Effect of tonsillectomy combined with steroid pulse therapy upon IgA nephropathy depending on proteinuria status at diagnosis: a nationwide multicenter cohort study in Japan.

BACKGROUND: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan. METHODS: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy. RESULTS: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively). CONCLUSION: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

Analysis of the impact of obesity on the prognosis of IgA nephropathy according to renal function and sex.

BACKGROUND: Few studies have observed the direct effect of obesity on renal prognoses in immunoglobulin A nephropathy (IgAN) or separately evaluated its effects according to sex. We aimed to evaluate the direct and indirect effects of obesity on the renal outcomes of IgAN and observe these effects separately according to renal function and sex. METHODS: We extracted patients with body mass index (BMI) descriptions from a multicenter retrospective cohort analysis in Japan, and excluded those with < 30 days of follow-up, diabetes mellitus, and steroid treatment. Patients were divided into normal (n = 720; 18.5 ≤ BMI < 25) and obese (n = 212; BMI ≥ 25) groups, which were then compared. The endpoints were a 1.5-fold increase in serum creatinine levels and the initiation of renal replacement therapy. RESULTS: The obese group was older, included more males, and was more likely have hypertension, dyslipidemia, proteinuria, tubular atrophy, and lower renal function than the normal group. Patients with an eGFR < 60 mL/min/1.73 m2 had well-matched characteristics between the groups; however, hypertension, low high-density lipoprotein cholesterol, and hypertriglyceridemia were more common in the obese group. Obesity contributed to tubular atrophy, even when adjusted for renal function. In addition, it contributed to proteinuria only in females. However, obesity itself was not a significant prognostic factor. CONCLUSIONS: Although no independent effect on renal prognosis was observed during the study period, the obese group had more risk factors for IgAN progression and obesity contributed to tubular atrophy and female proteinuria. Our results suggest that separately analyzing the prognostic effect of obesity according to sex is important.

Impact of a continuous quality improvement program on contrast-induced nephropathy in outpatients with chronic kidney disease: an interrupted time-series study.

BACKGROUND: Contrast-induced nephropathy (CIN) caused by exposure to radioactive contrast media can cause acute kidney injury in patients with chronic kidney disease (CKD). We developed a multifaceted approach in a CIN-quality improvement (QI) program based on a shorter saline hydration protocol for the prevention of CIN in outpatients and assessed the effect of our CIN-QI program on decreasing both the incidence rate of CIN and overall use of contrast agents in patients undergoing contrast-enhanced computed tomography (CT). METHODS: We conducted a multi-center prospective interrupted time-series study from 2006 to 2018 investigating the efficacy of a CIN-QI program in preventing CIN among outpatients with CKD. An automatic medical record system alert was implemented to instruct physicians to consult a nephrologist and administer prophylactic hydration and follow-up when ordering contrast-enhanced imaging in patients with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. The primary outcomes were the rates of prophylactic hydration and follow-up kidney function assessment, and the incidence of CIN for eligible patients. The usage rate of contrast-enhanced CT was also examined. RESULTS: A total of 95 594 patients who underwent contrast-enhanced CT were included in the study. The annual prophylactic hydration rate before the CIN-QI program ranged from 2.0% to 23.2% but increased to 59.2%-75.2% during the CIN-QI program (P < .001). The annual rate of follow-up kidney function testing also improved from 18.6%-25.8% to 34.1%-42.5% after implementation of the CIN-QI program (P < .001). The rate of CIN significantly declined in level by 10.0% at the start of the CIN-QI program (P = .002) and in trend by 2.9%/year (P < .001). The number of contrast-enhanced CT orders showed a positive level change in patients with advanced CKD, who were the CIN-QI program target group of patients with eGFR <45 mL/min/1.73 m2, at the start of the implementation of the CIN-QI program. After implementing the CIN-QI program, the number of contrast-enhanced CT orders showed a negative trend change across all patients, which decreased from -1.4%/year to -10.0%/year for patients with advanced CKD. CONCLUSION: The multifaceted approach in the CIN-QI program may be associated with the decreased incidence of CIN and increased rates of prophylactic hydration and follow-up kidney function testing.

