Naofumi Imai

Tubulointerstitial nephritis associated with IgG4-related systemic disease

We report three patients with tubulointerstitial nephritis (TIN) with high serum IgG4 concentrations. None of the patients had notable pancreatic lesions when the TIN developed, although one had a history of autoimmune pancreatitis (AIP). Nevertheless, the clinicopathological findings were quite similar to those of AIP. They were all middle-aged to elderly men. Sialadenitis and lymphadenopathy were often evident. Serum total IgG and IgG4 concentrations were elevated and hypocomplementemia was observed. Although antinuclear antibodies were positive, anti-Ro and anti-La antibodies were negative. Renal biopsy showed dense lymphoplasmacytic infiltration with fibrosis in the renal interstitium, and the infiltrated plasma cells had strong immunoreactivity for IgG4. Furthermore, lymphoplasmacytic infiltration and abundant IgG4-positive plasma cells were observed in the salivary glands of a patient. Steroid therapy was effective for TIN in all three patients. The present findings support the recently proposed concept of IgG4-related systemic disease, and suggest that IgG4 is associated not only with AIP but also with other systemic lymphoplasmacytic diseases, including TIN. The conditions responsible for the pathogenesis of TIN need to be considered, irrespective of the presence of AIP.

Immunohistochemical Characteristics of IgG4-Related Tubulointerstitial Nephritis: Detailed Analysis of 20 Japanese Cases

Although tubulointerstitial nephritis with IgG4+ plasma cell (PC) infiltration is a hallmark of IgG4-related kidney disease (IgG4-RKD), only a few studies are available about the minimum number of IgG4+ PC needed for diagnosis along with IgG4+/IgG+ PC ratio in the kidney. In addition, the significance of the deposition of IgG or complement as a reflection of humoral immunity involvement is still uncertain. In this study, we analyzed 20 Japanese patients with IgG4-RKD to evaluate the number of IgG4+ PCs along with IgG4+/IgG+ PC ratio and involvement of humoral immunity. The average number of IgG4+ PCs was 43.8/hpf and the average IgG4+/IgG+ or IgG4+/CD138+ ratio was 53%. IgG and C3 granular deposits on the tubular basement membrane (TBM) were detected by immunofluorescence microscopy in 13% and 47% of patients, respectively. Nine patients had a variety of glomerular lesions, and 7 of them had immunoglobulin or complement deposition in the glomerulus. In conclusion, we confirmed that infiltrating IgG4+ PCs > 10/hpf and/or IgG4/IgG (CD138)+ PCs > 40% was appropriate as an item of the diagnostic criteria for IgG4-RKD. A relatively high frequency of diverse glomerular lesions with immunoglobulin or complement deposits and deposits in TBM may be evidence of immune complex involvement in IgG4-related disease.

Clinicopathological findings of immunoglobulin G4-related kidney disease

Immunoglobulin (Ig) G4-related kidney disease characterizing tubulointerstitial nephritis (TIN) is an organ complication recognized in IgG4-related systemic diseases that has some unique aspects compared to other types of TIN. TIN lesions in the kidney can be tumor-like, focal or diffuse. Abnormal urinalysis is usually mild or absent even in the cases with deteriorated renal dysfunction. Some cases are accidentally diagnosed from radiological findings without renal dysfunction and/or abnormal urinalysis. The typical pathological findings of TIN are unique fibrosis and infiltration of massive lymphocytes and IgG4-positive plasma cells. Glomerular lesions are rare but the complication of mesangial proliferative glomerulonephritis and membranous nephropathy is occasionally reported. Pathogenic mechanisms are unclear until now; however, auto-immune and allergic mechanisms have been suspected from laboratory data. The initial response to steroid agents is generally favorable; however, recurrence is possible after the discontinuation of steroid treatment. Long-term follow-up is necessary with continuous systemic checks for organ disorders due to IgG4-related systemic diseases.

