Clinical Nephrology and Rheumatology

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1.Research Summary

The Division of Clinical Nephrology and Rheumatology actively conducts basic and clinical research, as follows:
We are further divided into the following groups: Genome and Molecular Biology Group; Renal pathology Group; Research Group for Diabetic Nephropathy and Renal Metabolism; Practical, experimental chronic kidney disease/ uremic toxin research (PRECURE) Group; and Rheumatology Group. Each group conducts technically high-level research using a variety of methods including molecular biology, genetics, biochemistry, histopathology, and epidemiology and also performs cross-sectional research by sharing research subjects with other groups.
A research goal of the Genome and Molecular Biology Group is to elucidate the underlying molecular mechanism of the pathogenesis and to prevent the progress of kidney diseases. This group strives to investigate them from the aspects of molecular, cellular to systemic-level dysfunction by introducing the study techniques of genomics and proteomics and the animal models mimicking kidney diseases.
The Renal pathology Group is in charge of the diagnosis of renal biopsy specimen collected from all our associated facilities in Niigata Prefecture and provides histological information to clinician. This group conducts research on renal transplant pathology in collaboration with the Department of Urology. In addition, this group studies new conditions based on pathological diagnosis.
The Research Group for Diabetic Nephropathy and Renal Metabolism approaches the pathology and complications of diabetes mellitus in terms of renal metabolism and studies the role of proximal tubule cells in particular. The group analyzes endocytic receptor molecules and studies the etiologies of diabetic nephropathy and nephropathy associated with metabolic syndrome based on these analyses.
The Practical, experimental chronic kidney disease/ uremic toxin research (PRECURE) Group studies CKD-induced various complications, such as bone fractures and cardiovascular disease. Those events increase with CKD progress; however, the mechanisms are incompletely understood. We try to elucidate them with both basic and clinical research, and make strategies to improve their QOL and ADL.
The Rheumatology Group is currently conducting research on the following: the pathology and therapy of nephropathy due to reactive amyloidosis in patients with rheumatoid arthritis; vascular lesions and arteriosclerotic lesions in patients with connective tissue diseases; and microfractures in patients with connective tissue diseases who are on oral bisphosphonate therapy. This group also performs psychosomatic research on the factors precipitating and ameliorating pain and physical symptoms in rheumatic and connective tissue disease patients.

2. Research Groups

3. The Nephrology and Rheumatology has the following subgroups as research teams

1) Genome and Molecular biology Group

Research subjects

Genome analysis of the development and progression of kidney diseases (focusing particularly on IgA nephropathy)
Effect of aging on the development and progression of kidney disease using mouse model

2) Renal pathology Group

Research subjects

Pathological diagnosis by renal biopsy—clinicopathological study about the onset and during progression of the primary glomerulonephritis and secondary nephropathy
Clinicopathological study of renal transplant rejection, and recurrent or de novo nephritis after renal transplantation
Long-term follow-up of IgA nephropathy

3) Research Group for Diabetic Nephropathy and Renal Metabolism

(Collaborated with Department of Applied Molecular Medicine and Department of Clinical Nutrition Science)

Research subjects

Clinical and basic research on diabetic nephropathy
Functional analysis and clinical application of megalin in the proximal tubule
Research on diet therapy in CKD
Research on protein and lipid metabolism in CKD
Research on drug-induced nephrotoxicity
Analysis of renin-angiotensin system in the kidney

4) Practical, experimental chronic kidney disease/ uremic toxin research (PRECURE)

Research subjects

Clinical studies of risk factors for CKD progression
Clinical studies of mortality and CKD-related complications in CKD patients, especially undergoing dialysis treatment
Mechanisms for CKD-induced acceleration of atherosclerosis, especially focused on uremic toxins
Mechanisms for CKD-mineral bone disorders and uremic osteoporosis
Pathogenesis of dialysis-related amyloidosis
Development of new blood purification system for more removal of uremic toxins
Convenient blood purification system at disaster for hemodialysis patients
Study about vascular access hemodialysis catheters

5) Rheumatology Group

Research subjects

Reactive amyloidosis associated with rheumatoid arthritis
Idiopathic osteonecrosis of femoral head in patients taking glucocorticoid
Atypical femoral fractures in patients with connective tissue diseases taking oral bisphosphonates
Long-term prognosis of patients with SLE / ANCA-associated vasculitis
Clinical characteristics of ANCA-associated otitis media

4.Research Results

[Area] Genome and Molecular Biology Group

[Research subject]

Bacterial composition in tonsillar crypts in patients with IgA nephropathy.

