Seitaro Iguchi

Expression of Osteopontin in Cisplatin-Induced Tubular Injury

Osteopontin (OPN) is considered as a key protein in cell regeneration. OPN is thought to have many functions in cell-cell binding and cell-matrix binding via OPN receptors in various organs. But there is little information on the precise role of OPN. To clarify the functional role of OPN in tubular injury, we performed in situ hybridization and immunohistochemical analysis of the expression of OPN in a renal cortical necrosis model induced by cisplatin from the acute injury to late recovery phases. In the acute injury phase, both mRNA and protein of OPN were markedly induced in damaged tubular lumens with cell debris. In the late recovery phase, on the other hand, OPN protein and mRNA were observed in dilated and flattened tubular epithelial cells showing a regenerative appearance. Most of these cells were also immunostained with CD44, a receptor of OPN. PCNA staining was also co-localized with these expressions. In light of the CD44 function regulating cell proliferation, these findings suggest that OPN may contribute to regeneration of tubular epithelial cells during the acute to late recovery phases of cortical tubular damage induced by cisplatin.

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.

Intratubular calcification in a post-renal transplanted patient with secondary hyperparathyroidism

Iguchi S, Nishi S, Shinbo J, Iino N, Kazama JJ, Shimada H, Ueno M, Saitou K, Tanigawa T, Takahashi K, Gejyo F. Intra‐tubular calcification in a post‐renal transplanted patient with secondary hyperparathyroidism. Clin Transplantation 2001: 15 (Supplement 5): 51–54. ©Munksgaard, 2001

Leiomyosarcoma of the abdominal aorta : A rare cause of renovascular hypertension

We describe the case of a 44-year-old woman who presented with renovascular hypertension caused by primary leiomyosarcoma of the abdominal aorta that had metastasized into the renal arteries. Despite an extensive radiological evaluation, the diagnosis was mistaken first for Takayasus arteritis and then for retroperitoneal hematoma or neoplasm. The patient developed renal failure due to bilateral renal infarction, and died 3 months after her initial presentation with ischemic colitis. Postmortem examination confirmed the diagnosis.

Rat kidney-targeted naked plasmid DNA transfer by retrograde injection into the renal vein

Kidney-targeted gene transfer is expected to revolutionize the treatment of renal diseases. Recently, we demonstrated that naked plasmid deoxyribonucleic acid (DNA) can be transferred into renal interstitial fibroblasts near the peritubular capillaries (PTCs) in normal rats, by retrograde injection into the renal vein with the renal vein and artery clamped. The PTC network is a main target of kidney transplant rejection and of progressive tubulointerstitial fibrosis, which typifies all progressive renal diseases. We retrogradely injected a lacZ expression plasmid in Ringer’s solution into the renal vein of rats using a 24-gage catheter. We detected lacZ expression exclusively in the interstitial fibroblasts near the PTCs of the kidney by immunoelectron microscopy. Nephrotoxicity from the gene transfer was not apparent. We then used a rat erythropoietin (Epo) expression plasmid vector pCAGGS-Epo in a reporter assay. We obtained maximal Epo expression when the DNA solution was injected within 5 s in a volume of 1.0 mL. We detected transgene-derived Epo messenger ribonucleic acid by reverse transcriptase polymerase chain reaction only in the kidneys receiving pCAGGS-Epo. In this article, protocols for naked plasmid DNA transfer into rat kidney using this hydrodynamics-based transfection method and the immunoelectron microscopic technique to determine the lacZ gene transfer site are described in detail.

Sequential adenovirus infection of type 14 hemorrhagic cystitis and type 35 generalized infection after cord blood transplantation

We report a case of a 29-year-old male patient with a generalized adenovirus (AdV) infection after cord blood transplantation (CBT) for acute myelocytic leukemia with maturation at 2nd complete remission. Before engraftment, hemorrhagic cystitis was caused by AdV, which resulted in hydronephrosis, renal failure, and adenoviremia on day 34. Forced diuresis, hemodialysis, withdrawal of cyclosporin A, and administration of γ-globulin or vidarabine were not effective and the patient died of pulmonary alveolar hemorrhage on day 67. At autopsy, old inflammatory change only was observed in the bladder section. In the lungs and kidneys, granular deposits in the nucleus and a high copy number of AdV-DNA were observed. Molecular diagnosis using PCR-restriction fragment length polymorphism analysis demonstrated that AdV with the serotype 14 caused the cystitis. However, retrospective genome typing using PCR sequencing revealed the infection of AdV serotype 35 in the kidneys, lungs, and serum. The present case suggested that Adv infection could not be always caused by a single AdV serotype, and suggested that multiple serotype infection was very difficult to treat. It is desired that a consensus regarding the treatment of AdV infections is established.

Patient with diffuse mesangial and endocapillary proliferative glomerulonephritis with hypocomplementemia and elevated anti-streptolysin O treated with prednisolone, angiotensin-converting enzyme inhibitor, and angiotensin II receptor antagonist.