Light-microscopic characteristics of IgG4-related tubulointerstitial nephritis: distinction from non-IgG4-related tubulointerstitial nephritis

BACKGROUND IgG4-related disease is a multi-organ disorder characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive cells into affected organs. In routine studies, however, IgG subclasses are not estimated. In the present study, we attempted to clarify the light-microscopic characteristics of IgG4-related tubulointerstitial nephritis (TIN) to facilitate distinction from non-IgG4-related TIN in specimens obtained by renal biopsy using routine staining. METHODS In specimens from 34 cases of TIN (13 IgG4-related and 21 non-IgG4-related), 9 nephrologists independently reviewed the following histological features of interstitial lesions: (i) cell infiltration extending into the renal capsule, (ii) cell infiltration into the renal medulla, (iii) regional lesion distribution, (iv) lymphoid follicles, (v) granulomatous lesions, (vi) necrotizing angiitis, (vii) eosinophil infiltration, (viii) neutrophil infiltration, (ix) tubulitis, (x) peritubular capillaritis, (xi) storiform fibrosis and (xii) the stage of interstitial fibrosis. The modified nominal group technique was applied to obtain a consensus in the pathological interpretation. RESULTS Consensus was successfully attained among the diagnosticians for all but one pathological feature (regional lesion distribution). Storiform fibrosis was demonstrated in 12 of 13 (92.3%) cases of IgG4-related TIN but in none of the cases of other types of TIN. Cell infiltration extending into the renal capsule was also observed only in IgG4-related TIN. Conversely, neutrophil infiltration, severe tubulitis, severe peritubular capillaritis, granulomatous lesions and necrotizing angiitis were evident only in non-IgG4-related TIN. CONCLUSIONS This study revealed some useful and characteristic features for distinguishing IgG4-related from non-IgG4-related TIN on the basis of light-microscopic observation.

Ultrastructural characteristics of diabetic nephropathy

Diabetic nephropathy is a major cause of chronic renal failure in Japan, and the prevalence rate has markedly increased during the past decade. Diabetic nephropathy shows various specific histological changes not only in glomeruli but also in the interstitial region. Nodular, diffuse, and exudative lesions, so-called diabetic glomerulosclerosis, are well known as glomerular lesions. At first, they were historically evaluated only by light microscopy, and thus which components of the glomeruli were modified was not sufficiently clear. Subsequent electron microscopic studies clarified that the expansion of the mesangial matrix was the true form of nodular and diffuse lesions, and that insudated serum substance was the real appearance of an exudative lesion. Interstitial lesions also exhibit specific features in diabetic nephropathy. In electron microscopic studies, it was proved that the size of mitochondria and thickness of the tubular basement membrane were increased in diabetic nephropathy. In this review, we introduce typical electron microscopic findings in diabetic nephropathy and recent opinions on the progression of diabetic nephropathy.

Identification of alternatively activated macrophages in new-onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion

Ikezumi Y, Suzuki T, Karasawa T, Hasegawa H, Yamada T, Imai N, Narita I, Kawachi H, Polkinghorne K R, Nikolic‐Paterson D J & Uchiyama M
(2011) Histopathology 58, 198–210
Identification of alternatively activated macrophages in new‐onset paediatric and adult immunoglobulin A nephropathy: potential role in mesangial matrix expansion

Histological Localization of Advanced Glycosylation End Products in the Progression of Diabetic Nephropathy

We studied the immunohistochemical localization of advanced glycosylation end products (AGEs) in the progression of diabetic nephropathy. Fourteen NIDDM patients with diabetic nephropathy were evaluated: 2 patients with normoalbuminuria, 4 with microalbuminuria (MA) and 8 with overt proteinuria (OP). Three patients with minor glomerular abnormalities were used as nondiabetic controls. Immunoreactivity to a monoclonal anti-AGE antibody (6D12) was recognized on the internal elastic membranes of arterial walls in every diabetic group. Hyaline lesions of arterioles of the MA and OP groups demonstrated strong reactions with 6D12. A portion of the nodular and exudative lesions in glomeruli of OP group patients also revealed immunoreactivity to 6D12. No immunoreactivity to 6D12 was observed in nondiabetic control specimens. We confirm that the accumulation of AGEs began in arterial walls of the early stage and presented in glomerular lesions of the late stage of the progression of diabetic nephropathy.

