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.

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.

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.

Initial decline in eGFR to predict tolvaptan response in autosomal-dominant polycystic kidney disease.

BACKGROUND: Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat autosomal-dominant polycystic kidney disease (ADPKD). Although tolvaptan curbs disease progression, a few reports have examined factors related to treatment response. The estimated glomerular filtration rate (eGFR) decreases soon after tolvaptan is initiated. We investigated whether initial eGFR decline affects renal prognosis of patients. METHODS: This was a single-center, retrospective observational cohort study. Eighty-three patients with ADPKD who initiated tolvaptan were selected. We analyzed the relationship of the initial eGFR change with clinical parameters and analyzed the annual eGFR change in terms of renal prognostic value using univariable and multivariable linear regression analyses. RESULTS: The initial eGFR change was - 4.6 ± 8.0%/month. The initial eGFR change correlated significantly with the annual eGFR change in multivariable analysis, suggesting that the larger decline in the initial eGFR change, the better the renal prognosis. Furthermore, the change in fractional excretion (FE) of free water (FEH2O) correlated positively with initial eGFR change. FEH2O and urea nitrogen FE (FEUN) increased significantly; however, sodium FE (FENa) level remained unchanged. In approximately half of the patients, FENa unexpectedly decreased. CONCLUSIONS: The initial eGFR decline might be caused by suppressing glomerular hyperfiltration, due to the pharmacological effect of tolvaptan, and/or by reducing renal plasma flow, due to potential volume depletion. The initial eGFR change reflects the tolvaptan effect, can be easily evaluated in clinical practice, and may be useful as one of the clinical indicator for predicting renal prognosis in patients under tolvaptan.

Impact of visceral fat area in patients with chronic kidney disease.

Longitudinal studies evaluating the association between visceral fat area (VFA) and kidney function decline in patients with chronic kidney disease (CKD) are limited, and little is known about VFA interactions contributing to the kidney prognosis (e.g. interactions between VFA ≥ 100 cm2 and age, sex, and CKD category). In this study, we stratified patients with CKD according to VFA category, as well as age, sex, CKD category, hyperglycemia, and diabetes mellitus, and determined the ability of obesity-related indicators (body mass index, waist circumference, subcutaneous fat area, visceral-to-subcutaneous fat ratio) to predict the renal prognosis. Kidney outcomes (≥ 50% estimated glomerular filtration rate decline or end-stage kidney disease) were examined in 200 patients with CKD (median follow-up, 12.3 years). On multivariable Cox analysis, an increase in VFA (10-cm2 increase) was significantly associated with kidney outcomes in the entire cohort, and VFA was significantly associated with kidney disease progression even in the VFA < 100 cm2 sub-cohort. Interestingly, the hazard ratio (HR) was higher for VFA (10-cm2 increase) than for the VFA ≥ 100 cm2 sub-cohort (HR 1.33 vs. 1.07). Overall, VFA was found to be the most versatile obesity-related indicator associated with kidney disease progression. VFA was associated with the primary outcome in the sub-cohorts of CKD stages 1-2, hyperglycemia, and diabetes mellitus. A high VFA was a significant kidney prognostic factor in the entire CKD cohort, with greater significance in patients with VFA < 100 cm2 than in patients with VFA ≥ 100 cm2. Our results may provide new insights into strategies for treating CKD.

Association between anemia and renal prognosis in autosomal dominant polycystic kidney disease: a retrospective study.

BACKGROUND: Though anemia is a sign of poor renal prognosis in chronic kidney disease (CKD), hemoglobin (Hb) levels are typically higher in autosomal dominant polycystic kidney disease (ADPKD) than in other kidney diseases, and anemia has not been examined as a potential prognosticator. Thus, we investigated anemia as a factor for renal prognosis in ADPKD. METHODS: In total, 115 non-dialysis patients, 48 men and 67 women, with ADPKD were evaluated. The renal outcome of a 50% reduction in the estimated glomerular filtration rate or renal replacement therapy was examined using the Cox regression analysis and Kaplan-Meier analysis. RESULTS: Patients were followed for a median of 5.5 years and 50 patients had reached the end point. The mean age of the patients at the first visit was 45.9 ± 13.3 years. The overall mean Hb was 12.90 ± 1.85 g/dL, and the mean Hb in men and women was 13.82 ± 1.72 g/dL and 12.25 ± 1.65 g/dL, respectively. Hb levels and uric protein content were statistically significant factors for poor renal prognosis, while hypertension and genetic mutations failed to reach significance. Furthermore, statistical significance was found in men with Hb < 12 g/dL and in women with Hb < 11 g/dL. Anemia had significant association with kidney disease progression in patients with ADPKD. CONCLUSIONS: We found that anemia might be a factor for poor renal prognosis in ADPKD. Furthermore, a sex difference was found, wherein men with Hb < 12 g/dL and women with Hb < 11 g/dL were at risk of renal disease progression.

