Tatsuo Yamamoto

Patients aged ≥50 years are predisposed to adefovir-related renal injury and switching to another antiviral agent rather than adefovir dose reduction is recommended when hypophosphatemia is observed.

The roles of rho-kinase (ROCK) and epidermal growth factor receptor (EGFR) were studied using an angiotensin II (AngII)-dependent hypertension rat model. Male Wistar rats were infused with AngII at a rate of 400 ng/kg body weight (BW)/min for 14 days. Effects of ROCK inhibitor, fasudil (20 mg/kg BW), and EGFR inhibitor, gefitinib (3 mg/kg BW), were studied. AngII infusion increased blood pressure (BP; 220 ± 19 mmHg) as well as the number of proliferating cells in glomeruli judged by Ki67 and proliferating cell nuclear antigen immunostaining and urinary protein excretion (118 ± 19 mg/day). AngII also decreased p27 expression and increased cyclin D1 expression in glomeruli, as well as induced dissociation of the nephrin- and podocin-immunostaining patterns in podocytes. Treatment with fasudil or gefitinib completely inhibited glomerular cell proliferation without changing the BP. Although the decreased p27 expression was reversed by both treatments, cyclin D1 induction was abolished only by gefitinib. Fasudil significantly reduced proteinuria (57.2 ± 17.5 mg/day), but not gefitinib (133.3 ± 30.9 mg/day). The dissociation of podocin and nephrin was ameliorated by fasudil, but not by gefitinib. ROCK and EGFR have distinct roles in proteinuria and glomerular cell proliferation in this model.

In chronic kidney disease (CKD), enhanced intrarenal angiotensin II (AngII) is involved in deterioration of renal function, but it is difficult to measure it. For assessment of the potential of urinary angiotensinogen as a marker of intrarenal AngII activity, the correlation of plasma and urinary renin-angiotensin system components, including angiotensinogen, with deterioration of renal function was investigated in 80 patients who had CKD and were not treated with AngII blocking agents. Changes that were induced by 14 d of losartan treatment (25 mg/d) were also measured in 28 patients. Angiotensinogen was measured by RIA of AngI after incubation with renin. Urinary angiotensinogen levels were greater in patients with low estimated GFR and elevated urinary protein and type IV collagen and correlated with renal AngII and type I collagen immunostaining intensities. The risk for deterioration of renal function (i.e., estimated GFR decline of >2.5 ml/min per yr) during a mean follow-up period of 23 mo (maximum 43 mo) was associated with urinary angiotensinogen of >3.0 nmol AngI equivalent per 1 g of urinary creatinine (AngI Eq/g Cre) at enrollment (hazard ratio 3.52). The event-free survival for deterioration of renal function was better in patients with urinary angiotensinogen 3.0 nmol AngI Eq/g Cre. Losartan reduced urinary and plasma angiotensinogen, urinary protein and type IV collagen, and systolic BP, despite concomitant increases in plasma renin and AngII. These data suggest that urinary angiotensinogen is a potentially suitable marker of intrarenal AngII activity associated with increased risk for deterioration of renal function in patients with CKD.

The nephrotic syndrome is defined by heavy proteinuria due to abnormal increase of glomerular permeability and following hypoalbuminemia, hyperlipidemia and edema. Disorders of size selective barrier, charge selective barrier, slit diaphragm and circulating permeability factors are thought to be the causes of proteinuria. Most patients with nephrotic edema have primary salt retention. Overproduction and impaired catabolism of lipoproteins are the causes of hyperlipidemia. Abnormality of coagulation factors is also associated with nephrotic syndrome. Nephrotic syndrome may be primary or secondary to systemic disorders. Once diagnosed, the cause for the nephrotic syndrome must be examined.

A 71-year-old man with bilateral renovascular disease was admitted to Hamamatsu University hospital because of appetite loss and acute shortness of breath due to acute pulmonary edema (APE) with accelerated hypertension and renal failure. Hypertension and APE were controlled by an angiotensin converting enzyme inhibitor (ACEI) and four sessions of hemodialysis with reduction of 1.8 kg bodyweight. Renal function was later stabilized and the patient required no ACEI or hemodialysis. A trial of right renal angioplasty 1 month after admission failed and renal function deteriorated (serum creatinine 7.1 mg/dL) with accelerated hypertension, gain of bodyweight and APE. Even after four sessions of hemodialysis with adequate reduction of bodyweight, APE was not controlled, but it rapidly improved after administration of an ACEI, without major bodyweight change. As no apparent cardiac dysfunction was evident, APE might have been caused by a direct action of angiotensin II on hyperpermeability in pulmonary capillaries. Blocking of angiotensin II should be considered in such patients even after introduction of hemodialysis.

Increases in transforming growth factor‐β (TGF‐β) expression and extracellular matrix accumulation are transient in acute self‐limited mesangial proliferative glomerulonephritis induced by a single injection of anti‐thymocyte serum (ATS), while these increases persist following repeated injections that produce chronic progressive sclerosing glomerulonephritis with tubulointerstitial lesions. However, little is known about the expression of TGF‐β receptors (TβRs) in cells involved in the proliferative and sclerosing renal lesions. A study of protein and mRNA expression for type I (TβRI), type II (TβRII), and type III (TβRIII) TβR in both forms of nephritis was therefore carried out by immunohistochemistry and in situ hybridization. Inhibition of cell proliferation and stimulation of matrix production by TGF‐β1 were assessed in isolated glomeruli using [³H]thymidine incorporation and [³H]proline metabolic labelling, respectively. In acute self‐limited nephritis, expression of TβRI, TβRII, and TβRIII increased in the glomerular and Bowman's capsular epithelial cells comprising the glomerular tuft adhesions to Bowman's capsules. However, TβRII expression was not prominent in proliferating mesangial cells. Glomeruli isolated from rats with acute self‐limited nephritis at day 7, when mesangial cell proliferation was maximal, were partially resistant to the mitoinhibitory effects of TGF‐β1. In contrast, expression of all three TβRs was elevated in glomerular and tubulointerstitial lesions in chronic progressive nephritis, and glomeruli isolated from rats with chronic progressive nephritis 7 days after the second ATS injection were sensitive to TGF‐β1. These data suggest that distinct cellular responses to TGF‐β1 resulting from differential expression of TβR underlie the difference between acute self‐limited mesangial proliferative and chronic progressive sclerosing ATS nephritis in the development of proliferative and sclerotic renal lesions. Copyright © 2002 John Wiley & Sons, Ltd.

We describe a 60-year-old man with nephrotic syndrome due to a glomerular thrombotic microangiopathy caused by the antiphospholipid syndrome (APS) associated with a lung adenocarcinoma. Although no significant aggravation of APS was noted following renal biopsy, catastrophic exacerbation of APS occurred 3 days after a lung adenocarcinoma biopsy while warfarin and prednisolone were being administered. The patient died of multiple organ failure 37 days after the lung adenocarcinoma biopsy. This case emphasizes the need for great caution for catastrophic exacerbation of malignancy associated APS following biopsy of the underlying malignancy.