Barriers to conservative kidney management for Japanese healthcare professionals involved in the treatment of end-stage renal disease.

BACKGROUND: Conservative kidney management (CKM) is a treatment alternative for patients with end-stage kidney disease (ESKD). Despite the increasing population of elderly dialysis patients in Japan, CKM is not as readily available compared with that in North America and Europe. Therefore, it is important to clarify the barriers to CKM in Japan. METHODS: We interviewed 11 experts to explore their beliefs and issues regarding CKM. Based on the interviews, we categorized the CKM barriers into eight categories and created a 24-item questionnaire. A questionnaire survey was conducted among 112 medical professionals involved in ESKD management. To investigate the types of barriers, we conducted an exploratory factor analysis using the questionnaire results. RESULTS: Responses were obtained from 53 (47.3%) of 112 subjects (18 doctors, 29 nurses, 6 clinical engineers), with 94.3% considering CKM as a treatment option for ESKD. Factor analysis categorized the questions into the following: (1) Lack of palliative care experience, (2) Ethics and responsibility, (3) Patient's problem, (4) Dialog with patients and families, and (5) Lack of support system. Regarding barriers to CKM, "lack of experience in palliative care" and "lack of support system" scored the highest, and "ethics and responsibility" scored the lowest. CONCLUSIONS: Barriers to CKM may be classified into five factors, with "lack of experience in palliative care" and "lack of support system" being the important barriers to overcome. Additionally, most healthcare professionals consider CKM as the fourth option for renal replacement therapy.

Changes in Metabolomic Profiles Induced by Switching from an Erythropoiesis-Stimulating Agent to a Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor in Hemodialysis Patients: A Pilot Study.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of medications for managing renal anemia in patients with chronic kidney disease (CKD). In addition to their erythropoietic activity, HIF-PHIs exhibit multifaceted effects on iron and glucose metabolism, mitochondrial metabolism, and angiogenesis through the regulation of a wide range of HIF-responsive gene expressions. However, the systemic biological effects of HIF-PHIs in CKD patients have not been fully explored. In this prospective, single-center study, we comprehensively investigated changes in plasma metabolomic profiles following the switch from an erythropoiesis-stimulating agent (ESA) to an HIF-PHI, daprodustat, in 10 maintenance hemodialysis patients. Plasma metabolites were measured before and three months after the switch from an ESA to an HIF-PHI. Among 106 individual markers detected in plasma, significant changes were found in four compounds (erythrulose, n-butyrylglycine, threonine, and leucine), and notable but non-significant changes were found in another five compounds (inositol, phosphoric acid, lyxose, arabinose, and hydroxylamine). Pathway analysis indicated decreased levels of plasma metabolites, particularly those involved in phosphatidylinositol signaling, ascorbate and aldarate metabolism, and inositol phosphate metabolism. Our results provide detailed insights into the systemic biological effects of HIF-PHIs in hemodialysis patients and are expected to contribute to an evaluation of the potential side effects that may result from long-term use of this class of drugs.

Role of the new bioimpedance monitoring device (Seca®) in assessing dry weight in hemodialysis patients.

BACKGROUND: In recent years, bioimpedance analysis has come to be widely used in clinical practice for dialysis patients, but there is not sufficient consensus on its significance. We aimed to examine the merits of performing bioimpedance analysis in addition to conventional evaluation methods for dry weight such as measuring human atrial natriuretic peptide (hANP), blood pressure, and cardiothoracic ratio in patients on chronic hemodialysis. METHODS: Body composition of 78 hemodialysis patients was performed by using a new and more accurate segmental multifrequency bioimpedance analysis device (Seca® medical body composition analyzer 525, Seca GmbH & Co. KG, Hamburg, Germany). Laboratory data including hANP at post-dialysis and demographic profile were collected. Statistical analysis was performed with SPSS software. RESULTS: Mean age of the patients was 66.9 ± 12.6 years and 80.8% were males. Mean value of hANP and the ratio of extracellular water to total body water (ECW/TBW) were 61.4 ± 36.4 pg/mL and 46.1 ± 3.9%, respectively. The calculated ECW/TBW cutoff point for hANP > 50 pg/mL was 45.0%, with sensitivity of 74.4% and specificity of 64.7%. Patients with an ECW/TBW of more than 45% and hANP value of > 50 pg/mL had a higher blood pressure and cardiothoracic ratio on chest X-ray examination. CONCLUSIONS: Our results suggest that the ratio of extracellular water to total body water of more than 45% and hANP value of ≥ 50 pg/mL were overhydrated in chronic hemodialysis patients. Whether monitoring levels of these parameters has a role in the outcome including patients' survival and cardiovascular events requires further study.

