Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers

BACKGROUND: Inflammation and oxidative stress have been incriminated in the pathogenesis of IgA nephropathy (IgAN). The aim of the present study was to assess whether markers reflecting these pathophysiologic processes, namely C-reactive protein (CRP) and advanced oxidation protein products (AOPP), would allow-in conjunction with clinical and histopathologic parameters-to predict disease progression. METHODS: Between 1994 and 1997, 120 adult patients with biopsy-proven IgAN were included in a prospective cohort study, and followed until the end of 2002 or start of dialysis. In every patient, we determined plasma levels of CRP and AOPP. These parameters were included, together with clinical data, in a multivariate Cox proportional hazard regression analysis, with halving of baseline creatinine clearance as the primary renal end point. RESULTS: A total of 51 patients reached the renal end point, including 30 who had to start dialysis. With multivariate analysis, the most potent independent risk factors of poor renal outcome were proteinuria > or =1 g/day [proportional hazard risk (HR) = 23.7, P= 0.0001], hypertension (HR = 8.13, P= 0.008), and AOPP plasma level (HR = 1.09 per 10 micromol/L, P= 0.042), whereas angiotensin II inhibitors were protective (HR = 0.19, P= 0.001). CONCLUSION: Our data support the role of oxidative stress in the pathogenesis of IgAN and suggest that patients with proteinuria > or =1 g/day should be eligible for early implemented antioxidant and/or anti-inflammatory therapeutic strategies, with AOPP plasma level as a surrogate marker to evaluate their effects.     

Uric acid correlates with the severity of histopathological parameters in IgA nephropathy.

BACKGROUND: Immunoglobulin-A nephropathy (IgAN) is the most common chronic glomerulonephritis worldwide. Many clinical and histopathological risk factors for progression have been found previously. Recently, metabolic risk factors, such as hyperuricaemia and hypertriglyceridaemia, also have been associated with the progression of IgAN. METHODS: In the present study we correlated clinical and metabolic risk factors with histopathological parameters in 202 patients with IgAN. Morphological changes in glomerular, tubulointerstitial and vascular tissue were semiquantitatively graded into three classes. Mesangial proliferation activity and the amount of inflammatory cells were also evaluated by immunohistochemical staining of Ki-67 (MIB-1), CD45 (LCA) and CD68 stainings. Serum uric acid, triglycerides and cholesterol, urine protein excretion (UPE), blood pressure and body mass index (BMI) were measured. Smoking habits and occurrence of diabetes mellitus also were evaluated. The independent role of serum uric acid in the development of renal morphological changes was evaluated in multivariate analysis. RESULTS: Serum uric acid and UPE level correlated with several histological parameters. Uric acid level showed the strongest correlation with tubulointerstitial changes and UPE with glomerulosclerosis. The level of serum triglycerides correlated with interstitial fibrosis and hyaline arteriolosclerosis. Blood pressure correlated with hyaline arteriolosclerosis, glomerulosclerosis and tubulointerstitial changes. BMI and diabetes mellitus correlated with both tubulointerstitial and vascular changes. We found no significant correlations between histopathological parameters and smoking habits or serum cholesterol level. Serum uric acid had independent associations with the presence of tubular atrophy and interstitial fibrosis and inflammation. CONCLUSIONS: We conclude that many metabolic factors are univariately associated with renal morphological findings in IgAN. These same factors are central in the metabolic or insulin resistance syndrome and may have a pathogenetic role in the progression of IgAN. Serum uric acid may have an independent role in development of tubulointerstitial lesions as well as being associated with inflammation in renal tissue of patients with IgAN.     

