TREATMENT (MEDICATIONS) FOR GLOMERULONEPHRITIS

Dyad Three (3):
Byron Webb A. Romero
Von Deneb H. Vitto
Raymond C. Ursal

Collins, et.al. (2008) conducted a study regarding Rituximab treatment of fibrillary GN (FGN). Accordingly, FGN belongs to a group of disorders characterized by pathogenic deposition of fibrils in the glomeruli. FGN is a glomerulopathy that tends to progress to ESRD, and there are currently no treatments of proven benefit. Since the glomerular deposits contain an immunoglobulin component, it was postulated that anti–B-cell therapy with rituximab, an anti-CD20 monoclonal antibody, may be effective in the treatment of patients with fibrillary glomerulonephritis. The researchers described 3 patients with fibrillary glomerulonephritis who were treated with the drug for nephrotic-range proteinuria. Each of the patients also received standard antiproteinuria therapy, including blockade of the renin-angiotensin system and strict blood pressure control. All the patients showed a decrease in the level of their proteinuria to less than 1.5 g/d of protein by 27 months, and kidney function was preserved throughout the duration of therapy and follow-up. Rituximab manifested no adverse drug effects.

The cases in the study suggest that anti-CD20 monoclonal antibody therapy may be useful in the treatment of patients with FGN. All patients improved after therapy, and there were no adverse effects caused by rituximab observed. One patient in the study experienced a relapse and received another cycle of rituximab therapy with improvement. There have been no previous reports of patients with FGN treated with anti–B-cell therapies. Concomitant immunotherapy was administered to 2 patients. In patient 1, rituximab was used with low-dose tacrolimus. Although the researchers cabbot determine whether the rapid improvement in proteinuria was caused by rituximab or tacrolimus, no study has shown a beneficial effect of tacrolimus, and the patient experienced a relapse on tacrolimus therapy. However, retreatment with rituximab alone induced a significant decrease in proteinuria within 2 months. In patient 2, urine sediment became inflammatory and proteinuria acutely worsened when B cells began to recover. A short course of corticosteroids was given. The inflammatory urine sediment cleared, and over time, proteinuria completely resolved. This response was believed to be caused by corticosteroid-induced remission of acute interstitial nephritis, rather than an FGN response to the brief administration of corticosteroids. The patient in case 3 was treated with only rituximab, showing that it can be effective without adjunctive immunosuppressive therapy and supporting a primary benefit from rituximab therapy in our other patients. Rituximab treatment of patients with other glomerulopathies characterized by immune complex or immunoglobulin-containing deposits provides additional evidence for a primary benefit of anti–B-cell therapy. Eight patients with idiopathic membranous nephropathy received 375 mg/m2/wk of rituximab for 4 weeks, and all showed improvement in proteinuria, with 5 patients showing a decrease in proteinuria greater than 50%. In a related prospective study, 15 patients with membranous disease were treated with 1 g of rituximab twice, and 60% achieved complete or partial remission by 12 months, with an average decrease in proteinuria of 48%. Similarly, 5 patients with hepatitis C–associated mixed essential cryoglobulinemia were treated with rituximab alone (375 mg/m2/wk for 4 weeks), and all showed significant decreases in proteinuria. Attenuation of proteinuria after rituximab therapy generally was seen within 1 to 3 months in the patients, although continued improvement often occurred during the next several months.A similar time course was found in patients with membranous nephropathy, cryoglobulinemia, and lupus nephritis. Taken together, these data suggest that if glomerular immunoglobulin deposition can be halted by depleting B cells, glomeruli can undergo repair. However, decreasing immunoglobulin production is not the only mechanism of action of rituximab. Depletion of B cells also modulates T-cell activity, probably because B cells can produce cytokines and growth factors, and present antigens to T cells. Collins, et.al. (2008) observed no adverse effects of rituximab, in agreement with its good safety profile in the treatment of patients with other immune-mediated diseases. The safety of rituximab therapy may be improved further by adjusting administration to B-cell levels. A recent study of patients with membranous nephropathy showed that circulating B cells disappeared in most patients within a week of the first dose. These patients showed a decrease in proteinuria similar to that of patients given 4 weekly doses. In addition to cost savings and avoidance of unnecessary exposure, dosing to effect rather than according to an arbitrary regimen may prevent infusion reactions and the development of antibodies to rituximab.

