Hypercalcemia and pneumocystis Pneumonia ... - Wiley Online Library

r 2011 John Wiley & Sons A/S Transplant Infectious Disease . ISSN 1398-2273

Case report

Hypercalcemia and Pneumocystis pneumonia after kidney transplantation: report of an exceptional case and literature review

C. Chatzikyrkou, C. Clajus, M. Haubitz, C. Hafer. Hypercalcemia and pneumocystis pneumonia after kidney transplantation: report of an exceptional case and literature review. Transpl Infect Dis 2011: 13: 496^500. All rights reserved Abstract: Pneumocystis jirovecii remains an important pathogen in solid organ transplant recipients. Although the overall incidence may be decreasing, after the adoption of e¡ective prophylactic measures, the risk has not been abolished, and pneumocystis pneumonia (PCP) can be observed even many years after successful transplantation. Hypercalcemia develops frequently after renal transplantation and is commonly associated with preexisting secondary hyperparathyroidism. But the pathogenesis of hypercalcemia occurring later in the course of transplantation may be di¡erent, and other disease states, such as malignancy and opportunistic infections, must be considered. Hypercalcemia in conjunction with PCP is being increasingly reported in renal transplant patients. In all the cases, respiratory symptoms were prominent, hypercalcemia was of mildto-moderate severity, parathyroid hormone concentration was decreased, and 1,25(OH)2 D levels were extraordinarily or inappropriately high.We report the ¢rst case to our knowledge of severe hypercalcemia accompanying PCP, in a patient with previous total parathyroidectomy.

Pneumocystis jirovecii (formerly Pneumocystis carinii) is an important opportunistic pathogen known to cause lifethreatening pneumonia in immunocompromised patients. It primarily a¡ects persons infected with the human immunode¢ciency virus (HIV) (1), but it is also observed after renal transplantation, especially in the ¢rst months following initiation of immunosuppressive therapy (2). Symptoms and signs of pneumonia are not typical, the onset is insidious, the progression can be rapid, and hypoxemia may be the sole ¢nding. The use of chemoprophylaxis has been shown to be extremely e¡ective in preventing the development of clinical disease, and most experts agree that it should be continued for at least 6 months post transplant for kidney recipients (3). Hypercalcemia is commonly encountered early after transplantation, and the severity and duration of parathyroid disease during dialysis appears to be the major risk factor (4). However, the pathogenesis of hypercalcemia occurring late after renal transplantation may be di¡erent, and other conditions must be distinguished, with malignancy and opportunistic infections being the most

496

C. Chatzikyrkou, C. Clajus, M. Haubitz, C. Hafer Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany

Key words: hypercalcemia; Pneumocystis jirovecii; transplantation; calcitriol; vitamin D Correspondence to: Christos Chatzikyrkou, Department of Nephrology and Hypertension, Hanover Medical School, Carl-Neuberg-Strasse 1, Hannover 30625, Germany Tel: 49 511 532 6319 Fax: 49 511 532 4005 E-mail: [email protected] Received 1 August 2010, revised 30 October 2010, accepted for publication 9 December 2010 DOI: 10.1111/j.1399-3062.2011.00623.x Transpl Infect Dis 2011

important. Pneumocystis pneumonia (PCP)-induced hypercalcemia has been reported previously in renal transplant recipients. We searched PubMed for published case reports using the following combination of terms: (Pneumocystis OR carinii OR jirovecii) AND (renal OR kidney) AND transplantation. Four articles were identi¢ed describing a total of 8 patients. In all these cases the opportunistic infection developed early in the course of transplantation and the respiratory symptoms and signs dominated the clinical picture. Hypercalcemia was of mild-to-moderate severity (with serum calcium levels ranging from 2.9 to 3.25 mmol/L), intact parathyroid hormone (iPTH) was decreased, and 1,25(OH)2D levels were extraordinarily or inappropriately high (5^8). A similar biochemical pro¢le has also been described in 2 patients with HIV infection (9, 10) and 1 patient with leukemia in remission (11), where their disease course was complicated by PCP and hypercalcemia. We report the ¢rst case to our knowledge of severe hypercalcemia in conjunction with PCP, occurring late after renal transplantation in a patient with previous total parathyroidectomy. Symptomatic

Chatzikyrkou et al: Hypercalcemia and PCP

hypercalcemia developed ¢rst and persisted despite adequate therapy including the use of bisphosphonates. PCP was diagnosed later during the diagnostic workup of hypercalcemia and was a rather unexpected ¢nding. Serum calcium levels normalized only after successful treatment of the pneumonia.

