Protocol for the nationwide registry of patients with polycystic kidney disease: japanese national registry of PKD (JRP).

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). METHODS: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). RESULTS: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. CONCLUSIONS: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.

Reduction in presynaptic dopamine transporter may be associated with future problematic delusion.

OBJECTIVES: Psychosis, especially in delusions, greatly impairs the quality of life of patients with Parkinson's disease (PD) and their caregivers. Few objective risk indicators of the association between psychosis and clinical features has been reported. It is unclear whether the reduction in DAT binding represents the underlying mechanism of delusion or its association. There are no long-term data on the objective prognostic value of DAT binding for delusions. We investigated whether DAT binding at baseline can be a prognostic risk factor for future development of PD delusions. MATERIALS AND METHODS: We reviewed the detailed clinical chart of patients with PD without a history of psychosis who underwent [123I]FP-CIT SPECT during the disease. The endpoint was defined as when the delusions occurred during the 5 years after the examination of [123I]FP-CIT SPECT. Specific binding ratio (SBR) values were calculated. RESULTS: Sixty-one patients with PD were included in the analysis, and 11 patients had delusions within 5 years of [123I] FP-CIT SPECT. The average (p = 0.004), minimum (p = 0.004), maximum (p = 0.001), right-sided (p = 0.002), and left-sided (p = 0.003) SBRs in the striatum were significantly smaller in patients with delusions than in patients without delusions. Each difference of each SBR was significantly smaller than those without delusions after adjusting after controlling for age, gender, disease severity, timing of [123I]FP-CIT SPECT, anti-parkinsonian medications, hospitalization, administering more or newly anti-parkinsonian drugs, and receiving DBS or LCIG. CONCLUSIONS: PD delusions is still problematic, and lowering DAT binding may be helpful for predicting future delusions, regardless of the timing of [123I]FP-CIT SPECT.

Factors associated with early-onset intracranial aneurysms in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Recently, the importance of attribute-based medicine has been emphasized. The effects of early-onset intracranial aneurysms on patients can be significant and long-lasting. Herein, we compared the factors associated with intracranial aneurysms in patients with autosomal dominant polycystic kidney disease (ADPKD) according to age categories (≥ 50 years, < 50 years). METHODS: We included 519 ADPKD patients, with a median age of 44 years, estimated glomerular filtration rate of 54.5 mL/min/1.73 m2, and total follow-up duration of 3104 patient-years. Logistic regression analyses were performed to determine factors associated with intracranial aneurysms. RESULTS: Regarding the presence of intracranial aneurysm, significant interactions were identified between the age category (age ≥ 50 years), female sex (P = 0.0027 for the interaction) and hypertension (P = 0.0074 for the interaction). Female sex and hypertension were associated with intracranial aneurysm risk factors only in patients aged ≥ 50 years. The presence of intracranial aneurysm was significantly associated with chronic kidney disease (CKD) stages 4-5 (odds ratio [OR] = 3.87, P = 0.0007) and family history of intracranial aneurysm or subarachnoid hemorrhage (OR = 2.30, P = 0.0217) in patients aged < 50 years. For patients aged ≥ 50 years, in addition to the abovementioned factors [OR = 2.38, P = 0.0355 for CKD stages 4-5; OR = 3.49, P = 0.0094 for family history of intracranial aneurysm or subarachnoid hemorrhage], female sex (OR = 4.51, P = 0.0005), and hypertension (OR = 5.89, P = 0.0012) were also associated with intracranial aneurysm. CONCLUSION: Kidney dysfunction and family history of intracranial aneurysm or subarachnoid hemorrhage are risk factors for early-onset intracranial aneurysm. Patients aged < 50 years with a family history of intracranial aneurysm or subarachnoid hemorrhage or with CKD stages 4-5 may be at an increased risk of early-onset intracranial aneurysm.

Daily light exposure profiles and the association with objective sleep quality in patients with Parkinson's disease: The PHASE study.

STUDY OBJECTIVES: Light information crucially influences the sleep initiation and continuity. The purpose of this study was to compare daily light exposure between patients with Parkinson's disease (PD) and non-PD older adults and evaluate the association of daily light exposure with objective sleep measures in patients with PD. METHODS: In this cross-sectional study of 189 outpatients with PD and 1101 community dwelling older adults (controls), daily light exposure was measured using wrist light meters during the daytime and light meters set in the bedrooms during the nighttime, and objective sleep quality was measured by wrist actigraphy. RESULTS: The median duration of exposure to ≥1000 lux light was significantly shorter in patients with PD than in controls. The median nighttime light intensity was higher in patients with PD than in controls. Among patients with PD, multivariable analysis suggested that the highest quartile of exposure to ≥1000 lux light during the daytime was linked to significantly higher sleep efficiency by 8.0% and shorter wake after sleep onset (WASO) by 36.9 min than the lowest quartile. During the nighttime, the highest quartile of mean light intensity had significantly lower sleep efficiency by 6.8%, longer WASO by 24.1 min, longer sleep onset latency, and higher fragmentation index, than the lowest quartile. Importantly, daytime and nighttime light levels were independently associated with objective sleep measures. CONCLUSION: The present study illustrated that greater daytime light exposure and lower nighttime light exposure are significantly associated with better objective sleep measures in patients with PD.

