Reduced Recurrence of Primary IgA Nephropathy in Kidney Transplant Recipients Receiving Everolimus With Corticosteroid: A Retrospective, Single-Center Study of 135 Transplant Patients.

BACKGROUND: Long-term kidney allograft survival remains a major clinical challenge. Recurrent glomerulonephritis disease, including recurrence of IgA nephropathy (IgAN), is a significant barrier to long-term kidney allograft survival. We performed a retrospective, observational study to evaluate the role of everolimus (EVR) in the risk of recurrent IgAN. METHODS: The study included data from 135 patients aged ≥16 years with biopsy-proven IgAN on native kidneys who underwent a kidney transplant (KT) between December 2002 and December 2018. RESULTS: Patients who underwent de novo KT received mycophenolate mofetil (MMF) (n = 107) or EVR (n = 28). The mean recipient age in the MMF and EVR groups was 44.9 ± 13.7 and 41.1 ± 10.1, respectively. The median (interquartile range) follow-up period was 90.9 (64.9-115.3) and 21.2 (11.4-30.6) months, respectively (< .0001). All patients received continuous corticosteroid and tacrolimus therapy. The death-censored graft survival rate after KT and the recurrence-free survival rate did not differ significantly between the groups. Univariate and multivariate Cox regression analyses identified EVR for de novo KT as an independent predictive factor for recurrence-free survival (P = .024). CONCLUSIONS: Our findings suggest that EVR-based regimens with tacrolimus and corticosteroid therapy for de novo KT reduce the recurrence of IgAN compared with MMF-based regimens with tacrolimus and corticosteroid therapy.

The protective effect and mechanism of rapamycin in the rat model of IgA nephropathy.

BACKGROUND: The pathogenesis of the development of IgA nephropathy has not been clear up to now. At present, some studies revealed that the mTOR pathway may participate in IgA nephropathy; however, the mechanism has not been systematically studied. In this study, we established an IgAN rat model to investigate the protective effects of rapamycin as a new type of immunosuppressant, as well as its therapeutic mechanisms. METHODS: After the establishment of IgA nephropathy model, rats were treated with different concentrations of rapamycin, and the protective effect of different concentrations of rapamycin on renal function of the rats was observed. The deposition of IgA was observed by immunofluorescence. The kidney expression of Akt and p70S6k proteins in mTOR pathway was examined using the western blot assay after rapamycin treatment. RESULTS: Morphology and immunofluorescence confirmed that the rat model of IgA nephropathy was successfully established. In particular, the level of proteinuria decreased with the increase of the dose of rapamycin, as well as the deposition of IgA in glomeruli. Moreover, the western blot analysis indicated that the expression of p70S6K in the downstream of mTOR pathway decreased and the upstream protein AKT of the mTOR pathway was overexpressed in the rats model. CONCLUSION: We found that rapamycin has protective effects in the IgA nephropathy rat model in a dose-dependent manner. In addition, the result of western blot assay suggested that rapamycin may display its therapeutic effects through interfering the AKT-mTOR-p70S6K signaling pathway.

Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily.

Background C3 glomerulopathy (C3G) is a life-threatening kidney disease caused by dysregulation of the alternative pathway of complement (AP) activation. No approved specific therapy is available for C3G, although an anti-C5 mAb has been used off-label in some patients with C3G, with mixed results. Thus, there is an unmet medical need to develop other inhibitors of complement for C3G.Methods We used a murine model of lethal C3G to test the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of C3G. CRIg-Fc binds C3b and inhibits C3 and C5 convertases of the AP. Mice with mutations in the factor H and properdin genes (FHm/mP-/-) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN.Results Treatment of FHm/mP-/- mice with CRIg-Fc, but not a control IgG, inhibited AP activation and diminished the consumption of plasma C3, factor B, and C5. CRIg-Fc-treated FHm/mP-/- mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores.Conclusions Therapeutics developed on the basis of the mechanism of action of soluble CRIg may be effective for the treatment of C3G and should be explored clinically.

Interleukin-6 is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice.

Immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is characterized by IgA depositions in the kidney. Deficiency of CD37, a leukocyte-specific tetraspanin, leads to spontaneous development of renal pathology resembling IgAN. However, the underlying molecular mechanism has not been resolved. Here we found that CD37 expression on B cells of patients with IgAN was significantly decreased compared to B cells of healthy donors. Circulating interleukin (IL)-6 levels, but not tumor necrosis factor-α or IL-10, were elevated in Cd37-/- mice compared to wild-type mice after lipopolysaccharide treatment. Cd37-/- mice displayed increased glomerular neutrophil influx, immune complex deposition, and worse renal function. To evaluate the role of IL-6 in the pathogenesis of accelerated renal pathology in Cd37-/-mice, we generated Cd37xIl6 double-knockout mice. These double-knockout and Il6-/- mice displayed no glomerular IgA deposition and were protected from exacerbated renal failure following lipopolysaccharide treatment. Moreover, kidneys of Cd37-/- mice showed more mesangial proliferation, endothelial cell activation, podocyte activation, and segmental podocyte foot process effacement compared to the double-knockout mice, emphasizing that IL-6 mediates renal pathology in Cd37-/- mice. Thus, our study indicates that CD37 may protect against IgA nephropathy by inhibition of the IL-6 pathway.

SPAK plays a pathogenic role in IgA nephropathy through the activation of NF-κB/MAPKs signaling pathway.

Sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) can stimulate production of proinflammatory cytokines and interact with inflammation-related molecules. However, it has yet to be determined whether SPAK plays a pathophysiological role in the complicated pathological mechanisms of IgA nephropathy (IgAN), which is mainly characterized by mesangial cell (MC) proliferation and is the most common form of glomerulonephritis. In the present study, we examined the pathophysiological role of SPAK in IgAN using a mouse model and cell models. Our results clearly showed that (1) SPAK deficiency prevents the development of IgAN and inhibits production of immune/inflammatory mediators and T cell activation and proliferation; and (2) when primed with IgA immune complexes (IgA IC), both peritoneal macrophages and primary MCs from SPAK knockout mice show markedly reduced production of proinflammatory cytokines and inhibition of NF-κB/MAPKs activation. We proposed that activation of SPAK and the NF-κB/MAPKs signaling pathway in MCs, macrophages and T cells of the glomerulus may be a mechanism underlying the pathogenesis of IgAN. The activation of SPAK in renal tubuloepithelial cells either directly by IgA IC or an indirect action of the activated MCs or infiltrating mononuclear leukocytes seen in the kidney may further aggravate the disease process of IgAN. Our results suggest that SPAK is a potential therapeutic target for the glomerular disorder.

Effect of tonsillectomy and its timing on renal outcomes in Caucasian IgA nephropathy patients.

PURPOSE: The role of tonsillectomy in the treatment of IgA nephropathy in Caucasian patients is controversial. METHODS: A retrospective cohort study was conducted in 264 patients with biopsy-proven primary IgA nephropathy to examine the association between tonsillectomy and long-term renal survival, defined as the incidence of estimated glomerular filtration rates (eGFRs) of ≤30 ml/min/1.73 m(2) or end-stage renal disease (the composite of initiation of dialysis treatment or renal transplantation). The association of tonsillectomy with renal end-points was examined using the Kaplan-Meier method and Cox models. RESULTS: One-hundred and sixty-six patients did not undergo tonsillectomy (Group I, follow-up 130 ± 101 months) and 98 patients underwent tonsillectomy (Group II, follow-up 170 ± 124 months). The mean renal survival time was significantly longer for both end-points between those patients who underwent tonsillectomy (Group II) versus patients without tonsillectomy (Group I) (p < 0.001 and p = 0.005). The mean renal survival time was significantly longer for both end-points between those patients who had macrohaematuric episodes versus patients who had no macrohaematuric episodes (p = 0.035 and p = 0.019). Tonsillectomy, baseline eGFR and 24-h proteinuria were independent risk factors for both renal end-points. CONCLUSION: Tonsillectomy may delay the progression of IgA nephropathy mainly in IgA nephropathy patients with macrohaematuria. Prospective investigation of the protective role of tonsillectomy in Caucasian patients is needed.

