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Year : 2013  |  Volume : 56  |  Issue : 3  |  Page : 294-296
Unusual case of pulmonary renal syndrome with autopsy findings

1 Department of Pathology, Armed Forces Medical College, Delhi, India
2 Department of Nephrology, Army Hospital (Research and Referral) Delhi, India

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Date of Web Publication24-Oct-2013


Scleroderma renal crises (SRC) is a serious complication of systemic sclerosis whose prognosis remains serious despite management with angiotensin-converting enzyme inhibitors, antihypertensives and dialysis. Pulmonary renal syndrome (PRS), characterised by diffuse alveolar hemorrhage (DAH) and SRC, is rare and carries a grave prognosis. This case report discusses the clinicopathological features of a 43-year-old male presenting with severe hypertension and rapidly progressive renal failure who subsequently developed DAH and died. The clinical course, exhaustive investigative work-up and autopsy findings led to a diagnosis of diffuse systemic sclerosis with PRS subcategorized into PRS with thrombotic microangiopathy. The index case came without a prior diagnosis of systemic sclerosis, thereby posing a serious diagnostic challenge and management issues.

Keywords: Diffuse alveolar hemorrhage, systemic sclerosis, thrombotic microangiopathy

How to cite this article:
Badwal S, Kotwal J, Varma PP. Unusual case of pulmonary renal syndrome with autopsy findings. Indian J Pathol Microbiol 2013;56:294-6

How to cite this URL:
Badwal S, Kotwal J, Varma PP. Unusual case of pulmonary renal syndrome with autopsy findings. Indian J Pathol Microbiol [serial online] 2013 [cited 2020 Jun 4];56:294-6. Available from: http://www.ijpmonline.org/text.asp?2013/56/3/294/120403

   Introduction Top

Patients with systemic sclerosis may experience life-threatening renal complications termed as scleroderma renal crises (SRC), estimated to affect 5% of all systemic sclerosis patients. [1] SRC typically causes an abrupt onset of severe hypertension and rapidly progressive renal failure (RPRF), constituting one of the few medical emergencies in rheumatology, requiring early identification and aggressive management. Diffuse alveolar hemorrhage (DAH) has been reported in the course of SRC and Bar et al. proposed the term "scleroderma pulmonary renal syndrome" (PRS) for this invariably fatal complication of systemic sclerosis. [2] We present an autopsy of a case of RPRF diagnosed subsequently as SRC with DAH with a view to discuss the clinicopathological features of this rare but devastating complication of systemic sclerosis.

   Case Report Top

A 43-year-old male was admitted with 5-7 days of progressively increasing dyspnea and renal dysfunction with severe hypertension. On admission, his blood pressure was 224/113 mmHg and his pulse was 130 beats/min with pallor and bilateral crepitation. Salient laboratory data were: Hemoglobin 6.7 gm/dl, total leucocyte count 15,000/cmm with 88% neutrophil, platelet count 80,000/cmm, schistocytes on peripheral blood smear, blood urea nitrogen 80 mg/dL and creatinine 5 mg/dL.

Urinalysis showed proteinuria and microscopic hematuria. Chest X-ray exhibited bilateral pulmonary opacities and high-resolution computed tomography was suggestive of interstitial lung disease. Ultrasound examination was suggestive of medical renal disease. Fundus showed grade III hypertensive changes. Viral markers and antineutrophil cytoplasmic antibodies (ANCA) studies were negative and complement levels along with coagulation screen were normal. Antinuclear antibody was positive and antidouble stranded DNA antibodies were negative. Renal biopsy revealed features of thrombotic microangiopathy (TMA). On re-evaluation, the patient was noticed to have thickening of skin over the hands, forearm, trunk and face, with deformity of the nails and digital infarcts. On direct questioning, he also gave a history suggestive of Reynaud's phenomenon since the last 1 year. Clinical suspicion of scleroderma was confirmed on skin biopsy and positive Scl-70 antibody (98.9 U/ml). The diagnosis was revised to SRC and the patient was managed with angiotensin-converting enzyme inhibitors (ACE-I). The general condition of the patient deteriorated, with signs of streaky hemoptysis. Fiberoptic bronchoscopy revealed pinkish bronchoalveolar lavage fluid with homogenous fluffy opacities on the radiograph. He was placed on ventilator support with stepping up of ACE-I and addition of injectable methylprednisolone and single-dose intravenous cyclophosphamide. The patient continued to remain hypertensive despite aggressive management and succumbed to his illness after 1 month of in-patient care.

