Aims/hypothesis. Type 1 diabetes is an autoimmune disorder associated with T-cell mediated injury to multiple endocrine tissues. T-cell infiltration of the juxtaglomerular apparatus could be associated with changes in local renin angiotensin system activity and, thus, with changes in the renal microenvironment. We examined the frequency of juxtaglomerular apparatus T-cell infiltration early in Type 1 diabetes and tested whether this is associated with renal structure and function. Methods. We classified 89 Type 1 diabetic patients by immunohistochemical analysis as either juxtaglomerular apparatus T-cell positive (n=37) or T-cell negative (n=38). Borderline cases (n=14) were not considered further.Results. T-cell positive patients had a shorter duration of diabetes (6.7±2.5 years) than T-cell negative patients (9.2±5.0 years, p=0.011) and lower albumin excretion rate, but they had a similar glomerular filtration rate and blood pressure. Renal biopsy morphometric analysis showed similar glomerular basement membrane width and mesangial fractional volume in these two groups. However, glomerular capillary surface density (p=0.0012) and filtration surface per glomerulus (p=0.0155) were greater in the T-cell positive patients. Conclusion/Interpretation. Increased filtration surface per glomerulus could be associated with glomerular filtration rate preservation in diabetes. Thus, juxtaglomerular apparatus immunologic injury in Type 1 diabetes patients could delay the clinical consequences of diabetic nephropathy. [Diabetologia (2004) Minneapolis, MN 55455, USA E-mail: mauer002@umn.edu Abbreviations: ECM, Extracellular matrix; RAS, renin-angiotensin-system; JGA, juxtaglomerular apparatus; NHDN, natural history of diabetic nephropathy; IP, immunoperoxidase; GV, mean glomerular volume; TGF-B, transforming growth factor-B; Vv(Mes/glom), mesangial fractional volume per glomerulus; GBM, glomerular basement membrane; Sv(PGBM/glom), surface density of the peripheral glomerular capillary perglomerulus ; TFS, total filtration surface per glomerulus; Vv(Int/cortex), fractional volume of renal cortical interstitium.

Caucasian type 2 diabetic patients with microalbuminuria (MA) or overt nephropathy (ON) show greater heterogeneity of renal lesions than type 1 diabetic patients. We examined whether a similar situation exists in 30 Japanese type 2 diabetic patients [21 male, age 48 ± (SD) 8 years, known duration 11 ± (SD) 8 years] without definable renal disease other than diabetic nephropathy. Six patients were normoalbuminuric (NA), 11 MA, and 13 had ON. Normal controls were 9 age-matched Japanese living-related renal transplant donors. Electron microscopic morphometry was performed on renal biopsy specimens and related to renal function. Glomerular basement membrane width and mesangial fractional volume [Vv(Mes/glom)] were increased in all type 2 diabetic patients groups (NA, MA, ON) as compared with normal controls. The Vv(Mes/glom) correlated directly with urinary albumin/creatinine. However, Vv(Mes/glom) as well as glomerular basement membrane width overlapped among the three functional categories (NA, MA, ON) and normal controls. In conclusion: (1) similar to Caucasian type 2 diabetic patients, Japanese type 2 diabetic patients have greater heterogeneity of renal structure than Caucasian type 1 diabetic patients, and (2) urinary albumin is not a reliable indicator of underlying renal structure in Japanese type 2 diabetic patients.

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Hepatoid adenocarcinoma is reviewed in its clinicopathological and oncogenetic aspects. This variant of adenocarcinoma has been found to be an alpha-fetoprotein (AFP) -producing carcinoma arising in extrahepatic organs, and it mimics hepatocellular carcinoma in terms of morphology and function. Vascular invasion, usually prominent, is often complicated by extensive liver metastases. A prompt and accurate diagnosis of hepatoid adenocarcinoma is important because the prognosis is very poor compared with that of common types of adenocarcinoma. The characteristic features of hepatoid adenocarcinoma are summarized on the basis of our own experiences and the literature. In addition, a possible molecular mechanism that under-lies the ectopic appearance of the hepatic phenotype is discussed.