Low HDL cholesterol as a predictor of chronic kidney disease progression: a cross-classification approach and matched cohort analysis.

Emerging epidemiological evidence indicates that low serum high-density lipoprotein cholesterol (HDL-C) levels are associated with the risk of progression of chronic kidney disease (CKD). However, the differences in the influence of serum HDL-C levels on CKD progression in different subcohorts have rarely been examined in detail in previous studies. The aim of this study was to investigate the significance of low serum HDL-C levels as a predictor of disease progression in CKD patients according to sub-analyses using a cross-classified subcohort. We reviewed data obtained from 120 CKD patients. Prognostic factors for renal outcome were identified by the multivariate Cox proportional hazards method. Kaplan-Meier analysis was performed to assess disease progression, which was defined as a > 30% decline in the glomerular filtration rate (GFR), or end-stage renal disease. The mean age of the included participants was 58.3 ± 13.6 years. The subjects were divided into two groups (low HDL-C vs. high HDL-C). The median follow-up period was 112.8 months. The kidney survival rate in the low HDL-C group was significantly lower than that in the high HDL-C group (P < 0.0001). However, the age-stratified analysis showed no difference between the two groups in the cohort of patients ≥ 70 years old. Multivariate Cox regression analyses showed a significant association between low HDL-C [hazard ratio (HR) 4.80, P = 0.009] and a ≥ 30% eGFR decline or ESRD. This association was more evident in the cohort of patients < 70 years old (HR 4.96, P = 0.0165), especially the female subcohort (HR 13.86, P = 0.0033). Multivariate analysis showed a significant correlation between visceral fat area and serum HDL-C levels among both male (P = 0.0017) and female (P = 0.0449) patients. In a propensity score-matched cohort (patients < 70 years old), the kidney survival rate of CKD patients was significantly lower in the low HDL-C group than in the high HDL-C group (P = 0.0364). A low serum HDL-C level is a significant predictor of CKD progression, especially in female patients with CKD under 70 years of age. This finding is of importance to clinicians when determining the expected prognosis of CKD in patients.

AL amyloidosis with non-amyloid forming monoclonal immunoglobulin deposition; a case mimicking AHL amyloidosis.

BACKGROUND: Immunoglobulin heavy-and-light-chain amyloidosis (AHL amyloidosis) is a newly established disease entity where both the immunoglobulin heavy-chain and light-chain compose amyloid fibrils. The immunoglobulins responsible for the amyloid fibrils are generally identified by immunostaining and/or laser microdissection-liquid chromatography-tandem mass spectrometry (LMD-LC-MS/MS). However, both techniques do not biochemically differentiate immunoglobulins that formed amyloid fibrils from non-responsible immunoglobulins. CASE PRESENTATION: We herein report a case of 67-year-old female patient with renal amyloidosis due to lymphoplasmacytic lymphoma secreting monoclonal immunoglobulin M (IgM)-kappa. Renal immunostaining monotypically positive for IgM-kappa and LMD-LC-MS/MS identification of mu heavy-chain and kappa light-chain were consistent with the diagnosis of AHL amyloidosis. In order to confirm that both the immunoglobulin heavy-chain and light-chain were forming amyloid fibrils, we performed LC-MS/MS of renal amyloid fibrils isolated by the traditional amyloid purification method. The additional LC-MS/MS identified kappa light-chain only without any heavy-chain component. These results were suggestive that amyloid fibrils were composed by kappa light-chain only and that the mu heavy-chain identified by immunostaining and LMD-LC-MS/MS was derived from the non-specific co-deposition of monoclonal IgM-kappa. CONCLUSION: The case was AL amyloidosis with non-amyloid forming monoclonal immunoglobulin deposition. While immunostaining and LMD-LC-MS/MS are irreplaceable techniques to classify amyloidosis, confident exclusion of the present condition should be required to diagnose AHL amyloidosis.

Myeloperoxidase-antineutrophil cytoplasmic antibody causes different renal diseases by immune-complex formation and pauci-immune mechanism: A case report.

Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO)-ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci-immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms.

Podocyte injury-driven lipid peroxidation accelerates the infiltration of glomerular foam cells in focal segmental glomerulosclerosis.

