—  SPECIALTY CONFERENCE  —

Renal Pathology

Case 4 - Severe Granulomatous Tubulointerstitial Nephritis and Granulomatous Arteritis,
Sarcoidosis And Sarcoid Vasculitis

Xochi J. Geiger
Mayo Clinic
Jacksonville, FL


Click on each slide thumbnail image for an enlarged view
Clinical History
A 44 year-old African-American female presented with worsening renal function over a several month period. Her serum creatinine had steadily increased from baseline of 1.9-2.0 mg/dL to 2.2, 2.7 and a current value of 2.9 mg/dL over the past two months. At her previous visit she was noted to have left maxillary sinusitis, for which she received antibiotics, but currently was without complaints, feeling well and denied shortness of breath, lower extremity edema, hematuria or rash. Her past medical history was significant for recurrent urinary tract infections, granulomatous hepatitis, sarcoidosis and Crohn's disease. She was afebrile with blood pressure 118/80 mm Hg and weight 111 kg. Physical exam revealed clear lungs, no hepatosplenomegaly and and no extremity edema. Laboratory examination revealed serum creatinine 2.9 mg/dL, urine protein /creatinine ratio 0.15, platelets 258,000/uL and hemoglobin and hematocrit 11.6 and 33.9 g/dL, respectively. Urinalysis showed trace protein and moderate blood. Renal biopsy was performed.

Material for review
1 glass slide (Jones' silver), 1 EM photocopy


Case 4 - Figure 1 - Granulomatous interstitial nephritis with several noncaseating granulomas, interstitial edema and inflammation. (Jones silver stain; x 100)
Case 4 - Figure 2 - Well-formed noncaseating granulomas and scattered giant cells, tubulitis and tubular injury. One globally sclerosed glomerulus is present, upper left. (Jones silver stain; x 200)
Case 4 - Figure 3 - Granulomatous inflammation infiltrating tubules with tubular basement membrane breaks. (Jones silver stain; x 400)


Case 4 - Figure 4 - Granulomatous arteritis with fibrinous exudates. Note infiltration of vessel wall by epithelioid granulomata and vessel wall injury. (Jones silver stain, x 200).
Case 4 - Figure 5 - Small artery with arteritis and surrounding granulomatous inflammation. (Jones silver stain; x 400)
Case 4 - Figure 6 - Glomerulus with ischemic change and periglomerular fibrosis. There are no proliferative or necrotizing lesions. Interstitial nephritis with tubulitis is also present. (PAS stain; x 400)

Renal biopsy findings

Light microscopy showed cortical tissue with 17 glomeruli, 4 of which were globally sclerosed. Many remaining glomeruli showed periglomerular fibrosis, mild mesangial matrix increase and ischemic change with moderate glomerular basement membrane corrugation and segmental splitting noted in a few glomeruli without increased loop cellularity. No prolilferative necrotizing lesions, fibrin thrombi or segmental sclerosis was seen. The tubulointerstitium contained a marked inflammatory infiltrate of mononuclear cells, many non-necrotizing granulomas with occasional multinucleated giant cells, and scattered eosinophils. There was diffuse edema, tubulitis and tubular injury with focal disruption of tubular basement membranes. Some tubules showed partial infiltration by granulomatous inflammation. Elastin stain highlighted one artery involved by granulomatous inflammation with infiltration of the vessel wall, disruption of the elastic layer and fibrinous exudate. Additional arteries showed moderate arteriosclerosis.

Immunofluorescent microscopy tissue contained 8 glomeruli, 4 of which were globally sclerosed. There was 1+ segmental arteriolar staining for C3 and focal trace mesangial IgM. IgG, IgA, C1q, kappa and lambda light chain were negative.

Electron microscopy was performed on one glomerulus and showed normal thickness glomerular basement membrane with segmental corrugation and mildly increased lamina rara interna. Podocytes showed mild microvillous transformation, a few cytoplasmic vacuoles and minimal (<10 %) foot process effacement. The mesangial matrix was mildly increased with normal cellularity. There were no subepithelial, subendothelial, mesangial or tubular basement membrane immune complex deposits, and no reticular aggregates.

Final Diagnosis
Severe granulomatous tubulointerstitial nephritis and granulomatous arteritis, consistent with renal sarcoidosis and sarcoid vasculitis.

Comment
Elastin stain highlights an unusual lesion of granulomatous arteritis with granulomas infiltrating one artery wall, destruction of the elastic layer and fibrinous exudates. These features are most consistent with a severe, destructive form of sarcoid, although other systemic granulomatous processes cannot be definitively excluded.