A complete autopsy was performed. The skin over the face, hands, forearms and trunk appeared shiny and stretched with digital ulcerations. The kidneys appeared edematous with petechial hemorrhages. Microscopically, the glomeruli exhibited ischemic changes in the form of wrinkling of the glomerular basement membrane. The afferent arterioles and interlobular and arcuate arteries showed narrowed lumina with concentric myointimal proliferation (onion skin lesions), mucoid intimal thickening and fibrinoid necrosis. The tubules showed protein casts. The interstitium appeared edematous and congested. Immunofluorescence microscopy showed focal immunostaining of the interlobular blood vessel by fibrinogen (3+ positivity) along with weak 2+ staining of IgM and C3 [Figure 1]. Similar vascular changes were also evident in other visceral organs.

The pleural surface of the lungs displayed cobblestone appearance with a hemorrhagic cut surface. Microscopically, the features of interstitial fibrosis were more evident in the subpleural areas with DAH. No evidence of capillaritis was seen. Instead, the features of TMA evident in the kidneys were also seen prominently in the lung vessels [Figure 2].
Figure 1: Photomicrographs from the renal parenchyma showing (a) interlobular artery exhibiting myointimal cellular proliferation (onion skinning) with markedly narrowed lumina (hemotoxylin and eosin, ×200), (b) small arcuate artery exhibiting narrowed lumina with mucoid intimal edema (hemotoxylin and eosin, ×200), (c) arterioles showing fibrinoid necrosis consisting of smudgy appearance of the wall (hemotoxylin and eosin, ×200) and (d) vascular immunostaining by fibrinogen (fluorescein isothiocyanate-tagged fibrinogen, ×200)

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Figure 2: (a) High-resolution computed tomography showing bilateral fluffy opacities, (b) autopsy lung specimen exhibiting subpleural cobblestone appearance, (c) photomicrograph of lung parenchyma exhibiting interstitial fibrosis with diffuse intraalveolar hemorrhage and parenchymal blood vessel exhibiting narrowed lumen with intimal proliferation (hematoxylin and eosin, ×100) and (d) interstitial fibrosis and diffuse alveolar hemorrhage (Masson's trichome stain, ×100)

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The esophagus and stomach revealed a thinned-out mucosa with collagenisation of the lamina propria, submucosa and muscularis propria. The diaphragm and the peritoneal folds also displayed collagenous fibrous replacement. A final diagnosis of diffuse systemic sclerosis with renal crises with DAH was offered.

   Discussion Top

The index case presented here is a rare combination of SRC and DAH, the pulmonary-renal syndrome, associated with high morbidity and mortality. PRS in systemic sclerosis patients can be broadly categorized into three subsets: Scleroderma PRS with TMA, scleroderma PRS with small vessel vasculitis and Goodpasture-like syndrome. PRS with small vessel vasculitis can be further subdivided into microscopic polyangiitis superimposed on systemic sclerosis and P-ANCA-associated pulmonary capillaritis with SRC. [3] Our patient who manifested with renal crises, DAH, microangiopathic hemolytic anaemia and thrombocytopenia can be categorized into scleroderma PRS with TMA.

The pathophysiology of scleroderma PRS with TMA remains incompletely understood, with the initial trigger being vascular endothelial injury resulting in a rapid increase in the endothelial permeability and intimal edema activating the coagulation cascade and vascular thrombosis. The proliferative endarteriopathy results in decreased renal perfusion as a result of arterial narrowing and increased renin secretion, leading to accelerated hypertension and progressive renal injury. [4] In the lungs, this manifests as widespread damage of the pulmonary vasculature consequent to microangiopathic phenomenon resulting in blood collection within the alveoli, thereby disrupting O 2 and CO 2 exchange.

The pathogenetic mechanisms that elicit endothelial injury are multifactorial. These include presence of antiendothelial antibodies and increased expression of endothelin-1/endothelin-B that plays an important role in vascular constriction. Positive staining of endothelin (ET)-1 on immunohistochemistry has been observed in the media of the small renal arteries in a subset of SRC patients. [5] Antiendothelial cell antibodies, which are capable of inducing endothelial cell apoptosis, have been detected in up to 85% of SRC patients. Alteration in cellular and/or humoral immunity associated with T helper lymphocyte type-2 (TH-2) activation, cytokine production (particularly IL-4, IL-13 and IL-17) and excess collagen accumulation results in epithelial-to-mesenchymal transdifferentiation and vasculopathy. [5] Proliferative endarteriopathy without clinical manifestations can often be observed in systemic sclerosis patients, emphasizing the underlying thrombogenic milieu. The progressive vascular injury results in persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration, scleroderma renal crises, pulmonary arterial hypertension and hemorrhage. [6],[7]

Naniwa et al. in their case series described three cases and 15 previously reported cases of PRS associated with systemic sclerosis. [3] Seven patients exhibited TMA while others showed crescentic glomerulonephritis and pulmonary capillaritis. In contrast to our case where the patient presented with SRC at the outset, the diagnosis of systemic sclerosis preceded the diagnosis of renal dysfunction with DAH in their case series. More than one-fifth of the patients with SRC may not carry a diagnosis of systemic sclerosis at presentation; hence, the emphasis on early recognition of systemic sclerosis as it is crucial to making the specific diagnosis.

