Pauci-Immune Necrotizing Glomerulonephritis

Pauci-immune necrotizing GN or ANCA-associated GN may present as a systemic small-vessel vasculitis, pulmonary renal syndrome, or renal limited disease. The spectrum of disease includes microscopic polyangiitis, Wegener’s granulomatosis, and Churg Strauss syndrome. Renal biopsy features crescentic GN, fibrinoid necrosis, and an absence of immunoglobulin or complement within the glomeruli by immunohistology. Either anti-myeloperoxidase (MPO) or anti-proteinase 3 (PR3) antibodies are detectable in most patients. However, some patients with characteristic clinical manifestations of these diseases and pauci-immune GN do not have detectable antibodies.

Mortality of untreated disease is roughly 90% at 2 years following disease onset.¹⁷ However, systematic studies of different treatment regimens have led to significant progress in this field and improved patient outcomes.¹⁸ Treatment consists of pulse intravenous (IV) methylprednisolone followed by oral corticosteroids and IV cyclophosphamide.^14,19–21 Even patients who are dialysis dependent on presentation often recover renal function with appropriate treatment. Poor prognostic indicators for patient and renal survival are the presence of DAH, severity of renal injury at diagnosis, degree of glomerular injury, extent of tubulointerstitial lesions on biopsy, and older age.^22–26 Patients with DAH have a high mortality rate, and plasma exchange improves patient survival.^17,27,28 For severe pulmonary disease, a few patients have been successfully treated with ECMO (extracorporeal membrane oxygenation).^29,30 Additionally, patients with severe renal disease have an increased likelihood of renal recovery when treated with plasma exchange.^{23,25,31–33} With appropriate treatment, roughly 80% to 90% of patients achieve remission.^{17,21,27,34,35} Treatment resistance is more common in females, African Americans, and patients with severe renal disease. Relapse is more common in patients with anti-PR3 antibodies and involvement of the pulmonary and upper respiratory systems. The ANCA-associated small-vessel vasculitides follow a remitting and relapsing course, making long-term monitoring a key component to patient and kidney survival.

Anti-Glomerular Basement Membrane Glomerulonephritis

Goodpasture’s syndrome or anti-GBM disease presents as DAH and RPGN with evidence of anti-GBM antibodies on serologic testing. However, roughly 30% to 40% of patients present with renal limited disease without pulmonary involvement. It commonly affects Caucasians in a bimodal age distribution with peaks during the third and sixth decades.^14,36–38 Renal biopsy shows linear deposition of antibodies, most commonly IgG and C3, along the GBM and glomerular crescent formation.

Untreated disease is highly fatal, and death is usually due to pulmonary hemorrhage or infection. Treatment with plasma exchange, cytotoxic agents, and corticosteroids was introduced in the 1970s, resulting in improved patient and renal survival.³⁹ Plasma exchange is crucial for rapid clearance of anti-GBM antibodies⁴⁰ and should be continued daily until antibodies are undetectable.³⁸ Long-term outcomes are related to the degree of pulmonary compromise and renal dysfunction at presentation. With appropriate treatment, survival rates may exceed 90% for acute disease, but patients requiring RRT on initial presentation have lower survival rates.^37,38,41 For those patients, only a very few recover renal function despite treatment with plasma exchange, corticosteroids, and cyclophosphamide. In contrast, those patients with creatinine (Cr) below 5.7 on presentation demonstrated 100% 1-year patient survival and 95% renal recovery in one study.^37,41 In addition to dialysis dependence and elevated creatinine, predictors of poor renal outcome include oligoanuria, high anti-GBM antibody titers, and high percentage of glomeruli with crescent formation and extensive tubulointerstitial disease on renal biopsy.^36,40,42,43 Although patient and renal survival is generally worse with anti-GBM disease than with ANCA-associated disease, late recurrence of anti-GBM disease is much rarer than recurrence of ANCA-associated disease.^12,38

Both ANCA-associated vasculitis and anti-GBM disease are rare diseases, and interestingly, a subset of patients actually demonstrates both types of antibodies on serologic studies. Roughly 15% to 30% of patients with ANCA-associated disease also have anti-GBM antibodies, while only 5% to 10% of patients with anti-GBM antibodies also have detectable ANCA titers.^{12,37,38,44–46} Although outcome data are limited in this small group of patients, the outcomes of these patients may be better than patients with only anti-GBM antibodies.

Lupus Nephritis

Lupus nephritis occurs in 40% to 70% of patients with SLE and often occurs in the first 2 years following diagnosis.^47–49 Less than 5% of patients present with RPGN or pulmonary renal syndrome. However, 10% to 20% of patients with lupus nephritis ultimately progress to ESKD. In addition to history and physical examination, evaluation includes analysis of urine sediment (because lupus nephritis may present as nephritic or nephrotic syndrome), assessment of proteinuria, complement levels, and serologies for ANA and anti-dsDNA antibodies. Cellular casts or proteinuria over 0.5 g/d is consistent with the diagnosis of lupus nephritis. Renal biopsy is critical for diagnosis, prognosis, and guiding treatment.

