Addition of Azathioprine to Corticosteroids Does Not Benefit Patients with IgA Nephropathy

The optimal treatment for IgA nephropathy (IgAN) remains unknown. Some patients respond to corticosteroids, suggesting that more aggressive treatment may provide additional benefit. We performed a randomized, multicenter, controlled trial to determine whether adding azathioprine to steroids improves renal outcome. We randomly assigned 207 IgAN patients with creatinine ≤2.0 mg/dl and proteinuria ≥1.0 g/d to either (1) a 3-day pulse of methylprednisolone in months 1, 3, and 5 in addition to both oral prednisone 0.5 mg/kg every other day and azathioprine 1.5 mg/kg per day for 6 months (n = 101, group 1) or (2) steroids alone on the same schedule (n = 106, group 2). The primary outcome was renal survival (time to 50% increase in plasma creatinine from baseline); secondary outcomes were changes in proteinuria over time and safety. After a median follow-up of 4.9 years, the primary endpoint occurred in 13 patients in group 1 (12.9%, 95% CI 7.5 to 20.9%) and 12 patients in group 2 (11.3%, CI 6.5 to 18.9%) (P = 0.83). Five-year cumulative renal survival was similar between groups (88 versus 89%; P = 0.83). Multivariate Cox regression analysis revealed that female gender, systolic BP, number of antihypertensive drugs, ACE inhibitor use, and proteinuria during follow-up predicted the risk of reaching the primary endpoint. Treatment significantly decreased proteinuria from 2.00 to 1.07 g/d during follow-up (P < 0.001) on average, with no difference between groups. Treatment-related adverse events were more frequent among those receiving azathioprine. In summary, adding low-dose azathioprine to corticosteroids for 6 months does not provide additional benefit to patients with IgAN and may increase the risk for adverse events.IgA nephropathy (IgAN) causes ESRD in a significant percentage of patients.^1–3 None of the treatment strategies currently used in clinical practice have proved to be more effective than another, although corticosteroids give some results.^4–6In 1999, we found that a 6-month steroid course significantly decreased the risk of a 50% increase in plasma creatinine from baseline at 5 years in comparison with supportive therapy; proteinuria also decreased.⁷ However, 6 months of steroid therapy may not be enough to ensure stable remission in some patients. Thus, we hypothesized that more aggressive treatment may lead to better results, especially in the long term. Previous studies have suggested the possibility that adding immunosuppressants (particularly azathioprine) to corticosteroids may be more effective in preserving renal function^8,9 and reducing proteinuria.¹⁰ However, azathioprine has mainly been given in combination with other drugs.⁸ Moreover, the sample size⁸ and study design⁹ were inadequate in two of three studies.The aim of this trial was to assess the efficacy and safety of adding low-dose azathioprine for 6 months to steroids in adult IgAN patients.¹¹ We decided to use azathioprine at low dose and for a relatively short period to decrease the risk of serious side effects of this immunosuppressant in relatively young and healthy subjects.     

Urine sediment analysis: Analytical and diagnostic performance of sediMAX® — A new automated microscopy image-based urine sediment analyser

BackgroundWe evaluated the analytical and diagnostic performance of sediMAX (77 Elektronika, Budapest, Hungary), a new automated microscopy image-based urine sediment analyser (which in some countries is also called Urised) in comparison with visual phase-contrast microscopy.MethodsPrecision, linearity, carry-over and method comparison were carried out according to well-established guidelines. The diagnostic performance with respect to visual phase-contrast microscopy was evaluated with results from two centres (n₁ = 910, n₂ = 1233). Uncentrifuged urine samples were used in visual microscopy in centre 1, while urine sediments were used in centre 2.ResultsWithin-run precision for RBC was 17.8% and 6.7% at 18 × E6 RBC/L and 447 × E6 RBC/L respectively and for WBC it was 17% and 4.4% at 4 × E6 WBC/L and 258 × E6/L respectively. Between-run imprecision for RBC was 14.7% for 30 × E6/L and 7.2% for 283 × E6/L. For WBC it was 5.4% at 25 × E6/L and 3% at 166 × E6/L. In both studies areas under ROC curves (AUC) were 80–90% for RBC, WBC, squamous epithelial cells, yeast and calcium-oxalate crystals. For non-squamous epithelial cells and pathological and hyaline casts the AUC ranged 73–74%. There was no carry-over.ConclusionsThe sediMAX is well able to count and identify RBC, WBC, squamous epithelial cells, yeast, bacteria and calcium-oxalate crystals. Recognition of pathological casts and non-squamous epithelial cells is adequate but needs to be improved.     

BK polyomavirus interstitial nephritis in a renal transplant patient with no previous acute rejection episodes

A renal transplant patient treated with tacrolimus and mycophenolate-mofetil (MMF) developed progressive graft function deterioration 10 months after transplantation. Biopsy of the graft showed severe, focally accentuated interstitial inflammation with focal tubulitis and tubular necrosis, and medium-severe interstitial fibrosis with focal tubular atrophy. Glomerular and vascular structures were preserved. On careful examination, in some sections, tubular epithelial cells showed a definite increase with deformation of the nuclear shape, chromatin irregularities with peripheral dislocation and inclusion bodies. These cytopathic changes suggested polyoma virus infection ("decoy cells"). Subsequent screening of the urinary sediment confirmed the presence of many "decoy cells". Immunohistochemical analysis of the biopsy showed many tubular cells were strongly positive for the SV 40 antigen, specific for BK polyoma virus. A diagnosis of interstitial nephritis due to BK polyoma virus was made, though the coexistence of cellular rejection could not be excluded. At variance with previous reports, our patient had not had repeated episodes of rejection before biopsy or heavy immunosuppressive treatment, such as ALG, OKT3, after transplantation. This case shows that even in the absence of vigorous anti-rejection therapy an immunosuppressive regimen based on tacrolimus and MMF may involve the risk of BK polyoma virus- associated interstitial nephritis.     

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.     

Quantification and identification of polyomavirus DNA in blood and urine of renal transplant recipients

A cohort of 201 kidney transplant recipients (KTR) including 7 patients with evidence of renal function deterioration (as defined by creatinine levels >20% over baseline values) was analyzed for polyomavirus DNA in blood and urine samples by a new quantitative polymerase chain reaction method. Of 201 patients, 14 (6.9%) were positive for polyomavirus DNA in blood (median level, 500 copies per milliliter of blood) including all 7 patients with renal function deterioration. Polyomavirus DNA detection in blood for diagnosis of renal function deterioration in KTR showed a sensitivity of 100% and a specificity of 96%, whereas positive and negative predictive values were 50% and 100%, respectively. Diagnostic value of decoy cells detection and polyomavirus DNA quantification in urine samples was negligible.     

Urinary red blood cells: not only glomerular or nonglomerular

Two main types of red blood cells, isomorphic and dysmorphic, are found in the urine sediment, indicating nonglomerular and glomerular hematuria, respectively. Occasionally, however, other types of red blood cells such as sickle cells, anisocytes, poikilocytes, elliptocytes and dacryocytes can be seen in the urine sediment of patients with hematuria. This paper describes such cases reported in the literature in which such unusual urinary red blood cells have been found and the experience of the authors on this subject.