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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 4  |  Page : 844-848
Scleroderma renal crisis in a case of mixed connective tissue disease

1 Department of Pathology, Global Health City, Chennai, Tamilnadu, India
2 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

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Date of Web Publication24-Jun-2014


Mixed connective tissue disease (MCTD) is an overlap syndrome first defined in 1972 by Sharp et al. In this original study, the portrait emerged of a connective tissue disorder sharing features of systemic lupus erythematosus, systemic sclerosis (scleroderma) and polymyositis. Scleroderma renal crisis (SRC) is an extremely infrequent but serious complication that can occur in MCTD. The histologic picture of SRC is that of a thrombotic micro-angiopathic process. Renal biopsy plays an important role in confirming the clinical diagnosis, excluding overlapping/superimposed diseases that might lead to acute renal failure in MCTD patients, helping to predict the clinical outcome and optimizing patient management. We herewith report a rare case of SRC in a patient with MCTD and review the relevant literature.

How to cite this article:
Vij M, Agrawal V, Jain M. Scleroderma renal crisis in a case of mixed connective tissue disease. Saudi J Kidney Dis Transpl 2014;25:844-8

How to cite this URL:
Vij M, Agrawal V, Jain M. Scleroderma renal crisis in a case of mixed connective tissue disease. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Dec 8];25:844-8. Available from: https://www.sjkdt.org/text.asp?2014/25/4/844/135177

   Introduction Top

Mixed connective tissue disease (MCTD) was first described in 1972 as a disease syn­drome with overlapping features of systemic sclerosis, systemic lupus erythematosus (SLE) and polymyositis associated with antibodies to RNAse-sensitive extractable nuclear antigen. [1],[2] When the antigen was subsequently charac­terized as a polypeptide on the U1-ribonuclear protein component of the splicesosome (U1RNP), MCTD became the first rheumatic disease syndrome to be defined by a serologic test. Clinical features include a high frequency of Raynaud's syndrome, swollen hands, sclero-dactyly, arthritis, polymyositis and interstitial lung disease. [1],[2] Scleroderma renal crisis (SRC) is an extremely infrequent but serious compli­cation that can occur in MCTD. The histologic picture of SRC is that of a thrombotic micro-angiopathic process with small vessel involve­ment manifesting as myxoid intimal changes, thrombi, onion skin lesions and/or fibro-intimal sclerosis. Renal biopsy plays an impor­tant role in confirming the clinical diagnosis, excluding overlapping/superimposed diseases that might lead to acute renal failure in patients with systemic sclerosis (SSc), helping to pre­dict the clinical outcome as well as optimizing patient management. We herewith report a rare case of SRC in a patient with MCTD and review the relevant literature.

   Case Report Top

The patient being reported is a 21-year-old male who presented in the Immunology Out­patient Department in February 2010 with complaints of arthritis involving small as well as large joints, low-grade fever, on and off, puffy fingers and proximal muscle weakness in both upper and lower limbs along with truncal weakness for two years. On general physical examination, the patient had inflam­matory symmetric additive polyarthritis invol­ving small and large joints, with no defor­mities. There was thickening of the facial skin, forearms, arms, legs and feet. Hematological investigations demonstrated hemoglobin (Hb) of 12.5 gm%, total leukocyte count (TLC) of 11.9 × 10 [3] /mm [3] , platelets of 4.37 × 10 [6] /mm [3] and erythrocyte sedimentation rate (ESR) of 20 mm/h. Biochemical investigations showed serum creatinine of 0.79 mg/dL, serum pro­teins and total/albumin of 7.0/3.7 gm%, serum glutamate oxaloacetate transaminase (SGOT) of 94 IU, serum glutamate pyruvate trans-aminase (SGPT) of 65 IU, alkaline phospha-tase of 215 u/L, creatine phophokinase (total/ muscle type isoenzyme (MM) of 1256/1196), C-reactive protein of 1.43 mg/dL and rheu­matoid factor of 20.4 IU/mL. The anti-nuclear antibody (ANA) showed 4+ nucleolar pattern at 1:80 dilution. An extractable nuclear antigen enzyme-linked immunosorbent assay (ELISA) (ENA) screen showed U1snRNP positivity. The patient was diagnosed as a case of MCTD and advised treatment. However, he refused any treatment and took some alternative medi­cine for six months.