Infrapopliteal 3-Vessel Occlusive Disease Is the Only Predictor of Wound Recurrence After Complete Wound Healing via Endovascular Therapy in Patients With Chronic Limb-threatening Ischemia.

PURPOSE: To determine the predictors of wound recurrence after complete wound healing in patients with chronic limb-threatening ischemia (CLTI) who underwent endovascular therapy (EVT) for infrapopliteal (IP) lesions with consideration of IP arterial anatomic severity, including classification by the Global Limb Anatomic Staging System (GLASS). MATERIALS AND METHODS: This retrospective single-center study assessed patients with de novo CLTI limbs with tissue loss treated via EVT for IP lesions from September 2016 to May 2021. Among these patients, 149 consecutive limbs from 133 patients who achieved complete wound healing were enrolled. The Kaplan-Meier method was used to estimate the wound recurrence rate after complete wound healing. The Cox proportional hazard model was used to assess the association between baseline characteristics and wound recurrence. RESULTS: The cumulative wound recurrence rate 1 year after complete wound healing was 30%. The mean time for wound recurrence was 7±5 months. Only IP arterial anatomic characteristics remained as a predictor of wound recurrence, whereas wound status and management, including the Wound, Ischemia, and foot Infection (WIfI) clinical stage and minor amputation, were not associated with wound recurrence. Multivariate analysis revealed independent associations between wound recurrence and IP 3-vessel occlusive disease (hazard ratio, 2.97; 95% confidence interval, 1.39-6.35), but not poor below-the-ankle runoff, IP Peripheral Arterial Calcium Scoring System (PACSS) grade, and the GLASS IP grade. CONCLUSION: The only independent predictor of wound recurrence after complete wound healing via EVT in patients with CLTI was IP 3-vessel occlusive disease. CLINICAL IMPACT: In patients with chronic limb-threatening ischemia (CLTI), wound recurrence after complete wound healing remains a challenge, and studies focused exclusively on wound recurrence are still limited. The present study aimed to determine the risk factors for wound recurrence after complete wound healing in patients with CLTI who underwent endovascular therapy (EVT) for infrapopliteal (IP) lesions, with consideration of IP arterial anatomic severity for the first time. The results showed that IP 3-vessel occlusive disease was the only predictor of wound recurrence, whereas wound status/management and other arterial anatomic characteristics including WIfI clinical stages and GLASS grades were not predictors.

Prognostic factors of IgA nephropathy presenting with mild proteinuria at the time of diagnosis (a multicenter cohort study).

BACKGROUND: Clinical factors affecting renal prognosis in patients with immunoglobulin A nephropathy (IgAN) and low urinary protein excretion (U-Prot) remain unclear. This study evaluated such factors in patients with clinical grade I (CG-I) IgAN with U-Prot < 0.5 g/day. METHODS: This secondary analysis of a previous retrospective study included 394 patients with CG-I IgAN. The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine levels from baseline. Factors related to renal prognosis were examined using univariate and multivariate Cox regression analyses. CG-I was divided into C-Grade Ia (CG-Ia) (n = 330) with baseline eGFR ≥ 60 ml/min/1.73 m2, and C-Grade Ib (CG-Ib) (n = 64) with baseline eGFR < 60 ml/min/1.73 m2. Outcome incidence was compared between conservative and aggressive therapy (corticosteroids and/or tonsillectomy) groups. RESULTS: Overall outcome incidence was significantly higher in CG-Ib than in CG-Ia; the cumulative incidence was significantly higher in CG-Ib (hazard ratio, 9.67; 95% confidence interval, 2.90-32.23). Older age, higher IgA levels, eGFR < 60 mL/min/1.73 m2, lower eGFR at baseline were independent prognostic factors for CG-I. Older age, lower eGFR, higher IgA levels at baseline, and U-Prot remission at 1-year post-diagnosis were independent prognostic factors for CG-Ib. Aggressive therapy tended to suppress the cumulative outcome incidence compared with conservative therapy in CG-Ib (p = 0.087). CONCLUSION: An eGFR < 60 mL/min/1.73 m2 is a significant predictor of renal prognosis in patients with IgAN and U-Prot < 0.5 g/day.

