of KEMS was 1.60 ± 0.47 Nm/kg. In multivariate linear regression analysis, skeletal muscle mass (p < 0.01), body fat mass (p < 0.01), hemoglobin (p = 0.01), and Cre/CysC (p < 0.01) was independently related to KEMS. The correlation between Cre/CysC and KEMS is stronger in high quantile of Cre/CysC. CONCLUSIONS: In predialysis CKD patients, KEMS showed lower as CKD stage advanced. Cre/CysC is significantly related to KEMS independently. Cre/CysC may be an alternative marker for leg strength in CKD patients and even more valuable to utilize in cases with high Cre/CysC.

Hemodialysis-related amyloidosis: Is it still relevant?

Accumulation of amyloid fibrils from ß2-microglobulin (ß2M) was first recognized as a characteristic osteoarticular complication in long-term hemodialysis (HD) patients and called "HD-related amyloidosis" (HRA). However, this syndrome can also be observed in end-stage renal diseases (ESRD) patients undergoing peritoneal dialysis, and even in patients with chronic renal failure before the initiation of dialytic therapy, suggesting that HD is not a direct cause but that accumulation of ß2M or some ß2M-associated molecules in the body is a common pathogenesis. Currently the term "dialysis-related amyloidosis" (DRA) is widely used for ß2M-amyloid (Aß2M) amyloidosis associated with ESRD, although DRA patients consist mostly of those undergoing long-term HD. Factors other than ß2M accumulation also play a role in the formation/local deposition of Aß2M and disruption of tissue architecture. Conformational changes of ß2M by misfolding/unfolding, and promoting/inhibitory effects induced by other coexisting molecules, advanced glycation and oxidation, and direct cell toxicity have also been documented. Two technological improvements of HD have been the keys to prevent the development and progression of DRA: the efficient removal of ß2M by using high-flux membranes, high-volume convection and adsorptive column/membrane, as well as the use of biocompatible membranes and dialysates (eg, ultrapure and acetate-free dialysates) have minimized both inflammation and ß2M production. Epidemiologically, a decrease in the incidence of DRA has recently been reported; however, longer survival of HD patients may contribute to the development of more DRA, though with a delayed onset. In this article, we describe the pathogenesis of DRA, the strategies developed for its prevention and minimization, and the favorable epidemiological data achieved by these efforts.

Renal compensatory adaptation for water handling in a patient with adipsic diabetes insipidus after clipping of a ruptured aneurysm of the anterior communicating artery
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A 38-year-old Japanese man who had undergone clipping surgery for a ruptured aneurysm of the anterior communicating artery 2 days prior, suddenly developed refractory hypernatremia (serum sodium (Na) 156 - 162 mmol/L). Symptoms included low plasma vasopressin, fluctuating urine osmolality (120 - 710 mOsm/kg) and lack of thirst, all suggesting adipsic diabetes insipidus (ADI). Hypernatremia was corrected by scheduled water intake with desmopressin administration. During 1-year follow-up after the surgery, his serum Na level normalized despite the suspension of desmopressin, but neither thirst nor osmolality-dependent vasopressin release recovered. Meanwhile, his urine osmolality shifted to a constant high level. The present case suggests that renal compensatory adaptation, apparently independent of the circulating vasopressin level, plays a major role in water handling in longitudinal ADI.
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Anaemia is an essential complication of ANCA-associated renal vasculitis: a single center cohort study.

BACKGROUND: Anaemia is a common complication of patients with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. Nevertheless, the cause and degree of such cases of anaemia have not been elucidated in detail. We aimed to investigate the prevalence, cause, pathogenesis of anaemia and the impact of anaemia on prognosis in patients with ANCA-associated renal vasculitis. METHODS: We identified 45 patients with ANCA-associated renal vasculitis that were clinically and/or histologically diagnosed and treated from 2003 to 2014 at University of Tsukuba Hospital. The relationships between anaemia and various clinicopathological findings were evaluated. RESULTS: At the time of diagnosis of ANCA-associated renal vasculitis, all patients showed anaemia, with a mean haemoglobin level of 7.5 ± 1.3 g/dL. Renal anaemia was diagnosed in 92% of patients, anaemia of chronic disease (ACD) in 56%, and anaemia due to hemorrhage in 20%. Next, the patients were divided into two groups according to anaemia severity: minimum haemoglobin (min Hb) < 7.5 (n = 24) and min Hb ≥ 7.5 (n = 21). A comparison of baseline characteristics showed that serum albumin, maximum serum creatinine, minimum estimated glomerular filtration rate (eGFR), serum cystatin C, and the area of tubulointerstitial damage were significantly different between the haemoglobin groups (p < 0.05). No significant intergroup differences were observed in iron-related or inflammation-related data. With regard to the relationship between anaemia severity and prognosis, patients in the min Hb < 7.5 group tended to have a lower eGFR. Anaemia severity was associated with markedly lower survival (Log-rank test, p = 0.03). CONCLUSIONS: In this cohort of patients with ANCA-associated renal vasculitis, all subjects exhibited anaemia. In regard to the cause and pathogenesis, the most prevalent form of anaemia was renal anaemia, not ACD, and a potential reason for the high prevalence of anaemia in our cohort may have been the interaction between renal anaemia and ACD. Moreover, anaemia severity was significantly associated with the degree of renal dysfunction and life prognosis.