Pertinent laboratory ¢ndings on admission and initial evaluation Laboratory parameter

Result

White blood cell count (per mm3 )

10,300

Hemoglobin (g/dL) Platelets

Case report

Diagnosis Pamidronate, normal saline, and furosemide were given intravenously, the vitamin D supplementation was discontin-

12.1

12^16

279,000

150,000^450,000

4.9

3.6^5.4

Sodium (mmol/L)

132

138^148

Calcium (mmol/L) Albumin (g/L)

A 55 -year-old woman presented to the emergency department of our hospital complaining of lightheadedness, headache, muscle weakness, joint pains, anorexia, and constipation. Her symptoms started a few days earlier and had gradually worsened. She denied fever, rigor, cough, dyspnea, back pain, abdominal discomfort, nausea, vomiting, or diarrhea. She had no exposures to ill persons and no recent travel activity. Seven years ago, she received a living-donor kidney transplant for end-stage renal disease secondary to vascular nephropathy. The patient’s medical history was notable for total thyroidectomy due to papillary thyroid cancer (T1N1M0) discovered 2 years after transplantation. Later in the course, she developed occasional episodes of hypocalcemia due to hypoparathyroidism. Other important medical history included hypertension, gastric bending, gastroesophageal re£ux disease, and diverticulitis requiring sigmoidectomy. Medications on presentation included tacrolimus, mycophenolate mofetil, prednisolone, amlodipine, metoprolol, doxazosin, furosemide, simvastatin, ezetimibe, darbepoetin, L-thyroxine, cholecalciferol, calcitriol, calcium carbonate, and pantoprazole. On evaluation, the patient appeared to be in obvious distress. The body mass index was 22, temperature was 36.91C, blood pressure 130/80 mmHg, pulse 80 beats/min, and respiratory rate was 20 breaths/min, with an oxygen saturation of 94% while she was at rest breathing ambient air. The heart sounds were normal and a grade 2/6 systolic murmur was present at the left upper sternal border. Lung auscultation revealed equal bilateral breath sounds, with no wheezes or crackles. The abdomen was soft with normal bowel sounds and no tenderness, masses or hepatosplenomegaly. No peripheral edema, rash, or other skin changes were noted. Neurologic examination was unremarkable. The presenting laboratory investigations are summarized in Table 1.

4400^11,300

Potassium (mmol/L)

Chloride (mmol/L)

Clinical history and laboratory data

Normal range

98

97^108

4.28

2.15^2.60

30

35^52

Ionized calcium (mmol/L)

2.21

1.14^1.27

Phosphorous (mmol/L)

1.56

0.83^1.76

Creatinine (mmol/L)

186

45^84

Urea nitrogen (mmol/L)

22.8

3.3^6.7

13

35^104

208

0^247

57

0^8

25 -OH vitamin D (ng/mL)

26.5

20^50

1,25 -(OH)2 vitamin D (pg/mL)

141

16^81

Intact PTH (pg/mL)

o2.5

10^65

PTHrP (pmol/L)

o0.50

o1.3

Calcitonin (pg/mL)

1.5

1.0^5.5

Alkaline phosphatase (U/L) Lactate dehydrogenase (U/L) C-reactive protein (mg/L)

Bold values were abnormal. PTH, parathyroid hormone; PTHrP, parathyroid hormone-related peptide.