Intracapillary foam cell infiltration with podocyte alterations is a characteristic pathology of focal segmental glomerulosclerosis (FSGS). We investigated the possible role of podocyte injury in glomerular macrophage and foam cell infiltration in a podocyte-selective injury model (NEP25 mice) and hypercholesterolemic model [low-density lipoprotein receptor deficiency (LDLR(-/-)) mice] with doxorubicin-induced nephropathy. Acute podocyte selective injury alone failed to induce glomerular macrophages in the NEP25 mice. However, in the doxorubicin-treated hypercholesterolemic LDLR(-/-) mice, glomerular macrophages/foam cells significantly increased and were accompanied by lipid deposition and the formation and ingestion of oxidized phospholipids (oxPLs). Glomerular macrophages significantly correlated with the amount of glomerular oxPL. The NEP25/LDLR(-/-) mice exhibited severe hypercholesterolemia, glomerular lipid deposition, and renal dysfunction. Imaging mass spectrometry revealed that a major component of oxidized low-density lipoprotein, lysophosphatidylcholine 16:0 and 18:0, was present only in the glomeruli of NEP25/LDLR(-/-) mice. Lysophosphatidylcholine 16:0 stimulated mesangial cells and macrophages, and lysophosphatidylcholine 18:0 stimulated glomerular endothelial cells to express adhesion molecules and chemokines, promoting macrophage adhesion and migration in vitro. In human FSGS, glomerular macrophage-derived foam cells contained oxPLs accompanied by the expression of chemokines in the tuft. In conclusion, glomerular lipid modification represents a novel pathology by podocyte injury, promoting FSGS. Podocyte injury-driven lysophosphatidylcholine de novo accelerated glomerular macrophage-derived foam cell infiltration via lysophosphatidylcholine-mediated expression of adhesion molecules and chemokines in glomerular resident cells.

Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated ß1-integrin endocytosis.

Podocyte-endothelial cell cross-talk is paramount for maintaining the filtration barrier. The present study investigated the endothelial response to podocyte injury and its subsequent role in glomerulosclerosis using the podocyte-specific injury model of NEP25/LMB2 mice. NEP25/LMB2 mice showed proteinuria and local podocyte loss accompanied by thrombotic microangiopathy on day 8. Mice showed an increase of glomerular plasminogen activator inhibitor type 1 (PAI-1) mRNA and aberrant endothelial PAI-1 protein already on day 1, before thrombosis and proteinuria. A PAI-1-specific inhibitor reduced proteinuria and thrombosis and preserved podocyte numbers in NEP25/LMB2 mice by stabilization of ß1-integrin translocation. Heparin loading significantly reduced thrombotic formation, whereas proteinuria and podocyte numbers were unchanged. Immortalized podocytes treated with PAI-1 and the urokinase plasminogen activator (uPA) complex caused significant cell detachment, whereas podocytes treated with PAI-1 or uPA alone or with the PAI-1/uPA complex pretreated with an anti-uPA receptor (uPAR) antibody failed to cause detachment. Confocal microscopy and cell surface biotinylation experiments showed that internalized ß1-integrin was found together with uPAR in endocytotic vesicles. The administration of PAI-1 inhibitor or uPAR-blocking antibody protected cultured podocytes from cell detachment. In conclusion, PAI-1/uPA complex-mediated uPAR-dependent podocyte ß1-integrin endocytosis represents a novel mechanism of glomerular injury leading to progressive podocytopenia. This aberrant cross-talk between podocytes and endothelial cells represents a feedforward injury response driving podocyte loss and progressive glomerulosclerosis.

Renal AH Amyloidosis Associated With a Truncated Immunoglobulin Heavy Chain Undetectable by Immunostaining.

AH amyloidosis is a rare type of amyloidosis caused by deposition of monoclonal immunoglobulin heavy chain. The key diagnostic feature is positive immunostaining for a single class of immunoglobulin heavy chain. We report a case of AH amyloidosis with immunoglobulin G (IgG) λ monoclonal gammopathy that was diagnosed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after immunostaining of renal tissue for immunoglobulin heavy chain gave negative results. The molecular weight of the purified renal amyloid protein was ∼11kDa, which was determined by LC-MS/MS analysis to correspond to an amino acid sequence comprising the variable region and a truncated portion of the constant region of IgG heavy chain. The exact same truncated heavy chain was detected by LC-MS/MS of a protein isolated from the patient's serum, suggesting that the truncated serum protein was the precursor of the amyloid protein. Because antibodies to immunoglobulin heavy chain recognize the Fc portion, the large deletion in the constant region could explain the negative results upon immunostaining. Direct protein detection by LC-MS/MS is a powerful aid to diagnose renal AH amyloidosis, particularly when the findings of immunoglobulin staining are inconsistent with the background monoclonal gammopathy.

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.

Slowly Progressive Male Alport Syndrome Evaluated by Serial Biopsy: Importance of Type IV Collagen Staining.

A slowly progressive middle-aged man initially diagnosed with thin basement membrane nephropathy based on extensive thinning of the glomerular basement membrane (GBM) was subsequently diagnosed with Alport syndrome (AS) by a serial renal biopsy eight years later. The ultrastructural analysis of the second biopsy indicated thickening and wrinkling with mild reticulation in the GBM, consistent with AS. However, a retrospective analysis of the first biopsy revealed mild attenuation of type IV collagen α5 chain staining, suggesting a potential diagnosis of AS, despite the lack of ultrastructural features of AS. We herein report the clinical usefulness of type IV collagen staining in the early diagnosis of AS.