Wolf-Hirschhorn syndrome candidate 1-like 1 epigenetically regulates nephrin gene expression.

Altered expression of nephrin underlies the pathophysiology of proteinuria in both congenital and acquired nephrotic syndrome. However, the epigenetic mechanisms of nephrin gene regulation remain elusive. Here, we show that Wolf-Hirschhorn syndrome candidate 1-like 1 long form (WHSC1L1-L) is a novel epigenetic modifier of nephrin gene regulation. WHSC1L1-L was associated with histone H3K4 and H3K36 in human embryonic kidney cells. WHSC1L1-L gene was expressed in the podocytes, and functional protein product was detected in these cells. WHSC1L1-L was found to bind nephrin but not other podocyte-specific gene promoters, leading to its inhibition/suppression, abrogating the stimulatory effect of WT1 and NF-κB. Gene knockdown of WHSC1L1-L in primary cultured podocytes accelerated the transcription of nephrin but not CD2AP. An in vivo zebrafish study involving the injection of Whsc1l1 mRNA into embryos demonstrated an apparent reduction of nephrin mRNA but not podocin and CD2AP mRNA. Immunohistochemistry showed that both WHSC1L1-L and nephrin emerged at the S-shaped body stage in glomeruli. Immunofluorescence and confocal microscopy displayed WHSC1L1 to colocalize with trimethylated H3K4 in the glomerular podocytes. Chromatin immunoprecipitation assay revealed the reduction of the association of trimethylated H3K4 at the nephrin promoter regions. Finally, nephrin mRNA was upregulated in the glomerulus at the early proteinuric stage of mouse nephrosis, which was associated with the reduction of WHSC1L1. In conclusion, our results demonstrate that WHSC1L1-L acts as a histone methyltransferase in podocytes and regulates nephrin gene expression, which may in turn contribute to the integrity of the slit diaphragm of the glomerular filtration barrier.

Association of illness perception and alexithymia with fatigue in hemodialysis recipients: a single-center, cross-sectional study.

Fatigue in hemodialysis recipients interferes with daily activities and renal rehabilitation, and its underlying causes and treatment remain unclear. Psychological factors, like illness perceptions and alexithymia, cause fatigue in other diseases; however, their contribution to hemodialysis-related fatigue is unknown. This cross-sectional study included 53 hemodialysis recipients. To assess participants' fatigue, we used a self-administered patient-reported outcome questionnaire whose items have shown correlation with those of established scales, such as the Profile of Mood States and Visual Analogue Scales. The associations among the scores of the revised Illness Perceptions Questionnaire (IPQ-R), Toronto Alexithymia Scale (TAS-20), and Hospital Anxiety and Depression Scale and fatigue were analyzed using bivariable and multivariable analyses. Patients with fatigue had significantly higher median scores for the IPQ-R subscales "Identity" and "Negative emotional representation about illness" than those without fatigue, suggesting the association of specific illness perception with fatigue. Median scores for the TAS-20 subscale "Difficulty identifying feelings" were also significantly higher among fatigued patients, suggesting the association of alexithymia with fatigue. Depression was not associated with fatigue. Multivariable logistic regression revealed the association of a high "Identity" score with the risk of fatigue (adjusted odds ratio, 1.32; 95% confidence interval, 1.00-1.73; P = 0.04), while there were no significant association between a high "Difficulty identifying feelings" score and the risk of fatigue (adjusted odds ratio, 1.09; 95% confidence interval, 0.95-1.24). Specific illness perception and alexithymia were slightly associated with hemodialysis-related fatigue. Cognitive-behavioral therapy for these conditions could reduce fatigue and promote renal rehabilitation.

Severe lactic acidosis with euglycemic diabetic ketoacidosis due to metformin overdose.

Metformin-associated lactic acidosis is a well-known metformin treatment complication; however, the development of euglycemic diabetic ketoacidosis (euDKA) has rarely been reported. Here we report a case of lactic acidosis and euDKA after metformin overdose. A 57-year-old female patient was transferred to our hospital with severe metabolic acidosis and acute kidney injury. She had type 2 diabetes mellitus and was on oral antidiabetic therapy of vildagliptin metformin hydrochloride daily. On the admission day, she had committed suicide by overdosing 50 tablets of vildagliptin metformin hydrochloride, which was equivalent to 25,000 mg of metformin and 2500 mg of vildagliptin. She had severe lactic acidosis 5 h after overdosing. However, after 34 h of overdosing, serum lactate levels decreased while serum anion gap levels increased. She received single hemodialysis treatment. Serum total ketone bodies, ß-hydroxybutyrate acetoacetic acid, and acetone were increased even after hemodialysis treatment. Her blood glucose levels have never exceeded 250 mg/dL since admission. Therefore, we considered that the cause of metabolic acidosis in this patient was not only lactic acidosis but also euDKA. The causes of euDKA in our patient might be hepatic production of ketone bodies due to metformin overdose in addition to type 2 diabetes mellitus, starvation, infection, and stressful physical conditions such as vomiting and diarrhea. We propose that not only lactic acidosis but also ketoacidosis is one of the important pathological conditions in patients with metformin overdose.