IgA nephropathy is a primary chronic glomerular disease that is characterized pathologically by deposits of galactose-deficient IgA1 and the mesangial proliferation. However, how galactose-deficient IgA1 is produced and deposits in mesangium remains to be elucidated.
IgA nephropathy patients sometimes present temporary exacerbation of hematuria at the time of tonsillar infection, and the efficacy of tonsillectomy for the treatment of IgA nephropathy has been reported. Therefore, it has been speculated that the bacterial flora present in tonsils causes some immunological modification in mucosal immunity and leads to the development of IgA nephropathy. The cultivation and isolation of bacteria have long been the gold standard for the identification and characterization of microbes. However, 99% or more of the bacteria are thought to be difficult to cultivate, which was an obstacle to detailed research of bacterial flora. We performed the comprehensive microbiome analysis in the palatine tonsils of IgA nephropathy patients, collaborating with Department of Otolaryngology Head and Neck Surgery in Niigata University, in a joint research with Tokyo Institute of Technology, National Institute of Genetics, and Juntendo University. Genomic DNA from tonsils of each patient was extracted, and the 16S ribosomal RNA gene was amplified and analyzed using a high-throughput multiplexed sequencing approach. We found that the patterns of bacteria in tonsils of IgA nephropathy patients are similar with those of recurrent tonsillitis patients. The host response to the bacteria might be important in the development of IgA nephropathy. The results were reported in Nephrology Dialysis Transplantation.



Bacterial composition in tonsillar crypts by 16S rRNA gene sequencing. IgAN, IgA nephropathy patients; RT, Recurrent tonsillitis patients; TH, Children with tonsillar hyperplasia.


Comparison of the relative abundance of each genus.

[Area] Renal pathology Group

[Research subject]

Light-microscopic characteristics of IgG4-related kidney disease

IgG4-related kidney disease (IgG4-RKD) is defined as renal lesions of IgG4-related disease, which is a new disease concept originating in Japan that is characterized by increased serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells, and often presents with tubulointerstitial nephritis. We conducted a multicenter collaborative study with Kanazawa University, Kobe University, Joetsu University of Education, and Nagaoka Red Cross Hospital to reveal light-microscopic differences between IgG4-RKD and other forms of tubulointerstitial nephritis. Specific interstitial fibril formation (storiform fibrosis, figure on the right) and cellular infiltration expanding into the renal capsule were observed only for IgG4-RKD. We concluded that these findings are crucial to distinct IgG4-RKD from other forms of interstitial nephritis.



Fig. 3. Interstitial fibrosis of IgG4-related TIN and non-IgG4-related TIN. Characteristic storiform fibrosis is evident in IgG4-related TIN (A) but not in non-IgG4-related TIN (B) (PAM Masson trichrome, X400).

[Area] CKD Pathology Group

[Research subject]

Uremic toxins-induced atherosclerosis and the therapeutic intervention

Advanced kidney disease increase cardiovascular event with progressive atherosclerosis as well as vascular calcification. Macrophage foam cell formation induced by functional abnormalities of macrophage and HDL cholesterol is one of pivotal roles for atherogenesis, and we focus on the effect of uremic toxins accumulated with kidney disease.
Indoxyl sulfate, one of uremic toxins with high protein-bound property, is accumulated in atherosclerotic lesion accelerated by kidney damage in a mouse model (Yamamoto S, Nephrol Dial Transplant 2011, Figure 1). In vitro study, indoxyl sulfate increases macrophage inflammatory cytokine production as well as reactive oxygen species (Matsuo K, Toxins 2015). Indoxyl sulfate also impair macrophage cholesterol efflux to normal HDL with less expression of ABC transporter (Matsuo K, Toxins 2015). HDL from kidney disease patients impairs lipid acceptor function from normal macrophages (Yamamoto S, J Am Coll Cardiol 2012). These results suggest that kidney disease, especially accumulation of uremic toxins including indoxyl sulfate, induces functional abnormalities both of macrophages and HDL which will lead to macrophage foam cell formation (Yamamoto S, Clin Chem Acta 2016, Figure 2).
Clinically, it is difficult to remove enough amount of uremic toxins with high protein-bound property using conventional hemodialysis treatment and we believe increase of uremic toxin removal will improve quality of life and survival in dialysis patients. We showed effect of using oral charcoal adsorbent (Yamamoto S, Sci Rep 2015, Figure 3) and a direct hemoperfusion with hexadecyl-immobilized cellulose beads (Yamamoto S, Artificial Organs in press) on the removal of protein-bound uremic toxins, and now are trying to develop a novel blood purification system.



[Area] Rheumatology Group

[Research subject]

Significant association between renal function and area of amyloid deposition in kidney biopsy specimens in both AA amyloidosis associated with rheumatoid arthritis and AL amyloidosis.

The purpose of this study was to clarify the difference in clinical features between AA and AL amyloidosis by the difference in the amount and distribution of amyloid deposition in the renal tissues. 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group) were retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. Serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed the different deposit patterns of amyloid in glomerular basement membrane, the mesangial area, and glomerular capillary between AA and AL groups, suggesting the cause of the different patterns of kidney dysfunctions in these 2 groups. (Kuroda T et al. Amyloid. 2017 Jun;24(2):123-130.)



Figure 1. amyloid deposition patterns in AA amyloidosis.


Figure 2. amyloid deposition patterns in AL amyloidosis.