A 24-year-old woman was admitted to Toyosaka Hospital with proteinuria, hematuria, lymphopenia, hypocomplementemia, positive anti-nuclear antibody (ANA), and elevation of anti-streptolysin O (ASO). Renal biopsy specimen revealed diffuse mesangial and endocapillary glomerulonephritis with crescent formation and duplication of the capillary loop on light microscopic examination. Mild to moderate proliferation of mesangial matrix and cells were observed. On immunofluorescence (IF) examination, deposition of IgG, IgA, IgM, C1q, C3, and C4 to the mesangium and capillary wall were observed. By electron microscopy (EM), mesangial, subendothelial, and subepithelial deposits were recognized. However, microtubular structure in glomerular endothelial cells, fingerprint structures, and circumferential mesangial interposition were not observed by EM. The patient was referred to our hospital, but there was no change in her proteinuria 3 weeks after admission. The elevation of ASO, hypocomplementemia, and endocapillary proliferation suggested acute glomerulonephritis, while lymphocytopenia, positive ANA, the persistent hypocomplementemia, and various deposits detected by IF and EM suggested lupus nephritis; however, she did not fulfill the classification criteria of systemic lupus erythematosus. We started prednisolone (40 mg/day) with the diagnosis of chronic glomerulonephritis revealing diffuse mesangial and endocapillary proliferative glomerulonephritis, but it was not effective for the proteinuria. Quinapril (10 mg/day) and losartan (25 to 50 mg/day) were administered and the proteinuria decreased. It is possible that this use of an angiotensin converting-enzyme inhibitor and an angiotensin II receptor antagonist was effective in reducing the proteinuria in this patient.

Membranoproliferative pattern of glomerular injury associated with complement component 9 deficiency due to Arg95Stop mutation

BackgroundArg95Stop mutation of exon 4 in complement component 9 (C9) gene is common in individuals in Japan with C9 deficiency (C9D); however, understanding of the influences of C9D on human glomerulonephritis remains elusive.MethodsA total of 1288 patients with chronic kidney disease (CKD) were recruited from the hospitals in Niigata prefecture. They were screened for the Arg95Stop mutation of C9 gene by allele-specific PCR.ResultsWe identified two individuals with C9D among 1,288 CKD patients, a frequency comparable to that of the general Japanese population (0.16%). Case 1 involved a 44-year-old man presenting with nephrotic proteinuria. The hemolytic activity of CH50 was low, and the concentration of C9 was not detected. Sequencing of exon 4 of the C9 gene showed the Arg95Stop mutation. Renal biopsy revealed diffuse global mesangial proliferation with extensive duplication of glomerular capillary walls. Mesangial, subendothelial and subepithelial deposits were noticed with light and electron microscopy. Immunofluorescent study showed predominant mesangial IgA deposition. Case 2 involved a 62-year-old man presenting with proteinuria and hematuria. His CH50 level was decreased. Renal biopsy revealed diffuse global mesangial proliferation with extensive duplication of glomerular capillary walls. Immune deposits were also confirmed. The percentage of C9D among patients with mesangial proliferation and duplication of GBM in this study was 5.1%.ConclusionThese results suggested that the lack of membrane attack complex because of an Arg95Stop mutation of the C9 gene predisposed patients to pathognomonic glomerulonephritis.

Results of physician licence examination and scholarship contract compliance by the graduates of regional quotas in Japanese medical schools: a nationwide cross-sectional survey

Objectives Responding to the serious shortage of physicians in rural areas, the Japanese government has aggressively increased the number of entrants to medical schools since 2008, mostly as a chiikiwaku, entrants filling a regional quota. The quota has spread to most medical schools, and these entrants occupied 16% of all medical school seats in 2016. Most of these entrants were admitted to medical school with a scholarship with the understanding that after graduation they will practise in designated areas of their home prefectures for several years. The quota and scholarship programmes will be revised by the government starting in 2018. This study evaluates the intermediate outcomes of these programmes. Design Cross-sectional survey to all prefectural governments and medical schools every year from 2014 to 2017 to obtain data on medical graduates. Settings Nationwide. Participants All quota and non-quota graduates with prefecture scholarship in each prefecture, and all the quota graduates without scholarship in each medical school. Primary outcome measures Passing rate of the National License Examination for Physicians and the percentage of graduates who have not bought out the scholarship contract after graduation. Results Most prefectures and medical schools in Japan participated in this study (97.8%–100%). Quota graduates with scholarship were significantly more likely to pass the National License Examination for Physicians than the other medical graduates in Japan at all the years (97.9%, 96.7%, 97.4% and 94.7% vs 93.9%, 94.5%, 94.3% and 91.8%, respectively). The percentage of quota graduates with scholarship who remained in the scholarship contract 3 years after graduation was 92.2% and 89.9% for non-quota graduates with scholarship. Conclusions Quota entrants showed better academic performance than their peers. Most of the quota graduates remained in the contractual workforce. The imminent revision of the national policy regarding quota and scholarship programmes needs to be based on this evidence.

The morphological compensatory change of peritubular capillary network in chronic allograft rejection

Abstract:  To clarify the compensatory hemodynamic alterations in the interstitium of renal allograft biopsies with chronic rejection, we evaluated the morphological changes in the peritubular capillary (PTC) network. Seven renal biopsy specimens from recipients with chronic rejection presenting with elevation of serum creatinine of 1.9 ± 0.5 mg/dL were examined. Renal biopsy specimens from their counterpart donors were used as normal controls. In each specimen, non‐pathological interstitial areas without fibrosis, tubular atrophy or cell infiltration were compared with pathological areas (PA) showing fibrosis and/or tubular atrophy using a computer image analysis. Morphological measurements revealed that the mean cut surface area of the PTC in the non‐pathological and pathological interstitial areas in the recipient biopsies were significantly larger than that of the normal controls (p < 0.001 and 0.001, respectively). In the recipient biopsies, both of the mean cut surface areas of the tubules and PTC in the non‐pathological areas were significantly higher than those in the PA (p < 0.001). The mean glomerular diameter in the recipient biopsies was also significantly higher than that of the donors (p < 0.01). In this study, we provided pathological evidence for the compensatory interstitial and glomerular hemodynamic alterations in kidney graft with chronic rejection and the condition as single kidney.