Lee's Grade Research Articles

Serum immunoglobulin A/C3 ratio predicts progression of immunoglobulin A nephropathy

The serum immunoglobulin A (IgA)/C3 ratio has been shown to be a good predictor of histological lesions and prognosis for patients with IgA nephropathy (IgAN) in Japanese. But its validity in the Chinese population is unclear. We sought to explore the long-term outcomes of IgAN, its clinical and histopathological predictors in Chinese patients. In particular, the role of serum IgA/C3 ratio in the course of IgAN was addressed. A total of 217 biopsy-diagnosed IgAN patients were recruited into this prospective cohort with a mean follow-up of 36 months (25-75th percentile, 27-48). Sociodemographics, serum IgA/C3 level, other clinical examinations and Lee's histological grade were measured. The patients with a decline of estimated glomerular filtration rate (eGFR) > 50% or developing end-stage renal disease (ESRD) were defined as progression. A total of 21 patients was found to progress (9.7%). In multivariate analysis, renal end point of IgAN was significantly predicted by proteinuria ≥1 g/day (relative risk (RR) = 2.65, 95% confidence interval (CI) 1.01-7.68), hypertension (RR = 3.15, 95% CI 1.07-9.29), higher Lee's histological grade (RR = 4.67, 95% CI 1.43-15.25) and serum IgA/C3 ratio ≥ 3.32 (RR = 4.31, 95% CI 1.33-13.96). A proportion of patients with IgAN developed end stage renal disease in a Chinese group. In addition to some traditional risk factors, we also confirmed that IgA/C3 ratio is a useful predictor of poor outcomes of IgAN in Chinese patients.

Potential of renal pathology on refining syndrome typing of Chinese medicine in IgA nephropathy

To investigate the potential of renal pathological index as a differential diagnosis factor for Chinese medicine (CM) syndromes typing in IgA nephropathy (IgAN). A total of 1,016 patients with IgAN was recruited from November 2001 to November 2004. All the signs and symptoms including picture of the tongue and pulse tracings were collected. All patients were typed according to the CM syndrome typing scheme for chronic primary glomerulopathy. The severity of glomerulus and tubulointerstitial lesions (mild, moderate-severe) were evaluated using lee's grading system and the Katafuchi score system. The syndrome types transform in turn by deficiency of both the Spleen (Pi) and Lung (Fei) qi, deficiency of both qi and yin, deficiency of Liver (Gan) and Kidney (Shen) yin and deficiency of Spleen-Kidney (Shen) yang, with the aggravation of pathogenetic condition and that the manifestation of deficiency of qi clinically showed proliferative lesion of glomerular mesangium, while the glomerular sclerosis pathologically showed the manifestation of yin deficiency. Renal pathological findings may be a candidate of objective factors to refine CM syndrome typing process.

Accelerated senescence of renal tubular epithelial cells is associated with disease progression of patients with immunoglobulin A (IgA) nephropathy

The aim of this study is to determine the potential correlation between the accelerated senescence of renal tubular epithelial cells (RTECs) and the disease progression of patients with immunoglobulin A nephropathy (IgAN). A total of 108 IgAN patients with different Lee's pathologic grades were enrolled. Additionally, 18 patients with renal resection were recruited as controls. Cellular senescence was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining and an immunohistochemical analysis of p21 and p16 protein expression. The expression of type III collagen (Col III) and fibronectin (FN) in renal interstitium and the levels of serum total and low-density lipoprotein (LDL) cholesterol, serum creatinine concentration (SCr), and 24-h urinary protein excretion were evaluated also. SA-β-gal staining and the expression of p16 and p21 were increased significantly in renal biopsy specimens obtained from grades I-II IgAN patients compared with controls (P < 0.05). The expression of these senescence-associated markers increased gradually with disease progression and correlated with the renal morphologic changes and the expression of Col III and FN in renal interstitium in IgAN patients. A correlation analysis showed that the expressions of p16, p21, and SA-β-gal staining were associated significantly with blood pressure and renal function (P < 0.05), but not with patient age, body mass index (BMI), LDL cholesterol level, or 24-h urinary protein value (P> 0.05). Our results indicated that the RTECs in IgAN patients exhibited features of accelerated senescence, which were unrelated to mechanisms associated with normal aging. Cellular senescence was associated closely with IgAN disease progression, which suggested the accelerated senescence of RTECs may contribute to this progression.

Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure

To estimate whether the association between nevirapine (NVP) and hepatotoxicity differs according to pregnancy status in HIV-infected women. The present analysis included HIV-infected pregnant women on antiretroviral therapy (ART) from two multicenter, prospective cohorts - the Women and Infants Transmission Study and the International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1025 - and HIV-infected nonpregnant women from one multicenter, prospective cohort - the Women's Interagency HIV Study. Using multivariate Cox proportional hazards regression, the interaction between NVP and pregnancy status in terms of hepatotoxicity was investigated. NVP use was dichotomized as use or no use and was further categorized according to ART exposure history. We investigated two outcomes: any liver enzyme elevation (LEE; grade 1-4) and severe LEE (grade 3-4). Data on 2050 HIV-infected women taking ART were included: 1229 (60.0%) pregnant and 821 (40.0%) nonpregnant. Among the pregnant women, 174 (14.2%) developed any LEE and 15 (1.2%) developed severe LEE as compared with 75 (9.1%) and 5 (0.6%), respectively, of the nonpregnant women. In multivariate adjusted models, NVP was not significantly associated with risk of LEE, regardless of pregnancy status; however, pregnancy was associated with an increased risk of any LEE (relative risk 4.7, confidence interval = 3.4-6.5) and severe LEE (relative risk 3.8, confidence interval = 1.3-11.1). The association of pregnancy and LEE was seen, regardless of prior ART and NVP exposure history. No significant association between NVP and LEE was observed, regardless of pregnancy status, but pregnancy was significantly associated with increased hepatotoxocity in HIV-infected women.

Focal segmental glomerulosclerosis in mild IgA nephropathy: a clinical-pathologic study

The significance of focal segmental glomerulosclerosis (FSGS) in mild IgA nephropathy is uncertain. All consecutive renal biopsies performed between 1996 and 2005 in adults with a diagnosis of mild IgA nephropathy (Lee Grade 1 or 2) at St Paul's Hospital, Vancouver, Canada, were reviewed. Seventy-five patients were included, 26 (35%) with IgA nephropathy and FSGS (FSGS+ group) and 49 (65%) with IgA nephropathy without FSGS (FSGS- group). The mean follow-up was 3 years. At the time of renal biopsy the FSGS+ group had a lower eGFR (60 versus 73 mL/min, P = 0.02), lower serum albumin (38 versus 41 g/L, P = 0.02), higher mean arterial pressure (103 versus 97 mmHg, P = 0.03) and greater protein excretion (3.0 versus 1.3 g/day, P < 0.01) than the FSGS- group. On histology, the FSGS+ group had a higher percentage of obsolete glomeruli (23.4% versus 12.7%, P < 0.01), and 31% of FSGS+ biopsies had >or=25% tubular atrophy/interstitial fibrosis while this was not observed in the FSGS- group (P < 0.01). The primary outcome measure, DeltaGFR, was -2.56 mL/ min/year in the FSGS+ group and +1.14 mL/min/year in the FSGS- group, difference: 3.70 mL/min/year (P = 0.03) (univariate). In the multivariate model, the FSGS+ group declined at 0.19 mL/min/year (-14.16, 13.78) and the FSGS- group improved at 2.85 mL/min/year (-11.64, 17.34), difference 3.04 mL/min/year, P = 0.18. Our study suggests that the focal segmental glomerulosclerosis lesion and associated clinical and pathologic findings in patients with mild IgA nephropathy are associated with a worse renal outcome.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy

Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-β- d-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.

Chronic Graft-Versus-Host Disease after Allogenaic Bone Marrow Transplantation in Japan: Identification of Risk Factors and Prognostication.

Objective: Chronic graft-versus-host disease (cGVHD) is an important complication of allogeneic hematopoietic stem cell transplantation (HSCT) involving various organs such as skin, eyes, mouth, liver, lung, and gastrointestinal tract, which is associated with major disability and diminished quality of life. There have been several studies to explore risk and prognostic factors in Western countries. However, because the genetic homogeneity is different among the ethnics, such models are not assured to be applicable for Japanese patients. To identify the incidence and risk factors of cGVHD, and prognostic factors for patients who developed cGVHD, we analyzed a series of patients.Methods: The incidence and prognostic factors for cGVHD were evaluated for 255 patients who survived more than 100 days after bone marrow transplantation (BMT) in Nagoya BMT Group.Results: One hundred and nineteen (47%) developed cGVHD. Prior acute GVHD (grade 2–4) and use of unrelated donor were significantly associated with the onset of cGVHD. Systemic immunosuppressive therapies were administered to 86 patients (78%), 42 (38%) of whom required secondary therapies. Presence of cGVHD did not have an impact on mortality (hazard ratio [HR]=0.89; 95% confidence interval [CI], 0.59–1.3). Proposed prognostic models from Western countries, Akpek's score and Lee's grading system did not successfully classify our patients. Three factors at diagnosis were associated with cGVHD-specific survival; i.e. presence of infection (HR=4.1; 95%CI, 1.6–10.3), ongoing use of corticosteroid at the onset of cGVHD (HR=3.9; 95%CI, 1.7–9.1), and a Karnofsky performance score<80 (HR=4.7; 95%CI, 2.0–11.3). The probability of cGVHD-specific survival at 4 years was 79% (95%CI, 70–86%).Conclusion: The severity and death rate of Japanese patients with cGVHD was lower than those for populations in Western countries, which might be the result of greater genetic homogeneity of Japanese ethnics. For prognostication, a different model was needed to identify high-risk patients.