Differential diagnosis
Granulomatous tubulointerstitial nephritis can be associated with drug reactions, Wegener's granulomatosis, infections, sarcoidosis, crystals, paraproteinemias and tubulointerstitial nephritis with uveitis. In a report by Mignon et al. of 32 patients with granulomatous interstitial nephritis, 28% were due to drugs, 16% to Wegener's granulomatosis and 9% each to tuberculosis and sarcoidosis [1]. Clinical history and review of medication lists can identify a possible drug-induced etiology. Glomerular involvement, pulmonary manifestations and certain serologies are more typical of Wegener's granulomatosis, although there have been a few reported cases of interstitial granulomas without glomerular involvement. Infectious causes, particularily fungal or mycobacterium, more frequently show necrotizing granulomas and special stains for microorganisms can be utilized. Additional serum and/or urine tests can identify a paraprotein, and crystals will be easily identified on biopsy. This case also had the unusual feature of granulomatous vasculitis. In addition to Wegener's granulomatosis, other renal vasculitides such as microscopic polyangiitis, Churgg Strauss and polyarteritis nodosa need to be considered, although granulomas are not typical in these latter processes. Lack of glomerular involvement, history of asthma or evidence of more systemic involvement also make these vasculitic entities unlikely.

Discussion

Clinical Features of Sarcoid
Sarcoidosis is a chronic multisystemic disease of unknown etiology. It derives from Greek roots meaning "the formation of abnormal flesh" and received its name because the lesions resemble a sarcoma. The histologic hallmark is formation of noncaseating granulomas. Lofgren described the classic triad of hilar adenopathy, erythema nodosum and arthritis [2], but sarcoidosis can affect virtually any organ and most commonly involves the lungs, lymph nodes, skin and eyes. Clinical symptoms are protean, depending upon the organ(s) involved. Renal involvement may be asymptomatic or present with renal insufficiency, nephrolithiasis, hypercalciuria or features of glomerulonephritis (discussed further below). The disease can be asymptomatic and self-limited or chronic with episodic relapse and remission. A few unfortunate individuals progress to multiorgan failure. Patients are typically between 20-40 years of age at diagnosis with a slight female predominance and there is a higher prevalence among U.S. African Americans. Laboratory abnormalities can include lymphocytopenia, elevated sedimentation rate, hyperglobulinemia, elevated serum angiotensin-converting enzyme and hypercalcemia (infrequent), although these are not consistent among all patients. Other laboratory features depend on the specific organ(s) involved.

Pathology and Immunology
The cause of sarcoidosis remains unknown and the diagnosis is one of exclusion. Tissue biopsy showing non-caseating granulomas is required. Previously heralded as specific diagnostic tests for sarcoidosis, measurement of serum angiotensin-converting-enzyme activity and flow cytometric analysis of bronchoalveolar lavage CD4+ to CD8+ cell ratios lack specificity [3, 4] .

Suggested etiologies have included infectious agents, noninfectious environmental exposures, genetic factors and autoimmunity [5, 6, 7] . Clinical disease and histologic similarities to environmental agents, such as beryllium, and geographically clustered or community outbreaks suggested environmental or occupational exposure. However, a large US multicenter study found lack of association with several environmental exposures previously hypothesized to be linked to sarcoidosis [8]. Case reports whereby sarcoidosis was transmitted by cardiac and bone marrow transplantation support a possible infectious cause [9, 10] . Mycobacteria, human herpes virus 8 and proprionibacteria have all been investigated, but studies cultivating organisms or isolating organism-specific DNA from sarcoid tissue via polymerase chain reaction have produced differing results. Genetic factors may play a role in the susceptibility of predisposed hosts as serologic studies have found positive associations with HLA-A1, B8 and DR3 markers. An autoantibody has yet to be identified.

Regardless of the specific etiology, sarcoidosis results from an overexuberant T cell-mediated immune response to antigen and subsequent complex interplay of proinflammatory cytokines and growth factors [4, 6, 11] . The first manifestation is accumulation of CD4 Th1 cells and monocytes-macrophages in involved organs. A cascade of interacting cytokines (IL-2, INF-gamma, TNF-alpha and others) result in an amplification loop involving antigen-recognition, proinflammatory cytokine release, and cell activation and recruitment. The end result is noncaseating granuloma formation with a central aggregate of epithelioid cells and macrophages surrounded by a rim of mostly CD4+ T cells, mast cells, fibroblasts and plasma cells. Changes in local cytokines (TGF-beta, IL-4, FGF) are likely responsible for progression from granuloma formation to fibrosis.