Outcome of tonsillectomy for recurrent IgA nephropathy after kidney transplantation.

Since 2007, we have performed tonsillectomies for patients with recurrent immunoglobulin A nephropathy (IgAN) after kidney transplantation. Seven patients with primary IgAN showed biopsy-proven recurrent IgAN after living-donor kidney transplantation. They had persistent proteinuria or hematuria for an average of 40.3 months, and tonsillectomy was performed, on average, 75.6 months after kidney transplantation. In six patients with observation periods of more than one year, good remission of urinary findings was observed after tonsillectomy. We classified the seven patients into three types of renal injury based on histological findings: severe, moderate, and mild. Two patients classified with severe renal injury at the time of tonsillectomy had other problems, such as refractory hypertension and bilateral sinusitis. They followed a rapidly progressive clinical course. One case already had moderate histological renal injury. He demonstrated prompt amelioration of urinary findings after tonsillectomy but immediate deviation from remission of proteinuria and hematuria. In the four cases presenting mild renal injury at tonsillectomy, the improved urinary findings and serum creatinine value after tonsillectomy have persisted. In conclusion, tonsillectomy may be a favorable treatment for cases of mild-grade IgAN. However, other treatments such as antihypertensive agents and diet therapy may be necessary in other grades.

Osthole mitigates progressive IgA nephropathy by inhibiting reactive oxygen species generation and NF-κB/NLRP3 pathway.

Renal reactive oxygen species (ROS) and mononuclear leukocyte infiltration are involved in the progressive stage (exacerbation) of IgA nephropathy (IgAN), which is characterized by glomerular proliferation and renal inflammation. The identification of the mechanism responsible for this critical stage of IgAN and the development of a therapeutic strategy remain a challenge. Osthole is a pure compound isolated from Cnidiummonnieri (L.) Cusson seeds, which are used as a traditional Chinese medicine, and is anti-inflammatory, anti-apoptotic, and anti-fibrotic both in vitro and in vivo. Recently, we showed that osthole acts as an anti-inflammatory agent by reducing nuclear factor-kappa B (NF-κB) activation in and ROS release by activated macrophages. In this study, we examined whether osthole could prevent the progression of IgAN using a progressive IgAN (Prg-IgAN) model in mice. Our results showed that osthole administration resulted in prevention of albuminuria, improved renal function, and blocking of renal progressive lesions, including glomerular proliferation, glomerular sclerosis, and periglomerular mononuclear leukocyte infiltration. These findings were associated with (1) reduced renal superoxide anion levels and increased Nrf2 nuclear translocation, (2) inhibited renal activation of NF-κB and the NLRP3 inflammasome, (3) decreased renal MCP-1 expression and mononuclear leukocyte infiltration, (4) inhibited ROS production and NLRP3 inflammasome activation in cultured, activated macrophages, and (5) inhibited ROS production and MCP-1 protein levels in cultured, activated mesangial cells. The results suggest that osthole exerts its reno-protective effects on the progression of IgAN by inhibiting ROS production and activation of NF-κB and the NLRP3 inflammasome in the kidney. Our data also confirm that ROS generation and activation of NF-κB and the NLRP3 inflammasome are crucial mechanistic events involved in the progression of the renal disorder.

Efficacy of tonsillectomy for patients with recurrence of IgA nephropathy after kidney transplantation.

From January 2007, we started to perform the tonsillectomy for every patient with recurrent IgA nephropathy (IgAN) after kidney transplantation. Up to September 2008, four recipients with primary IgAN had biopsy-proven recurrent IgAN. They had also progressive hematuria or proteinuria from on the average 14.3 months after transplantation. Then their specimens diagnosed as recurrent IgAN were collected and they underwent tonsillectomies on the average 52.3 months after transplantation. Abnormal urinary findings of all patients favorably improved after tonsillectomy. All cases but one had mild renal injury, where the severity of glomerular lesions, glomerular hypercellularity, segmental lesions, and sclerosis was mild, and no deteriorated serum creatinine (SCr) before their tonsillectomies. Even the case with exacerbated SCr and severe renal injury, where the severity of glomerular lesions was severe, had her urinary findings ameliorated promptly after tonsillectomy likely as others. At present, they have almost no symptoms after tonsillectomy and no remarkable change of SCr level compared with before and after tonsillectomy and maintain ameliorated urinary findings continuously. Tonsillectomy had possibility to be a favorable treatment of hematuria or proteinuria in recurrent IgAN recipients.