High Global Limb Anatomic Staging System Femoropopliteal Grade is Positively Associated with Wound Healing in Patients with Chronic Limb-Threatening Ischemia Undergoing Endovascular Therapy Only for Femoropopliteal Disease.

BACKGROUND: To investigate the prognostic impact of femoropopliteal (FP) arterial anatomic severity including classification by the global limb anatomic staging system (GLASS) on wound healing in patients with chronic limb-threatening ischemia (CLTI) who had undergone endovascular therapy (EVT) only for FP lesions. METHODS: This was a retrospective single-center study. We treated 349 consecutive de novo CLTI limbs with tissue loss from January 2017 to May 2021. Among these, 91 limbs treated via EVT only for FP lesions were enrolled. We compared the clinical background, infrapopliteal (IP)/FP arterial anatomical characteristics, and EVT results between the limbs with GLASS FP grade 1 or 2 (low GLASS FP, n = 20) and those with GLASS FP grade 3 or 4 (high GLASS FP, n = 71). The Kaplan-Meier method was used to estimate the wound healing rate. The Cox proportional hazard model was used to assess the association between baseline characteristics and wound healing. RESULTS: No patient underwent EVT for IP lesions. IP arterial anatomical characteristics did not show any significant difference between the low and high GLASS FP groups. The cumulative wound healing rate after EVT was significantly higher in the high GLASS FP group than in the low GLASS FP group (88% vs. 39% at 6 months; P < 0.001). Multivariate analysis revealed that low wound, ischemia, and foot infection (WIfI) clinical stage (stage 1 or 2) (hazard ratio [HR] 2.33; 95% confidence interval [CI] 1.32-4.17) and high GLASS FP (grade 3 or 4) (HR 5.18; 95% CI 1.99-13.51) were independent factors for wound healing. CONCLUSIONS: High GLASS FP grade was positively associated with wound healing after EVT only for FP lesions.

Predictors of delayed wound healing after simultaneous endovascular treatment and minor forefoot amputation for chronic limb-threatening ischemia with wound infection.

OBJECTIVES: To assess wound healing after simultaneous endovascular treatment (EVT) and minor forefoot amputation and identify the predictors of delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) and bacterial infections of the wounds. METHODS: In this single-center retrospective cohort study, we evaluated 79 consecutive limbs with tissue loss from 73 CLTI patients who underwent simultaneous EVT and minor forefoot amputation between November 2017 and May 2020. To estimate the rate of wound healing after the simultaneous procedure, we used the Kaplan-Meier method. To assess the association between baseline characteristics and delayed wound healing, we used the Cox proportional hazard model. RESULTS: All patients who underwent the simultaneous procedure had ischemic wounds with bacterial infection. The rate of wound healing at 6 months reached 82%. The median time for wound healing was 76 days. According to multivariable analysis, Lisfranc/Chopart amputation (hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.09-6.60), absence of above-the-knee (ATK) occlusive lesions (HR 1.89, 95% CI 1.04-3.45), and poor below-the-ankle (BTA) runoff (HR 1.77, 95% CI 1.01-3.11) were independent predictors of delayed wound healing. CONCLUSION: Lisfranc/Chopart amputation, absence of ATK occlusive lesions, and poor BTA runoff were independent predictors of delayed wound healing after simultaneous EVT and minor forefoot amputation in patients with CLTI and bacterial infections of the wound.

Impact of Antimicrobial-Resistant Bacterial and Polymicrobial Infection on Wound Healing After Minor Forefoot Amputation in Chronic Limb-Threatening Ischemia With Infection.

