Renal failure and hypercalcemia as initial manifestations of extrapulmonary sarcoidosis.

Abstract: Sarcoidosis is a granulomatous, multisystem disease. Rarely, sarcoidosis may present with both renal failure and hypercalcemia. A 27-year-old black man presented with severe abdominal pain and renal failure. A kidney biopsy demonstrated features of both interstitial nephritis and membranous glomerulopathy thought to be secondary to nonsteroidal anti-inflammatory drugs. His renal function and symptoms improved with short-term prednisone therapy. Discontinuation of steroids led to a recurrence of renal failure and severe hypercalcemia. On the basis of an elevated angiotensinconverting enzyme level of 160 U/L and anemia, a bone marrow biopsy was performed. Acid-fast bacillus-negative, noncaseating granulomas suggested the diagnosis of sarcoidosis. The patient recovered after restarting prednisone. Sarcoidosis may cause both interstitial and membranous nephritis from direct infiltration. Hypercalcemia results from increased calcium absorption secondary to 1,25-dihydroxyvitamin D production by sarcoid granulomas. Sarcoidosis must be considered in the differential diagnosis of renal failure in black patients. Serum calcium and angiotensin-converting enzyme levels may aid the diagnosis.

Key Words: hypercalcemia, renal failure, sarcoidosis

**********

Sarcoidosis is a multisystem disorder characterized by an increased cellular immune response to an unknown antigen and the formation of noncaseating granulomas in affected tissues. Although the lungs and lymph nodes are the predominant sites affected (75-90%), other organs such as the eyes, bone marrow, kidneys, liver, and spleen may also be involved. (1) Cases of extrapulmonary sarcoidosis affecting the kidneys are rare, with most cases presenting either with nephrocalcinosis or nephrolithiasis (3.6%). (1,2) Renal failure is an extremely uncommon manifestation. We report a rare case of extrapulmonary sarcoidosis presenting with acute renal failure and hypercalcemia as initial manifestations.

Case Report

A 27-year-old black man presented initially to the emergency room in April 2001 with complaints of crampy abdominal pain and vomiting of 1-month duration. He was admitted to the hospital for anemia, hypercalcemia, and acute renal failure (corrected calcium, 12.2 mg/dL; ionized calcium, 6.2 mg/dL; blood urea nitrogen [BUN], 72 mg/dL; creatinine, 7.6 mg/dL; white blood cell count, 6,300/m[m.sup.3]; hemoglobin, 8.4 g/dL; hematocrit, 25.6%; platelets, 210,000/m[m.sup.3]; and eosinophils, 2%). With a normal chest radiograph and kidneys, ureters, bladder film, an extensive workup was performed to isolate the causes of his renal failure and elevated calcium. Computed tomographic (CT) scan of the abdomen/pelvis, a kidney ultrasound, and a whole body gallium scan were negative. Other negative tests included antinuclear antibodies, C4, C3, perinuclear antineutrophil cytoplasmic antibodies, serum protein electrophoresis, urine protein electrophoresis, and human immuno-deficiency virus. Both hyperparathyroidism and vitamin D excess were excluded by a parathyroid hormone level of <7 pg/mL (normal, 10-65 pg/mL) and a 25-dihydroxyvitamin D (calcidiol) level <5 pg/mL (normal, 9-52 pg/mL). His 1,25-dihydroxyvitamin D (calcitriol) level was normal at 23 pg/mL (normal, 15-60 pg/mL). A 24-hour urine collection for calcium was also within normal limits.

Further history revealed the patient had been taking nonsteroidal anti-inflammatory drugs (NSAIDs) in previous months for joint pain. Interstitial nephritis as a possible cause of renal failure was considered in the differential diagnosis, leading to a kidney biopsy. The biopsy showed changes consistent with both acute interstitial nephritis and membranous glomerulonephritis (Figure). His renal failure and consequent hypercalcemia were thought to be secondary to NSAIDs. He was encouraged to stop NSAIDs and was immediately placed on a short, tapered course of prednisone at a starting dose of 60 mg. His renal failure and hypercalcemia improved dramatically thereafter. His blood urea nitrogen (BUN) and creatinine decreased to 23 mg/dL and 2.3 mg/dL, respectively, in 2 weeks. His corrected calcium level also decreased to 9.86 mg/dL, with an ionized level of 5.1 mg/dL.