Renal biopsy is used to classify lupus nephritis into six categories: class I (minimal mesangial lupus GN), class II (mesangial proliferative lupus GN), class III (focal proliferative lupus GN), class IV (diffuse proliferative lupus GN), class V (membranous lupus GN), and class VI (advanced sclerosis).^50–52 The most severe classes are the proliferative lesions of lupus nephritis (classes III and IV) and have poor renal survival without aggressive treatment. These classes often present with hematuria, proteinuria, hypertension, and AKI. Patients who present with RPGN are likely to have class IV lupus nephritis on renal biopsy. Sclerosing lupus nephritis is a chronic lesion that carries a poor prognosis.

Treatment of the more severe forms of lupus nephritis includes pulse methylprednisolone followed by oral corticosteroids and IV cyclophosphamide.^48,53–57 Similar to treatment of pauci-immune GN, pulse IV cyclophosphamide is preferred over oral cyclophosphamide. Over 80% of patients respond to treatment.^47,48 Importantly, about 5% to 10% of patients who require RRT initially recover enough renal function to become dialysis independent following treatment.⁴⁹ Recent studies suggest that mycophenolate mofetil (MMF) is similar to cyclophosphamide in inducing remission; however, relapse appears more common in patients treated with MMF.^58–62 Induction should be followed by maintenance therapy; the optimal maintenance regimen remains under intense investigation. Options for maintenance include additional cyclophosphamide, azathioprine, and MMF.^48,57,63,64

Poor prognostic indicators at the beginning of treatment include male gender, African American race, severe hypertension, antiphospholipid syndrome (APS), and delayed initiation of immunosuppressive therapy. Following induction treatment, poor prognostic indicators are failure to achieve remission at 6 months and uncontrolled hypertension.^48,49 Roughly one-third to half of patients will have relapse of disease. In some patients, recurrence of disease may be preceded by falling complement levels and rising anti-dsDNA titers. However, some patients with severe lupus nephritis have negative titers.^47,65 Patients with only partial remission often recur sooner than patients with complete remission, and they are more likely to progress to ESKD.⁶⁶ All patients with a history of lupus nephritis should be carefully monitored for recurrence of disease, and repeat renal biopsy is often needed to guide treatment decisions with relapsed disease.

Postinfectious Glomerulonephritis

Postinfectious glomerulonephritis (PIGN) presents as a classic nephritic syndrome occurring about 1 to 3 weeks after a group A β-hemolytic Streptococcus infection.^67–69 It commonly occurs in children following a skin or pharyngeal infection. Although PIGN remains the most common cause of acute nephritic syndrome in the pediatric population in developing countries, the incidence of this disease has declined dramatically in the industrialized world. Children present with a classic nephritic syndrome with hematuria, proteinuria, hypertension, edema, and mild renal impairment. Severe hypertension with encephalopathy and seizures is uncommon and may require admission to the ICU.^69–71 Laboratory findings demonstrate depressed complement levels (CH50 and C3) consistent with activation of the alternate complement cascade; levels return to normal by 8 to 12 weeks. Serologic studies may be used to confirm recent streptococcal infection, particularly with recent pharyngitis.^69,72,73 Renal biopsy demonstrates endocapillary proliferation and granular deposition of immune complexes by immunohistology.^{67,72,74–76}

The acute nephritic syndrome usually resolves in 7 days, and the prognosis of children with PIGN is excellent. However, roughly 10% to 20% of children have persistent urinary abnormalities including proteinuria and hematuria.^{68,69,73,77–79} Treatment is generally supportive with antihypertensives and diuretics as needed in the acute phase. Active infections should be treated, and prophylactic antibiotics are often indicated in endemic situations and for household contacts in regions with high prevalence of disease.