The patient again presented in August 2010 with complaints of rapidly progressive short­ness of breath with orthopnea, generalized swelling and reduced urine output of one week's duration. He had undergone hemo-dialysis at a local hospital and was referred to us for further management. General exami­nation showed pallor and pitting pedal and scrotal edema. The patient had scleroderma facies with thickening of facial skin, along with thickening of forearms, arms, legs and the feet. His blood pressure was 190/120 mm Hg. Examination of the chest showed evidence of pleural effusion on the left side. His muscle power was 4/5 in the proximal upper and lower limbs, with neck flexor and truncal weakness. Hematological investigations showed Hb of 9.9 gm%, TLC of 17.6 × 10 [3] /mm [3] and platelet count of 2.1 × 10 [6] /mm [3] . Biochemical investigations showed a blood urea of 61 mg%, serum creatinine of 5.9 mg%, serum proteins and total/albumin of 6.6/2.7 gm%, SGOT/SGPT of 78/47 IU, alkaline phospha-tase of 127 IU/dL, creatine phosphokinase, total/MM, of 1058/940 IU/L, lactate dehydro-genase of 1781 U/dL and C-reactive protein of 6.10 mg/dL, and the ANA showed 4+ speckled pattern at 1:80 dilution. Anti-dsDNA was <6.25 IU/mL while screening for anti-glome-rular basement membrane (ELISA) and anti-neutrophil cytoplasmic antibody was negative. Urinalysis demonstrated mild proteinuria and hematuria, with few granular casts evident on microscopy. Lupus anticoagulant was positive by dilute Russel viper coagulation time. The activated partial thromoplastin time was 42.7 s.

Clinically, a diagnosis of oliguric acute renal failure with accelerated hypertension with pos­sibility of SRC was considered. Renal biopsy was performed for diagnosis. A single core of renal tissue showing eight glomeruli was obtained. Most of the glomeruli showed blood­less appearance [Figure 1]A. They all appeared hypocellular with thickening of the glomerular capillary walls, along with swelling of the glomerular endothelial cells leading to occlusion of the capillary lumina [Figure 1]B. There was blending of the mesangial areas with capillaries. A fibrillar appearance of the glomerular mesangium was also appreciated in few glomeruli. Two interlobular blood vessels showed obliteration of the lumina by myxoid fibro-intimal hyperplasia [Figure 1]C. The tubules showed evidence of tubular injury with dilatation and flattening and denudation of the lining epithelium [Figure 1]D. The interstitium showed edema along with sparse lymphoma-nonuclear inflammatory cell infiltrate. Immuno-fluorescence was negative for IgG, IgM, IgA, C3 and C1q. A diagnosis of SRC was made. The patient was given multiple sessions of hemodialysis and three sessions of plasmapheresis. However, renal functions failed to improve. He developed abdominal pain and a possibility of pseudo-obstruction was considered. The patient was discharged on his request and the poor prognosis was explained.
Figure 1: Renal biopsy sections showing (A) bloodless glomeruli (H&E, 100), (B) glomerular capillary walls are thickened and the mesangial areas blend with the capillaries (H&E, 200), (C) interlobular vessel displaying fibro-intimal hyperplasia with obliteration of the capillary lumen (H&E, 400) and (D) tubular injury and interstitial edema (H&E, 400).

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   Discussion Top

The patient in our report had MCTD, which was complicated by SRC. This life-threatening complication results in oliguric renal failure, often with accelerated hypertension. Renal crisis occurs in approximately 10% of all scle-roderma patients. Few reports exist of patients with MCTD having SRC. [3],[4],[5],[6] MCTD is an overlap syndrome first defined in 1972 by Sharp et al. In this original study, the portrait emerged of a connective tissue disorder sharing features of SLE, systemic sclerosis and poly-myositis. Serologically, they were distinguished by high ANA titers (often greater than 1:1000 or even 1:10,000) and antibodies to a saline-extractable nuclear antigen (ENA) that is ribo-nuclease sensitive. Antibody to U1 small nu­clear RNP (U1-snRNP) and to heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 most closely identifies patients with a clinical syn­drome of MCTD. It was initially thought that there was a very low incidence of renal disease in MCTD, but, over time, this opinion was revised. [1],[2]

The clinical manifestations of renal involve­ment in MCTD are quite variable. Some pa­tients have renal lesions in the absence of any clinical manifestations. [1] Kobayashi et al re­ported on four such patients, with mesangial lesions in three and membranous nephropathy in the fourth. [7] The percentage of patients with cryptic renal disease is unknown, but is pro­bably significant. Approximately 20% of all patients with MCTD have trivial proteinuria of about 500 mg per 24 h, with or without mild micro-hematuria. However, about one-third of patients have heavy proteinuria, with a full­blown nephrotic syndrome developing in most. A few patients have had marked hypertension, micro-angiopathic hemolytic anemia and acute renal failure; the overall clinical picture was that of scleroderma kidney. [1] In a review by Bennett of 100 patients with MCTD and renal histologic analysis, 12% had normal histology, 35% had mesangial disease, 10% had proli-ferative glomerulonephritis, 36% had membranous glomerulonephritis, 15% had interstitial disease and 22% had vascular disease. [8]

SRC is typically characterized by a sudden and marked increase in systemic blood pres­sure (although normotensive SRC has been described) and acute renal failure, with or without significant micro-angiopathic hemo-lytic anemia or thrombocytopenia. [9],[10] SRC is often accompanied by headache, blurring of vision and dyspnea. [11] These symptoms can be attributed to hypertensive encephalopathy, congestive heart failure and/or pulmonary ede­ma, respectively, as consequences of the rapid increase in blood pressure. Because SRC can present as acute renal failure, one would ex­pect a significant elevation of serum crea-tinine and a considerable fall of glomerular filtration rate (GFR). [12]