OBJECTIVES: This study aimed to evaluate the relationship between bacteriological findings and wound healing after minor amputation in the treatment of chronic limb-threatening ischemia (CLTI) with infection. METHODS: This single-center retrospective study analyzed 135 consecutive limbs with tissue loss and infection from 120 patients who underwent endovascular therapy (EVT) and minor forefoot amputation for CLTI with wound infection between November 2017 and August 2021. The Kaplan-Meier method was used to assess the rate of wound healing after the procedure. The Cox proportional-hazards model was used to examine the impact of bacteriological findings and baseline characteristics on wound healing. RESULTS: The wound healing rate at 6 months was 72.6%. In a multivariate analysis, in addition to hemodialysis (hazard ratio [HR]=1.73; p=0.009) and amputation above the metatarsophalangeal (MP) joint (HR=1.81; p=0.006), antimicrobial-resistant bacterial infection (HR=1.80, p=0.004) and polymicrobial infection (H=1.51; p=0.049) were predictors of delayed wound healing. CONCLUSION: Antimicrobial-resistant bacterial infection, polymicrobial infection, hemodialysis, and amputation above the MP joint were independent predictors of delayed wound healing after EVT and minor forefoot amputation in patients with CLTI and bacterial wound infection. CLINICAL IMPACT: In this single-center retrospective study, we analyzed 136 consecutive limbs with tissue loss and infection from 120 patients who underwent endovascular therapy and minor forefoot amputation for chronic limb-threatening ischemia (CLTI) with wound infection between November 2017 and August 2021. Our main findings were that antimicrobial-resistant bacterial infection, polymicrobial infection, hemodialysis, and amputation above the metatarsophalangeal joint were independent predictors of delayed wound healing after minor amputation. This is the first report of the association between bacteriological studies and wound healing in CLTI with infection, and will be of great help in the future clinical practice.

Tubulointerstitial nephritis: a biopsy case series of 139 Japanese patients.

BACKGROUND: Tubulointerstitial nephritis (TIN) is an important cause of acute kidney injury (AKI) and advanced CKD. Only a limited number of studies have reported etiology-based differences in the clinical and/or histopathological properties and kidney outcomes of the biopsy-proven TIN. METHODS: Patients with biopsy-proven TIN identified from 2005 to 2016 in five hospitals were categorized based on the etiologies and were retrospectively analyzed in relation to the clinicopathological findings and kidney outcomes. RESULTS: Among 4815 biopsy cases screened, 153 Japanese TIN patients were identified, of whom 139 patients with ≥ 6 months of follow-up data (median 58 years old, 45.3% female, median 31.5 months follow-up) were further analyzed. TIN was drug-induced in 32.4%, autoimmune-related in 24.5%, of unknown etiology in 27.3% and other disease-related in 15.8%. Non-steroidal anti-inflammatory drugs and antibiotics were major causative drugs in drug-induced TIN, and IgG4-related disease, Sjögren's syndrome and sarcoidosis were common in autoimmune-related TIN. Among etiology groups, drug-induced TIN showed advanced AKI with elevated serum creatinine (sCr) and increased C-reactive protein levels at the diagnosis. TIN patients with autoimmune diseases showed less-severe AKI, but were more frequently treated with corticosteroids than others. Tubulointerstitial injury expansion in biopsy specimens was comparable among the groups. Complete or partial kidney function recovery at 6 months was more frequent in drug-induced and autoimmune-related TIN than in others. sCr levels at 6 months were similar among the groups. CONCLUSIONS: This largest case series study of the biopsy-proven TIN in Japan provides detailed information regarding both etiology-based clinicopathological properties and kidney outcomes.

The systemic immune response due to cholesterol crystal embolization syndrome: a case report.

