Treatment of IgA Nephropathy: Evolution Over Half a Century.

Fifty years into the original description of IgA nephropathy, there is still no specific therapy for this condition and general measures including blood pressure control with blockers of the renin-angiotensin-aldosterone system and salt restriction remain the cornerstone to slow disease progression. Although the paucity in treatment advances could be related to the disease's complex pathogenesis, which requires multiple hits, heterogeneity as reflected by diverse ethnic differences, and genetic predisposition and histopathologic variations, many nonspecific and immunomodulatory agents have been tested with variable degrees of success and tribulations. Here, we review the evolution of these different therapeutic approaches over time that culminated in the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Glomerulonephritis that presently is being updated, and provide an appraisal of recent data on various forms of immunosuppressive agents. Finally, we discuss the theoretical basis of ongoing and upcoming clinical trials that are more pathway- or cell-type-specific as knowledge in disease mechanisms advances.

Effects of Tripterygium wilfordii Induction Therapy to IgA Nephropathy Patients with Heavy Proteinuria.

Although some new drugs have been developed, Tripterygium wilfordii HOOK F. (TWHF) has the merits of relatively lower price and fewer side effects. Unfortunately, the efficacy and safety of the TWHF (especially dosage 120 mg/d) in the immunoglobulin A (IgA) nephropathy (IgAN) are still lacking. A cohort study including 49 IgAN patients with heavy proteinuria who received induction therapy was undertaken. Patients were divided into three groups: Prednisone (PRE), conventional-dose TWHF (CTW) and double-dose TWHF (DTW). The clinical features, laboratory data, histological manifestations and outcomes of the groups were compared. We found that urinary protein excretion and rates of elevated n-acetyl-ß-D-glucosaminidase (NAG) and retinol binding protein (RBP) were prominent in all groups. Neither histopathological changes nor the rates of renal insufficiency were significantly different among groups. Patients in the PRE (69.2%) and DTW groups (87.5%) achieved complete remission; none of the CTW group did. Furthermore, the total remission rate of the DTW group was substantially higher than that of the CTW group. The degree of hypoproteinemia, improved considerably in the PRE and DTW groups. Treatment was well tolerated in all patients, and no serious adverse events were observed. Our findings suggested that induction therapy with double dose TWHF significantly improved response rates in IgAN patients with heavy proteinuria, and did not considerably increase side effects.

Clinicopathological features, diagnosis, and treatment of IgA nephropathy with minimal change disease related to exposure to mercury-containing cosmetics: a case report
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AIM: Membranous nephropathy and minimal change disease (MCD) have been involved in mercury-induced nephrotic syndrome. IgA nephropathy is not known to be a common pathological type. In the present article, we report a case of IgA nephropathy with MCD following exposure to mercury-containing skin lightening cream. MATERIAL AND METHODS: The patient was a 39-year-old woman who presented with nephrotic syndrome. She had a 6-month history of using as many as 8 kinds of skin-lightening creams, and urinary mercury excretion was high. Renal biopsy revealed IgA nephropathy with MCD. The use of cosmetics was stopped and chelation therapy was given. After 4 courses (1 month) of chelation therapy, there was a complete remission of proteinuria and hematuria, and urine tests remained normal during the 5-year follow-up period. RESULTS AND CONCLUSIONS: The unique clinical and pathological features of IgA nephropathy with MCD had raised the controversial question of whether MCD and IgA deposition are separate entities or a common pathophysiology. Repeated renal biopsy and similar cases were helpful and should be carried out as far as possible.
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[Long-term Effect of the Treatment of IgA Nephropathy by Tonifying Shen, Activating Blood Stasis, Dispelling Wind-Dampness Combined with Western Medicine].

