1. Description of the problem
Glomerulonephritis (GN) has a varied clinical presentation although occasionally patients can present with a fulminant illness typically associated with a rapidly progressive decline in renal function, associated severe hypertension, extra-renal manifestations requiring admission to the intensive care unit (ICU).
Such patients with rapidly progressive glomerulonephritis (RPGN) typically present with the nephritic syndrome (severe hypertension, azotemia, and hematuria) with associated extra-renal manifestations (including pulmonary hemorrhage).These patients often require aggressive immunosuppression, plasmapheresis and renal replacement therapy with dialysis.
Due to the varied presentation, a high index of suspicion is paramount especially in those patients with unexplained acute respiratory compromise, lung infiltrate and renal failure. New onset hypertension, signs of vasculitis (leukocytoclastic rash, peripheral digit micro-infarctions etc.), associated proteinuria and hematuria with red blood cell casts and unexplained decline in renal function may all suggest a glomerulonephritis.
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Rapidly progressive glomerulonephritis (RPGN)
In this clinical situation glomerular injury is very acute and severe and results in a decline in renal function over days to weeks. Such patients present as a uremic emergency with a reduction in glomerular filtration and azotemia, proteinuria and/or hematuria with red cell casts, and hypertension which may be severe. Causes of RPGN are classified into three types:
Type I
Anti GBM disease
Type II
Lupus nephritis
Membrano-proliferative glomerulonephritis (MPGN)
IgA nephropathy
Post-streptococcal GN
Ig A nephropathy
Endocarditis associated
Type III
Wegener’s granulomatosis
Microscopic polyangiitis
Pauci-immune crescentic glomerulonephritis
Type 1: AntiGBM disease
This extremely rare condition typically affects young males who present with a rapidly declining renal function relating to an aggressive glomerulonephritis, pulmonary hemorrhage, and the presence of serum anti-bodies directed against Type-IV collagen on the glomerular and alveolar basement membranes.
Tissue diagnosis is best made by renal biopsy although this may be delayed if the patient is critically ill and in such instances the clinical presentation and the presence of anti-GMB anti-bodies suggest the diagnosis.
In the acute setting important principles of therapy of include general supportive care in the ICU including ventilation and dialysis where necessary, plasmapheresis, and immunosuppressive therapy. Plasmapheresis removes circulating anti-GBM anti-bodies and other mediators of inflammation (such as complement) whilst the immunosuppressive agents suppress further anti-body production.
Smoking, intercurrent infections, and previous hydro-carbon exposure may be precipitants of the condition.
Prompt therapy may be life-saving and plasmapheresis instituted early ( typically 1.5-2 l daily exchange) improves outcome.
Although the literature is sparse on the length of plasmapheresis required most recommend 14-21 days.
Corticosteroids given as a pulse of methyl-prednisolone (1 g daily for three days) followed by a 6 month tapering dose of oral prednisolone (start at 1 mg per kg body weight), are added to cyclophosphamide induction therapy given orally at 2 mg per kg body weight.
Levels of anti-GBM antibodies and clinical response are protean and relapses are more common in those patients who smoke.
Type II:
Lupus nephritis
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown etiology, which commonly affects the skin, joints, kidneys and serous membranes, although most organ systems can be involved. Distinct immunological abnormalities, especially the production of a number of antinuclear antibodies, are another prominent feature of the disease.
Women of childbearing age are affected more frequently than men and treatment is based on preventive measures, reversal of inflammation, prevention of organ impairment, and alleviation of symptoms.
Improvement in patient survival is related to increased disease recognition, earlier diagnosis and treatment, and judicious therapy of complications. However, SLE patient survival in the intensive care unit remains poor with more than 50% of patients dying in most series.
Lupus nephritis is the commonest visceral manifestation of the disease and most patients with LN have an immune complex-mediated glomerular disease. Diffuse proliferative LN (WHO type IV) is the most common and most severe form of LN and patients with this condition have a worse prognosis with a 10-year survival of < 60%.
This aggressive form of lupus nephritis is commonly associated with renal failure and requires high dose immunosuppression (corticosteroids and cyclophosphamide similar to patients with anti-GBM disease). The use of Mycophenolate Mofetil at 1.5-2 g bd may be used as an alternative to cyclophosphamide in severe Class IV lupus nephritis with a lower risk of infection and gonadal failure.