Table1

ued, and an extensive workup for the diagnosis of the cause of hypercalcemia was initiated. PTH concentration was o2.5 pg/mL, 25 -OH vitamin D 26.5 ng/mL (reference range 20^50 ng/mL), 1,25(OH)2 vitamin D 141 pg/mL (reference range 16^81 pg/mL), and PTH-related peptide (PTHrP) was undetectable (o0.50 pmol/L). The posteroanterior chest radiograph showed no abnormalities. A chest computed tomography obtained a week after admission, and performed primarily to rule out infection or malignancy, detected a bilateral multifocal consolidation sparing only the lower lobes and widespread ground-glass opacities a¡ecting all lobes (Fig. 1). The cardiac silhouette and pulmonary vasculature were unremarkable. Pulmonary function testing revealed normal forced vital capacity (FEV 5 3.02 L, 95% of the predicted value) and forced vital capacity in the ¢rst second (FEV1 5 2.57 L, 97% of the predicted value) with a normal FEV/FEV1 ratio. The carbon monoxide di¡using capacity was severely reduced, at 45% of the predicted value. Capillary blood gas analysis demonstrated a normal pH, a low PVCO2 of 33 mmHg, and a PVO2 67 mmHg, while the patient was breathing ambient room air.

Transplant Infectious Disease 2011: 13: 496^500

497


Fig. 1. Chest computed tomography (CT) obtained during the diagnostic workup of hypercalcemia. Axial CT images of the chest performed with the intravenous administration of contrast media showing bilateral multifocal consolidation and widespread ground-glass opacities

A bronchoscopy with bronchoalveolar lavage was performed. The diagnosis of P. jirovecii was con¢rmed by Wright^Giemsa stain and monoclonal-antibody stain of the bronchoalveolar lavage £uid. Testing and cultures for routine viral, bacterial, fungal, mycobacterial, and other organisms yielded negative results. A transbronchial biopsy was not done, because of the unequivocal diagnosis and the patient’s further clinical course. Clinical follow up Trimethoprim/sulfamethoxazole was administered intravenously at a dose adapted to renal function and her dose of prednisolone was temporarily increased to 60 mg/day, according to current treatment standards (1). Hypercalcemia, which was as yet refractory to treatment, resolved quickly thereafter. Serum calcium levels returned to normal and follow-up chest radiographs showed regression of the in¢ltrates. The patient’s status improved steadily, she made a full recovery, without the need to be transferred in the intensive care unit, and could be discharged home on the 30th day of her hospital stay.

Discussion Hypercalcemia can be a manifestation of a serious illness or can be detected coincidentally in a patient with no obvious disease, therefore providing a clue to its diagnosis. The symptoms associated with hypercalcemia generally correlate with the magnitude and the rapidity of the rise in serum calcium, and a serum calcium level 43.375 mmol/L constitutes a medical emergency, warranting aggressive intervention, independently of the presence of symptoms (12).

498


Hypercalcemia in conjunction with PCP is being increasingly reported in renal transplant recipients. It is postulated to result from increased conversion of 25 hydroxyvitamin D to 1,25 dihydroxyvitamin D due to interferon-g-mediated expression of 25-hydroxyvitamin D-1ahydroxylase by activated macrophages in granulomatous tissue. Although experimental evidence exists only for sarcoidosis, this mechanism is presumed to be operative in other disorders characterized by granuloma formation. However, the discrepancy in frequency of hypercalcemia between patients with sarcoidosis, where the incidence is increased, and patients with fungal infections, where it is less commonly observed, may re£ect variations in granuloma formation or also other underlying mechanisms, such as osteoclast activation via osteopontin or receptor activator of NF-kB ligand (RANKL) generation (13). The ¢rst case of a PCP-induced hypercalcemia was described by Chen et al. (5) in 2002. Mild hypercalcemia was accompanied by suppressed PTH and increased 1,25(OH)2D3 concentrations resolving after successful treatment of the pneumonia (5). In the second case (6), 1,25(OH)2D levels were not determined and an open lung biopsy was performed, but details about the presence of granulomas are not given. In the case reported by Aguirre et al. (7 ), 1,25(OH)2D levels could be measured only after initiation of therapy and were found to be in the normal range. Lastly, in a published case series from a single tertiary center, PCP developed in 15 patients during 2 years, raising concerns about nosocomial or environmental transmission. In 5 of those patients, the course of the disease was complicated by hypercalcemia. PTH was again decreased and 1,25(OH) 2D and 25 -OHD levels (determined in 3 of the 5 patients) were respectively in the upper normal range and decreased. Follow-up of the laboratory values were reported only for iPTH, which returned to normal after the resolution of the infection and the normalization of calcium levels (8). Pertinent laboratory and clinical data of the published cases are presented in Table 2 (5^8). Our case di¡ers from the others in several aspects. First, pneumocystosis developed late after renal transplantation, con¢rming the bene¢ts of trimethoprim/sulfamethoxazole prophylaxis during the ¢rst 6 months and underscoring the increased risk of opportunistic infections, even in the late post-transplantation period. Second, and in contrast with the previous reports, hypercalcemia was severe.The symptoms associated with hypercalcemia predominated in the clinical presentation, whereas the clinical manifestations of pneumonitis were subtle and suggestive signs nearly absent. PCP was a rather unexpected ¢nding during the diagnostic workup conducted to rule out malignant disease. Our patient suffered from surgical hypoparathyroidism and frequent episodes of hypocalcemia, necessitating replacement therapy