Objective To observe the long-term effect of tonifying Shen, activating blood stasis, dispelling wind-dampness (TSABSDWD) combined with Western drugs (WD) for IgA nephropathy. Methods A single center retrospective case-control study was used. The clinical and laboratory examinations, pa- thology of renal biopsy, and treatment programs of IgA nephropathy were obtained from primary IgA ne- phropathy patients (confirmed from renal biopsy at authors' hospital) from Jan 1st, 2008 to Dec 31 , 2008. Patients were assigned to Group A (basic treatment +Chinese herbs) and Group B (basic treatment +Chi- nese herbs + glucocorticoid and/or immune inhibitors). A follow-up visit started from the confirmation of re- nal biopsy to Dec 31, 2008, for at least 12 months. The end point event was defined as entering end stage renal disease (ESRD), estimated glomerular filtration rate (eGFR) decreased by more than 50%, or SCr was doubled. The differences in clinical manifestations, lab indicators and etc. were compared between be- fore treatment and after 1 year of treatment/till the end of follow-ups. The accumulative kidney survival rate was calculated using Kaplan-Meier method. The curve for accumulative kidney survival rate was drawn. Re- sults A total of 219 cases were included, 49 in Group A and 170 in Group B. In Group A, there were 7 pa- tients (14.0%) with Shen deficiency syndrome, 21 cases (43.0%) with Shen deficiency blood stasis syn- drome, 8 (16. 0%) with Shen deficiency wind-dampness syndrome, 13 cases (27. 0%) with Shen deficien- cy blood stasis wind-dampness syndrome. In Group B there were 12 patients (7.1%) with Shen deficiency syndrome, 47 cases (27. 6%) with Shen deficiency blood stasis syndrome, 22 (12.9%) with Shen defi- ciency wind-dampness syndrome, 89 cases (52.4%) with Shen deficiency blood stasis wind-dampness syndrome. No statistical difference in age, sex, or follow-up period between the two groups (P >0.05). Compared with Group A, the disease courser was shorter, 24 h urination increased more, levels of SCr and blood urea nitrogen (BUN) increased higher, plasma albumin decreased lower in Group B (P <0. 05). Compared with before treatment, 24 h urination and counts of urinary red blood cells (RBCs) decreased more in the two groups after 1-year treatment, and decreased further till the end of follow-up (P <0. 05). The total effective rate was 89. 0% (1951219). The total effective rate of Group A was 89. 8% (44/49), with no patient entry into endpoint event. The total effective rate of Group B was 88. 8%(151/170). Totally 5 pa- tients arrived at endpoint event in Group B, 4 in ESRD, 1 with eGFR decreased by more than 50%, or SCr doubled. Compared with Group B, the complete relief rate was higher in Group A (P <0. 01). The accumulative kidney survival rate was 100. 0%, 100. 0%, 98. 0% and 96. 1% in the 219 patients at year 1 , 3, 5, 7, re- spectively using Kaplan-Meier method. Conclusions Programs based on theory of Shen disease wind- dampness in CM and in integrative medicine could be used in treating IgA nephropathy according to differ- ent conditions. Long-term observation showed this program could significantly improve patients' conditions. The 7-year accumulative kidney survival rate was 96. 1%.

[IgA nephropathy]. / Glomérulonéphrite à dépôts mésangiaux d'immunoglobulines A.

IgA nephropathy is the most common form of primary glomerulonephritis worldwide and an important cause of chronic kidney disease and end-stage kidney failure. Its pathophysiology remains in part unsolved but it is recognized as an immune complex disease. Recent years have brought progress in the field through the discovery of several genetic susceptibility loci and the formulation of the multi-hit pathogenesis model. Presentation, clinical course and histology can be extremely variable, making any histological classification still difficult. Indeed, most therapeutic studies until now include patients based only on the severity of clinical criteria but the new classification of Oxford should change that. Only the management of patients with nephropathy with minimal change glomerular lesions and nephrotic syndrome, or extra-capillary glomerulonephritis and rapidly progressive renal failure, is consensual: Corticosteroids alone for the first and associated with immunosuppressive drugs for the latter. The recent Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guideline is still controversial, especially in light of the last clinical studies. Corticosteroid therapy can be discussed in patients with proteinuria greater than 1 g/day without renal failure. All IgA nephropathy patients should benefit from the global management of chronic glomerular disease, including a renin-angiotensin system blocker in the presence of hypertension or proteinuria.