Inhibitory ITAM signaling by Fc alpha RI-FcR gamma chain controls multiple activating responses and prevents renal inflammation.

Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcalphaRI or CD89) by anti-FcalphaRI Fab triggers potent inhibitory ITAM (ITAM(i)) signaling through the associated FcRgamma chain (FcalphaRI-FcRgamma ITAM(i)) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcalphaRI-FcRgamma ITAM(i) signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcalphaRI-Fcgamma ITAM(i) signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcalphaRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcalphaRI-FcRgamma ITAM(i) signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcalphaRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy?

BACKGROUND: IgA nephropathy (IgAN) is a frequent cause of end-stage renal disease (ESRD) and recurrent disease causes deterioration and graft loss in transplant recipients. No definitive management is known to reduce the risk or severity of recurrent IgAN, and the evidence to support the use of renin-angiotensin system blockade in such patients is limited. METHODS: All 1137 renal transplants performed at the Belfast City Hospital over a 27-year period were reviewed. A total of 75 patients with ESRD due to biopsy-proven IgAN were identified; 39 of them had been prescribed an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-II type I receptor blocker (ARB). RESULTS: The two groups were well-matched in terms of demographic details, immunosuppressive regimens and duration of follow-up (median 65 months, range 18-261 months). The 5- and 10-year graft survivals were higher in those prescribed ACEi/ARB therapy compared with those who were not, although these differences did not reach statistical significance (92.9 vs 86.5%; P = 0.34 and 81.6 vs 72.7%; P = 0.32, respectively). These results were similar when censored for death with a functioning graft. In the group where an ACEi/ARB was not prescribed, all four with biopsy-proven recurrent IgAN progressed to ESRD, compared with three out of nine in the group treated with an ACEi/ARB. CONCLUSIONS: In transplant recipients with ESRD due to biopsy-proven IgAN, a trend towards improved 5-year and 10-year graft survival was seen in those prescribed ACEi/ARBs. All with recurrent IgAN in their grafts who were not treated with ACEi/ARB therapy progressed again to ESRD.

Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil.

BACKGROUND: Transplantation offers an excellent option for patients with immunoglobulin-A nephropathy (IgAN) with severe renal dysfunction. However, IgAN frequently recurs in allografts treated with azathioprine. We examined the impact of mycophenolate mofetil immunosuppression on recurrence of IgAN. METHODS: We reviewed the charts of patients transplanted for IgAN at our institution in the cyclosporin era. Patients were excluded from further analysis if follow-up was <12 months or if immunosuppression at engraftment did not include azathioprine or mycophenolate mofetil. Laboratory data, medications and allograft biopsy findings were compiled. RESULTS: 152 kidney transplantations met the study criteria. At engraftment, 61 allografts were treated with azathioprine and 91 with mycophenolate mofetil. By 3 years post-transplant, IgAN developed in six of 60 (10.0%) azathioprine-treated allografts and five of 62 (8.1%) mycophenolate mofetil-treated allografts (P = 0.76). Overall, 13 azathioprine-treated and seven mycophenolate mofetil-treated allografts showed recurrence. As expected in this retrospective study, the duration of observation was longer in the azathioprine group. The interval between engraftment and diagnosis of recurrent disease was also longer. Survival of allografts with recurrent IgAN was similar in the two groups. Survival of allografts with recurrent IgAN was worse than for allografts without recurrence or allografts transplanted into patients with non-IgAN renal failure. Neither switching azathioprine to mycophenolate mofetil nor using an angiotensin-converting enzyme inhibitor or angiotensin-II type 1 receptor blocker ameliorated the clinical course after a biopsy documented recurrent IgAN. CONCLUSIONS: Mycophenolate mofetil, compared with azathioprine, did not lessen the recurrence of IgAN or its clinical impact.