Changes in biochemical profile that may be observed in patients with SRC include eleva­ted plasma creatinine, micro-angiopathic he-molytic anemia (MAHA), thrombocytopenia and hyper-reninemia. Elevated serum crea-tinine is seen in approximately 96% of the patients, and the prevalence of MAHA and thrombocytopenia is estimated to be 60% and 50%, respectively. High levels of renin may induce hypertension, which may be alleviated following nephrectomy. Urinalysis commonly shows mild proteinuria and hematuria, with granular casts evident on microscopy. The overall microscopic picture is that of a throm-botic micro-angiopathic process. Early patho­logical changes comprise mucin accumulation in arcuate and interlobular arteries, mucoid intimal thickening and fibrinoid necrosis of arterioles with fibrin thrombi. Subsequent manifestations include hypertensive vascular damage, glomerular ischemia, thrombotic vas­cular occlusion and fibrosis and proliferation of intimal cells. [9],[10]

Multiple factors are associated with a higher risk of development of SRC. An association with recent treatment with high-dose cortico-steroids has been reported. It has been postu­lated that the ability of corticosteroids to inhibit prostacyclin production, which may result in increased angiotensin-converting en­zyme (ACE) activity, contributes to the development of SRC. SRC has been reported in both hypertensive and normotensive patients, in patients already on ACE inhibitors, in pa­tients without prior steroid treatment, in asso­ciation with cyclosporine initiation, in associa­tion with cyclosporine withdrawal, after use of essential (volatile) oils and without any ante­cedent factors. [9],[10]

The patient in our report developed accele­rated hypertension and acute renal insuffi­ciency. Renal biopsy showed glomerular and arteriolar changes, which were similar to those of SRC. Renal histology can help to predict renal prognosis and may contribute to unders­tanding better the mechanisms and pathologic manifestations of SRC, ultimately leading to optimization of treatment strategies.

   References Top

1.Vivette D. D'Agati. Renal Disease in Systemic Lupus Erythematosus, Mixed Connective Tissue Disease, Sjogren's Syndrome, and Rheumatoid Arthritis. Jennette, J. Charles; Olson, Jean L.; Schwartz, Melvin M.; Silva, Fred G. Eds: In Hepinstall's Pathology of the Kidney, 6 th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.  Back to cited text no. 1
2.Venables PJ. Mixed connective tissue disease. Lupus 2006;15:132-7.  Back to cited text no. 2
3.Celikbilek M, Elsurer R, Afsar B, Ozdemir HB, Sezer S, Ozdemir NF. Mixedconnective tissue disease: A case with scleroderma renal crisis followingabortion. Clin Rheumatol 2007; 26:1545-7.  Back to cited text no. 3
4.Andersen GN, Vasko J. Scleroderma renal crisis and concurrent isolated pulmonary hyper­tension in mixed connective tissue disease and overlap syndrome: Report of two cases. Clin Rheumatol 2002;21:164-9.  Back to cited text no. 4
5.Greenberg SA, Amato AA. Inflammatory myo-pathy associated with mixed connectivetissue disease and scleroderma renal crisis. Muscle Nerve 2001;24:1562-6.  Back to cited text no. 5
6.Satoh K, Imai H, Yasuda T, Wakui H, Miura AB, Nakamoto Y. Sclerodermatousrenal crisis in a patient with mixed connective tissue disease. Am J Kidney Dis 1994;24:215-8.  Back to cited text no. 6
7.Kobayashi S, Nagase M, Kimura M, Ohyama K, Ikeya M, Honda N. Renal involvement in mixed connective tissue disease. Report of 5 cases. Am J Nephrol 1985;5:282-9.  Back to cited text no. 7
8.Bennett R. Mixed connective tissue disease. In: Grishman E, Churg J, Needle MA, Venkataseshan VS, eds. The Kidney in Collagen Vascular Diseases. New York: Raven Press; 1993. p. 167.  Back to cited text no. 8
9.Denton CP, Lapadula G, Mouthon L, Müller-Ladner U. Renal complications and sclero-derma renal crisis. Rheumatology (Oxford) 2009;48 Suppl 3:32-5.  Back to cited text no. 9
10.Batal I, Domsic RT, Medsger TA, Bastacky S. Scleroderma renal crisis: A pathology perspec­tive. Int J Rheumatol 2010;2010:543704.  Back to cited text no. 10
11.Haviv YS, Safadi R. Normotensive sclero-derma renal crisis: Case report and review of the literature. Ren Fail 1998;20:733-6.  Back to cited text no. 11
12.Lewandowski B, Domys³awska I, Klimiuk PA, Sierakowski S. Kidney crisis in systemic sclerosis. Rocz Akad Med Bialymst 2005;50 Suppl 1:294-6.  Back to cited text no. 12

Correspondence Address:
Mukul Vij
Department of Pathology, Global Health City, Chennai, Tamilnadu, 600100
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DOI: 10.4103/1319-2442.135177

PMID: 24969199

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