Diffuse Proliferative Glomerulonephritis Guidelines

In its clinical practice guidelines for glomerulonephritis, Kidney Disease: Improving Global Outcomes (KDIGO) offers the following general principles in the management of glomerular disease ^[34] :

• Kidney biopsy is required for diagnosis; repeat biopsy should be considered when a change in therapy is considered or following a relapse 
• Key outcome measures for the management of glomerulonephritis include assessment of kidney function, particularly measurement of proteinuria and glomerular filtration rate (GFR)

The following complications are a consequence of the clinical presentation rather than the specific histolopathologic pattern. Active management of should always be considered and may have a significant positive impact on the natural history of the disease ^[34] :

• Hypertension
• Proteinuria
• Hyperlipidemia
• Nephrotic edema
• Hypercoagulability
• Risk of infection

In its clinical practice guidelines for glomerulonephritis, KDIGO makes the following recommendations for evaluation of patients with IgA nephropathy ^[29] :

• All patients should be assessed by biopsy for secondary causes of IgA nephropathy
• Risk of progressession should be evaluated by measurement of proteinuria, blood pressure, and estimated glomerular filtration rate (eGFR) at the time of diagnosis and during follow-up
• Pathological findings can be used to assess prognosis

KDIGO recommendations for IgA nephropathy treatment include the following ^[29] :

• Long-term therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is recommended for patients with proteinuria >1 g/day with up-titration of the dose based on blood pressure (grade 1B).
• ACEI or ARB therapy is suggested for proteinuria of 0.5-1 g/d (grade 2D).
• Upward titration of the ACEI or ARB as far as tolerated is suggested, to achieve proteinuria of 1 g/d (grade 2C).
• Blood pressure treatment goals: < 130/80 mm Hg with proteinuria of 1 g/d; < 125/75 mm Hg if initial proteinuria is >1 g/d (not graded)
• A 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a GFR >50 ml/min/1.73m ² (grade 2C).
• Fish oil may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control) (grade 2D).

KIDGO guidelines recommend against using mycophenolate mofetil, antiplatelet agents, or tonsillectomy for the treatment of IgA nephropathy (grade 2C). In addition, the following treatments are recommended against unless the patient has crescentic IgA nephropathy with rapidly deteriorating kidney function ^[29] :

• Corticosteroids combined with cyclophosphamide or azathioprine (grade 2D)
• Immunosuppressive therapy in patients with GFR < 30 ml/min/1.73m ² (grade 2C)

Crescentic IgA nephropathy is defined by KIDGO as IgA nephropathy with crescents in more than 50% of glomeruli in the renal biopsy with rapidly progressive renal deterioration. ^[29]

Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN) Guidelines

Clinical guidelines for managment of IgA nephropathy have been developed by the Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN). These guidelines are meant to to address the clinical situation and establish a standard treatment in Japan, and recommend focusing the managent of IgA nephropathy on prevention of renal dysfunction. Treatments to suppress IgA nephropathy progression are based on the following patient factors ^[35] :

• Kidney function
• Urinary protein level
• Age
• Renal histopathological findings

Treatments to be considered, if necessary. are as follows:

• Reduce blood pressure
• Reduce salt intake
• Normalize lipid and glucose metabolism
• Reduce body weight
• Smoking cessation 

In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-3b, the guidelines give a strong recommendation (grade A) for the use of ACEI or ARB therapy to control progression of renal dysfuntion. In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-2, the guidelines recommendations include the following ^[35] :

• High-dose oral steroid therapy: prednisolone at 0.8–1.0 mg/kg for about 2 months, followed by gradual tapering over about 6 months (grade B)
• Steroid pulse therapy: methylprednisolone 1 g for 3 days by infusion (or IV) every other month, 3 times plus prednisolone 0.5 mg/kg, every other day, for 6 months (grade B) 

The following treatment options may be considered, but only weak evidence supports these recommendations (grade C1) ^[35] :

• ACEI or ARB therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day
• Steroid therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day and CKD stage G1-2
• Tonsillectomy alone or combined with steroid pulse therapy to improve urinary findings and lower the progression of renal dysfunction
• Off-label use of cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, and mizoribine to improve the renal prognosis
• Antiplatelet agents: dipyridamole to reduce proteinuria and control the progression of kidney dysfunction; dilazep to reduce proteinuria
• Fish oil to improve the renal prognosis

In its clinical practice guidelines for glomerulonephritis, KDIGO makes the following recommendations for treatment of class IV lupus nephritis (LN) ^[6] :

• Initial therapy with corticosteroids (grade 1A), combined with either cyclophosphamide (grade 1B) or mycophenolate mofetil (MMF) (grade 1B)
• In cases of increasing serum creatinine level and/or worsening proteinuria during the first 3 months of treatment, a change should be made to an alternative initial therapy, or a repeat kidney biopsy should be performed to guide further treatment. (grade 2D)
• After completion of initial therapy, maintenance therapy is initiated with azathioprine or MMF, and low-dose oral corticosteroids (grade 1B)
• For maintenance therapy in patients intolerant of MMF and azathioprine, calceineurin inhibitors (CNIs) with low-dose corticosteroids may be used. (grade 2C)
• After complete remission is achieved, maintenance therapy should be continued for at least 1 year before tapering the immunosuppression. (grade 2D);  If complete remission has not been achieved after 1 year of maintenance therapy, consider performing a repeat kidney biopsy before determining if a change in therapy is indicated. (Not graded)
• While maintenance therapy is being tapered, if kidney function deteriorates and/or proteinuria worsens, increase treatment to the level of immunosuppression that controlled the LN. (grade 2D)
• For patients who have failed more than one initial regimen consider treatment with rituximab, intravenous immunoglobulin IVIG), or CNIs. (grade 2D)