Efficacy of renin-angiotensin-aldosterone system blockades for acute phase hypertensive emergencies in patient complicating severe acute kidney injury.

Renin-angiotensin-aldosterone system (RAAS) is primarily involved with pathological mechanism of developing hypertensive emergencies. However, none of clinical practice guidelines mention RAAS blockers for the treatment of hypertensive emergencies. A 44 year-old woman presented with severe hypertension, brain stem posterior reversible encephalopathy syndrome and severe acute kidney injury (AKI). We started anti-hypertensive therapy with continuous intravenous nitroglycerin and oral calcium channel blocker (CCB) and spironolactone. Since severe AKI persisted despite this therapy, we administered losartan potassium, which resulted in improvement in her blood pressure and creatinine. Clinical course of our patient suggests that timely initiation of ARB and spironolactone for hypertensive emergencies could be beneficial in terms of blood pressure control and for protection of target organs from this condition.

A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region.

A 37-year-old African-British man was referred to our hospital for detailed examination because of persistent fever, swelling and pain in both ankle joints, and blurred vision for two months. Inguinal lymph node biopsy showed a large number of epithelioid granulomas without necrosis. Granulomatous anterior uveitis, nephropathy, high serum angiotensin-converting enzyme activity, and high serum-soluble interleukin-2 receptor were observed, and the diagnosis of systemic sarcoidosis was made. His serum creatinine was 1.4 mg/dL and hematuria, leukocyturia, and urine protein were also seen. The renal biopsy finding was mesangial proliferative glomerulonephritis, with no findings of granuloma formation or tubular interstitial nephritis. Immunofluorescence staining showed deposition of IgG, C3, and C1q in the mesangial region. IgG3 was dominant in subclass staining. There was no monoclonality on kappa and lambda staining. Electron microscopy showed predominant deposition in the mesangial region with some subepithelial and endothelial deposition. His hematuria and leukocyturia disappeared with steroid therapy, suggesting sarcoidosis-related nephropathy. A case of systemic sarcoidosis with mesangial proliferative glomerulonephritis showing predominant deposition of IgG in the mesangial region is presented. No cases of such histological findings have been reported so far, and it is necessary to analyze further cases to clarify the pathogenic significance of the renal biopsy findings observed in this case.

mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome.

Although podocyte damage is known to be responsible for the development of minimal-change disease (MCD), the underlying mechanism remains to be elucidated. Previously, using a rat MCD model, we showed that endoplasmic reticulum (ER) stress in the podocytes was associated with the heavy proteinuric state and another group reported that a mammalian target of rapamycin complex 1 (mTORC1) inhibitor protected against proteinuria. In this study, which utilized a rat MCD model, a combination of immunohistochemistry, dual immunofluorescence and confocal microscopy, western blot analysis, and quantitative real-time RT-PCR revealed co-activation of the unfolded protein response (UPR), which was induced by ER stress, and mTORC1 in glomerular podocytes before the onset of proteinuria and downregulation of nephrin at the post-translational level at the onset of proteinuria. Podocyte culture experiments revealed that mTORC1 activation preceded the UPR that was associated with a marked decrease in the energy charge. The mTORC1 inhibitor everolimus completely inhibited proteinuria through a reduction in both mTORC1 and UPR activity and preserved nephrin expression in the glomerular podocytes. In conclusion, mTORC1 activation may perturb the regulatory system of energy metabolism primarily by promoting energy consumption and inducing the UPR, which underlie proteinuria in MCD.

Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis.

Crb2 is a cell polarity-related type I transmembrane protein expressed in the apical membrane of podocytes. Knockdown of crb2 causes glomerular permeability defects in zebrafish, and its complete knockout causes embryonic lethality in mice. There are also reports of Crb2 mutations in patients with steroid-resistant nephrotic syndrome, although the precise mechanism is unclear. The present study demonstrated that podocyte-specific Crb2 knockout mice develop massive albuminuria and microhematuria 2-month after birth and focal segmental glomerulosclerosis and tubulointerstitial fibrosis with hemosiderin-laden macrophages at 6-month of age. Transmission and scanning electron microscopic studies demonstrated injury and foot process effacement of podocytes in 6-month aged podocyte-specific Crb2 knockout mice. The number of glomerular Wt1-positive cells and the expressions of Nphs2, Podxl, and Nphs1 were reduced in podocyte-specific Crb2 knockout mice compared to negative control mice. Human podocytes lacking CRB2 had significantly decreased F-actin positive area and were more susceptible to apoptosis than their wild-type counterparts. Overall, this study's results suggest that the specific deprivation of Crb2 in podocytes induces altered actin cytoskeleton reorganization associated with dysfunction and accelerated apoptosis of podocytes that ultimately cause focal segmental glomerulosclerosis.

