Akihiro Tsuchimoto

Development and Validation of a Prediction Rule Using the Oxford Classification in IgA Nephropathy

BACKGROUND AND OBJECTIVES The risk assessment for developing ESRD remains limited in patients with IgA nephropathy (IgAN). The aim of this study was to develop and validate a prediction rule for estimating the individual risk of ESRD in patients with IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 698 patients with IgAN diagnosed by renal biopsy at Kyushu University Hospital (derivation cohort) between 1982 and 2010 were retrospectively followed. The Oxford classification was used to evaluate the pathologic lesions. The risk factors for developing ESRD were evaluated using a Cox proportional hazard model with a stepwise backward elimination method. The prediction rule was verified using data from 702 patients diagnosed at Japanese Red Cross Fukuoka Hospital (validation cohort) between 1979 and 2002. RESULTS In the derivation cohort, 73 patients developed ESRD during the median 4.7-year follow-up. The final prediction model included proteinuria (hazard ratio [HR], 1.30; 95% confidence interval [95% CI], 1.16 to 1.45, every 1 g/24 hours), estimated GFR (HR, 0.84; 95% CI, 0.74 to 0.96, every 10 ml/min per 1.73 m(2)), mesangial proliferation (HR, 1.85; 95% CI, 1.10 to 3.11), segmental sclerosis (HR, 3.21; 95% CI, 1.37 to 7.51), and interstitial fibrosis/tubular atrophy (T1: HR, 5.30; 95% CI, 2.63 to 10.7; T2: HR, 20.5; 95% CI, 9.05 to 46.5) as independent risk factors for developing ESRD. To create a prediction rule, the score for each variable was weighted by the regression coefficients calculated using the relevant Cox model. The incidence of ESRD increased linearly with increases in the total risk scores (P for trend <0.001). Furthermore, the prediction rule demonstrated good discrimination (c-statistic=0.89) and calibration (Hosmer-Lemeshow test, P=0.78) in the validation cohort. CONCLUSIONS This study developed and validated a new prediction rule using clinical measures and the Oxford classification for developing ESRD in patients with IgAN.

Pseudorenal failure due to intraperitoneal bladder rupture after blunt trauma: usefulness of examining ascitic fluid sediment

A 42-year-old man noted decreased urine output and visited our emergency department. He said that 3 days previously, he had gotten drunk and fallen down a set of stairs. Blood tests and abdominal contrast-enhanced computed tomography revealed no abnormalities. A serum creatinine level of 5.89 mg/dL led to a diagnosis of acute renal failure and his hospitalization. After admission, his ascitic fluid level gradually increased, suggesting urine leakage into the peritoneal cavity. Microscopic examination of his ascitic fluid sediment revealed the presence of hyaline casts enclosing renal tubular epithelial cells. Cystography demonstrated contrast medium leakage into the peritoneal cavity, which led to a diagnosis of bladder rupture. Examination of ascitic fluid sediment is simple and very useful for diagnosing bladder rupture.

Protocol biopsy findings in living donor kidney transplant patients treated with once-daily or twice-daily tacrolimus formulation

BACKGROUND Once-daily extended-release tacrolimus (Tac-QD) has been shown to have equivalent efficacy and safety to the twice-daily formulation (Tac-BID) in kidney transplant patients. However, detailed comparison of allograft pathology found on a protocol biopsy (PB) in Tac-QD- versus Tac-BID-based regimens has not been described. METHODS We retrospectively investigated 119 de novo living donor kidney transplant patients treated with Tac-QD (n = 90) or Tac-BID (n = 29) and their 3- and 12-month PB results. Other immunosuppressive drugs administered included basiliximab, mycophenolate mofetil, and methylprednisolone. We evaluated daily doses and trough levels of Tac and serum creatinine levels, and compared pathologic findings. RESULTS Daily doses were higher in the Tac-QD group, but trough levels and serum creatinine levels were comparable. On 3- and 12-month PB, the frequency of subclinical rejection was similar between the groups, whereas interstitial fibrosis and tubular atrophy (IF/TA) were less common in the Tac-QD group at 12 months (42.2% vs 20.6%, P = .04). Univariate and multivariate logistic regression analyses revealed that allograft rejection (borderline changes or higher) was associated with IF/TA (odds ratio 4.09, 95% confidence interval 1.76-10.10, P = .001). The Tac-QD-based regimen showed a trend toward the absence of IF/TA but it did not reach statistical significance. Tubular vacuolization and arteriolar hyaline changes were also comparable in the two groups. CONCLUSIONS We found a trend toward milder IF/TA, but no significant differences in kidney allograft pathology in patients who were administered Tac-QD- versus Tac-BID-based regimens at 12 months. The effects of Tac-QD on chronic allograft injury must be studied by longer observation.

Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction

Renal fibrosis is the final common pathway of chronic kidney diseases. Lymphatic vessel (LV) proliferation is found in human renal diseases and other fibrotic diseases, suggesting that lymphangiogenesis is associated with the progression or suppression of kidney diseases. However, the purpose of LV proliferation is not completely understood. We investigated the effect of vascular endothelial growth factor (VEGF)-C on lymphangiogenesis, inflammation, and fibrosis in the mouse kidney using the unilateral ureteral obstruction (UUO) model. In UUO mice, significant proliferation of LVs was accompanied by tubulointerstitial nephritis and fibrosis. We continuously administered recombinant human VEGF-C to UUO model mice using an osmotic pump (UUO+VEGF-C group). Lymphangiogenesis was significantly induced in the UUO+VEGF-C group compared with the vehicle group, despite similar numbers of capillaries in both groups. The number of infiltrating macrophages, and levels of inflammatory cytokines and transforming growth factor-β1 were reduced in the UUO+VEGF-C group compared with the vehicle group. Renal fibrosis was consequently attenuated in the UUO+VEGF-C group. In cultured lymphatic endothelial cells, administration of VEGF-C increased the activity and proliferation of lymphatic endothelial cells (LECs) and expression of adhesion molecules such as vascular cell adhesion molecule-1. These findings suggest that induction of lymphangiogenesis ameliorates inflammation and fibrosis in the renal interstitium. Enhancement of the VEGF-C signaling pathway in LECs may be a therapeutic strategy for renal fibrosis.

A J-shaped association between serum uric acid levels and poor renal survival in female patients with IgA nephropathy

Recently, low serum uric acid (SUA) levels and high SUA levels, have emerged as risk factors for cardiovascular disease, as well as for the incidence of acute kidney injury and chronic kidney disease (CKD). However, the effect of low SUA on the progression of CKD remains unclear. To evaluate the association between SUA and renal prognosis in patients with immunoglobulin A nephropathy (IgAN), one of the most common causes of CKD, we retrospectively followed 1218 patients who were diagnosed with primary IgAN by kidney biopsy between October 1979 and December 2010. Patients were divided into three groups on the basis of SUA level tertiles: low (L group), middle (M group) and high (H group) tertiles (<6.1, 6.1–7.0, and >7.0 mg dl−1, respectively, for men and <4.4, 4.4–5.3, and >5.3 mg dl−1, respectively, for women). The risk factors for developing end-stage renal disease (ESRD) were estimated using a Cox proportional hazards model. After a median follow-up of 5.1 years, 142 patients (11.7%) developed ESRD. The hazard ratio (95% confidence interval) showed a J-shaped trend with the tertiles in both men (1.18 (0.55–2.54), 1.00 (reference), and 1.80 (1.01–3.10) in L, M and H groups, respectively) and women (2.73 (1.10–6.76), 1.00 (reference) and 2.49 (1.16–5.34) in L, M and H groups, respectively). Notably, low SUA was significantly associated with incident ESRD in women. This finding suggests that SUA has a J-shaped association with ESRD in patients with IgAN, especially women.

The Successful Treatment of Calciphylaxis with Sodium Thiosulfate and Hyperbaric Oxygen in a Non-dialyzed Patient with Chronic Kidney Disease.

We present the case of a non-dialyzed patient with chronic kidney disease and biopsy-proven calciphylaxis who presented with painful cutaneous ulcers on both legs. The skin ulcers drastically improved within 6 months after the initiation of hemodialysis, aggressive wound care, the control of a mineral and bone disorder, and the administration of sodium thiosulfate and hyperbaric oxygen therapy. Notably, the patients serum levels of C-reactive protein and calciprotein particles decreased and her serum albumin and fetuin-A levels increased in parallel with the alleviation of her calciphylaxis. This case highlights the importance of applying combined medical treatment to calciphylaxis and suggests the possible involvement of calciprotein particles in the pathogenesis of calciphylaxis.

Temporal serum creatinine increase and exacerbation of tubulointerstitial inflammation during the first two months in resolving polyomavirus BK nephropathy

Polyomavirus BK nephropathy (BKVN) is an important complication in kidney transplantation. After immunosuppressive agents are reduced, some patients experience a temporal increase in serum creatinine (sCr) before viral clearance. The histological characteristics of re‐biopsies were therefore investigated to evaluate the time course of remission.

