Study Of Clinico-Pathological Features And Outcomes Of IgA Nephropathy Patients With Mild Proteinuria And/or Hematuria

Background and ObjectiveIgA nephropathy (IgAN) is one of the most common form of primary glomerulonephritis wordwide as well as in China. It accounts for 30%-40% of all biopsy cases. IgAN has various clinical characteristics, ranging from asymptomatic urine abnormalities to nephrotic syndrome, or even decreasing of renal function. Most of the patients with IgAN are asymptomatic and more commonly detected through routine urine analysis. But routine renal biopsy is also not indicated for patients with mild proteinuria and/or hematuria occasionally. Nowdays studies have shown that some patients with mild proteinuria and/or hematuria have relatively severe renal pathologic lesions. Apparently, there is a limited amount of studies conducted on clinico-pathological characteristics and clinical outcomes of IgAN patients with mild proteinuria and/or hematuria. Understanding the correlation between the clinical features and the renal pathologic lesions in these patients are of crucial importance in clinical practices including renal biopsy, diagnosis and treatment of IgAN.MethodsClinicopathological data from 316 biopsy-proven IgAN cases were studied retrospectively. The patients with urinary excretion of protein less than lg/24h and/or hematuria and serum creatinine less than 133μmol/L recorded between January 1993 and October 2009 were included. Clinical data including age, sex, duration of disease,24h urinary protein excretion, hematuria, blood urea nitrogen, serum creatinine(Scr), uric acid, estimated glomerular filtration rate(eGFR), hemoglobin, serum IgA, blood pressure, onset symptoms, and prediposing infections. Renal pathological lesions were evaluated according to Lee's grading and by using Katafuchi semi-quantative standards renal pathologic changes were distinguished as chronic lesions (glomerulosclerosis, adhesion, interstitial fibrosis, tubular atrophy, arterial lesion) or active lesions (mesangial proliferations, crescent formation, interstitial infiltration) to investigate the correlation between the clinical and pathological characteristics and to evaluate risk factors for severe renal pathologic lesions. Results1.27.4% of the overall IgAN cases presented mild proteinuria and/or hematuria. Male to female ratio was 1:1.57, average age of onset was 31.51±10.71 (ages 6-63), 81.6% were patients aged under 45, mean duration of disease was 21.9 months(2days-30years).2. Among 316 cases,72(22.8%) patients with urine abnormalies were found during a regular health examination.132(41.8%) patients were asymptomatic,126 patients (39.9%) reported frequent lumbar pain,144 (45.6%) reported gross hematuria. Upper respiratory tract infection was the most common predisposing infection in patients with gross hematuria, occurs in 62.6% of patients.267 patients (84.5%) had both proteinuria and hematuria,24 (7.6%) had isolated hematuria and 25 patients (7.9%) had isolated proteinuria.The percentages of CKDⅠ,Ⅱ,Ⅲstage were 76.9%,20.9% and 2.2% respectively. About 1/3(98 cases) of all patients had any infections at the time of renal biopsy or within 1 month before renal biopsy. The most common infection was the upper respiratory tract infection, occurs in 71.4% of patients. Also the serum IgA levels and the prevalence of elevation of serum IgA levels in these patients were higher than patients who were not infected at the renal biopsy(P<0.05).Also 8.9% of the patients had hyperuricemia,16.4% hypertension, and 17.2% showed increase in serum IgA,5.7% had hypercholesterolemia,26% had hypertriglyceridemia and 21.8% were overweight. Prevalence of these disorders including hypertension, decreasing of renal function, hypercholesterolemia, hypertriglyceridemia and obesity are increasing along the patient's ages (P<0.05). Male patients had higher prevalence of hypertension and hyperuricemia than the female patients (P<0.05).3. According to Lee's grading system,66 patients were classified as Lee's I grade, 151 cases as Lee'sⅡgrade,91 cases as Lee'sⅢgrade,8 cases as Lee's IV grade, respectively. No patient was identified as Lee's V grade. About one third of the patients were classified as Lee's III grade or more severe. Among all cases,12.7% of the patients showed minor lesion,2.8% focal segmental sclerosis,66.8% focal proliferative glomerulonephritis,17.7% mesangial proliferative glomerulonephritis. 