Selected clinical and laboratory data of reported renal transplant patients with hypercalcemia and Pneumocystis jirovecii pneumonia Author (reference)

N

Chen et al. (5)

1

Hung (6)

1

Ca (Dx) (mmol/L)

25-(0H)D (Dx) (ng/mL)

1,25-(OH)2D (Dx) (pg/mL)

iPTH (Dx) (pg/mL)

25-(OH)D p(Dx) (ng/mL)

1,25(0H)2D p(Dx) (pg/mL)

iPTH p(Dx)

Histology1

3

3.25

5.30

123

8.5

9.93

5.10

59

No

3

1.42

NR

NR

12

NR

NR

NR

NR

T|me (pTx) (months)

Aguirre et al. (7)

1

4

2.875

NR

50

8.5

NR

NR

^

No

Hajji et al. (8)

5

11

2.90

13.93

54.63

20

NR

NR

893

No

1 Histological con¢rmation of granulomas in lung tissue is not available in all cases. In Hung (6), a lung biopsy was performed; in the other cases, the diagnosis was con¢rmed only by bronchoalveolar lavage. 2 Levels of free serum calcium. 3 Mean values (range: 2.2^26.5 for 25-OH, 50^63 for 1.25(OH)2, 3^7 for parathyroid hormone (PTH) at diagnosis, and 49^108 for PTH after recovery). N, number of cases; pTx, post transplantation (in months); Ca, calcium; Dx, at diagnosis of pneumonia; p(Dx), after recovery of pneumonia; iPTH, intact parathyroid hormone; NR, not reported.

Table 2

with vitamin D/calcitriol and oral calcium administration on a regular basis. The dosages remained unchanged during the previous months (0.5 mg/day calcitriol, 20,000 IU cholecalciferol monthly, and 500^1000 mg/day calcium acetate) and her adherence was rather low, as re£ected by the frequent diagnosis of hypocalcemia during visits at our outpatient clinics before and after the current admission (Fig. 2). Nonetheless, we can assume that vitamin D and calcium supplementation were responsible for the severity of the calcium abnormalities primarily induced by PCP. One week after admission and despite the maximal supportive therapy and discontinuation of vitamin D/calcitriol/calcium supplementation, the 1,25(OH)2D levels returned to the upper normal limits and moderate hypercalcemia persisted. Third, as can be inferred from Figure 2, the exceptionally positive correlation between the higher 25 -(OH)D levels and the increased circulating concentrations of 1,25 (OH)2D at diagnosis lends further support to the hypothesis of vitamin D metabolite-mediated hypercalcemia in PCP. Hypercalcemia is known to reduce the renal production of 1,25(OH)2D, and 1,25(OH)2D decreases its own synthesis through negative feedback control on the renal 1a-hydroxylase (14). Additionally, our patient was usually in a state of vitamin D de¢ciency.Thus, the inappropriately increased concentrations of 1,25(OH)2D related to the calcium levels, even after discontinuation of the exogenously administered vitamin D (calcitriol), point to an extrarenal dysregulated side of generation. The availability of 25(OH)D in su⁄cient concentrations, probably because of the correct or increased intake of the prescribed medication (cholecalciferol) before the acute illness, provided the substrate to the 25 -hydroxyvitamin D-1a-hydroxylase of activated macrophages. Our results contrast with the published reports, where the 25 -OH vitamin D de¢ciency was rather severe, presum-

