Minoru Kashiwagi

Dialysis-Related Hypotension as a Cause of Progressive Frontal Lobe Atrophy in Chronic Hemodialysis Patients: A 3-Year Prospective Study

Background/Aim: Brain atrophy is known to develop more rapidly in hemodialysis (HD) patients than other individuals. The present study was designed to examine the role of HD-related hypotension in brain atrophy in patients on chronic HD. Methods: By using magnetic resonance imaging, whole brain atrophy was assessed by the ventricular-brain ratio (VBR; ventricular area/whole brain area). Frontal brain atrophy was assessed by the frontal atrophy index (FAI; frontal brain area/intracranial frontal space). The number of lacunae was also counted. We studied 32 HD patients without symptomatic neurological abnormalities or diabetes mellitus: male/female ratio 19/13; mean age ± SD 53 ± 10 (range 28–77) years; mean HD duration ± SD 11 ± 6 (range 1–22) years. Magnetic resonance imagings were taken in 1995 and 1998. All dialysis-related hypotension episodes during the same period were identified from the medical records and counted. Results: The VBR ranged from 8.8 to 18.7% in 1995 (12.8 ± 2.2%) and was not different in 1998 (13.1 ± 2.7%). However, the VBR increased by more than 5% in 14 patients, and their HD duration of 13 ± 6 years was significantly longer than that of 18 patients with stable VBR (p < 0.05). The FAI in 1995 was 62.2 ± 4.2% (range 55.8–71.3%) and decreased significantly to 59.7 ± 4.7% (range 50.2–70.9%) in 1998 (p < 0.05). The change in FAI correlated significantly with both the total number of dialysis-related hypotension episodes (r = 0.45, p < 0.05) and the increase in number of lacunae (r = 0.42, p < 0.05). Conclusion: Our results suggest that dialysis-related hypotension plays a role in progressive frontal lobe atrophy in HD patients.

Strong polarization toward Th1 immune response in ANCA-associated glomerulonephritis

AIM Human immune response can be classified into 2 different subsets of T helper cells (Th1 and Th2) based on the pattern of cytokine production. In modern immunology, Th1/Th2 paradigm helps to explain the different inflammatory effector pathways and outcomes in human diseases. The present study was designed to determine the type of immunological response that influences anti-neutrophil cytoplasmic antibody-(ANCA) associated glomerulonephritis (GN) using cytokine analysis of peripheral T cells and diseased kidney tissues. PATIENTS AND METHODS We analyzed peripheral blood Th1/Th2 ratio in 91 patients with primary GN, including 10 cases of ANCA-associated GN. Tissues were immunostained with markers of T cells and macrophages and osteopontin (OPN). Intrarenal expression of IFN-gamma and IL-4 mRNAs was evaluated by reverse transcriptase (RT)-PCR. RESULTS Peripheral Th1/Th2 ratio was significantly higher in ANCA-associated GN (19.4 +/- 9.4, mean +/- SD, n = 10), than those in healthy controls (7.6 +/- 4.1, n = 27), IgA nephropathy (9.6 +/- 5.6, n = 45), membranous nephropathy (7.1 +/- 4.4, n = 13), minimal-change nephrotic syndrome (8.2 +/- 4.5, n = 13) and focal segmental glomerulosclerosis (8.3 +/- 3.9, n = 10) (p < 0.01, each). In 7 of 10 cases of ANCA-associated GN, Th1/Th2 ratio decreased significantly after treatment with corticosteroid from 21.0 +/- 12.0 to 9.0 +/- 6.6 (p < 0.05). Immunohistochemical staining showed numerous infiltrating T cells, macrophages and OPN-positive cells in both glomerular tuft and cellular crescent; OPN-positive cell distribution was similar to that of macrophages. Intrarenal expression of IFN-gamma mRNA was strongly enhanced whereas a weak expression of IL-4 mRNA was observed especially in advanced cases showing tubulointerstitial injury. CONCLUSION Both peripheral and renal immune responses are strongly polarized toward Th1 type immune response in ANCA-associated GN. Peripheral Th1/Th2 ratio may reflect the immune responses in renal injury of ANCA-associated GN.

MCP-1 and RANTES are expressed in renal cortex of rats chronically treated with nitric oxide synthase inhibitor. Involvement in macrophage and monocyte recruitment.

Long-term inhibition of nitric oxide synthase (NOS) in rats is known to cause systemic hypertension and renal parenchymal injury. We have previously reported that activation of intra-renal renin-angiotensin system was a major contributing factor for renal injury in chronically NOS-inhibited rats. Massive interstitial infiltration of monocytes/macrophages (M/M) was characteristically seen in this model. The present study was performed to elucidate the role of chemokines, RANTES and MCP-1, in promoting M/M recruitment into the renal cortex. The number of infiltrating ED-1-positive cells was examined in association with the level of expression of RANTES and MCP1 mRNAs in the renal cortex of rats treated orally for 12 weeks with L-NAME. Compared to controls rats, the number of infiltrating ED-1-positive cells was significantly higher in L-NAME-treated rats. The mRNA expressions of both RANTES and MCP-1 were significantly higher in L-NAME-treated rats than the control. In L-NAME-treated rats, the high number of ED-1-positive cells and increased expression of both RANTES and MCP-1 were suppressed by ACE inhibitor, but not by hydralazine. In contrast, neither ED-1 counts nor RANTES mRNA expression were affected by angiotensin (Ang) II type 1 receptor antagonist. These results suggest the likely involvement of RANTES and MCP-1 in the recruitment of M/M into the renal cortex of rats with chronic NOS inhibition. Furthermore, it is also indicated that Ang II stimulates MCP-1 expression via Ang II type 1 receptor, whereas RANTES expression is mediated via Ang II type 2 receptor.