Myllymaki, et.al. (2003) mentioned in their study that while proteinuria may react to steroid treatment, steroid dependency is common. Long-term remission of proteinuria was achieved in only 14% of patients which indicates the necessity for a more effective treatment. The case study reported was about a 26-year-old man who presented with recurring IgM nephropathy following transplantation and reacted with complete remission of proteinuria after rituximab therapy. This was the first case report of a patient with a diagnosis of IgM nephropathy that undergone rituximab therapy, that results in complete remission with sustained response 1 year later. Barely a few case reports have been published that documents the recurrence of biopsy-proven IgM nephropathy in a transplant kidney and/or treatment of patients with IgM nephropathy with rituximab.

The researches therefore suggest that rituximab as treatment is one that is promising in terms of management approach of FGN, an entity which was previously considered to be refractory to therapy. In addition, based on the results of the 3 cases, the findings suggest that rituximab can be used safely to induce complete or partial remission in patients with FGN. Several questions remain, including the optimal dosing regimen, duration of response, ultimate outcome in terms of chronic kidney disease and end-stage kidney disease, relevance of re-treatment in patients who experience relapse or achieve only partial remission, and whether rituximab should be combined with other immunosuppressive agents. Nonetheless, this report provides evidence for conducting a prospective trial of anti–B-cell therapy in patients with a disease traditionally considered treatment resistant and of poor renal prognosis.

References:

Collins, M., Navaneethan, S.D., Chung, M., Sloand, J., Goldman, B., Appel, G., & Rovin, B.H. (2008). Rituximab Treatment of fibrillary Glomerulonephritis. American Journal of Jideney Diseases. 52 (6), 1168-1162.

Ghiggeri, G.M., Musante, L., Candiano, G, et al (2007). Protracted remission of proteinuria after combined therapy with plasmapheresis and anti-CD20 antibodies/cyclophosphamide in a child with oligoclonal IgM and glomerulosclerosis. Pediatric Nephrology. 22:1953-1956.

Myllymaki, J., Saha, H., Mustonen, J., Helin, H., & Pasternack, A. (2003). IgM nephropathy: Clinical picture and long-term prognosis. American Journal of Kidney Diseases. 41:343-350.

Response
D2- Gil Legarda and Joanalyn Balino

Treatment of idiopathic membranoproliferative glomerulonephritis
with mycophenolate mofetil and steroids

Gareth Jones, Maciej Juszczak, Edward Kingdon, Mark Harber, Paul Sweny and Aine Burns


A retrospective quasi -experimental study was used by Jones, G., Juszczack, M et al. in order to investigate whether mycophenolate mofetil (MMF) in combination with prednisolone could improve renal outcomes in Idiopathic membranoproliferative glomerulonephritis (IMPGN). There were a total of 11 IMPGN patients participated in this study. There were 5 patients taking oral prednisolone and MMF. These 5 patients belong to the treatment group. The control group comprised of 6 patients with IMPGN. The data of these 11 patients were recorded from the time the treatment was initiated and subsequent data was recorded from follow-up visits which is 6, 12 and 18 months after the initiation of treatment. The data of the 11 MPGN patients were taken from the medical record, electronic pathology resources, and electronic patient databases. Exclusion criteria include: (1) with a known secondary cause for MPGN; (2) Patients with hepatitis B, C, and HIV negative and had negative serology for a panel of autoantibodies (double-stranded DNA, ANA and extractable nuclear antigens; and age over 17 at baseline. The treatment group received 60 mg of oral prednisolone and tapering it to 20 mg within 2 months and withdrawn by 1 year. They started receiving MMF with a dose of 500 mg/day and it was increased gradually (depending on patient’s tolerance) to a maximum of 2g daily. 1.1g/day is the maximum dose for MMF. Treatment group also received 20 mg of omeprazole, 480 mg co-trimoxazole, and 1ml of nystatin suspension. Omeprazole and co-trimoxazole were taken daily, and nystatin suspension was taken QID for at least 6 months. Repeated measures ANOVA was the statistical analysis that was used to know the inter- and intra- group differences. T-test was used to analyze the change in mean values between baseline and 18 months.

There was a significant reduction in proteinuria in the treatment group from a baseline of 5.09 to 1.97 g/24 h. The reduction in proteinuria was associated with a non-significant increase
in serum albumin concentration from 29 g/l at baseline to 36.6 g/l at 6 months, 38.2 g/l at 12 months and 37 g/l after 18 months. In the control group, there was no change in proteinuria over 18 months
The control and treatment groups were compared by repeated measures ANOVA, the result is P=0.03 so, there was a significant difference in proteinuria between the two groups The serum albumin concentration in the control group has a small but insignificant change in, from 30.8 g/l at baseline to 33.7 g/l at 6 months, 34.5 g/l at 12 months and 33.5 g/l after 18 months. The Serum Creatinine concentration did not change significantly in the treatment group over 18 months. The control group, has stable serum creatinine during the first 12 months but rose significantly from baseline at 18 months.
For the comparison of the two the result is there was no significant difference between the control and treatment groups using repeated measures ANOVA (P=0.19). The Measured creatinine clearance
Creatinine clearance did not change significantly in the treatment group. The control group creatinine clearance was significantly reduced from baseline at 6, 12 and 18 months; Using the repeated measures ANOVA, the difference did not reach statistical significance (P=0.06).