In the ICU, distinguishing active lupus from infectious complications (e.g. secondary to immunosuppressive therapy), toxic effects of drugs, and from unrelated disease is always a challenge. High titres of anti-DSDNA may allude to underlying lupus activity especially if supported by associated clinical criteria and of course hypocomplementemia.
Markers of infection (ESR, blood cultures, gram stains, CRP, Procalcitonin) may prove diagnostic of sepsis rather than a lupus flare, remembering that an elevated erythrocyte sedimentation rate is difficult to interpret in the setting of renal failure.
Patients with lupus nephritis may occasionally present with an RPGN with an active urinary sediment (dysmorphic red cells and casts), hypertension (which may be severe if associated with the anti-phospholipid syndrome), proteinuria and in some cases pulmonary hemorrhage. Such pathology is explained by a small vessel vasculitis and thrombotic micro-angiopathy factors precipitating lupus nephritis in the ICU.
Leukopenia is common in patients with SLE, as is hypocomplementemia. Furthermore, immunosuppressive agents are commonly used in such patients and all these factors predispose SLE patients to infections. Infections can precipitate a flare and can initiate SLE itself. Acute, severe exacerbations of SLE require a step up in immunosuppressives, an obvious risk in an infected ICU patient.
Membrano-proliferative glomerulonephritis.
This uncommon cause of GN can result in acute renal failure in up to 30% of patients and is associated with hypertension, peripheral edema and hematuria especially when crescentic glomerulonephritis is present.
The disease may be primary and classified into three types or secondary to lupus, hepatitis C and HUS/TTP. Patients have a low serum compliment and treatment includes that of the underlying disease as well as supportive therapy for the patient with nephritic syndrome and the complications of acute renal failure.
Post streptococcus glomerulonephritis.
Considering the high incidence of group A and M streptococcus in the developing World, post-streptococcus GN (an immune complex disorder) is not uncommon in these areas. Patients history suggests a preceding streptococcal infection including pharyngitis, tonsillitis, and skin infections associated with dark urine, peri-orbital edema as well as malaise, anorexia and fever in most.
Clinical signs include acute hypertension which may be severe, oliguria, hematuria and acute renal failure.
Ig A nephropathy
This condition is usually an asymptomatic disease associated with microscopic hematuria or recurrent macroscopic hematuria. However in up to 5% of patients a necrotizing GN results in acute renal failure associated with edema, hypertension and oliguria may require ICU intervention.
Endocarditis associated
Abnormal renal function and changes in urinary analysis should raise a suspicion of infective endocarditis (IE) since it might be the first manifestation of the disease. There are three forms of renal disease associated with IE and all may result in an acute decline in renal function.
Firstly the use of nephrotoxic drugs including aminoglycosides together with any surgical intervention (resulting in acute tubular necrosis and/or interstitial nephritis); secondly an immune-complex GN with low compliment levels and occasionally the presence of cryoglobulins in the serum; and thirdly embolic disease resulting in the typical flea-bitten kidney and positive urine cultures.
A multitude of organisms may be involved in patients developing glomerulonephritis which may be very difficult to culture especially in those patients previously receiving anti-biotics. The most common are Staphylococcus aureus, Streptococcus viridansand Staphylococcus epidermidis.
Elderly patients with IE and those with acute renal failure have a particularly poor prognosis and the disease requires aggressive and prolonged courses of appropriate anti-biotics and support often in the ICU
Type III: Typically with ANCA positivity
Wegener’s granulomatosis is a necrotizing vasculitis affecting small to medium sized vessels typically in the respiratory tract and in the kidney where it results in a necrotizing glomerulonephritis. In the acute setting pulmonary hemorrhage and acute nephritic syndrome with renal failure may present to the ICU clinician.
Microscopic polyangiitis and pauci-immune crescent glomerulonephritis are the most common cause of RPGN where more than 90% of these patients have renal involvement. Patients present with acute severe nephritic syndrome and renal failure and their aggressive immunological nature requires vigilant suspicion, rapid confirmatory diagnosis and active immunosuppresion similarly to Type I disease.
2. Emergency Management
Management of RPGN
RPGN is a nephrological emergency and requires a rapid diagnosis after clinical suspicion as well as prompt treatment including high dose corticosteroids, plasmapheresis and or cyclophosphamide.