Although it is often impossible to ascertain the specific cause of TMA based on histologic evaluation alone, the extraglomerular small vessel vascular lesions often predominate in SRC while primary glomerular capillary microangiopathic changes are relatively infrequent. Small vessel thrombi outnumber glomerular thrombi in SRC, while the opposite is seen in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) syndrome. [5]

Histologic manifestations may vary during the course of the disease. Microthrombi, onion skinning, myxoid material and fibrinoid necrosis are indicators of acute process and are associated with poor prognosis, while fibrointimal and adventitial sclerosis are manifestations of chronic ongoing damage. [5] Our case exhibited the predominance of acute features, although chronic damage was also discernible. In late stages, histological findings may reflect advanced chronic renal damage. Hence, it is often difficult to distinguish chronic vascular changes associated with organized SRC from pre-existing accelerated hypertension.

PRS can occur in systemic sclerosis due to etiologies other than SRC. ANCA-mediated pauci-immune crescentic glomerulonephritis and anti-glomerular basement membrane disease superimposed on systemic sclerosis may result in a similar clinical picture. It is important to distinguish PRS with TMA from crescentic glomerulonephritis as immunosuppression is required in the latter. Renal biopsy is therefore mandatory and critical to initiate specific management. [8]

High-dose corticosteroids have been implicated in precipitating DAH, especially in diffuse systemic sclerosis patients with recent-onset SRC. In our case, the patient was treated with methylprednisolone pulses for 3 days, but no antecedent history of prior use of high-dose steroid was obtained from the patient. PRS in systemic sclerosis has a grave prognosis irrespective of the subset. Prognosis is worse for males, for patients aged more than 53 years and for patients who are normotensive. Patients who present in renal failure without hypertension or without a prior diagnosis of systemic sclerosis present a serious diagnostic challenge. [9],[10]

To conclude, it is imperative to examine the hands and feet of a patient presenting with severe hypertension for underlying connective tissue disorder with appropriate investigations and autoimmune workup. Once identified, it becomes important to define the subset of PRS to which the patient belongs to impart prompt and specific management to reduce the morbidity and mortality of this life-threatening complication.

   References Top

1.Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM, et al. Scleroderma renal crises: Patient characteristics and long term outcomes. Oxford J Med 2007;8:485-94.  Back to cited text no. 1
2.Bar J, Ehrenfeld M, Rozenman J, Perelman M, Sidi Y, Gur H. Pulmonary renal syndrome in systemic sclerosis. Semi Arthritis Rheum 2001;30:403-10.  Back to cited text no. 2
3.Naniwa T, Banno S, Sugiura Y, Yokota K, Oosawa T, Maeda S, et al. Pulmonary renal syndrome in systemic sclerosis: A report of three cases and review of literature. Mod Rheumatol 2007;17:37-44.  Back to cited text no. 3
4.Cossio M, Menon Y, Wilson W, deBoisblanc BP. Life-threatening complications of systemic sclerosis. Crit Care Clin 2002;18:819-39.  Back to cited text no. 4
5.Batal I, Domsic RT, Medsger TA, Bastacky S. Scleroderma renal crises: A pathology perspective. Int J Rheumatol 2010;2010:54-3704.   Back to cited text no. 5
6.Mouthon L, Mehrenberger M, Teixeira L, Fakhouri F, Bérezné A, Guillevin L, et al Endothelin-1 expression in scleroderma renal crisis. Hum Pathol 2011;421:95-102.  Back to cited text no. 6
7.Fleming JN, Nash RA, Mahoney WM Jr, Schwartz SM. Is scleroderma a vasculopathy? Curr Rheumatol Rep 2009;11:103-10.  Back to cited text no. 7
8.Denton CP, Lapadula G, Mouthon L, Muller-Ladner U. Renal complications and scleroderma renal crises. Rheumatology 2009;48:32-5.  Back to cited text no. 8
9.Kamen DL, Wigley FM, Brown AN. Antineutrophil cytoplasmic antibody-positive crescentic glomerulonephritis in scleroderma - a different kind of renal crisis. J Rheumatol 2006;33:1886-8.   Back to cited text no. 9
10.Naniwa T, Banno S, Takahashi N, Maeda S, Hayami Y, Ueda R. Normotensive scleroderma renal crisis with diffuse alveolar damage after corticosteroid therapy. Mod Rheumatol 2005;15:134-8.  Back to cited text no. 10

Correspondence Address:
Sonia Badwal
Department of Pathology, Armed Forces Medical College, Solapur Road, Pune - 411 040
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.120403

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