Microvascular disease and the progression of IgA nephropathy

In order to examine the role of microvascular disease in the evolution of IgA nephropathy (IgAN), the interrelationships among vascular sclerosis, glomerular sclerosis, age, and hypertension were determined by morphometric analysis of renal biopsies in 71 patients with IgAN; 63 age- and sex-matched individuals with minimal change nephrotic syndrome (MCNS) served as normal controls. The following parameters in glomeruli and in vessels with an outer diameter of 60 microns or less were analyzed by multiple regression analysis: (1) percentage of glomeruli with segmental and/or global sclerosis; (2) percentage of vessel area in renal cortical tissue measured by the point-counting method; (3) index of hyaline change estimated as the percentage of the number of arteries showing hyaline change; (4) index of vessel wall thickness determined by the ratio of mural thickness to outer diameter of arteries; (5) number of vascular cross sections counted per 6.25 microns2. The results of the multiple regression analysis demonstrate that glomerular and vascular sclerosis are interrelated and that hypertension and vessel area are almost equally important as predictors of glomerular sclerosis. Vessel area proved to be an early marker of vasculopathy, as its values in IgAN, even in the absence of hypertension and/or glomerular sclerosis, exceeded those in age- and sex-matched controls (with MCNS). These data, obtained by the use of quantitative methods, establish a role for vessel disease and hypertension in the progression of IgAN.     

Hyperuricemia aggravates the progression of IgA nephropathy

International Urology and Nephrology - The relationship between hyperuricemia and IgA nephropathy (IgAN) was evaluated systematically in this research. The Preferred Reporting Items for Systematic...     

IgA nephropathy: prognostic significance of proteinuria and histological alterations

A retrospective study of 166 patients with IgA nephropathy was undertaken to clarify possible correlations between clinical and histological features, and the severity and prognosis of the disease. At the time of biopsy, impaired renal function, with creatinine clearance (Ccr) below 90 ml/min was found in 61 cases. At the final examination, after a mean follow-up period of 34 months, 82 patients had impaired renal function, 12 of these patients went into terminal renal failure requiring hemodialysis treatment. The presence of proteinuria of more than 1.0 g/day was closely correlated with impairment of renal function both at the time of biopsy and at the final observation. An unfavorable outcome was also anticipated in the presence of hypertension. In contrast, microhematuria, macrohematuria or high serum IgA levels did not appear to be related to the outcome. Histologically, sclerotic lesions such as mesangial or global sclerosis, interstitial fibrosis and tubular atrophy, and some active changes such as mesangial hypercellularity and tuft adhesion were more frequent and severe in patients with impaired renal function. Impressive localization of IgA and C3 in the mesangium as well as in capillary loops was observed more often in these patients. These results clearly indicate that IgA nephropathy may follow a slowly progressive course in about half of the patients, and that marked proteinuria and severe histological changes appear to correlate closely with an unfavorable course.     

IgA nephropathy: markers of progression and clues to pathogenesis

The unpredictable progression of IgA nephropathy hinders its treatment. The correlation of renal dysfunction with the immunophenotype of leukocytic infiltrates revealed interstitial CD20(+) cells and tubular NKG7(+)(GMP-17(+))/CD8(+) intraepithelial cells as predictive markers of progression in early-phase IgA nephropathy. This suggests that adaptive and innate immune responses mediate progression.     

Lithium-induced nephropathy: Rate of progression and prognostic factors

BACKGROUND: Long-term lithium administration in humans may lead to chronic tubulointerstitial nephritis, which develops very slowly. Its progression to end-stage renal disease (ESRD) has been rarely reported. The aim of this study is to document the rate of progression of lithium-induced nephropathy and its prognostic factors, and to provide an estimation of the percentage of lithium-induced ESRD in France. METHODS: Two groups have been studied: 54 patients with lithium-induced renal failure, nine of whom underwent renal biopsy; and 20 patients who were referred for systematic renal biopsy, 14 of whom were subsequently followed up. In addition, a survey of lithium-induced ESRD was conducted in French dialysis centers. RESULTS: The mean annual loss of creatinine clearance in patients with lithium-induced nephropathy was 2.29 mL/min. Among 74 patients, 12 reached ESRD at a mean age of 65 years. Creatinine clearance at referral and at last follow-up was inversely related to the duration of lithium therapy in both univariate and multivariate analyses adjusting for age, gender, hypertension, and proteinuria. The degree of interstitial fibrosis on renal biopsy was also related to the lithium duration and cumulative dose. It was predictive of the final creatinine clearance. About 35% of the patients tested had moderate hypercalcemia, due to hyperparathyroidism. The prevalence of lithium-related ESRD in France was estimated as two per 1000 dialysis patients. The average latency between onset of lithium therapy and ESRD was 20 years. CONCLUSION: Lithium-induced chronic renal disease is slowly progressive. Its rate of progression is related to the duration of lithium administration. Lithium-related ESRD represents 0.22% of all causes of ESRD in France. Regular monitoring of estimated creatinine clearance is mandatory in long-term lithium-treated patients.     

