Case 4 -
Severe Granulomatous Tubulointerstitial Nephritis and Granulomatous Arteritis,
Sarcoidosis And Sarcoid Vasculitis
Xochi J. Geiger
Click on each slide thumbnail image for an enlarged view
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
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
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.
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
Severe granulomatous tubulointerstitial nephritis and granulomatous arteritis, consistent with renal
sarcoidosis and sarcoid vasculitis.
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.
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 . 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.
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 , 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
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
Suggested etiologies have included infectious agents, noninfectious environmental exposures, genetic
factors and autoimmunity
. 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 . Case reports whereby
sarcoidosis was transmitted by cardiac and bone marrow transplantation support a possible infectious
. 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
. 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 . Untreated sarcoid vasculitis has a poor
prognosis, but steroid therapy (and cytotoxic agents in some cases) can induce remissions.
Unfortunately, relapse is common.
The prevalence of renal involvement in sarcoidosis is variable, with an incidence
reported from 7-27% . 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
. 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
Not all patients with sarcoidosis require treatment. A multicenter study of patients
with new onset sarcoidosis showed almost 40% had spontaneous resolution without therapy . 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
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 . 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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