In contrast to children, outcomes for PIGN in adults in the industrialized world are much worse, particularly for patients with underlying chronic disease.^{67,68,80–82} PIGN can be associated with almost any infection, including most streptococcal and staphylococcal strains, gram-negative bacteria, mycobacteria, viruses, fungi, and parasites. Elderly patients often present with AKI, congestive heart failure, and nephrotic-range proteinuria. Up to half of these patients have underlying chronic diseases or risk factors including diabetes mellitus, liver disease or alcoholism, cancer, and IV drug use.^80–83 Some patients demonstrate skin or pharyngeal infections, but many have other infections such as endocarditis and pulmonary infections. Streptococcal and staphylococcal infections account for only half of cases. Treatment consists of supportive care and eradication of infection. Although recent studies of adults with PIGN remain small, one-quarter to one-half of patients have persistent renal dysfunction, and as high as 15% may progress to ESKD.^80–8284 In one small study, patients with underlying diabetic nephropathy had an extremely poor prognosis, with 81% progressing to ESKD.⁸²

IgA Nephropathy

IgA nephropathy (IgAN) is an extremely common form of GN worldwide. However, IgAN is a renal-limited disease, with only 3% of patients presenting with AKI⁸⁵ and most patients diagnosed in the outpatient setting. It commonly presents in the second or third decade of life and affects males more often than females.⁸⁶ The majority of patients present with macroscopic or microscopic hematuria. Many patients have episodic hematuria, often associated with a concurrent upper respiratory tract or gastrointestinal infection. Patients may develop hypertension and varying degrees of proteinuria. Crescentic IgAN is associated with nephrotic-range proteinuria, severe hypertension, and rapidly declining renal function.⁸⁷ No specific laboratory study to date can establish the diagnosis; renal biopsy is required. The extent of changes by light microscopy is variable, and the diagnosis is based on the demonstration of mesangial IgA deposits by immunohistology.

The long-term prognosis of patients with IgA nephropathy is highly variable, but many patients develop progressive renal failure. Between 15% and 40% of patients reach ESKD within 10 to 20 years of diagnosis.^88,89 No consensus on the optimum treatment of IgAN is available owing to the lack of well-designed controlled trials. Progress is hampered by the fact that renal failure develops slowly over decades, and short clinical trials have limited usefulness.^74,88,90,91 In all patients, hypertension should be aggressively treated with renin-angiotensin blockade. Patients with significant proteinuria and declining renal function may benefit from corticosteroids or immunosuppressive agents. Corticosteroids appear to reduce the risk of progression to ESKD and decrease proteinuria in selected patients.^89,90,92 The small percentage of patients presenting with RPGN and crescentic GN are usually treated with pulse corticosteroids and cyclosphosphamide.^87,88 Predictors of disease progression include renal dysfunction at diagnosis, significant proteinuria, hypertension, and evidence of chronic disease by renal biopsy.^86,88,93,94

Henoch-Schönlein Purpura

On renal biopsy, Henoch-Schönlein purpura (HSP) is indistinguishable from IgAN. However, HSP is a systemic disease characterized by a distinct purpuric rash and gastrointestinal involvement. It occurs in children much more commonly than adults. The classic presentation is sudden onset of rash, progressing from nonblanching erythematous macules to urticarial papules to purpura with a symmetrical distribution on the extensor surfaces of the distal extremities and buttocks.^95,96 Children present more frequently with gastrointestinal manifestations and fevers, whereas adults often have more severe renal involvement as well as joint symptoms.^97,98 Renal involvement occurs in roughly one-third of children and two-thirds of adults.^99,100

Renal involvement in HSP is usually more severe at presentation than IgAN, but most children completely recover.^97,101,102 Estimates of recovery and chronic kidney disease vary widely, but the prognosis for renal recovery is worse in adults. Poor prognostic indicators include renal dysfunction and significant proteinuria at presentation, hypertension, and extensive glomerular disease by renal biopsy.^{98,99,102,103} Treatment is primarily supportive care, and trials to date do not support any specific treatment regimen.¹⁰⁴ Corticosteroids may be useful in the short term, but there is no clear evidence that prednisone prevents serious long-term renal disease.^100,105 Recently, two adults with severe systemic manifestations refractory to corticosteroids and immunosuppressive agents were treated with plasmapheresis with subsequent improvement.¹⁰⁶

Thrombotic Microangiopathies

Thrombotic microangiopathy (TMA) is characterized by widespread thrombosis of arterioles and capillaries, with intraluminal platelet aggregation and vessel wall thickening.^107–109 The underlying pathophysiologic cause of TMA is endothelial damage due to a variety of insults. The classic diseases associated with TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), but it may also be seen with catastrophic antiphospholipid syndrome (APS) and scleroderma renal crisis. TMA is also associated with a variety of medications including chemotherapeutic agents, calcineurin inhibitors (cyclosporine and tacrolimus), antiplatelet agents (ticlopidine and clopidogrel), and quinine.¹⁰⁷ The classic pentad of findings in TTP includes microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms and signs, impaired renal function, and fevers.^107–109 Neurologic symptoms may dominate, presenting as confusion, headache, seizures, and coma. The renal manifestations are usually more prominent in HUS, and the typical presentation in children includes microangiopathic hemolytic anemia, thrombocytopenia, and AKI. Laboratory hallmarks include microangiopathic hemolytic anemia with schistocytes on peripheral smear, elevated lactate dehydrogenase levels, and thrombocytopenia, with platelets usually less than 60,000.