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We herein report a 58-year-old Japanese woman who survived 14 years after surgery for lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) exon 19 deletion. She developed recurrence, for which she underwent multimodal therapy, including EGFR-tyrosine kinase inhibitor (TKI) administration. She ultimately died from a rapidly progressive right lung tumor that was resistant to EGFR-TKI. According to the autopsy findings, she had combined large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma in the right lung, which retained an EGFR exon 19 deletion in both components. Therefore, the histological transformation to LCNEC can be a mechanism of acquired EGFR-TKI resistance.

OBJECTIVE-Reduced nephron number is hypothesized to be a risk factor for chronic kidney disease and hypertension. Whether reduced nephron number accelerates the early stages of diabetic nephropathy is unknown. This study investigated whether the rate of development of diabetic nephropathy lesions was different in type 1 diabetic patients with a single (transplanted) kidney compared with patients with two (native) kidneys.RESEARCH DESIGN AND METHODS-Three groups of volunteers were studied: 28 type 1 diabetic kidney transplant recipients with 8 -20 years of good graft function, 39 two-kidney patients with duration of type 1 diabetes matched to the time since transplant in the one-kidney group, and 30 age-matched normal control subjects. Electron microscopic morphometry was used to estimate glomerular structural parameters on 3.0 Ϯ 1.4 glomeruli per biopsy.RESULTS-In the one-versus two-kidney diabetic subject groups, respectively, serum creatinine (means Ϯ SD 1.3 Ϯ 0.4 vs. 0.9 Ϯ 0.2 mg/dl; P Ͻ 0.001), systolic blood pressure (133 Ϯ 13 vs. 122 Ϯ 11 mmHg; P Ͻ 0.001), and albumin excretion rate (median [range] 32.1 g/min [2-622] vs. 6.8 g/min [2-1,495] ; P ϭ 0.006) were higher. There were no differences in the one-versus two-kidney diabetic subject groups, respectively, in glomerular basement membrane width (median [range] 511 nm [308 -745] However, these glomerular structural parameters were statistically significantly higher in both diabetic subject groups compared with normal control subjects. Results were similar when patients receiving ACE inhibitors were excluded from the analyses. R educed nephron number has been proposed as a risk factor for and is implicated in association with diabetic nephropathy in humans (1), but direct studies so far have been unavailable or limited in numbers of diabetic subjects (2). This study investigates whether nephron number, decreased by approximately one-half, accelerates the early lesions of diabetic nephropathy by comparing the rate of development of glomerular lesions in kidneys exposed to the diabetic state for 8 -20 years in patients with one transplanted kidney versus those with two native kidneys. CONCLUSIONS-Reduced RESEARCH DESIGN AND METHODSTransplant (one-kidney) group. Twenty-five type 1 diabetic patients received living related kidneys (eight HLA identical), and three received cadaveric transplants. All patients at least 8 years' posttransplantation with serum creatinine Յ2.5 mg/dl volunteering for studies of allograft diabetic nephropathy recurrence were included. These patients received transplants between 1969 and 1987 at the University of Minnesota. None received a pancreas transplant. All together, 8 patients were on cyclosporine, azathioprine, and prednisone; 3 were on cyclosporine and prednisone; 13 were on azathioprine and prednisone; 1 was on cyclosporine and azathioprine; 1 was on azathioprine; 1 was on cyclosporine; and 1 was on mycophenolate mofetil and prednisone. Six were receiving ACE inhibitors. All studies were approved by the Committee for the Us...

To study the pathophysiology of hyperlipidemia in nephrotic syndrome, we compared lipid metabolism in the nephrotic stage (stage 1) and in stage 2, when albuminuria had subsided, in 11 patients with minimal-change disease treated with corticosteroid. High-density lipoprotein (HDL) levels were decreased and HDL contained more cholesterol and triglyceride per unit of protein in stage 1 in the patients than in age-matched healthy controls. The urinary protein level was positively correlated only with low-density lipoprotein (LDL) levels, suggesting that the increased albumin clearance stimulated LDL production. Serum cholesterol levels were positively correlated with apolipo-protein E levels and were negatively correlated with lecithin-cholesterol acyltransferase activity in the nephrotic stage; the opposite correlations were seen in controls. Although triglycerides in HDL had normalized at stage 2, triglycerides in LDL and very-low-density lipoprotein did not return toward normal until stage 3, when serum cholesterol levels were normalized.