The study revealed that there is a significant reduction in proteinuria for those patients who received prednisolone and MMF for the past 6 months. A reduction of proteinuria in response to treatment predicts a long-term renal survival and also protenuria is one of the best predictor of renal outcome in non-diabetic kidney disease (Peterson et al., 1995). This prospective study done by Jones, G., Juszczak, M. et al suggest the combination of MMF and prednisolone in short term can significantly reduce proteinuria and in result may preserve the IMPGN patients’ renal functions. This study also plays a role in giving an insight in the treatment option for Idiopathic membranoproliferative glomerulonephritis.


Jones G., Juszczak, M. et al. (2004). Treatment of idiopathicmembranoproliferative glomerulonephritis with mycophenolate mofetil and steroids. Nephrol Dial Transplant (2004) 19: 3160–3164. Retrieved June 24, 2009 from
http://ndt.oxfordjournals.org/cgi/reprint/19/12/3160?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=20&resourcetype=HWCIT



Peterson JC, Adler S, Burkart JM et al.(1995). Blood pressure control,proteinuria and the progression of renal disease. The modification of diet in renal disease study. Ann Intern Med 1995; 123: 754–762

Dyad 1 : Nancelle Dumlao/ Rodel Perez

Treatment and Medications for Glomerulonephritis

Efficacy and safety of ‘rescue therapy’ with mycophenolate mofetil in resistant primary glomerulonephritis—A multicenter study
by: Alfons Segarra, M Luisa Amoedo, Jose M Martinez Garcia, Salvador Pons, Manuel Praga, Elvira Izquierdo Garcia, Juan Carlos Alonso, Joan M. Gascó, L. Pou and Luís Piera.

End-stage renal disease is currently on the rise and primary glomerular diseases is considered the leading cause especially in young patients. There are several measures being utilized to prevent deterioration of a patient with primary glomerular diseases such as blood pressure control, salt restrictions and ACE inhibitors, glucocorticoids and classic immunosuppressive drugs. However, adverse effects of the drugs and inability to sustain positive outcomes warrants the need to discover new treatments for the disease. There are two transplant immunosuppressants now being used for primary glomerulonephritis: (1) calcineurin inhibitors (such as ciclosporin A) and (2) mycophenolate mofetil (MMF). For the former, many clinical studies have proven that it resulted to sustained remission for many patients with idiopathic focal segmental glomerulosclerosis (FSGS) or membranous nephropathy, (MN). There is a drawback though, which is chronic nephrotoxicity for the long-term use of ciclosporin A. However, for mycophenolate mofetil (MMF) there is still a need to further study how best to utilize the drug. Hence, the undertaking of this multicenter large cohort study which intends to analyse the efficacy and safety of MMF as a monotherapy for primary glomerulonephritis for those patients that are nonresponding to conventional treatments. This is only a 12-month study to determine short-term efficacy data, minimum treatment period, potential predictors of outcome and response rates in each type of disease. The 98 subjects from 8 hospitals had renal biopsy-proven primary glomerulonephritis and are not responding to other drugs were given MMF for 1 year. Outcomes of the study were measured using urinary protein excretion, complete (defined as PR < 0.3 g/day in two consecutive measurements within 3 months) or partial remission of proteinuria (defined for IgAN as PR 0.3 and
1 g/day), changes in the slope of creatinine clearance.


The result of the large cohort study showed that fifty-four percent (54%) of the patients had either complete or partial remission of proteinuria in any type of glomerulonephritis. The treatment with MMF only induced complete remissions of proteinuria in a minority of patients. On the other hand, it improved urinary protein excretion in more than 50% of the patients with resistance to other immunosuppressant drugs and who had persistent proteinuria, even if they have ACEI or AIIRA and a low-salt diet. Furthermore, there was higher reduction in urinary protein excretion in patients with basal nephrotic proteinuria and preserved renal function. Also, the mean blood pressure decreased significantly resulting to reduction in antihypertensive drugs.