BACKGROUND: Cholesterol crystal embolization syndrome (CES) occurs when an atherosclerotic plaque causes small-vessel embolization, resulting in multi-organ damage. Although CES is pathologically characterized by an infiltration of eosinophils, the implication of the systemic inflammatory response represented by hypereosinophilia is unclear in clinical practice. Herein we present the case of a patient diagnosed with CES who developed multiple allergic organ injuries, including daptomycin-related dermatitis and later vancomycin-induced acute tubulointerstitial nephritis, which was successfully treated by the withdrawal of each medicine with or without corticosteroid therapy, one by one. CASE PRESENTATION: A 76-year-old Japanese man diagnosed with thoracic aneurysm rupture underwent total arch replacement through the open stent graft technique. Postoperatively, he developed methicillin-resistant Staphylococcus epidermidis bacteremia, which was treated with daptomycin. Subsequently, he presented with palpable purpura on both dorsal feet, erythema around his body, and hypereosinophilia. Daptomycin was replaced with vancomycin due to suspicion of drug-induced erythema. The erythema gradually faded. On nine days after vancomycin therapy, the systemic erythema rapidly reappeared followed by acute renal failure. The renal function decline prompted hemodialysis. A skin biopsy revealed cholesterol embolization, whereas a kidney biopsy revealed acute tubulointerstitial nephritis. After vancomycin discontinuation and initiation of systemic corticosteroid treatment, his kidney function was restored to the baseline level. CONCLUSIONS: The present case highlights cholesterol embolization can cause allergic complications in addition to direct organ damage.

Impact of the number of steroid pulses in tonsillectomy combined with steroid pulse therapy: a nationwide retrospective study in Japan.

BACKGROUND: Steroid pulse therapy with tonsillectomy is known as a major treatment for IgA nephropathy (IgAN). However, its protocol was different among institutions and the effects of varying the number of steroid pulses remain unclear. METHODS: From a total of 1,174 IgAN patients in a multicenter retrospective cohort analysis in Japan, 195 patients were treated by tonsillectomy combined with corticosteroid. They were divided into four groups based on the number of administered steroid pulses from 0 to three (TSP0-3), and remission of urinary abnormalities and renal survival until 1.5-fold increase in serum creatinine level from baseline were analyzed among the four groups and between TSP1 and TSP3. RESULTS: Among the four groups, renal function was relatively good when the estimated glomerular filtration rate was approximately 80-90 mL/min/1.73m2 and proteinuria was relatively mild (< 1.0 g/gCre). The ratio of patients who developed renal dysfunction was < 5% in all groups, and the cumulative renal survival rate by Kaplan-Meier analysis was similar among groups (log-rank test, p = 0.37), despite varying clinical backgrounds and treatments. After adjustment of the background variables between TSP1 and TSP3, the remission rates of urinary abnormalities were similar and the renal survival rate also remained similar (66.8 vs. 85.4%, p = 0.45). CONCLUSIONS: In patients with mild proteinuria and good renal function, the number of steroid pulses did not affect the renal outcome in steroid pulse therapy with tonsillectomy. The adaptation and protocols, such as the number of steroid pulses, should be determined for each IgAN patient's background.

A new serine protease family with elastase activity is produced by Streptomyces bacteria.

We found an elastolytic activity in the culture supernatant of Streptomyces sp. P-3, and the corresponding enzyme (streptomycetes elastase, SEL) was purified to apparent homogeneity from the culture supernatant. The molecular mass of purified SEL was approximately 18 kDa as judged by SDS-PAGE analysis and gel-filtration chromatography. Utilizing information from N-terminal amino acid sequencing of SEL and mass spectrometry of SEL tryptic fragments, we succeeded in cloning the gene-encoding SEL. The cloned SEL gene contains a 726 bp ORF, which encodes a 241 amino acid polypeptide containing a putative signal peptide for secretion (28 amino acid) and pro-sequence (14 amino acid). Although the deduced primary structure of SEL has sequence similarity to proteins in the S1 protease family, the amino acid sequence shares low identity (< 31.5 %) with any known elastase. SEL efficiently hydrolyses synthetic peptides having Ala or Val in the P1 position such as N-succinyl-Ala-Ala-(Pro or Val)-Ala-p-nitroanilide (pNA), whereas reported proteases by streptomycetes having elastolytic activity prefer large residues, such as Phe and Leu. Compared of kcat/Km ratios for Suc-Ala-Ala-Val-Ala-pNA and Suc-Ala-Ala-Pro-Ala-pNA with subtilisin YaB, which has high elastolytic activity, Streptomyces sp. P-3 SEL exhibits 12- and 121-fold higher, respectively. Phylogenetic analyses indicate that the predicted SEL protein, together with predicted proteins in streptomycetes, constitutes a novel group within the S1 serine protease family. These characteristics suggest that SEL-like proteins are new members of the S1 serine protease family, which display elastolytic activity.