Where pulmonary hemorrhage is also involved the ICU team should include a pulmonologist/intensivist together with the nephrologist. Clinical suspicion in the patient with an acute decline in renal function with symptoms and signs to suggest the nephritic syndrome (hypertension, hematuria, azotemia) must be accompanied by rapid serological testing as well as a prompt renal biopsy and histological diagnosis and confirmation.
Any acute hypertensive emergency should be appropriately managed with intravenous loop diuretics, intravenous nitrates, and /or oral anti-hypertensives
3. Diagnosis
Clinical suspicion after a thorough history and examination is paramount.
Patients may complain of systemic symptoms such as lethargy, swelling (face, hands and/or feet), fevers, headaches, dyspnea, cough and hemoptysis (if there is a respiratory component). There may be a family history of associated auto-immune conditions particularly in those patients suffering from systemic lupus.
The symptoms may be indolent and fairly non-specific or acute and rapidly changing.
Clinical signs depend on the primary and secondary organ involvement and the general examination should include an accurate blood pressure in both arms; signs of pallor; basal pulmonary crepitations; pedal, facial or sacral edema; fundoscopy and capillaroscopy; skin examination for signs of vasculitis; a thorough cardiac examination if infective endocarditis is suspected; signs of peripheral and central nerve involvement
Important initial investigations include:
Urinalysis (by dipstix and microscopy and culture)
Renal function and complete blood count
Serum compliment including C3 and C4
Myeloperoxidase (peri-nuclear staining ANCA) and proteinase 3 (cytoplasmic staining ANCA)
Screen for systemic lupus including anti-nuclear factor and anti-double stranded DNA
Anti-GBM antibody
Anti-DNAse B and ASOT
Confirmatory renal histology is critical in diagnosing RPGN and once the patient has been medically stabilized including control of hypertension and correction of any clotting abnormalities (including a prolonged bleeding time associated with acute renal failure), a renal biopsy under ultrasound guidance should be performed.
An histologist experienced in assessing renal biopsies should be present at the biopsy procedure and my own centre an initial result and opinion is available in 12-24 hours including light microscopy, fixation and staining patterns and after 72 hours, electron microscopy.
Figure 1 demonstrates a normal glomerulous, while
Figure 2 and Figure 3 demonstrate cellular crescents and necrotizing foci in the glomeruli of a patients with ANCA positive pauci-immune GN.
Figure 1.
Figure 2.
Figure 3.
4. Specific Treatment
When a RPGN is diagnosed in the ICU prompt immunosuppressive therapy may not only reverse of halt the rapid decline in renal function but also be life-saving. Depending on clinical associations (PIGN, post strep GN, IE), serological markers (lupus, anti-GBM, ANCA) and histology immunosuppression is tailored to the specific diseases
Drugs and dosages
If an immune related RPGN is present and there is no evidence of an infective etiology, initial therapy should include the use of intravenous methyl-prednisolone at 1 g daily for three days whilst monitoring clinical and serological response. The corticosteroids should be continued by mouth at 1 mg/kg reducing weekly to response.
The use of cyclophosphamide as a daily oral therapy is recommended at 3 mg/kg in patients with anti-GBM disease. No reduction in dose is necessary for renal failure, although the dose should be lower in the elderly. In the patient with lupus nephritis and RPGN, methyl-prednisolone is the initial therapy combined with either oral cyclophosphamide at 2-3 mg /kg or mycophenolate mofetil at 1-1.5 g bd by mouth. Small studies suggest that Rituximab may be used in refractory cases although long-term results are disappointing.
Where anti-GBM antibodies are present plasma exchange is recommended with 3.5-4 l of plasma exchanged for 5% human serum albumin, daily for at least 14 days or until the anti-GBM anti-bodies are negative or dramatically reduced at least.
The presence of dialysis requiring acute renal failure in patients with RPGN portrays a poor long-term prognosis and after initial therapy maintenance therapy is paramount and may include azathioprine at 2-3 mg per kg, mycophenolate mofetil at 1-1,5 g bd and in some cases leflunomide and rituximab are indicating although evidence for long-term efficacy is lacking.
What do I do about particularly refractory cases?
Prolonged immunosuppression may be required together with vigilant monitoring of response to therapy including clinical signs (blood pressure control, renal function tests), serological markers and anti-body levels where appropriate.
