Corticosteroid Treatment Influences TA-Proteinuria and Renal Survival in IgA Nephropathy.

The clinical course of IgA nephropathy (IgAN) and its outcome are extremely variable. Proteinuria at baseline has been considered one of the most important risk factors. More recently, mean proteinuria of follow-up (time-average proteinuria: TAp) was described as a stronger marker of renal survival, suggesting to consider it as a marker of disease activity and response to treatment. We evaluated predictors of renal survival in IgAN patients with different degrees of renal dysfunction and histological lesions, focusing on the role of the therapy in influencing TAp. We performed a retrospective analysis of three prospective, randomized, clinical trials enrolling 325 IgAN patients from 1989 to 2005. Patients were divided into 5 categories according to TAp. The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16.6%) and renal survival was much better in groups having lower TAp. The median follow up was 66.6 months (range 12 to 144). The primary endpoint of the 100% increase of serum creatinine occurred in 54 patients (16,6%) and renal survival was much better in groups having lower TA proteinuria. At univariate analysis plasma creatinine and 24h proteinuria, systolic (SBP) and diastolic (DBP) blood pressure during follow-up and treatment with either steroid (CS) or steroid plus azathioprine (CS+A) were the main factors associated with lower TAp and renal survival. At multivariate analysis, female gender, treatment with S or S+A, lower baseline proteinuria and SBP during follow-up remained as the only variables independently influencing TAp. In conclusion, TA-proteinuria is confirmed as one of the best outcome indicators, also in patients with a severe renal insufficiency. A 6-month course of corticosteroids seems the most effective therapy to reduce TAp.

Changes in Proteinuria and Side Effects of Corticosteroids Alone or in Combination with Azathioprine at Different Stages of IgA Nephropathy.

BACKGROUND AND OBJECTIVE: Time-average proteinuria (TAp) is the strongest predictor of renal survival in IgA nephropathy (IgAN). Little is known about the utility and safety of corticosteroids (CS) to obtain TAp<1 g/d in patients with advanced IgAN. This study sought to evaluate TAp at different degree of baseline renal function and histologic severity during CS use and to investigate treatment safety. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed one-stage individual-patient data meta-analysis among 325 patients with IgAN enrolled in three prospective, randomized clinical trials. Patients were divided into three groups according to treatment: no treatment (NT; supportive therapy), CS, and CS plus azathioprine (CS+A). Associations of TAp with histologic grading, treatment, and eGFR at baseline were performed with linear regression models for repeated measures. The median follow-up duration was 66.6 months (range, 12-144 months). RESULTS: In the first 6 months, proteinuria did not change in the NT group and decreased substantially in the other groups(CS: from a mean±SD of 2.20±1.0 to 0.8 [interquartile range, 0.4-1.2] g/d; CS+A: from 2.876±2.1 to 1.0 [interquartile range, 0.5-1.7] g/d), independent of the degree of histologic damage and baseline eGFR. The percentage of patients who maintained TAp<1 g/d was 30.2% in the NT, 67.3% in the CS, and 66.6% in the CS+A group. Thirty-four patients experienced adverse events: none in the NT, 11 (6.4%) in the CS, and 23 (20.7%) in the CS+A group. The risk of developing adverse events increased with decreasing levels of eGFR (from 2.3% to 15.4%). The addition of azathioprine to CS further increased the percentage of patients with adverse events (16.8% versus 5.7% in study 2 and 30.0% versus 15.4% in study 3; overall P<0.001). CONCLUSIONS: In patients with IgAN, CS can reduce proteinuria and increase the possibility of maintaining TAp<1 g/d, regardless of the stage of CKD and the histologic damage. The risk of major adverse events is low in patients with normal renal function but increases in those with impaired renal function and with the addition of azathioprine.

Treatment of IgA nephropathy with renal insufficiency.

IgA Nephropathy leads young people to dialysis more often than other glomerular diseases, because often diagnosis and therapy are made late. Nephrologists waive to treat IgAN pts with chronic renal insufficiency, believing that treatment may not be effective and safe. Moreover, studies in IgAN pts with reduced renal function are lacking. Small studies seem to indicate a possible utility of RAS blockers and corticosteroids in these patients. Recently, VALIGA study showed that corticosteroids and immunosuppressants were more frequently used in pts with eGFR <30 ml/min than in those with eGFR >30 ml/min (60 vs. 44 %, respectively; p = 0.004). The goal of treating IgAN pts is to obtain a time-average proteinuria <1 g/day, regardless of the degree of renal function and histological damage. RASB and corticosteroids seem to be able to obtain this result. However, it's important to pay attention to the appearance of adverse events of CS. In the literature, major side effects occurred in 29 of 463 (6.2 %) patients enrolled in RCTs. However, scarce informations are obtained about the safety of CS in patients with reduced renal function. To better evaluate this aspect, we considered three studies, that used similar schemes of therapy and included patients with different degrees of renal function (1: GFR 90 ml/min/1.73 m(2), 2: 81 ml/min/1.73 m(2), 3: 34 ml/min/1.73 m(2)). The occurrence of adverse events increased with the worsening of renal function (2.3, 5.7 and 15.4 % in studies 1, 2 and 3 respectively). The aim of the treatment for a patient with an eGFR <30 is to slow the progression and to delay the need for dialysis. Therefore, in stage CKD 2, 3 and 4 with a proteinuria >1 g/day a 6-month course of corticosteroids could be useful and safe.

-374 T/A RAGE polymorphism is associated with chronic kidney disease progression in subjects affected by nephrocardiovascular disease.

BACKGROUND: Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. METHODS: 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6-9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. RESULTS: Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. CONCLUSIONS: -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.

[The ambiguous concept of predialysis: proposal for a model]. / L'ambiguita' del concetto di predialisi: proposta di un modello.

In 2009, 90% of nephrology centers in Lombardy declared to have a ''predialysis'' outpatient department, without, however, specifying its meaning. Research carried out in 2008 among nephrology centers in Piemonte showed how ambiguous this term was. According to the 2007 EDTA-ERA Registry, about 68% of European nephrology centers stated that they had an outpatient department for stage 4-5 CKD patients, but no information was available about the role of patients in the choice of dialysis. It is known that when the predialysis phase is poorly managed, the patient's rehabilitation will be more difficult. Dissatisfaction with dialysis often leads to withdrawal from dialysis, as several registries have shown. For this reason, we created a predialysis course at our center, involving a nephrologist, a nurse, and a dietician. The nephrologist helps the patient choose the most suitable therapeutic strategy, which means that doctor and patient share the responsibility for the treatment choice. The offered options are hemodialysis, peritoneal dialysis, preemptive kidney transplant, and a conservative dietary-pharmacological program. The nurse plans at least 4 meetings: 1) to talk with the patient in order to get to know him or her and his/her family; 2) to provide information about the dialysis procedure and establish the patient's preferences; 3) to clear any doubts about the treatment and deliver a booklet with information about the chosen dialysis procedure; 4) to explain the chosen dialysis procedure; 5) to meet the patient after their preparation for dialysis (vascular access or peritoneal catheter). The dietician manages the dietary programs both for patients who are close to starting dialysis and those on a longlasting conservative program. The predialysis course includes a meeting among all those involved with the patient (nephrologists, nurses, dieticians) to exchange information with the purpose of shared evaluation and decision-making.