Histological grading of IgA nephropathy predicting renal outcome: revisiting H. S. Lee's glomerular grading system

The glomerular grading system is useful to compare biopsy specimens and to predict the natural course of disease in IgA nephropathy (IgAN), although no grading system can be perfect. H. S. Lee's grading system for IgAN was refined as follows: grade I, normal or focal mesangial cell proliferation; grade II, diffuse mesangial cell proliferation, or <25% of glomeruli with crescent (Cr)/segmental sclerosis (SS)/global sclerosis (GS); grade III, 25-49% of glomeruli with Cr/SS/GS; grade IV, 50-75% of glomeruli with Cr/SS/GS; grade V, >75% of glomeruli with Cr/SS/GS. This refined H. S. Lee grading system was then tested for clinical relevance on 187 patients with IgAN followed up for an average of 6.5 years (minimum, 3 years). In the survival analysis, a modified primary end-point (progressive renal disease) was used. The glomerular grades were significantly related to hypertension, serum creatinine levels and the amounts of proteinuria at time of biopsy. By univariate analysis, glomerular grades, hypertension, renal insufficiency and significant proteinuria (> or =1 g/day) were significantly associated with progressive renal disease. By multivariate analysis using the Cox regression model, glomerular grades, renal insufficiency and significant proteinuria were independent prognostic factors for progressive renal disease. At the end of follow-up, glomerular grades were significantly related to serum creatinine levels, amounts of proteinuria, hypertension and progressive renal disease. These findings indicate that the refined H. S. Lee grading system for IgAN is useful in assessing the patients' clinical outcome and is sufficiently simple and easy to reproduce as to be universally applicable in prognostic work.

Imbalances in serum proinflammatory cytokines and their soluble receptors: a putative role in the progression of idiopathic IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis, and a potential target of immunoglobulin therapy?

Following recent experimental data suggesting an aggravating effect of circulating proinflammatory cytokines on the histological lesions of IgAN, we studied changes in serum proinflammatory cytokines and their soluble receptors and antagonists in patients treated with polyvalent immunoglobulins (15 with severe nephropathy who had indicators of poor prognosis: heavy proteinuria, hypertension, altered renal function and Lee's histological grade III or IV; and 14 with moderate forms of IgAN who had permanent albuminuria > 300 mg/day and < 2000 mg/day, Lee's histological grade II and a glomerular filtration rate > 70 ml/min) in comparison with healthy controls (n = 20) and patients with non-IgA nephritides (n = 50). These were measured by means of specific immunometric assays before and after 9 months of immunoglobulin therapy. Total tumour necrosis factor (TNF) serum and IL-6 levels were elevated in IgAN patients before therapy, relative to controls, and normalized after immunoglobulin therapy. Levels of soluble TNF receptor of type I (sR55) and type II (sR75) increased on immunoglobulin therapy. TNF index alpha-55,75 used to assess biologically available TNF-alpha (ratio of total TNF-alpha divided by levels of soluble TNF receptors sR55 and sR75) was elevated before therapy and was below healthy control values after 9 months of immunoglobulin administration. Levels of serum IL-1 receptor antagonist were low prior to immunoglobulin administration in patients with severe forms of IgAN, and normalized on therapy. Serum interferon-gamma was unmodified. The histological activity index correlated with serum total TNF-alpha, TNF index alpha-55,75 and serum IL-6 levels, whereas proteinuria correlated with serum total TNF-alpha and TNF index alpha-55,75 but not with serum IL-6. These data suggest that the overproduction of proinflammatory cytokine is unbalanced by their natural antagonists in IgAN and Henoch-Schönlein syndrome. This process may play a role in the progression of the disease and be one of the targets of immunoglobulin therapy.