Risk of undiagnosed coronary artery disease associated with infrapopliteal artery occlusion from a multicenter study.

Peripheral artery disease (PAD) is associated with high cardiovascular mortality. Which part of PAD with lower extremities is related to coronary artery disease (CAD) remains unknown. We hypothesized that PAD including infrapopliteal artery (IPA) occlusion was associated with CAD. A total of 260 patients who have no history of CAD or the anginal symptom, complain of the claudication or critical limb ischemia and underwent peripheral angiography were retrospectively analyzed. IPA occlusion was diagnosed with peripheral angiography, and CAD was diagnosed with the coronary angiography. A multivariate logistic regression analysis was performed to determine the predictors of silent CAD. Among them, a total of 146 patients (56.2%) had IPA occlusion. Baseline characteristics were significantly different between two groups as to the proportions of age, male, dyslipidemia (with vs. without IPA occlusion; 72.4 ± 10.8 vs. 69.1 ± 10.2; 62.3% vs. 75.4%; 38.6% vs. 52.6%, respectively, all comparisons P < 0.05). Notably, the prevalence of CAD was significantly higher in patients with IPA occlusion (50.7% vs. 34.2%, P = 0.008). On a multivariate analysis, IPA occlusion was an independent predictor for the presence of silent CAD (OR, 1.94; CI, 1.09-3.44, P = 0.024), but aortoiliac artery occlusion (OR, 1.16; CI, 0.53-2.56, P = 0.71) and femoropopliteal artery occlusion (OR, 1.02; CI, 0.57-1.83, P = 0.96) were not. IPA occlusion was associated with silent CAD. Vascular surgeons, interventional radiologists, as well as interventional cardiologists should recognize IPA occlusion as a risk factor of silent CAD.

Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury.

Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARγ was expressed in proximal tubules both with and without injury, and αB-crystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.

An overview of percutaneous coronary intervention in dialysis patients: Insights from a Japanese nationwide registry.

OBJECTIVES: This study sought to provide an overview of percutaneous coronary intervention (PCI) in dialysis patients from a Japanese nationwide registry. BACKGROUND: Little is known about dialysis patients undergoing PCI because few are enrolled in clinical trials. METHODS: We analyzed 624,900 PCI cases including 41,384 dialysis patients (6.6%) from 1,017 Japanese hospitals between 2014 and 2016. We investigated differences in characteristics and in-hospital outcomes between dialysis and nondialysis patients, and assessed factors associated with an increased risk of adverse outcomes. RESULTS: Dialysis patients had more comorbidities than nondialysis patients and higher rates of complications including in-hospital mortality (3.3% vs. 1.5%, respectively, in the acute coronary syndrome [ACS] cohort, 0.2% vs. 0.1% in the non-ACS cohort) and bleeding complications requiring blood transfusion (1.1% vs. 0.4% in ACS, 0.5% vs. 0.2% in non-ACS). Dialysis was significantly associated with an increased risk of in-hospital mortality (odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.24-1.62 in ACS, OR: 2.25, 95% CI: 1.66-3.05 in non-ACS) and bleeding (OR: 1.60, 95% CI: 1.30-1.96 in ACS, OR: 1.55, 95% CI: 1.27-1.88 in non-ACS). For dialysis patients, age, acute heart failure, and cardiogenic shock were associated with an increased risk of in-hospital mortality in the ACS cohort, whereas age, female gender, and history of heart failure were associated with higher in-hospital mortality in the non-ACS cohort. CONCLUSIONS: PCI was widely performed for dialysis patients with either ACS or non-ACS in Japan. Dialysis patients had a greater risk of adverse outcomes than nondialysis patients after PCI.