Hyponatremia presenting with hourly fluctuating urine osmolality.

SUMMARY: The etiology of hyponatremia is assessed based on urine osmolality and sodium. We herein describe a 35-year-old Asian man with pulmonary tuberculosis and perforated duodenal ulcer who presented with hyponatremia with hourly fluctuating urine osmolality ranging from 100 to 600 mosmol/kg, which resembled urine osmolality observed in typical polydipsia and SIADH simultaneously. Further review revealed correlation of body temperature and urine osmolality. Since fever is a known non-osmotic stimulus of ADH secretion, we theorized that hyponatremia in this patient was due to transient ADH secretion due to fever. In our case, empiric exogenous glucocorticoid suppressed transient non-osmotic ADH secretion and urine osmolality showed highly variable concentrations. Transient ADH secretion-related hyponatremia may be underrecognized due to occasional empiric glucocorticoid administration in patients with critical illnesses. Repeatedly monitoring of urine chemistries and interpretation of urine chemistries with careful review of non-osmotic stimuli of ADH including fever is crucial in recognition of this etiology. LEARNING POINTS: Hourly fluctuations in urine osmolality can be observed in patients with fever, which is a non-osmotic stimulant of ADH secretion. Repeated monitoring of urine chemistries aids in the diagnosis of the etiology underlying hyponatremia, including fever, in patients with transient ADH secretion. Glucocorticoid administration suppresses ADH secretion and improves hyponatremia even in the absence of adrenal insufficiency; the etiology of hyponatremia should be determined carefully in these patients.

Development of acute kidney injury with massive granular casts and microscopic hematuria in patients with COVID-19: two case presentations with literature review.

BACKGROUND: Complications of acute kidney injury (AKI) are common in patients with coronavirus disease in 2019 (COVID-19). However, clinical characteristics of COVID-19-associated AKI are poorly described. We present two cases of severe COVID-19 patients with AKI. CASE PRESENTATION: A 77-year-old woman was suspected of having vancomycin-associated AKI, and a 45-year-old man was suspected of having heme pigment-induced AKI caused by rhabdomyolysis. The granular cast, which is known to be a valuable diagnostic tool for confirming the diagnosis of acute tubular necrosis, was detected in both patients at the onset of AKI. Interestingly, both patients also developed microscopic hematuria at the occurrence of AKI, and one patient had elevated d-dimer and low platelet levels simultaneously. CONCLUSIONS: Some reports suggested that COVID-19-associated microangiopathy contributed to the kidney damage. Therefore, it is possible that our patients might have accompanied renal microangiopathy, and that this pathological background may have caused exaggerated tubular damage by vancomycin or heme pigment. The etiology of AKI in patients with COVID-19 is multifactorial. Superimposition of nephrotoxin(s) and virus-associate intra-renal microangiopathy may be a crucial trigger of kidney injury leading to severe AKI in COVID-19 patients. Therefore, in COVID-19 patients, risk factors for AKI should be taken into consideration to prevent its progression into severe AKI.

Granulomatosis with polyangiitis associated with IgA nephropathy.

Granulomatosis with polyangiitis (GPA), previously referred to as Wegener's granulomatosis, is a rare necrotizing granulomatous vasculitis, especially in children. GPA affects small- to medium-sized vessels, leading to involvement of multiple organs, including the upper and lower respiratory tracts and kidneys. Glomerular lesions associated with GPA typically present as crescentic glomerulonephritis with necrotizing lesions, with little or no staining for immunoglobulins and complement proteins. We report a unique pediatric case of GPA associated with IgA nephropathy, a representative immune-mediated glomerular disease. The initial renal biopsy specimen revealed fibrous sclerosis and mild mesangial proliferation without deposition of IgA. However, after clinical remission of GPA by treatment, the serum IgA level continued to be significantly higher than normal, and her paranasal sinusitis was poorly controlled. An acute upper respiratory infection resulted in worsened urinary findings without any systemic signs of GPA. The second renal biopsy specimen revealed deposition of IgA and C3 in the mesangium. The patient was treated with oral prednisolone alone, which led to complete remission of proteinuria within 1 month. IgA nephropathy is possibly associated with GPA during remission stage, and serum IgA level may be a valuable indicator to predict its association.