Update on treatment of immunoglobulin A nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and the most common cause of end-stage renal disease in young adults. However, there are still no specific therapies capable of targeting key pathways involved in disease pathogenesis. Recently, many large randomized controlled trials have been reported, such as Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy, Targeted-release Budesonide Versus Placebo in Patients with IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global, which are considered to update the 2012 Kidney Disease: Improving Global Outcomes Guideline. More importantly, with a deeper understanding of the roles of mucosal immunity, B-cell activation and complement activation in IgAN, the studies of targeting pathogenic pathways are ongoing. In this review, by systemically searching the clinical trials in IgAN on ClinicalTrials.gov (https://clinicaltrials.gov/), we update the evidence for corticosteroids/immunosuppressive therapy in IgAN and explore the promising targeting pathogenic pathway therapeutic options. With better understanding of pathogenesis of IgAN, emerging therapies will soon become a reality in future.

How to treat patients with chronic kidney disease: With special focus on IgA nephropathy.

Chronic kidney disease has become a worldwide problem. Among chronic kidney disease patients, IgA nephropathy is common in the world. Serum levels of galactose deficient (Gd)-IgA1 and Gd-IgA1-specific antibodies are elevated in most IgA nephropathy patients. Glomerular Gd-IgA1 deposition has been observed by immunofluorescence. There are many reports that the anti-proteinuric effect is significantly greater in groups who receive tonsillectomy with steroid pulse therapy in IgA nephropathy patients. Furthermore, patients with tonsillectomy with steroid pulse therapy have shown a strong down-regulation of delta serum IgA/C3 per year and have conserved their renal function. New treatments, that is, Atacicept and glucocorticoid budesonide, have been developed for this disease.

Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis.

Henoch-Schönlein purpura nephritis and immunoglobulin A nephropathy are common glomerulopathies in the pediatric population that deserve special attention. In some cases the primary care provider can follow the patient but others need more intensive management. Delaying this treatment can lead to worse morbidity. This article provides information on the pathogenesis, outcomes, and follow-up strategies that will aid in the diagnosis and referral of patients at risk for kidney disease.

The role of tonsillectomy in IgA nephropathy.

The IgA nephropathy (IgAN) is a very common glomerulonephritis and can result in end-stage renal disease. From a clinical point of view, IgAN is characterised by repeated events of macrohaematuria associated with infections of the upper airways. In IgAN, the IgA released by the tonsillar lymphatic tissue into blood circulation are defective in glycosylation. These aberrant IgA can reach the glomeruli and deposit into mesangium causing an inflammation with cellular proliferation. The treatment is not yet well defined: steroids and immunosuppressive drugs are suggested in cases with a progressive disease. Tonsillectomy was proposed to reduce the infective events of upper airways and the lymphatic tissue producing undergalactosylated IgA. The experiences in literature coming from Asia report positive effects of tonsillectomy on IgAN. In patients with tonsillectomy, the renal signs improved (less haematuria and proteinuria) and the renal outcome was better (slower progression of renal damage). These were uncontrolled studies and tonsillectomy was associated with steroid and immunosuppressive treatment, so it is not possible to tell the real effect of tonsillectomy. In contrast, the European studies reported that the tonsillectomy was not associated with a better outcome of IgAN. A critical review of the subject reveals that most of the papers with positive results were uncontrolled retrospective experiences, while in a randomised controlled trial paper the advantages of tonsillectomy disappeared. In conclusion, this review, in agreement with the international guidelines, concludes that tonsillectomy does not play any role in the progression of IgAN.

[Development of mesangial immunoglobulin IgA glomerulonephritis and p-ANCA positivity in a patient with psoriatic arthritis]. / Insorgenza di glomerulonefrite a depositi mesangiali di IgA e positività di p-ANCA in un paziente affetto da artrite psoriasica in trattamento con etanercept.

Tumor necrosis factor (TNF) inhibitors are widely used for the treatment of various rheumatic diseases. These agents may lead to development of systemic autoimmune diseases and renal complications. We report a patient with psoriatic arthritis and renal failure treated with two TNF inhibitors (Etanercept and then Adalimumab). After this treatment he developed proteinuria with nephrotic syndrome. A renal biopsy was performed highlighting GN with mesangial IgA deposits. Then he developed p-ANCA positivity. Following that, etanercept and adalimumab were stopped and a treatment by corticosteroids was initiated, but renal function decreased. Currently the patient is treated by haemodialysis. In our patient, the pathogenic role for anti-TNF therapy is suggested by the close temporal relationship with development of glomerular disease and by the improvement in proteinuria after drug withdrawal. However, the patient was treated once more with TNF agents, so he developed end stage renal disease.

IgA nephropathy associated with hyper IgAnemia, psoriasis or pustulosis and ossification.