Trans-radial percutaneous coronary intervention for patients with severe chronic renal insufficiency and/or on dialysis.

Periprocedural bleeding is associated with an increased risk of mortality during percutaneous coronary intervention (PCI), especially in patients with severe chronic renal insufficiency. Therefore, trans-radial intervention (TRI) should be considered in these patients; however, PCI operators usually avoid this approach because of the risk of radial artery occlusion. We aimed to investigate the associations of TRI and in-hospital complications in these patients. This study included 306 consecutive patients with severe chronic renal insufficiency and/or on dialysis who underwent PCI. Patients were prospectively enrolled and divided according to the access site into TRI group and trans-femoral intervention group. Severe renal insufficiency was defined as estimated glomerular filtration rate < 30 mL/min/1.73 m2. Radial access was limited to the opposite side of the arteriovenous fistula in patients on hemodialysis. The primary study endpoint was the composite of in-hospital bleeding complications and death. TRI benefit was evaluated by inverse probability treatment weighted analysis. TRI was performed in 112 (37.3%) patients. TRI group included older patients with significantly lower rates of diabetes mellitus, dialysis, and three-vessel disease. Crossover to the other approach occurred only in TRI group (2.6%). The primary endpoint was significantly lower in TRI group (11.5% vs. 2.6%, P = 0.006). After an inverse probability treatment weighted analysis, TRI was an independent prognostic factor for a decrease in the primary endpoint (OR 0.19; 95% CI 0.051-0.73; P = 0.015). Radial artery occlusion occurred in three patients on dialysis (9.1%). TRI may determine better in-hospital outcomes in patients with severe chronic renal insufficiency and/or on dialysis.

Optimal follow-up intervals for different stages of chronic kidney disease: a prospective observational study.

BACKGROUND: Chronic kidney disease (CKD) is a public health challenge; however, evidence-based, optimal follow-up intervals for patients with CKD have not been identified. This study aimed to identify appropriate follow-up intervals for different stages of CKD. METHODS: We studied 2682 patients with CKD. The number of patients experiencing a 50% increase in creatinine and those reaching end-stage renal failure were examined on the basis of their CKD stage. The renal function testing interval was defined as the estimated time for 0.1% of the patients with CKD to have a composite renal outcome, after adjusting for clinical risk factors. Transitions from CKD stage-based subgroups were analyzed using parametric cumulative incidence models. Other sensitivity analyses involved estimation of the time to renal event occurrence for 1% of patients. RESULTS: Of the 913 patients (34%) who had a composite renal event, 29 had stage 3A (10.5%), 151 had stage 3B (16.3%), 429 had stage 4 (41.0%), and 304 had stage 5 CKD (70.9%). The estimated renal function testing intervals for patients with CKD were 6.0 months for stage 3A, 3.4 months for stage 3B, 2.0 months for stage 4, and 1.2 months for stage 5. CONCLUSIONS: The optimal follow-up intervals were longer for patients with lower CKD stages. These estimates are longer than those recommended by the current guidelines and serve as a reference for nephrologists in selecting an appropriate follow-up interval for each patient. TRIAL REGISTRATION: UMIN clinical trial registry number: UMIN000020038.

Negative impact of proteinuria on circulating myeloid dendritic cells.