Early Disappearance of Urinary Decoy Cells in Successfully Treated Polyomavirus BK Nephropathy

BACKGROUND Polyomavirus BK nephropathy (BKVN) is an important infectious complication in kidney transplant patients. Regular screening using polymerase chain reaction for BK virus DNA in plasma and urinary cytology is effective for early diagnosis of BKVN. However, methods of follow-up and therapeutic targets are not well described. METHODS Ten patients with BKVN who received biweekly urinary cytology and repeat biopsies after diagnosis were retrospectively studied. Histological remission of BKVN was determined when biopsy revealed negative SV40 large T-antigen (TAg) staining. Results of urinary cytology and repeat biopsy findings were compared. RESULTS Urinary decoy cells disappeared in 8 of 10 patients 55 ± 25 (range 13-79) days after index biopsies. In those cases, allograft function was preserved and the final serum creatinine level was 2.14 ± 1.19 (0.80-4.55) mg/dL after 962 ± 393 (325-1563) days of follow-up. Two cases with persistent urinary decoy cells shedding lost their graft 195 and 362 days later. Amongst 29 repeat biopsies, there were 13 TAg-positive and 16 negative biopsies. In 12 of 13 TAg-positive biopsies (92%), urinary decoy cells were still positive, whereas at the same time in 15 TAg-negative biopsies, decoy cells had already disappeared (94%). CONCLUSIONS Cytology testing is advantageous because of its cost effectiveness. Clearance of decoy cells from urine was closely related to histological remission of BKVN, and may possibly be a therapeutic target in BKVN.

Subclinical nephrosclerosis is linked to left ventricular hypertrophy independent of classical atherogenic factors

Recently, cardio–renal interactions have been considered to be important and it has been demonstrated that mild renal dysfunction is associated with left ventricular hypertrophy (LVH). However, the correlation between LVH and subclinical renal damage is unclear. We investigated this association by assessing pretransplant biopsies from living kidney donors with normal renal function. We retrospectively categorized 238 living kidney donors into tertiles according to the percentage of global glomerulosclerosis (%GGS) observed in pretransplant biopsies (low, 0–3.45% (n=80); moderate, 3.46–11.76% (n=78); high, ⩾11.77% (n=80)) to analyze trends in their left ventricular mass index (LVMI) measured by echocardiography and baseline factors. LVH was defined as LVMI >110 g m−2 in female and >125 g m−2 in male subjects. We used a logistic regression model to evaluate any correlations between %GGS and LVH. LVMI increased significantly with increasing tertiles of %GGS, as did the prevalence of left ventricular remodeling and LVH. According to multivariate logistic regression analysis, subjects with high %GGS tertiles had a sevenfold greater risk of LVH than did those with low tertiles, even after adjusting for age, sex, systolic blood pressure, history of diabetes mellitus, total serum cholesterol and glomerular filtration rate (GFR) measured by a radioisotopic technique. There is an association between GGS and LVH in subjects with normal renal function. This association is significant after adjustment for age, sex, blood pressure, GFR and other atherogenic factors.

Renal interstitial fibrosis in 0-hour biopsy as a predictor of post-transplant anemia.

Background/Aims: Anemia is common in kidney transplant patients and may cause adverse cardiovascular events. Several studies have reported some predictors of post-transplant anemia. However, associations between the pathological findings in the 0-hour biopsy and anemia have not been well described. Methods: 258 consecutive kidney transplant patients were enrolled in this retrospective study. The patients were divided into two groups, according to the presence or absence of interstitial fibrosis and tubular atrophy (IF/TA) in the 0-hour biopsy: the IF/TA group with fibrotic area ≥5% (n = 131) and the non-IF/TA group with fibrotic area <5% (n = 127). We examined the association between IF/TA and post-transplant anemia. Results: Serial changes in hemoglobin levels in the IF/TA group were lower than in the non-IF/TA group (p = 0.007). Anemia at 12 months was found in 53% of the IF/TA group, and 35% of the non-IF/TA group (p = 0.004). Even after adjustment for several confounders including graft function, the presence of IF/TA was independently associated with post-transplant anemia at 12 months (odds ratio 1.88, 95% confidence interval 1.06-3.36, p = 0.031). This association was still significant in a subgroup with normal graft function. Conclusions: IF/TA in the 0-hour biopsy specimen is one of the predictors for post-transplant anemia and can be used to identify patients who need the treatment with erythropoiesis-stimulating agents.