The study was beneficial in ascertaining that another important immunosuppressive drug which is the mycophenolate mofetil (MMF) could be helpful in prolonging the lives of patients with primary glomerulonephritis. The MMF monotherapy was used to gain moderate decrease in proteinuria in more than half of the patients who do not have other treatment options. The positive outcome of the therapy was largely due to a patient having preserved renal function and having sustained MMF treatment.

This new treatment option, particularly to those unresponsive to the current available drugs, have given new hope for a better and longer life for the patients. Considering the high cost of the immunosuppressive drugs, the study is also beneficial in lowering their medical bills by reducing the use of antihypertensive drugs since MMF has contributed in controlling the mean blood pressure of the patients.

Reference:

Segarra,A.; Amoedo, L; Garcia, J.; Pons, S.; Praga,M.; Garcia, E.; Alonso,J.; Gascó, J.; Pou,L.; and Piera, L. Efficacy and safety of ‘rescue therapy’ with mycophenolate mofetil in resistant primary glomerulonephritis—A multicenter study. Oxford University Journal. 2007.

DYAD 4
BALAJADIA, BOND
ZANO, ALEXIS

We find this study pertinent for additional resource on the treatment and management of Glumerulonephritis

Fibrillary glomerulonephritis with small fibrils in a patient with the antiphospholipid antibody syndrome successfully treated with immunosuppressive therapy

Fibrillary glomerulonephritis (FibGN) is a rare cause of progressive renal dysfunction. The majority of patients who develop the disease require dialysis within a few years. It was first described by Rosenmann and Eliakim in 1977 as an amyloid-like glomerulopathy but with negative congo red staining. Alpers et al introduced the term FibGN in 1987. It is characterized by the deposition of randomly arranged fibrils in the mesangium and glomerular basement membrane. The fibrils are generally less than 30 nm in diameter, with the majority measuring approximately 20 nm. This condition is closely related to immunotactoid glomerulopathy. There is some overlap between these two conditions, which has led some pathologists to propose that they should be classified together as one entity.

A 56 year old woman with the antiphospholipid antibody syndrome (IgM anticardiolipin antibodies) was seen in the nephrology clinic with haematuria, proteinuria, and worsening renal function. A renal biopsy demonstrated a mesangial proliferative glomerulonephritis on light microscopy and smaller fibrils (10.6–13.8 nm in diameter) than is usual for fibrillary glomerulonephritis (typically 18–22 nm) on electron microscopy. Amyloidosis was excluded following detailed evaluation. On account of rapidly worsening renal failure she was started on cyclophosphamide and prednisolone which led to the partial recovery and stabilization of her renal function.

This case highlights the need for routine electron microscopy in native renal biopsies, where the differential diagnosis is wide and varied and the light and immunofluorescence microscopic findings may be non specific.
The diagnosis of FibGN cannot be made on the basis of the size of the fibrils alone. A therapeutic trial of cyclophosphamide and prednisolone in patients with progressive renal dysfunction who are able to tolerate the treatment, and who understand the risks is worthwhile. This may prevent or slow down the progression of renal failure.

Javaid, M et. al. Fibrillary glomerulonephritis with small fibrils in a patient with the antiphospholipid antibody syndrome successfully treated with immunosuppressive therapy. PMC. May 2007

Dyad 6 guomanman and chenya

Treatment of glomerulonephritis and your outcome depend on:

Whether you have an acute or chronic form of the disease
The underlying cause
The type and severity of your signs and symptoms
Some cases of acute glomerulonephritis, especially those that follow a strep infection, often improve on their own and require no specific treatment.

To control your high blood pressure and slow the decline in kidney function, your doctor may prescribe one of several medications, including:

Diuretics
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin II receptor agonists
Your doctor also may prescribe other drugs to treat the underlying cause of glomerulonephritis:

Strep or other bacterial infection. Your doctor likely will prescribe an appropriate antibiotic.
Lupus or vasculitis. Doctors often prescribe corticosteroids and immune-suppressing drugs.
IgA nephropathy. Fish oil supplements have been successful in some people with IgA nephropathy and are under study.
Goodpasture's syndrome. Plasmapheresis is sometimes used to treat people with Goodpasture's syndrome. Plasmapheresis is a mechanical process that removes antibodies from your blood by taking the plasma out of your blood and replacing it with fluid or donated plasma.
Therapies for associated kidney failure
For acute glomerulonephritis and acute kidney failure, temporary dialysis can help remove excess fluid and control high blood pressure. The only long-term therapies for end-stage kidney failure are kidney dialysis and kidney transplantation. When a transplant isn't possible, often because of poor general health, dialysis becomes the only option.