Role of proteinuria reduction in the progression of IgA nephropathy

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function. AIM: to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression. METHODS: multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinine < or = 1.5 mg/ dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-g i.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months). RESULTS: Proteinuria significantly decreased in the treated patients (from 2.0+/-0.60 g/24 h at baseline to 1.0+/-0.68 g/24 h at six months) and remained stable till the 6th year (0.67+/-0.5 g/24 h), it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end-point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow-up. CONCLUSIONS: Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.     

Clinicopathological and prognostic analysis of IgA nephropathy patients with anemia

Objective To analyze the clinicopathological features of IgA nephropathy (IgAN) patients with anemia and the influencing factors of prognosis. Methods The clinical and pathological data of patients diagnosed with primary IgAN at the First Affiliated Hospital of Fujian Medical University from January 1, 2006 to December 31, 2016 were retrospectively analyzed. The patients were divided into anemia group and non-anemia group according to whether the patient was anemia or not. The clinical and pathological data of the two groups were collected. All of them were followed up from the date of renal biopsy to January 1, 2018. Survival curves of the two groups were drawn by Kaplan-Meier method, and compared by Log-rank test. Multivariate Cox proportional hazards regression model was adopted to explore the influencing factors of prognosis in IgAN patients. Results A total of 231 subjects were enrolled, including 122 males (52.8%), and the male-female ratio was 1.12∶1. Their age was (34.8±10.1) years (15-68 years). There were 70 patients (30.3%) in anemia group, 161 cases (69.7%) in non-anemic group. Compared with non-anemia group, anemia group had higher proportion of females, lower serum albumin, higher proportion of tubular atrophy/interstitial fibrosis (T1/2), endothelial cell proliferation (E1) and crescent formation (C1/2), which were statistically significant (all P＜0.05). The patients had a median follow-up time as 6.3 years (0.3-12.9 years). Survival analysis showed that patients in anemia group had lower cumulative renal survival rate than that in non-anemia group ( χ2=15.234, P＜0.001). Multivariate Cox hazards regression analysis revealed that anemia (HR=3.820, 95%CI 1.674-8.719, P=0.001), tubular atrophy/interstitial fibrosis (T1/2) (HR=3.770, 95%CI 1.026-13.852, P=0.046), glomerular segmental sclerosis/adhesion (S1) (HR=4.211, 95%CI 1.139-15.576, P=0.031), hypertension (HR=2.988, 95%CI 1.276-6.999, P=0.012), increased 24 h urinary protein (HR=1.103, 95%CI 1.046-1.163, P＜0.001) and estimated glomerular filtration (eGFR)＜60 ml?min-1?(1.73 m2)-1 (HR=3.725, 95%CI 1.639-8.462, P=0.002) were the independent risk factors for poor renal prognosis in patients with IgAN. Conclusions The clinicopathological features of IgAN patients with anemia are relatively serious, and the renal cumulative survival rate is lower. Anemia, tubular atrophy/interstitial fibrosis (T1/2), glomerular segmental sclerosis/adhesion (S1), hypertension, increased urinary protein and eGFR＜60 ml?min-1?(1.73 m2)-1 are the independent risk factors for poor renal prognosis in patients with IgAN.     