PLA2R-positive membranous nephropathy in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory disease that affects multiple organs, including the pancreas, lacrimal glands, salivary glands, periaortic/retroperitoneum, and kidney. Interstitial nephritis is a typical renal disorder associated with IgG4-RD, but membranous nephropathy is also seen in some cases. CASE PRESENTATION: Herein we report on the case of a 77-year-old male patient with nephrotic syndrome and IgG4-related lung disease. His serum phospholipase A2 receptor (PLA2R) antibody was positive. His renal biopsy specimen was also positive for PLA2R. The renal biopsy specimen showed membranous nephropathy with equal IgG3 and IgG4 immunofluorescence staining and no interstitial nephritis, suggesting IgG4-RD manifesting as membranous nephropathy. CONCLUSIONS: Nephrotic syndrome caused by membranous nephropathy is sometimes associated with IgG4-RD. In such cases, even if serum PLA2R antibody is positive, it should be considered that the membranous nephropathy may be secondary to IgG4-RD.

Immediate drop of urine osmolality upon tolvaptan initiation predicts impact on renal prognosis in patients with ADPKD.

BACKGROUND AND HYPOTHESIS: Tolvaptan, a vasopressin V2 receptor antagonist, is used for treating autosomal dominant polycystic kidney disease (ADPKD). We focused on changes in urinary osmolality (U-Osm) after tolvaptan initiation to determine whether they were associated with the therapeutic response to tolvaptan. METHODS: This was a single-centre, prospective, observational cohort study. Seventy-two patients with ADPKD who received tolvaptan were recruited. We analysed the relationship between changes in U-Osm and annual estimated glomerular filtration rate (eGFR) in terms of renal prognostic value using univariable and multivariable linear regression analyses. RESULTS: The mean value of U-Osm immediately before tolvaptan initiation was 351.8 ± 142.2 mosm/kg H2O, which decreased to 97.6 ± 23.8 mosm/kg H2O in the evening. The decrease in U-Osm was maintained in the outpatient clinic 1 month later. However, the values of U-Osm showed higher variability (160.2 ± 83.8 mosm/kg H2O) than did those in the first evening of tolvaptan administration. Multivariate analysis revealed that the baseline eGFR, baseline urinary protein, and U-Osm change in the evening of the day of admission (initial U-Osm drop) were significantly correlated with the subsequent annual change in eGFR. CONCLUSIONS: U-Osm can be measured easily and rapidly, and U-Osm change within a short time after tolvaptan initiation may be a useful index for the renal prognosis in actual clinical practice.

Lidocaine as a potential therapeutic option for super-refractory status epilepticus: A case report.

New-onset refractory status epilepticus (NORSE) is a rare and devastating condition and the prognosis is often poor, with half to two-thirds of survivors experiencing drug-resistant epilepsy, residual cognitive impairment, or functional disability, and the mortality rate is 16% to 27% for adults. We describe a patient with cryptogenic NORSE and favorable recovery from drug-resistant super-refractory SE after the use of intravenous lidocaine. The patient experienced fever and presented with refractory generalized tonic-clonic seizures. The cause was not found by performing extensive examinations, including cell surface autoantibodies and rat brain immunohistochemistry evaluations. The refractory SE with unresponsiveness to multiple anti-epileptic and prolonged sedative medications, which are necessary for prolonged mechanical ventilation, were ameliorated by additive treatment with intravenous lidocaine initiating at 1 mg/kg/h and maintaining at 2 mg/kg/h for 40 days, which led to freedom from intravenous sedative medication and mechanical ventilation. The patient was able to return to school. Lidocaine may be an optional treatment for cryptogenic NORSE.

Glomerular hyperfiltration and hypertrophy: an evaluation of maximum values in pathological indicators to discriminate "diseased" from "normal".