52.8% of patients were reported with varies degree of glomerulosclerosis(GS), crescent formations 20.3%, varies degree of mesangial proliferations 97.8%, adhesion 33.2%, tubular atrophy 22.5%, interstitial fibrosis 16.8%, interstitial inflammation cell infiltration 75.0%, arterial lesions 24.7%,6 cases with severe diffuse necrotizing lesions. It suggests that renal pathological changes in some of IgAN patients was not mild.4. The urinary excretion of protein and Scr were increased with the growing in Lee's grading, while eGFRs were decreased with the growing in Lee's grading (P<0.001). Patients with Lee's III grade and more severe grade had significantly high prevalence of hyperuricemia and decreased levels of hemoglobin than patient's Lee's I and II grade (P<0.05).5. Among patients with more severe degree of chronic pathological lesion were more seen older the patient's age and high urinary excretion of protein, and lower eGFR (P<0.01). Percentage of hypertensive patients also showed significant increase with the deterioration in degree of chronic pathologic lesion. In particular, degree of GS showed positive correlation with the urinary excretion of protein and negative correlation with eGFR. Extent of tubulointertitial fibrosis was positively correlated with the urinary excretion of protein and negative correlation with both eGFR and hemoglobin (P<0.05).Degree of active lesion had significant positive correlation to increase of urinary excretion of protein and hematuria, and significant negative correlation to decrease of the eGFR and hemoglobin (P<0.05), especially mesangial proliferation was associated with increase of proteinuria and decrease of eGFR, interstitial inflammation cell infiltration was significantly related to increase of proteinuria, decrease of eGFR and hemoglobin, extent of crescent formation was related to decrease hemoglobin (P<0.05).In addition to these results, we found that the degree of glomerular lesion were affected more severe with the increase of the proteinuria and the decrease of eGFR (P<0.05), degree of tubular lesion were affected more severe with increase of the proteinuria and the decrease of eGFR and hemoglobin levels (P<0.05), degree of the vascular lesion was more severe with the increase of the blood pressure and the decrease of eGFR (P<0.05).6. As the most commonly observed deposits, IgA+IgM+C3 and IgA+C3 deposits were found in 111 cases (35.1%) and 81 cases (25.6%), respectively. With the increase in intensity of IgA deposition, the excretion of urinary protein and the degree of mesangial proliferation increased significantly (P<0.05).7. Multifactor logistic regression analysis showed that proteinuria, serum creatinine and hemoglobin at the time of renal biopsy were the independent risk factors for severe renal pathologic lesions (Lee's III grade or more severe) with odds ratio of 8.564,1.031 and 0.975, respectively (P<0.01). 8. Patients with both proteinuria and hematuria had noticeable increase in Katafuchi grades, degree of glomerular and active renal lesions(P<0.05), also had tended more severe crescent formation and interstitial inflammation cell infiltration than patients with isolated hematuria. Patients with isolated proteinuria tended to have more severe pathologic lesions than the patients with isolated hematuria. There is no significant difference in degree of renal pathologic lesion between male and female patients. (P>0.05). GS and vascular lesion were more severe in patients aging over 45 (P<0.05). The degree of chronic lesion, including GS, tubulointertitial fibrosis and vascular lesion were noticeably more severe in hypertensive patients than normotensive patients(P<0.05). Patients with hyperuricaemia on the other hand, had more severe mesangial proliferation, interstitial inflammation cell infiltration and tubular atrophy than the patients without hyperuricaemia(P<0.05).9.212 normotensive patients who with urinary protein excretion over 0.15g/24h showed a comparatively severe renal pathologic lesions especially active lesions than patients with proteinuria less than 0.15g/d (P<0.05). Among 243 patients (CKD I stage) who had normal renal function (including both hypertensive and normotensive patients), patients with proteinuria less than 0.5g/24h and hypertension showed a noticeably more severe arterial lesions than patients who had proteinuria ranging from 0.5g to 1.Og a day, but had normal blood pressure(P<0.05).10. We have also analysed the relationship between proteinuria and pathological changes of these IgAN patients by using two different methods to evaluate the amounts urinary protein excretion, such as 24 h proteinuria (g/24h) and body weight adjusted proteinuria (24h proteinuria/body weight, g/kg). Our results present maybe the proteinuria/weight index will be more effective indicator to reflect disease appearance than the amounts of proteinuria. Futher, should be conduct more wide comparative study on this field.ConclusionsOur study shows that IgAN with mild proteinuria and/or hematuria is very common in IgAN. Females were seen slightly frequent than males, average age of onset was 31.57±10.71 years and almost 80% of the patients aged under 45 years. Nearly half of the patients have the history of gross hematuria and upper respiratory tract infection is the most common predisposing infection. Hypertension and mild to moderate decreasing of renal function is not rare. Out of these patients, about 1/2 were classified as Lee's II grade, and 1/3 were Lee'sⅢgrade or more severe. A number of patients had varying degree of GS, crescent formation, tubular atrophy, interstitial fibrosis, vascular lesion, indicating that extent of renal pathologic lesions are not to be ignored in this group of IgAN patients. Clinical characteristics also showed close correlation with the pathological changes. Proteinuria, Scr and hemoglobin at