The influence of familial factors on the progression of IgA nephropathy

Background. Vascular risk factors in first degree relatives of patients with insulin dependant diabetes mellitus are known to increase the risk of that patient developing diabetic nephropathy. We explored the influence of vascular risk factors in first degree relatives on patients with stable (serum creatinine <150 &mgr;mol/l for >5 years) and progressive (serum creatinine >200 &mgr;mol/l, and >150% serum creatinine at presentation, after minimum follow-up at 2 years) IgA nephropathy (IgAN). Methods. We compared sodium-lithium countertransport activity (SLC Vmax), plasma lipoprotein(a) and von Willebrand factor (vWf) concentrations, incidence of vascular disease, and incidence of hypertension in 37 first degree relatives of 23 patients with stable IgAN and 33 first degree relatives of 17 patients with progressive IgAN. The two groups of relatives were comparable with respect to other risk factors: age, smoking, blood pressure, and plasma glucose, creatinine, cholesterol and triglyceride concentrations. Results. SLC Vmax was higher in relatives of stable patients (mean 0.37 mmol/h/l RBC [S.D. 0.18] vs 0.30 [S.D. 0.09]; P=0.034 two-sample t-test). There was no difference between the relatives of stable and progressive patients in plasma lipoprotein(a) concentration (median 11.5 mg/l vs 13.0: P=0.45; 95% C.I. -12 to 3; Mann-Whitney test), plasma vWf concentration (149.4 IU/dl [S.D 55.6] vs. 163.2 IU/dl [S.D. 57.3]; P=0.31 two-sample t-test), or incidence of hypertension (13/37 [35.1%] vs 10/33 [30.3%]; &khgr;²=0.185; P=0.667). Relatives of patients with progressive IgAN had a slightly higher incidence of vascular disease (10/33 [30.3%] vs 8/37 [21.6%]; &khgr;²=0.688; P=0.407). Conclusions. Familial vascular risk may increase the likelihood of progressive renal failure in patients with IgAN but the influence is likely to be small and unrelated to the factors we measured. SLC Vmax was significantly higher in relatives of patients with stable disease which contrasts with data from other studies and is unexplained.     

Reproducibility for pathological prognostic parameters of the Oxford classification of IgA nephropathy: a Japanese cohort study of the Ministry of Health,Labor and Welfare

Clinical and Experimental Nephrology - The Oxford classification of IgA nephropathy (IgAN) was proposed by international working group in 2009. Interobserver reproducibility of each pathological...     

New parameters to monitor the progression of diabetic nephropathy

The possible differential elimination of the anionic IgG4 and of the other cationic IgG molecules whose pH differs but whose other characteristics are similar, has been hypothesized as a possibly useful parameter in monitoring preclinical diabetic nephropathy. An enzyme-linked immunosorbent assay method has been developed, based on a sandwich technique with subclass-specific antiimmunoglobulin monoclonal antibodies, which detects about 2 ng/mL IgG4. A sensitive radioimmunoassay method has been used to detect IgG. Normoalbuminuric, microalbuminuric, and macroalbuminuric patients, together with normal control subjects, were included in the cross-sectional study. Whereas IgG levels were elevated, as expected, in macroalbuminuric patients, it was interesting to note that IgG4, but not total IgG, levels were elevated in microalbuminuric patients. The IgG4/IgG ratio was increased almost to the same extent in microalbuminuric and macroalbuminuric patients. These findings are strongly in favor of the selective elimination of the acid medium-sized protein, IgG4, in incipient diabetic nephropathy. The measurement of immunoglobulin subclasses in the urine appears to be a promising parameter to characterize and subgroup diabetic patients with preclinical diabetic nephropathy.     