5. Disease monitoring, follow-up and disposition
What is expected response to treatment (include brief discussion of prognosis)?
In those patients with RPGN secondary to infective conditions treatment of the underlying infection is paramount. Immune complex and auto-immune conditions require vigilant clinical and serological monitoring realizing the excessive risk of infection in patients requiring immunosuppression in the ICU.
The presence of advanced acute renal failure carries a particularly poor renal recovery prognosis as well as mortality risk and over or inappropriate immunosuppression at the risk of loosing the patient must be avoided.
Maintenance therapy for Lupus and immune-related RPGN include mycophenolate mofetil 1.5 g bd by mouth (higher dosage required in African American patients) or azathioprine 2-3 mg per kg per day.
What follow-up should this patient receive?
Once recovered from the acute event patients require vigilant nephrological follow-up. Regular clinical assessment, serological tests for specific conditions, and monitoring of renal function, complete blood count where appropriate, and monitoring of extra-renal disease, together with judicious immunosuppressive tailoring and tapering must be entertained.
Prognosis
Recurrence rate is high especially in Wegener’s granulomatosis, lupus and ANCA vasculitis and thus maintenance therapy is critical once the patient with acute severe disease is discharged from the ICU. Clinicians experienced in treating these conditions must be involved in initial management and of course follow up.
Prognosis is related to disease activity and response to treatment especially when instituted early. Sepsis remains an inherent risk from both the disease process and the immunosuppression.
Mortality remains high in patients admitted to the ICU with RPGN and acute renal failure.
What’s the evidence?
RPGN
Rutgers, A, Sanders, JSF, Stegeman, CA. “Pauci-immune glomerulonephritis”. Rheum Dis Clin North Am. vol. 36. 2010 Aug. pp. 559-572. (Comprehensive review on this complicated entity with excellent detail on immunosuppression.)
Walters, GD, Willis, NS, Craig, JC. “Interventions in renal vasculitis in adults. A systematic review”. BMC Nephrol. vol. 11. pp. 12(Detail on immunosuppression and follow up medication and serological tests.)
Peto, P, Salama, AD. “Update on antiglomerular basement membrane disease”. Current opin Rheumatol. vol. 23. 2011 Jan. pp. 32-7.
Jayne, D. “Review article: Progress in treatment of ANCA-vasculitis”. Nephrology (Carlton). vol. 14. 2009 Feb. pp. 42-48. (This detailed paper covers all aspects of ANCA vasculitis drawing from the authors extensive clinical experience.
Puechal, X. “Anti-neutrophil cytoplasmic antibody-associated vasculitis”. Joint Bone Spine. 2007; Oct. pp. 427-35.
Lupus nephritis
Bomback, AS, Appel, GB. “Updates on the treatments of Lupus Nephritis”. J Am Soc Nephro. 2010 Dec 21. pp. 2028-35. (Dr Appel is world renowned in this field. This review on the subject from presentation to follow up is very comprehensive.)
Laskari, K, Mavragani, CP, Tzioufas, AG, Moutsopolous, HM. “Mycophenolate Mofetil for maintenance therapy for proliferative lupus nephritis: a long-term observational prospective study”. Arthritis Res Ther. vol. 12. 2010 Nov. pp. R208(Encouraging single centre study.)
Avihingsanon, Y, Hirankarn, N. “Major lupus organ involvement: severe Lupus Nephritis”. Lupous. vol. 19. 2010. pp. 1391-8.
Ig A nephropathy.
Wen, YK, Chen, ML. “The spectrum of acute renal failure in IgA nephropathy”. Ren Fail. vol. 32. 2010 May. pp. 428-33. (A single centre retrospective review of this unusual presentation.)
Wegener’s granulomatosis
Hellmich, B, Lamprecht, P, Gross, WL. “Advances in the therapy of Wegeners granulomatosis”. Curr Opin Rheumatol 2006. vol. 18. Jan. pp. 25-32.
Management: dialysis treatment in ICU
Kielstein, JT, Schiffer, M, Hafer, C. “Back to the future: extended dialysis for thr treatment of acute kidney injury in the intensive care unit”. J Nephrol. vol. 23. 2010; Sep-Oct. pp. 494-501.
Ricci, Z, Ronco, C. “Kidney diseases beyond nephrology-Intensive Care”. Nephrol Dial Transplantation,. vol. 22. 2007. pp. 708-11.
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