Most granulomas are non-necrotizing, but small foci of necrosis can occur and can be extensive in variants of sarcoid (necrotizing sarcoid granulomatosis and nodular sarcoidosis). The granulomas may also have a pronounced vasculocentric distribution, but true vasculitis with intimal involvement mostly occurs in pulmonary sarcoidosis. Extrapulmonary vascular involvement, such as seen in this renal biopsy, is uncommon and can range from a cutaneous leukocytoclastic vasculitis to involvement of large vessels, including aorta, iliac, mesenteric and renal arteries [12]. Untreated sarcoid vasculitis has a poor prognosis, but steroid therapy (and cytotoxic agents in some cases) can induce remissions. Unfortunately, relapse is common.

Renal Involvement
The prevalence of renal involvement in sarcoidosis is variable, with an incidence reported from 7-27% [13]. Sarcoid as a cause of renal dysfunction is rare, occurring in 1-2% of patients, and renal failure as an isolated manifestation of sarcoidosis is quite uncommon. Renal manifestations include hypercalcemic nephropathy, granulomatous interstitial nephrtis, and less frequently glomerulonephritis [14, 15, 16] . Undetected hypercalcemia and hypercalciuria, present in 10-20% and 40% of patients respectively, can lead to nephrocalcinosis and renal stones. In sarcoidosis, as with other granulomatous disorders, hypercalcemia is due to dysregulated endogenous overproduction of 1,25-(OH2)D3 (calcitrol) by activated macrophages in the granulomas. The production appears to be aggravated by sunlight, thus being more pronounced in the spring and summer. Angiotensin converting enzyme is also a product of granuloma epithelioid cells and serum levels may be elevated in some patients.

Approximately 20% of patients with sarcoidosis show granulomatous inflammation in the kidney, but renal dysfunction due solely to this is unusual. The pathogenesis is infiltration of the interstitium and tubules by inflammatory cells and granulomas with tubular injury and tubular dysfunction. Most cases of sarcoid granulomatous interstitial nephritis respond to steroid therapy, however, prolonged treatment may be necessary and some may progress to irreversible renal damage. Glomerular involvement is uncommon. Membranous GN is the most frequently reported glomerular lesion and is identical to that of idiopathic MGN. Other described lesions include membranoproliferative GN, focal GN (including IgA}, mesangioproliferative GN, crescentic GN and minimal change disease [17, 18] .

Treatment
Not all patients with sarcoidosis require treatment. A multicenter study of patients with new onset sarcoidosis showed almost 40% had spontaneous resolution without therapy [19]. For those who are asymptomatic or with limited symptoms initial observation-only may be warranted, because of the potential for spontaneous resolution; whereas significant ocular, cardiac, pulmonary or neurologic involvement may require immediate treatment.

Corticosteroids are generally considered first-line therapy [6, 20, 21] . Glucocorticoids suppress cellular immune and inflammatory events at sites of disease and can also reduce the endogenous production of calcitrol, lowering serum calcium levels in several days. As organ function improves, steroids can be tapered over weeks to months to establish a minimum effective dose or discontinued altogether. For patients with steroid-refractory disease or who cannot tolerate the side effects, cytotoxic agents (methotrexate, azathioprine and cyclophosphamide) can be used as second-line agents, either in combination with one another or in combination with steroids to reduce long-term dosage and toxicities. Antimalarial agents chloroquine and hydroxychloraquine have low toxicity and appear effective for cutaneous disease and controlling hypercalcemia and hypercalciuria. Likewise ketoconazole, through cytochrome p450 inhibition, also lowers circulating calcitrol levels, but its overall efficacy in sarcoidosis is unclear. Despite the ability of cyclosporine to suppress T cell activity, its efficacy in sarcoidosis has not been proven and the side effects may outweigh any benefits.

Focus is also being directed to immunomodualtors, which can block cytokine effect or alter the immune response. Both pentoxifylline and thalidomide suppress tumor necrosis factor release by alveolar macrophages and have shown promising results in cutaneous sarcoidosis (pentoxifylline) and acute pulmonary sarcoidosis (thalidomide). More recently the drug infliximab, a murine monoclonal antibody that directly inhibits TNF- alpha, demonstrated marked improvement and reduced steroid dosage in several cases of refractory sarcoidosis [22]. The effect of long-term infliximab therapy is unknown and an important complication has been an increased rate of tuberculosis, which may limit its usage.

Sarcoidosis remains a complex disease process of unknown etiology with a variety of clinical presentations. Noncaseating granulomas are the major pathologic feature, although small or large vessel vasculitis can be an unusual complication. Renal involvement includes granulomatous interstitial nephritis, complications of hypercalcemia and hypercalciuria or glomerulonephritis, of which membranous GN is the most common. Treatment involves reduction of cellular and inflammatory responses and control of calcium homeostasis. Development of immunologic strategies to inhibit cytokine activity at sites of disease activity remains promising for advances in the clinical management of sarcoidosis.

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