Docosahexaenoic acid attenuates mycotoxin-induced immunoglobulin a nephropathy, interleukin-6 transcription, and mitogen-activated protein kinase phosphorylation in mice.

The purpose of this investigation was to evaluate the dose-dependent effects of docosahexaenoic acid (DHA) on deoxynivalenol (DON)-induced IgA nephropathy in mice and their relation to proinflammatory gene expression and mitogen-activated protein kinase (MAPK) activation. Consumption of a modified AIN-93G diet containing 1, 5, and 30 g/kg DHA resulted in dose-dependent increases of DHA in liver phospholipids with concomitant decreases in arachidonic acid compared with control diets. DHA dose dependently inhibited increases in serum IgA and IgA immune complexes (IC) as well as IgA deposition in the kidney in DON-fed mice; the 30 g/kg DHA diet had the earliest detectable effects and maximal efficacy. Both splenic interleukin-6 (IL-6) mRNA and heterogeneous nuclear RNA (hnRNA), an indicator of IL-6 transcription, were significantly reduced in DON-fed mice that consumed 5 and 30 g/kg DHA; a similar reduction was observed for cyclooxygenase (COX-2) mRNA. In a subsequent study, acute DON exposure (25 mg/kg body weight) induced splenic IL-6 mRNA and hnRNA as well as COX-2 mRNA in mice fed the control diet, whereas induction of both RNA species was significantly inhibited in mice fed 30 g/kg DHA. These latter inhibitory effects corresponded to a reduction in DON-induced phosphorylation of p38, extracellular-signal related kinase 1/2, and c-Jun N-terminal kinase 1/2 MAPKs in the spleen. Taken together, the results indicate that DHA dose-dependently inhibited DON-induced IgA dysregulation and nephropathy, and that impairment of MAPK activation and expression of COX-2 and IL-6 are potential critical upstream mechanisms.

Docosahexaenoic acid and eicosapentaenoic acid, but not alpha-linolenic acid, suppress deoxynivalenol-induced experimental IgA nephropathy in mice.

Diets enriched in the (n-3) PUFAs, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and their precursor alpha-linolenic acid (ALA), were evaluated for efficacy in ameliorating the development of IgA nephropathy (IgAN) induced in mice by the mycotoxin deoxynivalenol (DON). The effects of DON were compared in mice that were fed for 18 wk with AIN-93G diets containing 1) 10 g/kg corn oil plus 60 g/kg oleic acid (control); 2) 10 g/kg corn oil plus 35 g/kg oleic acid and 25 g/kg DHA-enriched fish oil (DHA); 3) 10 g/kg corn oil plus 33 g/kg oleic acid and 27 g/kg EPA-enriched fish oil (EPA); and 4) 10 g/kg corn oil plus 37 g/kg oleic acid and 23 g/kg DHA + EPA (1:1) enriched fish oil (DHA + EPA). The DHA, EPA and DHA + EPA diets attenuated induction by dietary DON (10 mg/kg) of serum IgA and IgA immune complexes, kidney mesangial IgA deposition, and ex vivo IgA secretion by spleen cells. Consumption of the DHA + EPA diet for 8 wk significantly abrogated the DON-induced gene expression of interleukin (IL)-6, a requisite cytokine for DON-induced IgA nephropathy, in spleen and Peyer's patches. Finally, incorporation of ALA-containing flaxseed oil up to 60 g/kg in the AIN-93G diet did not affect DON-induced IgA dysregulation in mice. Taken together, both DHA and EPA, but not ALA, ameliorated the early stages of IgAN, and these effects might be related to a reduced capacity for IL-6 production.

Renal transplantation in patients with primary immunoglobulin A nephropathy.