For relapsed disease, KDIGO offers the following recommendations ^[6] :

• Treat with the initial therapy followed by the maintenance therapy that was effective in inducing the original remission (grade 2B)
• If resuming the original therapy would put the patient at risk for excessive lifetime cyclophosphamide exposure, then a non–cyclophosphamide-based regimen should be used (grade 2B)
• Consider a repeat kidney biopsy if there is suspicion that the histologic class of LN has changed, or there is uncertainty whether increasing serum creatinine level and/or worsening proteinuria represents disease activity or chronicity. (not graded)

KDIGO guidelines recommend cyclophosphamide and corticosteroids plus plasmapheresis for treatment of anti–glomerular basement membrane (GBM) glomerulonephritis, except in patients who are dialysis dependent and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage (grade 1B). Treatment should be initiated immediately upon diagnosis confirmation. If the diagnosis is strongly suspected, high-dose corticosteroids and plasmapheresis can be administered until diagnosis is confirmed (not graded). Maintenance immunosuppressive therapy is not recommended (grade 1D) and kidney transplantation should be deferred until anti-GBM antibodies have been undetectable for a minimum of 6 months (not graded). ^[7]

For the initial treatment of of pauci-immune glomerulonephritis with or without circulating antineutrophil cytoplasmic antibody (ANCA), KDIGO guidelines recommend cyclophosphamide and corticosteroids (grade 1A). Rituximab with corticosteroids can be used as an alternative initial treatment in patients without severe disease or if cyclophosphamide is contraindicated (grade 1B). Cyclophosphamide therapy should be discontinued after 3 months in patients who remain dialysis-dependent and who do not have any extrarenal manifestations of disease (grade 2C). The addition of plasmapheresis is recommended for the following  ^[3] :

• Patients requiring dialysis or with rapidly increasing serum creatinine level (grade 1C)
• Patients with diffuse pulmonary hemorrhage (grace 2C)
• Patients with overlap syndrome of ANCA vasculitis and anti-GBM disease (grade 2D)

Rituximab should be added for treatment of disease resistant to induction therapy with cyclophosphamide and corticosteroids (grade 1C). IVIG  (grade 2C) or plasmapheresis (grade 2D) may be considered as alternative therapies. ^[3]  

KDIGO guidelines recommend maintenance therapy for patients who have achieved remission (grade 1B) and should be continued for at least 18 months in patients who remain in complete remission. (grade 2D) No maintenance therapy is recommended for patients who are dialysis-dependent and have no extrarenal manifestations of disease (grade 1C). Recommendations for choice of agent include the following ^[3] :

• Azathioprine is the preferred maintenance therapy (grade 1B)
• MMF may be used for maintenance therapy if azathioprine is contraindicated (grade 2C) 
• Methotrexate is an alternative if both azathioprine and MMF are contraindicated (grade 1C)
• Trimethoprim-sulfamethoxazole can be used as an adjunct therapy in patients with upper respiratory tract disease (grade 2B)
• Etanercept is not recommended for adjunctive therapy (grade 1A)

Severe relapse (life- or organ-threatening) of ANCA vasculitis should be treated following the recommendations for initial treatment above (grade 1C).  For other relapses, immunosuppressive therapy should be reinstated or increased in intensity with agents other than cyclophosphamide, including instituting or increasing corticosteroids, with or without azathioprine or MMF. (grade 2C) ^[3]  

Kidney transplantation should be delayed until patients are in complete extrarenal remission for 12 month. (grade 1C) However, transplantation should not be delayed  for patients who are in complete remission but are still ANCA-positive (grade 1C). ^[3]

European League Against Rheumatism (EULAR), European Renal Association (ERA) and European Dialysis and Transplant Association (EDTA) Guidelines

Joint guidelines for the management of ANCA-associated vasculitis were released by the European League Against Rheumatism (EULAR), European Renal Association (ERA) and European Dialysis and Transplant Association (EDTA) in 2016. For initial treatment or major relalpse of life or organ-threatening disease, glucocorticoids with either cyclophosphamide or rituximab is recommended; and, for initial treatment of non-organ- threatening disease, glucocorticoids and either methotrexate or MMF is recommended. Similar to KDIGO, the addition of plasmapheresis is recommended for thepatients with either of the following ^[2] :

• A serum creatine level of ≥500 mmol/L (5.7 mg/dL) due to rapidly progressive glomerulonephritis
• Severe diffuse alveolar hemorrhage

For treatment of disease resistant to induction therapy, the guidelines recommend switching from cyclophosphamide to rituximab or from rituximab to cyclophosphamide. At least 24 months of maintence therapy with a combination of low-dose glucocorticoids plus azathioprine, rituximab, methotrexate, or MMF is recommended for patients who have achieved remission. ^[2]

Additionally the guidelines recommend the investigation of persistent unexplained hematuria in patients with prior exposure to cyclophosphamide. Because hypoimmunoglobulinemia has been reported after treatment with rituximab, testing of serum immunoglobulin levels prior to each course of rituximab and in patients with recurrent infection is recommended. ^[2]