Treating IgA nephropathy: quid novi?

IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy.

Potential of renal pathology on refining syndrome typing of Chinese medicine in IgA nephropathy.

OBJECTIVE: To investigate the potential of renal pathological index as a differential diagnosis factor for Chinese medicine (CM) syndromes typing in IgA nephropathy (IgAN). METHODS: A total of 1,016 patients with IgAN was recruited from November 2001 to November 2004. All the signs and symptoms including picture of the tongue and pulse tracings were collected. All patients were typed according to the CM syndrome typing scheme for chronic primary glomerulopathy. The severity of glomerulus and tubulointerstitial lesions (mild, moderate-severe) were evaluated using lee's grading system and the Katafuchi score system. RESULTS: The syndrome types transform in turn by deficiency of both the Spleen (Pi) and Lung (Fei) qi, deficiency of both qi and yin, deficiency of Liver (Gan) and Kidney (Shen) yin and deficiency of Spleen-Kidney (Shen) yang, with the aggravation of pathogenetic condition and that the manifestation of deficiency of qi clinically showed proliferative lesion of glomerular mesangium, while the glomerular sclerosis pathologically showed the manifestation of yin deficiency. CONCLUSION: Renal pathological findings may be a candidate of objective factors to refine CM syndrome typing process.

Treatment of IgA nephropathy: an update.

OBJECTIVE: To review current literature regarding treatment options for immunoglobulin A nephropathy (IgAN). DATA SOURCES: A MEDLINE search was performed using the terms IgA nephropathy, Berger's disease, immunoglobulin A nephropathy, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, fish oil, omega-3 fatty acids, statins, hydroxymethylglutaryl-CoA reductase inhibitors, immunosuppressive therapy, corticosteroids, mycophenolate mofetil, cyclophosphamide, cyclosporine, azathioprine, leflunomide, antiplatelets, anticoagulants, vitamin E, infliximab, calcitriol, and intravenous immunoglobulins. A date limit was not set; however, focus was on publications from 1999 to June 2011 to review recent literature and therapeutic recommendations. STUDY SELECTION AND DATA EXTRACTION: All articles in English, including studies conducted in humans, meta-analyses, review articles, guidelines, statements, and reference citations, were identified and evaluated. DATA SYNTHESIS: IgAN is the most common primary glomerulonephritis worldwide, leading to end-stage renal disease in 20-30% of patients. Evidence guiding management of IgAN has been sparse and clinical trials have not conclusively demonstrated effective treatments, largely due to suboptimal methodologies. Treatment strategies have included management of blood pressure and lipids, improvement or stabilization of kidney function, and reduction of proteinuria. This review of IgAN provides an update regarding standard and nonconventional treatment options based on recently published literature. CONCLUSIONS: Supportive therapies, including angiotensin blockade, should be considered as first-line therapy for patients with urine protein >0.5 g/day and/or blood pressure >140/90 mm Hg. Corticosteroids could be considered as add-on or monotherapy for patients with urine protein >1 g/day with preserved renal function. Conclusive data are lacking for general treatment recommendations for the use of other therapies for IgAN.