BACKGROUND: A decrease in absolute numbers (abs.) of circulating dendritic cells (DCs) and recruitment into target organs has been reported, but whether the level of proteinuria associates with circulating DC abs. has not been clarified. METHODS: We conducted a cross-sectional study of 210 patients with kidney disease aged 21-96 years who were admitted to our hospital for kidney biopsy in 2007-2010. For accuracy, the level of proteinuria was thoroughly measured by 24-h urine collection from patients in their admitted condition. The abs. of total DCs (tDCs), myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) was measured by three-color fluorescence-activated cell sorting (FACS). Patients were divided into four groups based upon the quartile of each DC abs. and one-way ANOVA, and multivariable-adjusted regression analyses were performed. RESULTS: Quantile analysis showed that the level of daily proteinuria decreased with increasing blood mDC abs., with mean proteinuria levels (g/day) of 2.45, 1.68, 1.68, 1.10 for those in mDC abs. quartiles ≤ 445, < 686, < 907, ≥ 907 cells/102 µL (p = 0.0277), respectively. Multivariate-adjusted regression analysis revealed that the mDC abs. was negatively associated with proteinuria (95% CI - 57.0 to - 8.5) and positively associated with male gender (95% CI 66.2-250.5). Independent associations were also shown between pDCs abs. and estimated glomerular filtration rate (eGFR) (95% CI 0.14-2.67) and C-reactive protein (95% CI - 49.4 to - 9.9) and between tDCs abs. and male gender (95% CI 54.5-253.6) and C-reactive protein (95% CI - 80.5 to - 13.4). CONCLUSION: We first reported that circulating mDC abs. has a negative association with the level of proteinuria.

A grading system that predicts the risk of dialysis induction in IgA nephropathy patients based on the combination of the clinical and histological severity.

Histological classification is essential in the clinical management of immunoglobulin A nephropathy (IgAN). However, there are limitations in predicting the prognosis of IgAN based on histological information alone, which suggests the need for better prognostic models. Therefore, we defined a prognostic model by combining the grade of clinical severity with the histological grading system by the following processes. We included 270 patients and explored the clinical variables associated with progression to end-stage renal disease (ESRD). Then, we created a predictive clinical grading system and defined the risk grades for dialysis induction by a combination of the clinical grade (CG) and the histological grade (HG). A logistic regression analysis revealed that the 24-h urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) were significant independent variables. We selected UPE of 0.5 g/day and eGFR of 60 ml/min/1.73 m2 as the threshold values for the classification of CG. The risk of progression to ESRD of patients with CG II and III was significantly higher than that of patients with CG I. The patients were then re-classified into nine compartments based on the combination of CG and HG. Furthermore, the nine compartments were grouped into four risk groups. The risk of ESRD in the moderate, high, and super-high-risk groups was significantly higher than that in the low-risk group. Herein, we are giving a detailed description of our grading system for IgA nephropathy that predicted the risk of dialysis based on the combination of CG and HG.

Adductome-based identification of biomarkers for lipid peroxidation.

Lipid peroxidation is an endogenous source of aldehydes that gives rise to covalent modification of proteins in various pathophysiological states. In this study, a strategy for the comprehensive detection and comparison of adducts was applied to find a biomarker for lipid peroxidation-modified proteins in vivo This adductome approach utilized liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) methods designed to detect the specific product ions from positively ionized adducts in a selected reaction monitoring mode. Using this procedure, we comprehensively analyzed lysine and histidine adducts generated in the in vitro oxidized low-density lipoproteins (LDL) and observed a prominent increase in several adducts, including a major lysine adduct. Based on the high resolution ESI-MS of the adduct and on the LC-ESI-MS/MS analysis of the synthetic adduct candidates, the major lysine adduct detected in the oxidized LDL was identified as Nϵ-(8-carboxyoctanyl)lysine (COL). Strikingly, a significantly higher amount of COL was detected in the sera from atherosclerosis-prone mice and from patients with hyperlipidemia compared with the controls. These data not only offer structural insights into protein modification by lipid peroxidation products but also provide a platform for the discovery of biomarkers for human diseases.