The success of sodium-glucose cotransporter 2 inhibitors and bariatric surgery in patients with chronic kidney disease has highlighted the importance of glomerular hyperfiltration and hypertrophy in the progression of kidney disease. Sustained glomerular hyperfiltration and hypertrophy can lead to glomerular injury and progressive kidney damage. This article explores the relationship between obesity and chronic kidney disease, focusing on the roles of glomerular hyperfiltration and hypertrophy as hallmarks of obesity-related kidney disease. The pathological mechanisms underlying this association include adipose tissue inflammation, dyslipidemia, insulin resistance, chronic systemic inflammation, oxidative stress, and overactivation of the sympathetic nervous system, as well as the renin-angiotensin aldosterone system. This article explains how glomerular hyperfiltration results from increased renal blood flow and intraglomerular hypertension, inducing mechanical stress on the filtration barrier and post-filtration structures. Injured glomeruli increase in size before sclerosing and collapsing. Therefore, using extreme values, such as the maximal glomerular diameter, could improve the understanding of the data distribution and allow for better kidney failure predictions. This review provides important insights into the mechanisms underlying glomerular hyperfiltration and hypertrophy and highlights the need for further research using glomerular size, including maximum glomerular profile, calculated using needle biopsy specimens.

Public support for patients with intractable diseases in Japan: impact on clinical indicators from nationwide registries in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD. METHODS: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020. RESULTS: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001). CONCLUSIONS: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment.

Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

AIM: To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. METHOD: Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. RESULTS: A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). CONCLUSION: Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.

Increased depressive symptoms in Parkinson's disease during the COVID-19 pandemic: Preliminary findings from longitudinal analysis of the PHASE study.

Introduction: The cumulative number of patients has increased through the four waves of the pandemic in Japan. Many people experienced mental stress due to the fear of infection, and restrictions of leaving the house and leisure activities. No longitudinal study has assessed the fluctuation of neuropsychiatric symptoms during the COVID-19 pandemic using the same scale. We examined changes in non-motor symptoms, and the scores of a Parkinson's Disease (PD)-specific questionnaire between the early and later periods during the COVID-19 pandemic. Methods: We conducted a questionnaire survey during the first wave (from February to April 2020) and the fourth wave of the COVID-19 pandemic (from March to April 2021). We compared the number of symptoms from the two periods. Results: Compared with the first wave, the Geriatric Depression Scale score was significantly higher in the fourth wave of the pandemic (median score of GDS: 4.00 vs. 5.50, p = 0.022). Consistently, the scores of symptoms on MDS-UPDRS part 1 in the fourth wave were significantly higher in hygiene (p = 0.033), handwriting (p = 0.033), performing hobbies and other activities (p = 0.035), and turning in bed (p = 0.046) than in the first wave. Conclusions: Our observation over a year between the early and later phases of the COVID-19 pandemic showed an increase in the severity of depression in patients with PD.

Gradual increase of avacopan dose with concomitant ursodeoxycholic acid use may help avoid the risk of C5a receptor inhibitor-induced liver injury in antineutrophil cytoplasmic antibody-associated vasculitis.

Microscopic polyangiitis is a necrotising vasculitis characterised by anti-neutrophil cytoplasmic antibodies against myeloperoxidase. The complement component 5a receptor inhibitor avacopan effectively sustains remission in microscopic polyangiitis with a reduction in prednisolone dosage. Liver damage is a safety concern for this drug. However, when it occurs and how to treat it remain unknown. A 75-year-old man developed microscopic polyangiitis and presented with hearing impairment and proteinuria. Methylprednisolone pulse therapy followed by 30 mg/day prednisolone and two doses of weekly rituximab were administered. Avacopan was initiated to taper prednisolone for sustained remission. After 9 weeks, liver dysfunction and sparse skin eruptions developed. The cessation of avacopan and the initiation of ursodeoxycholic acid improved liver function without discontinuation of prednisolone and other concomitant drugs. After 3 weeks, avacopan was rechallenged with a small dose that was gradually increased; ursodeoxycholic acid was continued. Full-dose avacopan did not induce recurrence of liver injury. Therefore, gradually increasing the dose of avacopan with concomitant ursodeoxycholic acid use may help avoid possible avacopan-induced liver injury.

Visceral fat and attribute-based medicine in chronic kidney disease.

Visceral adipose tissue plays a central role in obesity and metabolic syndrome and is an independent risk factor for both cardiovascular and metabolic disorders. Increased visceral adipose tissue promotes adipokine dysregulation and insulin resistance, leading to several health issues, including systemic inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system. Moreover, an increase in adipose tissue directly and indirectly affects the kidneys by increasing renal sodium reabsorption, causing glomerular hyperfiltration and hypertrophy, which leads to increased proteinuria and kidney fibrosis/dysfunction. Although the interest in the adverse effects of obesity on renal diseases has grown exponentially in recent years, the relationship between obesity and renal prognosis remains controversial. This may be attributed to the long clinical course of obesity, numerous obesity-related metabolic complications, and patients' attributes. Multiple individual attributes influencing the pathophysiology of fat accumulation make it difficult to understand obesity. In such cases, it may be effective to elucidate the pathophysiology by conducting research tailored to individual attributes from the perspective of attribute-based medicine/personalized medicine. We consider the appropriate use of clinical indicators necessary, according to attributes such as chronic kidney disease stage, level of visceral adipose tissue accumulation, age, and sex. Selecting treatments and clinical indicators based on individual attributes will allow for advancements in the clinical management of patients with obesity and chronic kidney disease. In the clinical setting of obesity-related nephropathy, it is first necessary to accumulate attribute-based studies resulting from the accurate evaluation of visceral fat accumulation to establish evidence for promoting personalized medicine.