BACKGROUND: Opinions on the clinical course and outcome of renal transplantation in patients with primary immunoglobulin A nephropathy (IgAN) have been controversial. METHODS: We conducted a retrospective single-centre study on 542 kidney transplant recipients over the period 1984-2001. Long-term outcome and factors affecting recurrence in recipients with primary IgAN were analysed. RESULTS: Seventy-five patients (13.8%) had biopsy-proven IgAN as the cause of renal failure, and their mean duration of follow-up after transplantation was 100 +/- 5.8 months. Fourteen (18.7%) of the 75 patients had biopsy-proven recurrent IgAN, diagnosed at 67.7 +/- 11 months after transplantation. The risk of recurrence was not associated with HLA DR4 or B35. Graft failure occurred in five (35.7%) of the 14 patients: three due to IgAN and two due to chronic rejection. Three (4.9%) of the 61 patients without recurrent IgAN had graft failure, all due to chronic rejection. Graft survival was similar between living-related and cadaveric/living-unrelated patients (12-year graft survival, 88 and 72%, respectively, P = 0.616). Renal allograft survival within the first 12 years was better in patients with primary IgAN compared with those with other primary diseases (80 vs 51%, P = 0.001). Thereafter, IgAN patients showed an inferior graft survival (74 vs 97% in non-IgAN patients, P = 0.001). CONCLUSIONS: Our data suggested that around one-fifth of patients with primary IgAN developed recurrence by 5 years after transplantation. Recurrent IgA nephropathy in allografts runs an indolent course with favourable outcome in the first 12 years. However, the contribution of recurrent disease to graft loss becomes more significant on long-term follow up.

Dietary fish oil suppresses experimental immunoglobulin a nephropathy in mice.

Dietary fish oil (FO) supplementation reportedly retards the progression of renal disease in patients with immunoglobulin (Ig)A nephropathy (IgAN), the most common glomerulonephritis worldwide. Using an experimental mouse model in which early immunopathological hallmarks of IgAN are induced by the mycotoxin vomitoxin (VT), the ameliorative effects of FO ingestion on this disease were evaluated in two studies. In Study 1, the capacity of VT to induce IgAN was evaluated in mice fed for 12 wk AIN-76A diets containing 50 g/kg corn oil (CO), 50 g/kg CO plus 9 mg/kg tert butylhydroquinone (TBHQ), or 5 g/kg CO plus 45 g/kg menhaden FO that contained 200 mg/kg TBHQ. Serum IgA, serum IgA immune complexes and kidney mesangial IgA deposition were greater in mice fed VT + CO compared with the CO control group, whereas all three variables were significantly attenuated in mice fed VT + FO. Although TBHQ also had attenuating effects, these were significantly less than those for the VT + FO group. In Study 2, the effects of feeding modified AIN 93G diets containing either 70 g/kg CO or 10 g/kg CO plus 60 g/kg FO for 20 wk on VT-induced IgAN were compared. Again, consumption of FO attenuated all three immunopathological variables. In addition, spleen cell cultures from the VT + FO group produced markedly less IgA than those cultures from mice fed VT + CO. Taken together, the results suggested that diets containing FO may impair early immunopathogenesis in VT-induced IgAN and that this was not totally dependent on the presence of the antioxidant TBHQ.

Prognostic factors in immunoglobulin-A nephropathy.

AIM: To study the course, identify prognostic factors and a model predictive for development of end stage renal failure (ESRF) in adults with immunoglobulin-A nephropathy (IgA-N). DESIGN: Retrospective cohort. SETTING: Madras Medical College and Government General Hospital, Chennai, Tamil Nadu. PARTICIPANTS: Ninety eight adult patients with diagnosis of primary IgA nephropathy. RESULTS: Out of 98 patient 64 (65.3%) were men. Mean age of presentation was 25.7 years. The predominant renal lesions included nephrotic syndrome in 25 (25.5%), rapidly progressive renal failure and accelerated malignant hypertension in 21 (21.4%) each, chronic renal failure in 13 (13.3%), hypertension in nine (9.2%) haematuria in five (5.1%) and acute renal failure in four (4.1%). Sixty (61%) had renal failure at diagnosis. Age > 25 years, glomerular histology of Hass subclass V and interstitial fibrosis were significant factors. Forty (48.2%) (IR) patients developed ESRF during follow up. Serum creatinine > 5 mg/dl (hazard ratio: 5.37, 95% confidence interval CI 2.49-11.58) Hass-V (3.74, 1.60-8.76), crescents (4.08, 1.52-10.94) and IF (6.15, 2.0-19.0) were associated with disease progression in the multivariate analysis. Five years renal survival (CI) was 38.5% (24.6%-52.3%). Among those with no risk factor, 95% had not reached ESRF by 42 months. The median ESRF-free survival with one, two and three or four risk factors was 65, 16 and four months, respectively. CONCLUSIONS: Serum creatinine > 5 mg/dl, crescents: Hass-V histology and interstitial fibrosis predict the progression to ESRF. Renal biopsies should include a detailed assessment of the tubulointerstitium.