A histopathological study on the prognosis of childhood IgA nephropathy and glomerular basement membrane lesions

Seventy-three patients with IgA nephropathy (IgAGN), under the age of 15 years at the time of the discovery of the disease, were investigated with respect to glomerular basement membrane (GBM) lesions. Irregular attenuation or widening of GBM, especially on the epithelial side, was observed in 28 cases (38%). These two changes are referred to aslysis of GBM and were considered to be the primary and specific changes among the GBM lesions in IgAGN. GBM thickening with layering of lamina densa was found in 37 of 73 cases (51%), but this change has been observed in other types of glomerular diseases. GBM lesions similar to those seen in IgAGN were also observed in Henoch-Schönlein purpura nephritis (HSPN) and poststreptococcal acute glomerulonephritis (PSAGN). Lysis of GBM was observed only in IgAGN, HSPN and PSAGN. Subepithelial and intramembranous deposits appeared to have an important role in the development of these GBM lesions. The presence of GBM lesions was correlated with a high incidence of cellular crescents but not with other clinical or light microscopic findings. The presence of these GBM lesions in IgAGN does not have a significant effect on the prognosis, at least in childhood. The affected GBM seemed to recover without leaving any significant residual damage in most cases. In the long-term prognosis of the disease non-immunological factors, such as ageing or hypertension, seem to be important.     

Role of cytokines in the progression of renal damage in IgA nephropathy

Summary: IgA nephropathy, or Berger's disease (IgAN), is a worldwide disease which is characterized by a slowly progressive loss of renal function accompanied by decreasing kidney size with the development of glomerulosclerosis and interstitial fibrosis. Immunologic and non-immunologic factors are implicated in the progression of renal damage, since they are potent inducers in stimulating glomerular, tubular and interstitial cells and non-resident cells to produce free oxygen radicals, cytokines, growth factors, chemokines, etc. Recent data from our laboratory and other groups, synthesized in this review, have demonstrated the remarkable involvement of these humoral factors in the progression of renal damage in IgAN patients. Therefore, prospective therapeutic approaches have been suggested in blocking the inflammatory mediators during the pathophysiologic sequelae of immune and non-immune mechanisms which may intervene in the outcome of the disease.     

Hypertriglyceridaemia and hyperuricaemia are risk factors for progression of IgA nephropathy.

BACKGROUND: The prognosis of IgA nephropathy (IgAN) is variable and about 10-20% of patients progress to end-stage renal disease (ESRD) in 10 years. Hypertension, proteinuria and renal insufficiency at the time of diagnosis are risk factors associated with poor prognosis. Lipid abnormalities may have a role in the progression of glomerulonephritides, and glomerulosclerosis and atherosclerosis may have similar pathophysiological mechanisms. We therefore evaluated factors associated with cardiovascular diseases, especially hypercholesterolaemia, hypertriglyceridaemia, and hyperuricaemia, as predictors of the progression of IgAN. METHODS: A total of 223 patients with IgAN (141 men, 82 women; median age 41 years, range 8-78 years) were studied. The following parameters were recorded at the time of renal biopsy: presence of hypertension or diabetes, smoking habits, body mass index (BMI), serum creatinine, total and HDL-cholesterol, triglycerides, and urate and 24-h urinary protein excretion. The patients were followed up for 0.2-17 years (median 10 years) with respect to progression of renal disease defined as elevation of serum creatinine above 125 micromol/l in men or 105 micromol/l in women, and over 20% elevation from baseline. RESULTS: Forty-one patients (18%) showed progression. Hypertriglyceridaemia and hyperuricaemia were significantly more common at the time of renal biopsy in patients with progressive than in those with stable disease. In patients with normal renal function at the time of diagnosis initial hypertriglyceridaemia, hyperuricaemia, hypertension and proteinuria were independent risk factors for progression of IgAN in the Cox regression hazard model. CONCLUSIONS: Our results show that hypertriglyceridaemia and hyperuricaemia at the time of diagnosis are important, previously underestimated predictors of poor outcome in IgAN, although causality between these factors and progression cannot be inferred from the present study.