Non-immunosuppressive treatment for IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease with approximately 30% to 40% of patients progressing to end-stage kidney disease (ESKD) within 20 years. The most common regimens include immunosuppressive agents, however the risks of long-term treatment often outweigh the potential benefits. Non-immunosuppressive options, including fish oils, anticoagulants, antihypertensive agents and tonsillectomy have also been examined but not reviewed systematically. OBJECTIVES: To assess the benefits and harms of non-immunosuppressive treatments for treating IgAN in adults and children. SEARCH STRATEGY: In July 2010 we searched the Cochrane Renal Group's specialised register, CENTRAL (in The Cochrane Library), MEDLINE (from 1966) and EMBASE (from 1980). We also searched reference lists of included studies, review articles and contacted local and international experts. SELECTION CRITERIA: Randomised controlled trials (RCTs) of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. MAIN RESULTS: We included 56 studies (2838 participants). Antihypertensive agents were the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB) or combinations of both, versus other antihypertensives and other agents. The benefits of antihypertensive agents, particularly inhibitors of the renin angiotensin system, appear to potentially outweigh the harms in patients with IgAN. The benefits are largely manifest as a reduction in proteinuria, a surrogate outcome. There is no evidence that treatment with any of the antihypertensive agents evaluated affect major renal and/or cardiovascular endpoints or long-term mortality risk beyond the benefit that arises from controlling hypertension in patients with IgAN. The RCT evidence is insufficiently robust to demonstrate efficacy for any of the other non-immunosuppressive therapies evaluated here. AUTHORS' CONCLUSIONS: IgAN remains a disease in search of adequately powered RCTs to reliably inform clinical practice. More and better evidence is needed to understand the magnitude of benefit and the possible risks of anti-hypertensive or more specifically of ACEi/ARB therapy alone or in combination and which specific types of patients with the IgAN might have the greatest potential for benefit. For other non-immunosuppressive therapies, where neither benefit nor significant harm has yet to be demonstrated, there remains some justification for further exploration of the potential benefits.

Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy.

BACKGROUND: Proteinuria (UP) >1.0 g/24 h at diagnosis is a well-known indicator of progressive renal disease in patients with IgA nephropathy (IgAN). To determine if persistent UP is a more sensitive marker for later progression of IgAN, the hypothesis was tested that the prior level and trend (slope) in UP for 1 year was better at predicting later end-stage renal disease (ESRD) (dialysis or transplant) than a current 24-h UP, serum creatinine (SC), SC slope, hypertension, or total glomerular histopathological score on index renal biopsy in an observational study of 154 high-risk patients enrolled in two clinical trials (IgAN 1, IgAN 2). METHODS: Measurements of 24-h UP and SC were made at time 0, 6 weeks, 6 months and 1 year in all patients, who were then followed for an additional 5.76 years and 1.63 years in the two studies, respectively. The Cox proportional hazards model was used to identify predictors of ESRD following the 1-year visit. RESULTS: Adjusting only for randomized treatment, nearly all UP variables (number of high readings, 1-year level, slopes), SC at 1 year, and SC trends (slopes) over the prior year were significantly associated with subsequent ESRD (all P values <0.05) in both studies. However, among the UP variables, the 1-year readings had the strongest association with ESRD in IgAN 1 (hazard ratio (HR), 95% CI, for a 1g increase: 1.5, 1.2,1.9), and the second strongest association (similar to UP trends) in IgAN 2 (1.4, 1.2,1.6). Males had lower rates of ESRD in both studies (IgAN 1 HR: 0.5, 0.2,1.2, P=0.11; IgAN 2 HR: 0.2, 0.1,0.6, P=0.002). In the multivariate analyses that examined all clinical and histological variables, 1-year levels of 24-h UP and SC, and female gender were independently associated with subsequent ESRD. CONCLUSION: In a high-risk patient with IgAN, the current 24-h UP and SC measurements are as good predictors of subsequent ESRD as UP and SC trends and levels over the prior year. Additionally, it appears that females have poorer outcomes than males.

Evidence-based assessment of treatment options for children with IgA nephropathies.

We present an evidence-based evaluation of published data on therapy for children with various presentations of the IgA nephropathies--idiopathic IgA nephropathy (IgAN) and Henoch-Schonlein purpura nephritis (HSPN). Particular attention has been paid to the outcome markers used in the studies reviewed, with the best evidence provided by markers highly associated with progressive renal failure. No treatment modality for either IgAN or HSPN in pediatric patients has been shown to be effective by a properly designed and administered randomized controlled trial (i.e., the highest level of evidence--level 1). Lower levels of evidence support the use of a variety of corticosteroid regimens, often in combination with other agents, although there are some conflicting studies in this area. No convincing evidence has been published to date to support the use of fish oil, angiotensin-converting enzyme inhibitors or tonsillectomy for the treatment of children with IgAN or HSPN. Well designed randomized controlled trials in children with the IgA nephropathies need to be undertaken.