Shuzo Kobayashi

Applications of LDL-apheresis in nephrology

LDL-apheresis (LA) was originally used for familial hyperlipidemia, and then in Japan extended to use for the treatment of patients with peripheral arterial disease (PAD) and nephrotic syndrome due to steroid-resistant focal glomerular sclerosis (FGS). The reason why this treatment is applicable for these disorders is due to the fact that LA exerts its favorable effects beyond the lipid-lowering effect. The main underlying mechanisms, for example, in the case of LA application in patients with PAD are: (1) improvement of hemorheology, (2) improvement of endothelial dysfunction, (3) elevations of serum levels of NO and bradykinin, (4) increase in serum levels of vascular endothelial growth factor, and (5) reduction of adhesion molecules on monocytes. Furthermore, we have reported that LA could have anti-inflammatory effects because LA reduces serum levels of P-selectin, which is known to play an important role in the development of atherosclerosis as well as a reduction of serum C-reactive protein levels as standard biomarker of atherosclerosis. Massive proteinuria is also an important challenge in nephrology. The possible mechanisms besides removal of toxic lipids are the reduction of the vasoconstrictive prostanoid and thromboxane A2 (TXA2) and an improvement in macrophage function evidenced by a significant amelioration of interleukin-8 production by lipopolysaccharide-stimulated peripheral blood mononuclear cells. It is intriguing to note that in terms of pharmacodynamics, LA improves steroid and cyclosporine uptake into lymphocytes. Although there are no randomized controlled trials, it is clear that LA has various effects beyond lowering lipids. Making the device more concise and changing it into a whole blood adsorption type, we need to collect more clinical cases and to study the underlying mechanisms further.

Juxtaglomerular cell tumor with retroperitoneal fibrosis and secondary immune-complex glomerulonephritis: A possible contribution of the renin angiotensin system to renal fibrosis

We present a case of a 25-year-old woman with a renin-secreting juxtaglomerular cell tumor, retroperitoneal fibrosis associated with glomerular hypertrophy, glomerulonephritis, and marked tubulointerstitial alterations. Myofibroblasts, as shown by positive immunostaining for alpha-smooth muscle actin, were found along with transforming growth factor-beta (TGF-beta) in the interstitium of the tumor-free kidney. Regarding the pathogenesis of renal fibrosis and glomerular hypertrophy, this case may provide evidence not only experimentally but also clinically that the renin-angiotensin system plays an important role because angiotensin II is known to induce renal fibrosis associated with increased TGF-beta and the appearance of myofibroblasts.

Differential Effect of Nephrectomy on Renal Expressions of IGF-I and IGFBPs mRNA in Selective Growth Hormone-Deficient Rats

It is known that growth hormone (GH) contributes to glomerulosclerosis and that this probably occurs via insulin-like growth factor-I (IGF-I). However, the manner by which GH and nephrectomy (Nx) alter IGF-binding protein (IGFBP) mRNA in the kidney has not been fully explained. The effects of GH on renal IGF-I and IGFBP-1, 2, 3, 4, and 5 following Nx were examined in spontaneous dwarf rats (SDRs) which have a complete and specific lack of GH among pituitary hormones. In normal Sprague-Dawley rats (SDs), Nx resulted in significant decreases in levels of IGFBP-1 mRNA and IGFBP-5 mRNA to 62.7 ± 4.9 and 56.5 ± 5.0% those of sham-operated kidneys, respectively. Nx did not alter the IGF-I mRNA level in SDs. The levels of IGFBP-2, IGFBP-3, and IGFBP-4 mRNAs were likewise unchanged following nephrectomy. In SDRs, Nx significantly decreased the levels of IGFBP-1, IGFBP-4, and IGFBP-5 mRNA, to 57 ± 2.6, 46 ± 12, and 64 ± 8.1% of sham-operated animals. However, Nx did not alter the levels of IGF-I, IGFBP-2, and IGFBP-3 mRNA. GH injections of nephrectomized SDRs fully normalized the decreased IGFBP-4 mRNA levels, whereas levels of IGFBP-1 and IGFBP-5 mRNA were not reversed. The altered expression of IGFBP-4 mRNA following Nx of SDRs compared to that of SDs appears highly significant since it is known that, unlike SDs, glomerulosclerosis does not fully develop in SDRs following renal ablation. The change in the IGFBP-4 mRNA level might be related to the development of glomerulosclerosis in SDs.

Clinicopathologic study of glomerulonephritis showing double-contour lesions

BackgroundTo elucidate the pathologic significance of double-contour lesions of glomerular capillary walls, we determined how the clinical course of patients with diffuse and global double-contour lesions differs from that of patients with segmentally located double-contour lesions.MethodsIn 26 out of 308 cases of idiopathic glomerulonephritis double contour lesions and serum complement 3 (C3) deposition along capillary walls were histologically examined.ResultsMost patients with diffuse (affecting more than 80% of all glomeruli) and global (affecting more than 75% of each glomerulus) double-contour lesions exhibited a persistent profound proteinuria and a deterioration of renal function (assessed via serum creatinine measurements) during a mean observation period of 66 months, even when a transient remission was observed. The amelioration of hypocomplementemia correlated significantly with an improvement in proteinuria (P<0.05). A follow-up biopsy of patients revealed some cases in which there was: (1) no amelioration of the glomerular lesion despite improvements in renal function, proteinuria and hypocomplementemia; (2) an amelioration of the glomerular lesion paralleling an increasing stability in renal function and a reduction in proteinuria; or (3) deterioration of the glomerular lesion paralleling a decrease in renal function, an increase in proteinuria, and persistent hypocomplementemia.ConclusionsThese findings indicate that the clinical characteristics of mesangiocapillary glomerulonephritis differ from those of other types of mesangial proliferative glomerulonephritis with segmentally-located double-contour lesions. A spot, unrepeated biopsy in cases of atypical mild mesangiocapillary lesions provides insufficient information to reach a diagnosis of mesangiocapillary glomerulonephritis.