Role of dietary fish oil supplementation in IgA nephropathy. Mechanistic implications.

IgA nephropathy (IgAN) is now recognized as the most common primary glomerulonephritis worldwide. Although the clinical course is variable, many patients develop slowly progressive renal disease, culminating in end-stage renal disease 10-20 years after diagnosis. Some recent randomized clinical trials have suggested that dietary fish oil supplementation may be a relatively safe long-term therapeutic option for preventing the development of progressive renal disease in patients with IgAN. However, other studies have failed to demonstrate a protective effect of dietary fish oil supplementation in treatment of IgAN. Although in vitro studies have provided a theoretical basis for the use of dietary fish oil supplementation, potential mechanisms underlying the protective effect of fish oil have not been well defined. In this overview, recent clinical and experimental data providing a basis for the use of dietary fish oil supplementation in treatment of IgAN and other progressive renal diseases are reviewed.

Prognosis of tonsillectomy in patients with IgA nephropathy.

IgA nephropathy (IgAN) is a type of chronic glomerulonephritis characterized by IgA deposits mainly in the mesangial area. It does not have so favourable a prognosis as was initially thought. This nephropathy is one of the diseases affected by tonsillar focal infections, and there have been patients in whom tonsillectomy has been effective. In this study, 24 patients with IgAN were followed for more than 2 years after tonsillectomy and studied clinicopathologically. Remission of proteinuria was observed in 41.7% of the patients 6 months after surgery and in 50.0% 2 years after surgery. At 2 years after surgery, patients with minor and focal segmental renal lesions showed a significantly higher rate of remission of proteinuria than patients with diffuse renal lesions. There was no statistically significant difference between positive and negative patients in the rate of remission of proteinuria based on any parameter of the tonsillar provocation test at any time after surgery.

Tonsillectomy does not prevent a progressive course in IgA nephropathy.

BACKGROUND: IgA nephropathy, or Berger's disease, is a primary mesangioproliferative glomerulonephritis, usually with a favourable prognosis. PATIENTS AND METHODS: To investigate the effect of tonsillectomy we conducted a retrospective investigation on renal outcome in 55 patients with IgA nephropathy in an outpatient university clinic between 1968 and 1994. Established risk factors for progressive IgA nephropathy were equally distributed in 16 patients subjected to tonsillectomy and in 39 patients without tonsillectomy. Renal survival and impact of risk factors were estimated by Kaplan-Meier analysis and Cox regression model. RESULTS: Seen in terms of the bivariate Kaplan-Meier analysis the probability of renal survival 10 years after biopsy was 0.37 for the 16 patients with tonsillectomy and 0.63 for the 39 patients without tonsillectomy (log-rank test p = 0.49, not significant). In the multivariate Cox regression model with 6 independent clinical covariates, initially high serum creatinine concentration had the strongest impact on renal outcome (p = 0.002), with a hazard ratio of 8.9 (95% CI: 2.3-35.0). Tonsillectomy had no significant influence in the Cox model (p = 0.37), displaying a hazard ratio of 1.7 (95% CI: 0.5-5.7). CONCLUSION: In conclusion, tonsillectomy does not reduce the risk of developing renal failure or prevent a progressive course of IgA nephropathy.