Hypocomplementemia of unknown etiology: an opportunity to find cases of IgG4-positive multi-organ lymphoproliferative syndrome

Recently, a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome (IgG4+ MOLPS), characterized by hyper-IgG4 gammaglobulinemia and IgG4-positive plasma cell tissue infiltration, has been proposed. It includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and many other inflammatory conditions affecting multiple organs. However, diagnosis is difficult if the disease is not suspected because serum IgG subclasses are not measured routinely and the affected organs vary. Because hypocomplementemia is often observed in this condition, we investigated the serum subclasses of IgG in patients with hypocomplementemia, especially of unknown etiology. We found 6 patients with high serum IgG4 levels among 10 patients with hypocomplementemia of unknown etiology who visited our hospital between December 2004 and September 2007. The results of additional pathological and imaging examinations in the 6 patients with high serum IgG4 levels were compatible with IgG4+ MOLPS. Our results suggest that hypocomplementemia of unknown etiology offers an opportunity to find cases of IgG4+ MOLPS.

Functional Characterization of a Novel Missense CLCN5 Mutation Causing Alterations in Proximal Tubular Endocytic Machinery in Dent’s Disease

Background/Aims: Mutations of the endosomal chloride/proton exchanger gene, CLCN5, cause Dent’s disease, an X-linked recessive proximal tubular disorder. The renal endocytic system was found to be affected in clcn5 knockout mice. However, the impaired endocytic machinery of Dent’s disease patients has not been thoroughly investigated. Methods: The CLCN5 gene was sequenced in a Japanese patient with Dent’s disease and his family. The loss-of-function phenotype of the missense CLCN5 mutation was investigated by gene expression in Xenopus oocytes and CHO cells. Immunohistochemical analysis was performed on kidney biopsy specimens for endocytic machinery proteins, megalin, cubilin, and disabled-2 (Dab2) in proximal tubules. Results: Genomic analysis revealed a novel G-to-A transition at the first nucleotide of the 333rd codon of CLCN5, causing a substitution of glycine with arginine. Inefficient expression of the mutant gene in Xenopus oocytes resulted in abolished chloride currents. Impaired N-glycosylation of the mutant protein was evident in the DNA-transfected CHO cells. Proximal tubular expression of megalin, cubilin, and Dab2 was markedly reduced and irregular staining in some portions was observed in the patient compared with controls. Conclusions: A novel G333R CLCN5 mutation caused defective expression of megalin, cubilin, and Dab2 in a patient with Dent’s disease.

A clinicopathological study on the long-term efficacy of tonsillectomy in patients with IgA nephropathy.

Our study evaluated the clinical efficacy of tonsillectomy on the long-term renal survival in patients with primary IgA nephropathy (IgAN). Forty-six patients underwent tonsillectomy, and 74 patients did not. The mean of follow-up duration of all patients was 197.0±29.3 months (61–339 months). The baseline clinical and histological data at renal biopsy were not statistically different between the two groups with and without tonsillectomy. Five (10.9%) of the tonsillectomy group reached end stage renal failure (ESRF), whereas 19 (25.8%) of the non-tonsillectomy group did. The chi-square test between the two groups showed a significant difference (p<0.05). The renal survival of the tonsillectomy group was significantly higher than that of the non-tonsillectomy group by the Kaplan-Meier method with log-rank test (p<0.05). The Cox regression model also revealed that tonsillectomy had a significant favorable impact on the renal survival in long-term follow-up duration (p<0.05). Although our study was done by retrospective analyses, all the results proved that tonsillectomy had significant favorable effects on the long-term renal survival in patients with IgAN.