Short term-efficacy and tolerability of Rheocarna, a novel direct hemoperfusion adsorptive column, for chronic limb-threatening ischemia in dialysis patients: A single-center case series.

INTRODUCTION: With population aging and lifestyle changes, the number of patients with chronic limb-threatening ischemia (CLTI) is increasing, and refractory or recurrent lesions are more common, especially in chronic dialysis patients. In March 2021, a new type of adsorptive cellulose bead column immobilized with dextran sulfate and L-tryptophan for direct hemoperfusion (DHP) was approved by Japan's medical insurance system as a treatment for CLTI. METHODS: We retrospectively analyzed 17 cases of CLTI in dialysis patients treated with DHP using the novel column (Rheocarna) (DHP-R) at our hospital from May 2021 to October 2022. The short-term of efficacy of DHP-R was judged qualitatively by the foot care team every 2 weeks based on the assessment of skin color, warmth, ulcer epithelialization or shrinkage of the ulcer area, and foot pain. The final judgment of efficacy was made after the final DHP-R session. RESULTS: The median age of patients was 66 years, the median dialysis duration was 10 years, 15 cases (88%) were male, and 15 cases (88%) had diabetes. The median total number of sessions was eight. In comparing the groups in which DHP-R was effective and ineffective, there was no significant difference in any factors including patient background data (i.e., age, diabetes, low-density lipoprotein cholesterol, hemoglobin, dialysis duration, etc.), type of anticoagulants, and presence of episodes of blood pressure drop or circuit clotting during session. Three cases with symptomatic hypotension during the session and two cases with circuit clotting that did not improve with increased heparin dose all resolved immediately after changing the anticoagulant from heparin to nafamostat mesylate (NM). CONCLUSION: Identification of patients' characteristics in which DHP-R is favorable and some reliable index that allow a rapid decision to continue DHP-R are needed. In addition, validating whether the use of NM as anticoagulant affects the efficacy of DHP-R for CTLI treatment remains a challenge to resolve.

Successful Use of Granulocyte and Monocyte Adsorptive Apheresis in a Patient with Post-COVID-19 Multisystem Inflammatory Syndrome in Adults.

Multisystem inflammatory syndrome in adults (MIS-A) is a life-threatening disease that can develop weeks after coronavirus disease 2019 (COVID-19). MIS-A symptoms include multiorgan involvement, especially gastrointestinal tract and heart involvement, and Kawasaki disease-like symptoms. We herein report a 44-year-old Japanese man with MIS-A who had contracted COVID-19 five weeks ago and went into shock after acute gastroenteritis, acute kidney injury, and Kawasaki disease-like symptoms. Methylprednisone pulse and high-dose intravenous immunoglobulin resulted in recovery of shock and his renal function, but diffuse ST-segment elevation on electrocardiography and pericardial effusion with a fever emerged after therapy. Additional granulocyte-monocyte adsorptive apheresis successfully ameliorated the cardiac involvement.

Development of IgA vasculitis with severe glomerulonephritis after COVID-19 vaccination: a case report and literature review.

With the worldwide spread of the COVID-19 vaccine program during the COVID-19 pandemic, the numbers of reported cases with new-onset or relapsed kidney disease/vasculitis such as minimal change nephrotic syndrome, immunoglobulinA (IgA) nephropathy, and IgA vasculitis (IgAV) that developed after COVID-19 vaccination are increasing. We present the case of a 67-year-old Japanese woman who developed IgAV with purpura on her extremities and trunk in the evening of the day that she received the second dose of the Pfizer-BioNTech COVID-19 vaccine. She subsequently presented with acute kidney injury and nephrotic syndrome, and a kidney biopsy performed 14 days after the second vaccination showed diffuse mesangial and endocapillary glomerulonephritis with necrotizing crescent formation, accompanied by IgA deposition. One steroid pulse plus four administrations of a monthly intravenous cyclophosphamide injection were applied, followed by oral azathioprine during oral steroid tapering. Her response to this treatment was unsatisfactory and intractable for some time. Eventually, her renal function improved and nephrotic syndrome was resolved, while microscopic hematuria and proteinuria at ~ 1 g/gCr remained at 6 months post-vaccination. Unlike the previous milder renal-involved IgAV cases following COVID-19 vaccination, our patient's case presented severe glomerulonephritis and took a long time to recover despite intensive initial immunosuppressive treatment.