Within 2 weeks of discontinuing his steroids, the patient presented again with crampy abdominal pain, renal failure, and hypercalcemia. This time, laboratory values revealed that his BUN was 37 mg/dL, his creatinine was 3.0 mg/dL, his corrected calcium was 16.2 mg/dL, his ionized calcium was 8.7 mg/dL, and his hemoglobin was 9.5 mg/dL. Adrenal insufficiency was excluded with a cosyntropin stimulation test, with a normal increase in serum cortisol from a baseline of 13 [micro]g/dL to 24 [micro]g/dL. A repeat chest radiograph showed no change from the previous one. His nonspecific abdominal complaints prompted obtaining a repeat CT scan of his chest/abdomen/pelvis. This showed nodular thickening of several small bowel loops, along with mesenteric adenopathy and an increased number of borderline axillary lymph nodes. Follow-up esophagogastroduodenoscopy was not helpful in diagnosis, showing nonspecific chronic inflammation with lymphoid aggregates at the terminal ileum. In light of the patient's anemia and an elevated angiotensin-converting enzyme level of 160 U/L (normal, 8-52 U/L), a bone marrow biopsy specimen was obtained. Acid-fast bacillusnegative, noncaseating granulomas in the bone marrow suggested sarcoidosis to be a likely cause. He was started on oral prednisone, showing marked improvement in symptoms and resolution of his renal failure. Follow-up laboratory values revealed that his calcium was 9.0 mg/dL, his ionized calcium was 4.5 mg/dL, his BUN was 19 mg/dL, and his creatinine was 1.3 mg/dL. The patient is currently on 20 mg of prednisone daily and has not had further episodes of hypercalcemia or renal failure in more than 1 year. His hemoglobin also increased to 12.3 mg/dL after 3 months of prednisone therapy.

Discussion

This patient's renal failure was initially believed to be from interstitial nephritis secondary to the use of NSAIDs for arthritis. Although NSAIDs may cause interstitial nephritis, his hypercalcemia could not be explained. Recurrence of renal failure and hypercalcemia after discontinuation of prednisone, along with evidence of mesenteric lymphadenopathy on abdominal CT scan and an elevated angiotensin-converting enzyme level, prompted further searches for sarcoidosis. In light of anemia, a bone marrow biopsy was performed, which suggested sarcoidosis to be a likely diagnosis. Both interstitial nephritis and membranous glomerulonephritis may be seen in sarcoidosis. Interstitial nephritis results from granulomatous parenchymal infiltration causing impaired filtration. Membranous glomerulonephritis results from an immune-mediated process. Immunoglobulins and complement (immunoglobulins G and A, and C3) attack the glomerular basement membrane and impair renal function.

Hypercalcemia in sarcoidosis is uncommon, accounting for approximately 10% of cases. (3) It is usually caused by an autonomous production of 1,25-dihydroxyvitamin D (calcitriol) by macrophages within the granuloma. These macrophages are able to convert 25-hydroxyvitamin D, produced by the liver, into calcitriol by possessing the 1[alpha]-hydroxylase enzyme. (4,5) Calcitriol then travels to the intestinal cells and promotes luminal absorption of calcium and phosphate into the circulation. Systemic corticosteroids are used in therapy because they inhibit the production of calcitriol within the macrophages. Long-term therapy is often required to maintain normocalcemia. Hypercalcemia may also cause renal failure by inducing renal vasoconstriction, thereby reducing the glomerular filtration rate with consequent renal insufficiency.

Conclusion

Extrapulmonary forms of sarcoidosis often go unrecognized. Every effort should be made to diagnose this condition, because it is easily treatable with steroids or cytotoxic agents such as methotrexate. (6,7) Ketoconazole may also be considered in patients who have contraindications to corticosteroids. (8) In our patient, hypercalcemia and renal failure reversed completely with steroid treatment. Sarcoidosis should be considered an important differential diagnosis in cases of hypercalcemia and renal failure, occurring singly or in combination. After excluding other causes of renal failure and hypercalcemia, diagnosis may be made by obtaining biopsy specimens from extrapulmonary tissue.

[ILLUSTRATION OMITTED]

Accepted June 25, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0590

References

1. Rizzato G. Extrapulmonary presentation of sarcoidosis. Curr Opin Pulm Med 2001;7:295-297.

2. Utas C, Dogukan A, Patiroglu TE, et al. Granulomatous interstitial nephritis in extrapulmonary sarcoidosis. Clin Nephrol 1999;51:252-254.

3. Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med 2000;6:442-447.

4. Monkawa T, Yoshida T, Hayashi M, et al. Identification of 25-hydroxyvitamin D3 1[alpha]-hydroxylase gene expression in macrophages. Kidney Int 2000;58:559-568.

5. Niimi T, Tomita H, Sato S, et al. Vitamin D receptor gene polymorphism and calcium metabolism in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis 2000;17:266-269.

6. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA 2002;287:1301-1307.

7. Vucinic VM. What is the future of methotrexate in sarcoidosis? A study and review. Curr Opin Pulm Med 2002;8:470-476.

8. Glass AR, Cerletty JM, Elliott W, et al. Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis. J Endocrinol Invest 1990;13:407-413.

RELATED ARTICLE: Key Points

* Sarcoidosis should be considered an important differential diagnosis in cases presenting with renal failure and hypercalcemia.

* Tissue biopsy from kidney and other sites should be obtained to confirm the diagnosis.

Carlos Ponce, MD, and Jaspal S. Gujral, MBBS, FACP, MRCP (UK)

From the Section of General Internal Medicine, Department of Medicine, Medical College of Georgia, Augusta, GA.

We acknowledge no financial support was received from any source toward the preparation of this case report. We have no commercial or proprietary interest in any drug, device, or equipment mentioned in this case report.

Reprint requests to Jaspal S. Gujral, MBBS, FACP, MRCP (UK), Section of General Internal Medicine, Department of Medicine, Medical College of Georgia, 1120 15th Street, Suite HB-2010, Augusta, GA 30912-3104. Email: [e-mail]