the time of biopsy were found to be the independent risk factors for determining the degree of renal pathological lesions. Thus, we conclude that renal biopsy provides extremely important value for clinical practices including predicting disease prognosis and determining individual therapy for patients of IgAN presenting mild proteinuria and/or hematuria. Background and ObjectiveIgAN is considered to be the progressive renal disease,20%-30% of the IgAN patients developing ESRD 20 years after diagnosis. It is the most common cause of ESRD in China. Many studies have shown that large amount of proteinuria, various degree of decreasing of renal function and pathological changes are the strong predictors of disease prognosis. Generally, IgAN patients who presented with proteinuria less than Ig/d were considered to have good prognosis. However, recent studies showed that a substantial number of this kind of patients experienced deteriorations of renal function or even ESRD.Recent studies has reported IgAN patient's renal survavil rate at 5,10,15,20 years after renal biopsy was 94.1%,82.1%,73.1%and 60.3%. There is a limited number of studies particularly on clinical prognosis of IgAN patients presenting with mild proteinuria less than lg/d.The aim of our study was to investigate the prognosis of IgAN patients with normal renal functions and mild proteinuria and/or hematuria.MethodsSeventy four IgAN cases presenting mild proteinuria and/or hematuria (Scr at the time of renal biopsy<115μmol/L) between January 1993 and February 2009 in our nephrology department were followed up. Clinical outcome criteria included hematuria:remission or persistent; proteinuria:complete remission(24 hour urine protein<0.2g or negative on routine urine analysis), partial remission (24 hour urine protein decrease by more than 50% or±on routine urine analysis), persistent (24 hour urine protein increase by more than 50%) or progressed (24-hour urinary protein increase to>1 g); renal function:stable renal function (a difference of SCr<50%), deterioration (Scr double or Scr>115μmol/L, ESRD, Dialysis, Transplantation). The disease progress is defined as proteiuria exceeding lg/24h or over 50%, new onset of proteinuria, hematuria and hypertension, renal function deterioration. The method of follow up was collected from medical history in outpatient department or by telephone. Results1. Totally,74 patients were follow-up,with 25 males and 49 female; At the time of renal biopsy, patients aged 35.27±9.89 years old. Urine abnormalities as follows: isolated hematuria 8.1%, both proteinuria and hematuria 86.1%, isolated proteinuria 5.4%.13.5% of patients had hypertension, CKD1,2 accounts for 79.7%,20.3% respectively. Lee'sⅠ,Ⅱ,Ⅲ,Ⅳgrade accounted for 16.2%,47.3%,33.8% and 2.7%, respectively; The median follow-up time of 57.46 months (12-180 months).2. Clinical outcomes as follows:Among all 74 patients,68 patients had proteinuria at the time of renal biopsy, and 4 patients were detected with new onset of proteinuria during the follow up. As respect to proteinuria,35 (48.6%) cases experienced complete remission,9 (12.5%) cases were partial remission,18 cases (25.0%) remained at biopsy range, while in 5(6.9%) cases, urinary protein increased over 50%, and in 5 (6.9%) cases, urinary protein exceeded 1 g.70 out of overall 74 patients had hematuria at the time of renal biopsy, and 1 patient showed new onset of hematuria. As respect to hematuria,18 (25.7%) cases experienced remission,53 patients (74.6%) remainded persistent hematuria.In addition,3 patients still had no hematuria.Among 74 patients,2 patients experienced renal function deterioration. Serum creatinine levels at renal biopsy and end points of follow-up had no significant difference (P>0.05).3. Among 74 patients, in 5 (6.7%)cases exceeding lg, in 5(6.7%)cases increased over 50%, in 4 (5.4%) patients reported a new onset of proteinuria, one case (1.35%) presented a new onset of hematuria. Deterioration of renal function was reported in 2 (2.7%) patients and a new onset of hypertension in 5 patients (6.7%). Totally,15 (20.3%) patients had disease progress. Additionally,57(77%) patients had persistent urine abnormalities.4. Renal survival rates are 1,5,10 and 15 years after onset was 100%,98.1%. 93.1% and 93.1% respectively in IgAN patients with mild proteinuria and/or hematuria.5. Among 69 patients followed-up,29 cases had treated ACEIs/ARBs and 33 patients had glucocorticoids with ACEIs/ARBs, and 7 patients had glucocorticoids and/or immnuno-suppressive agents with ACEIs/ARBs. Proteinuria was detected complete remission in 46.4%, and partial remission in 13% of all patients. Hematuria was showed remission in 24.6% of all patients. Amounts of 24h proteinuria was significantly decreased in patients using ACEIs/ARBs (P<0.01) ConclusionsOutcome of IgAN with mild proteinuria and/or hematuria is good in most of the patients. ACEIs/ARBs maybe enough in the treatment of patients with minor lesion. For patients with slight severe pathologic change, further study should be carried out to determine if combination therapy of glucocorticoids with ACEIs/ARBs can be improve the disease outcome.