Mitochondrial DNA deletion-dependent podocyte injuries in Mito-miceΔ, a murine model of mitochondrial disease.

Focal segmental glomerulosclerosis (FSGS) is a major renal complication of human mitochondrial disease. However, its pathogenesis has not been fully explained. In this study, we focused on the glomerular injury of mito-miceΔ and investigated the pathogenesis of their renal involvement. We analyzed biochemical data and histology in mito-miceΔ. The proteinuria began to show in some mito-miceΔ with around 80% of mitochondrial DNA deletion, then proteinuria developed dependent with higher mitochondrial DNA deletion, more than 90% deletion. Mito-miceΔ with proteinuria histologically revealed FSGS. Immunohistochemistry demonstrated extensive distal tubular casts due to abundant glomerular proteinuria. Additionally, the loss of podocyte-related protein and podocyte's number were found. Therefore, the podocyte injuries and its depletion had a temporal relationship with the development of proteinuria. This study suggested mitochondrial DNA deletion-dependent podocyte injuries as the pathogenesis of renal involvement in mito-miceΔ. The podocytes are the main target of mitochondrial dysfunction originated from the accumulation of mitochondrial DNA abnormality in the kidney.

Immunohistological score of transcription factor 21 had a positive correlation with its urinary excretion and proteinuria in immunoglobulin A nephropathy.

Transcription factor 21 (TCF21) contributes to mammalian nephrogenesis, and especially to glomerular maturation. Our previous study suggested its influence on glomerular injury, showing that TCF21 expression in podocytes had a positive correlation with the urinary protein value and also with the urinary TCF21 concentration. We now focus on its influence on the clinical course of immunoglobulin A nephropathy (IgAN), as patients with IgAN constitute the largest population of individuals with primary chronic glomerulonephritis in the world. Twenty cases of IgAN were divided into two groups according to the immunohistological score (IHS) of glomerular TCF21 expression: group IHS1 (n=7) and group IHS2+3 (n=13). Sixteen of the 20 cases were followed up for 2 years. Group IHS2+3 had heavier urinary protein (p=0.03) and a greater urinary TCF21 level (p<0.001) compared to group IHS1 at baseline. None of the other factors including hematuria, estimated glomerular filtration rate (eGFR), or the Oxford classification showed a statistically significant difference between these two groups. At the 2-year follow-up, even though the rate of remission in urinary protein, hematuria and the eGFR decline were not statistically correlated to IHS, the IHS2+3 group had a slight tendency toward a steeper eGFR decline compared to IHS1 (p=0.31). The present study suggested that the higher IHS of TCF21 corresponded to heavier proteinuria and a higher urinary TCF21 level in IgAN. This could be the first step in determining the TCF21 value for predicting the prognosis for IgAN.

Anti-glomerular Basement Membrane Glomerulonephritis During the First Trimester of Pregnancy.

A 28-year-old woman was admitted during the eighth week of her pregnancy because her clinical course was consistent with rapid progressive glomerulonephritis (RPGN). Anti-glomerular basement membrane antibody (anti-GBM Ab) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, and the anti-GBM Ab titer being extremely high. She was treated with hemodialysis, plasma exchange and prednisolone. She survived the illness; however, neither the fetus nor her kidney function could be rescued. She had human leukocyte antigen (HLA)-DRB1*1502:01, which differs from the DRB1*1501 associated with anti-GBM GN. When patients have particular symptoms, we should check the urine and serum creatinine to exclude RPGN, even in cases of pregnancy.

Anti-PM/Scl Antibody-positive Systemic Sclerosis Complicated by Multiple Organ Involvement.

A 40-year-old Japanese woman developed malignant-phase hypertension complicated by thrombotic microangiopathy, progressing to end-stage renal disease. Five years later, she was diagnosed with pulmonary arterial hypertension and interstitial pneumonia. Despite a lack of overt skin sclerosis, nucleolar staining in our indirect immunofluorescence analysis and nailfold capillaroscopy facilitated the diagnosis of anti-PM/Scl antibody-positive systemic sclerosis. We observed the persistent presence of anti-PM/Scl antibodies throughout the clinical course, suggesting that her kidney disease was scleroderma renal crisis. Anti-PM/Scl antibodies can be associated with multiple organ diseases. Careful attention to a patient's antinuclear antibody pattern and dermatological findings may help clarify the etiology of undiagnosed diseases.