Remarkable progress has been made in elucidating the molecular basis for TTP and HUS. TTP occurs as familial and acquired forms, and both forms are related to abnormalities in the function of a zinc metalloprotease, ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13).^108–110 This protein is involved in the cleavage of von Willebrand factor (vWF), and deficiency of ADAMTS 13 leads to the accumulation of large multimers of vWF which bind platelets, leading to microvascular thrombosis. Familial TTP is associated with mutations of ADAMTS 13 leading to decreased or undetectable activity, and acquired TTP is caused by antibodies which inhibit its activity. Historically, untreated TTP had a mortality rate of over 90%. However, mortality has fallen to 10% to 20% with the advent of treatment using plasma exchange. Familial forms require chronic treatment with fresh frozen plasma or cryosupernatant that contains the active metalloprotease.

Hemolytic uremic syndrome is the most common cause of AKI in children and presents with hemolytic anemia, thrombocytopenia, and AKI.^{107,111–113} The classic or diarrheal form of HUS (D+ HUS) occurs most commonly following diarrheal infection with Shiga-like toxin–producing Escherichia coli (SLTEC). The peak incidence occurs in children younger than 5 years of age, and outbreaks often occur in association with E. coli O157:H7. The illness begins with abdominal cramps and nonbloody diarrhea, following by hemorrhagic diarrhea in 70% of patients. Within days, patients develop severe renal failure, anemia, and thrombocytopenia. These children are often critically ill, and roughly one-half to two-thirds of patients require RRT. About 70% of patients will require RBC transfusions, and 25% will have neurologic involvement. Over the last few decades, mortality rates have fallen from roughly 40% to 50% to 3% to 5%, primarily due to aggressive supportive care with red blood cell transfusions and RRT as needed. Numerous therapies for HUS have been investigated without clear benefit, and treatment remains largely supportive. Treatment of the diarrheal illness associated with E. coli O157:H7 with antibiotics is associated with increased risk of developing HUS. Spontaneous resolution occurs 1 to 3 weeks following disease onset, and the majority of patients demonstrate renal recovery. Unfortunately, some children develop ESKD, and up to 40% have long-term sequelae including chronic kidney disease, persistent proteinuria, and hypertension. Non–diarrheal associated HUS occurs in a minority of patients and may be associated with other infections such as Streptococcus pneumoniae.

A small percentage of patients with HUS have sporadic or familial forms. These patients have defects in the alternative complement pathway, and mutations have been described in complement factor H, complement factor I, and membrane cofactor protein.^108–110 Mortality rates are over 50%, and most survivors progress to ESKD. Therapies with fresh frozen plasma, plasma exchange, and monoclonal antibodies targeting the alternative complement pathway are under investigation for treatment of this devastating disease.

A small percentage of patients with antiphospholipid syndrome (APS) present with “catastrophic” APS characterized by acute TMA involving the small vessels of multiple organs.¹¹⁴ The disease progresses over days to weeks and commonly affects the kidneys, lungs, central nervous system, heart, and skin. The kidney is the most common organ affected, with renal involvement in over 70% of patients. Renal disease manifests as malignant hypertension and AKI, with 25% of patients requiring RRT. Mortality is estimated at 50% of patients, and treatment based on case reports includes anticoagulation, corticosteroids, plasmapheresis, and intravenous immunoglobulin.

Scleroderma renal crisis presents as accelerated hypertension, and AKI and may be accompanied by encephalopathy with seizures or flash pulmonary edema.¹¹⁵ Roughly 10% of patients develop scleroderma renal crisis, usually occurring within 4 years of disease onset. The risk is greatest with diffuse cutaneous disease, and antecedent treatment with high-dose corticosteroids increases the risk of scleroderma renal crisis.^116,117 Patients demonstrate microangiopathic hemolytic anemia, thrombocytopenia, proteinuria, microscopic hematuria, and marked increases in plasma renin. In the past, untreated disease had a dismal prognosis with less than 10% survival. The use of angiotensin-converting enzyme (ACE) inhibitors has revolutionized treatment; acute mortality rates are now below 25% with appropriate treatment.^115,118,119 About half to two-thirds of patients will require RRT, but half of those patients recover enough renal function to become dialysis independent. Poor outcomes are associated with Cr above 3 at the initiation of ACE inhibitor therapy, poor blood pressure control, male gender, older age, and congestive heart failure. Patients with scleroderma renal crisis who do not require RRT have 90% survival rates at 5 years. In contrast, patients who become dialysis dependent have only 40% survival at 5 years. Early recognition and treatment are critical for both patient and renal outcomes. ACE inhibitors should be initiated rapidly and continued even if patients develop progressive renal failure or require RRT.