Persistent intolerable abdominal pain in patients with Parkinson's disease.

OBJECTIVES: In Parkinson's disease (PD), pain is common, increases motor disability, and makes daily life unpleasant. Few patients reportedly have a low prevalence of abdominal pain. The pathophysiology of such abdominal pain has not been confirmed. We clinically studied patients with PD and persistent intolerable abdominal pain to determine the pathophysiology and effective therapy. MATERIALS AND METHODS: We obtained detailed clinical information from medical records, including the disease course before and after the onset of abdominal pain. The maximal thickness of the rectus muscle at the L4 and L5 corpus vertebral level of the abdomen on axial computed tomography was calculated, and the relative muscle thickness ratio was calculated by dividing the maximal thickness by the distance from the fascia between the bilateral rectus muscles of the abdomen and the dorsal part of the corpus vertebrae. RESULTS: In six patients with PD (three men, age range 71-85 years), the Hoehn-Yahr stage, disease duration, and daily levodopa equivalent dose were 3.1 ± 0.7, 107 ± 44 months, and 636.7 ± 451.4 mg/day, respectively. The pain occurred daily and often during the night and was not related to the timing of food intake. The pain in two patients was related to wearing-off. One patient showed constant hypertonic activity in the rectus abdominis on surface electromyography. The rectus abdominis showed that the maximal thickness and relative muscle thickness ratio of patients with abdominal pain were significantly higher than those of patients without pain. Therapeutic usefulness of antiparkinsonian medications was short and limited. CONCLUSIONS: Although intolerable abdominal pain is likely to be infrequent, it alleviates the quality of life of patients with PD. The pathophysiology seems to vary, and our observations found wearing-off of related pain and muscle contraction, suggesting dystonia. Among persistent abdominal pain, organic abnormalities, such as the precursor state of megacolon, may be lurking.

High-dose steroid-responsive COVID-19-related encephalopathy with a sudden onset of dysarthria mimicking stroke: a case report.

There has been limited research on encephalitis/encephalopathy, which is a less common coronavirus disease 2019 (COVID-19) neurological complication. The differentiation between stroke and encephalopathy with stroke mimickers is challenging in patients with COVID-19. Here, we describe a case of COVID-19-related encephalopathy mimicking stroke that was successfully treated with high-dose steroid pulse therapy. The patient suddenly experienced language disturbance with a left facial droop and symmetric numbness in his upper limbs. Magnetic resonance imaging (MRI) scans revealed hyperintensities in both the white matter and splenium. No pneumonia was observed. MRI abnormalities and neurological symptoms resolved after steroid pulse therapy and administration of remdesivir. High-dose steroid pulse treatment (for 3 days) might alleviate COVID-19-related encephalopathy.

Machine learning for morbid glomerular hypertrophy.

A practical research method integrating data-driven machine learning with conventional model-driven statistics is sought after in medicine. Although glomerular hypertrophy (or a large renal corpuscle) on renal biopsy has pathophysiological implications, it is often misdiagnosed as adaptive/compensatory hypertrophy. Using a generative machine learning method, we aimed to explore the factors associated with a maximal glomerular diameter of ≥ 242.3 µm. Using the frequency-of-usage variable ranking in generative models, we defined the machine learning scores with symbolic regression via genetic programming (SR via GP). We compared important variables selected by SR with those selected by a point-biserial correlation coefficient using multivariable logistic and linear regressions to validate discriminatory ability, goodness-of-fit, and collinearity. Body mass index, complement component C3, serum total protein, arteriolosclerosis, C-reactive protein, and the Oxford E1 score were ranked among the top 10 variables with high machine learning scores using SR via GP, while the estimated glomerular filtration rate was ranked 46 among the 60 variables. In multivariable analyses, the R2 value was higher (0.61 vs. 0.45), and the corrected Akaike Information Criterion value was lower (402.7 vs. 417.2) with variables selected with SR than those selected with point-biserial r. There were two variables with variance inflation factors higher than 5 in those using point-biserial r and none in SR. Data-driven machine learning models may be useful in identifying significant and insignificant correlated factors. Our method may be generalized to other medical research due to the procedural simplicity of using top-ranked variables selected by machine learning.

Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.