This is a report on two cases of IgA nephropathy associated with psoriasis vulgaris, having hyper IgAnemia (above 500 mg/dl) and ossification. Case 1 is a 47-year-old woman with a 7-year history of psoriasis vulgaris, and case 2 is a 57-year-old man with a 17-year history of this disease. IgA was 526 and 1,356 mg/dl, respectively. HLA analysis showed A2, A26 (10), Bw62 (15), Bw46, Cw3, DRw12 (5), and DRw8 in the former, and A2, A11, B13, Bw46, Cw11, DR4, and DRw8 in the latter. Renal biopsy specimens disclosed mild mesangial proliferative glomerulonephritis and moderate mesangial proliferative glomerulonephritis with predominant IgA deposition in mesangial area, respectively. A bone-scintigraphy revealed a high uptake of radioisotopes in the left shoulder, the vertebra, the sacroiliac joint, both sides of the knees and ankles, and the sterno-cost-clavicular area. An X-ray study showed ossification of the posterior longitudinal ligament (OPLL) in the former, and ankylosing spinal hyperostosis (ASH) in the latter. A review of the literature discloses three other case reports of hyper IgAnemia, IgA nephropathy, psoriasis or pustulosis, and ossification. The alertness of dermatologists, orthopedic surgeons, rheumatologists, and general practitioners will be required to attain to a more frequent diagnosis of the above combination.

Quantitative analysis of interleukin 6 (IL-6) in patients with IgA nephropathy after tonsillectomy.

The biological response to tonsillectomy was studied in 21 patients suffering from chronic tonsillitis with or without IgA nephropathy (IgAN). Serum and urinary interleukin-6 (IL-6) levels were measured before and after tonsillectomy. Serum IL-6 levels in case of IgAN peaked 3 h after tonsillectomy and more rapidly than control cases. No significant differences were observed between two cases through the time. Urinary IL-6 levels were significantly higher before and at 6 and 48 h after tonsillectomy in IgAN cases. Stimulation of tonsils caused serum IL-6 elevation and changes in urinary IL-6 levels in IgAN cases. Elevation of urinary IL-6 levels after tonsillectomy in patients with IgAN may reflect an increase in the production of IL-6 in the kidneys. Measurement of urinary IL-6 levels after tonsillectomy is useful to elucidate the efficacy of tonsillectomy in IgAN patients.

Tonsillectomy with steroid pulse: a curative therapy for IgA nephropathy.

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis progressing to end-stage renal disease (ESRD), has been regarded as an incurable disease. However, in recent years, it has been demonstrated that combined tonsillectomy with steroid pulse (TS) therapy, if administrated in the relatively early stage of the disease, can yield clinical remission in patients with IgAN. However, clinical remission is no longer obtained when the same treatment is administrated in cases with more advanced disease and/or a longer duration of nephropathy. Thus, the paradigm of managing IgAN patients is shifting in Japan from 'slowing the progression and the delaying the onset of ESRD' (by conventional therapy using a RAS inhibitor and/or corticosteroids at low doses in selected patients with advanced IgAN) to 'achieving remission' by the TS therapy in patients with early disease. In the new paradigm aimed at clinical remission, the principle for initiation of TS therapy should be 'the earlier, the better'.

Immunomodulatory agents against IgA nephropathy.

Synthesis of aberrant IgA molecules as the key pathogenetic mechanism of immunoglobulin A nephropathy (IgAN) apparently forms a potential scientific rationale for applying immunomodulatory agents in the treatment of IgAN. There is evidence that corticosteroids can steadily reduce proteinuria and slow down renal progression. Evidence that pulse steroid plus intravenous or oral cyclophosphamide can retard the rate of progression of advanced IgAN was provided by several groups worldwide. Cyclosporin is generally not used to treat IgAN. The efficacy of azathioprine is equivocal. Mycophenolate mofetil reduces proteinuria by up to 30% and favorably impacts renal survival in Chinese patients with mild histologic lesions, but these results were not achieved in Caucasians with more advanced disease. In conclusion, the choice of immunomodulatory therapy remains controversial. We advocate the use of immunomodulatory agents as an adjunctive therapy in patients with proteinuria>1 g/day despite achieving target blood pressure with full renin-angiotensin blockade. More aggressive therapy should be reserved for patients with nephrotic-range proteinuria, crescentic lesions and/or rapidly progressive renal failure.

MPO-ANCA-positive IgA nephropathy successfully treated with tonsillectomy.

A 20-year-old Japanese woman was admitted to a hospital because of gross hematuria. She was diagnosed with IgA nephropathy with a poor prognosis, based on the formation of many crescents in the glomerulus and monocyte infiltration in the interstitium in a renal biopsy specimen in February 2003. Myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) was not identified at that time. After treatment with high-dose steroid pulse therapy and heparin/warfarin, her urinary protein improved, to 0.5 g/day. However, 1 year after the steroid pulse therapy, urinary protein was increased to 1.2 g/day, associated with repeated episodes of tonsillitis. A second renal biopsy was performed, and showed an improving tendency, compared to the findings of the previous one, although some crescent formation and adhesions of Bowman's capsule remained. Interestingly, MPO-ANCA was positive in the serological examination done at this time. One month and a half after the second renal biopsy, she had a tonsillectomy, followed by a regimen of 5 mg oral prednisolone daily, in order to prevent the progression of IgA nephropathy. After the tonsillectomy, her urinary protein level was markedly improved, at 0.14 g/day. Her creatinine clearance was ameliorated, at 102 ml/min, and in addition, MPO-ANCA had disappeared. This case suggests that an inflammation such as tonsillitis may be associated not only with the activity of IgA nephropathy but also with the production of MPO-ANCA.