ably owing to its increased use for the production of 1,25(OH)2D. But follow-up data are not available and, in the case reported by Chen et al. (5), severe 25 -hydroxyvitamin D de¢ciency was still present 3 months after the resolution of PCP. Although vitamin D replacement therapy was a confounder, our case is the ¢rst to provide

Fig. 2. Changes in the levels of 25 -OH vitamin D, 1,25 -(OH)2 vitamin D, total serum calcium, and intact parathyroid hormone (PTH) over time. Line graphs showing the course of these levels before, during, and after the acute disease.


499


su⁄cient follow-up laboratory data to substantiate the hypothesis of increased active vitamin D production, as a mechanism of hypercalcemia during PCP. A further strength is the fact that, because of her prevailing hypoparathyroidism, vitamin D and calcium metabolism were independent of the in£uential impact of circulating iPTH. Lastly, vitamin D de¢ciency appears to be highly prevalent among renal transplant recipients (15) and, because the evidence about the abundant pleiotropic actions of vitamin D is accumulating (14, 16), current clinical practice advocates its supplementation (17 ). Thus, in the era of active implementation of vitamin D replacement strategies, increased awareness of causes of hypercalcemia is warranted to avoid serious and potentially life-threatening complications. Hypercalcemia resolved quickly in our patient after the institution of speci¢c antimicrobial therapy and the concomitant increase in the dose of corticosteroids, presumably owing to the resolution of granulomas after eradication of the pathogenic microorganism. However, it is di⁄cult to appreciate the relative e¡ects of each treatment modality. Corticosteroids are primarily given to prevent lung injury and gas exchange deterioration during the treatment of PCP (1). But they also directly target granulomatous host responses, as is the case in sarcoidosis, where prednisolone decreases 1,25(OH)2D and serum calcium levels within only a few days after its administration (18).

Conclusion In conclusion, successful management of hypercalcemia usually depends upon determining its etiology. In most patients the cause is obvious from the clinical setting and the results of serum assays of PTH, PTHrP, and vitamin D metabolites. Hypercalcemia after kidney transplantation is generally considered to result from PTH-induced osteoclast activation and bone resorption, but malignancy and infection must be included in the di¡erential diagnosis, especially in long-term transplanted patients. PCP is an increasingly recognized cause of hypercalcemia in renal transplant recipients and fortuitous detection of increased calcium levels should raise clinical suspicion about its presence. Awareness of this becomes even more imperative in the setting of vitamin D supplementation.

500


Con£icts of interest: None.

References 1. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004; 350: 2487^2498. 2. Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357: 2601^2614. 3. Martin SI, Fishman JA, AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplant recipients. Am J Transplant 2009; 9 (Suppl 4): S227^S233. 4. Torres A, Lorenzo V, Salido E. Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002; 13: 551^558. 5. Chen WC, Chang SC,Wu TH,Yang WC,Tarng DC. Hypercalcemia in a renal transplant recipient su¡ering with Pneumocystis carinii pneumonia. Am J Kidney Dis 2002; 39: E8. 6. Hung YM. Pneumocystis carinii pneumonia with hypercalcemia and suppressed parathyroid hormone levels in a renal transplant patient. Transplantation 2006; 81: 639. 7. Aguirre AR, Balbo BE, Ianhez LE, da Costa MC, Andrade L. Hypercalcemia and suppressed PTH levels in a renal transplant patient infected with Pneumocystis carinii. Ren Fail 2007; 29: 513^516. 8. Hajji K, Dalle F, Harzallah A,Tanter Y, Ri£e G, Mousson C.Vitamin D metabolite-mediated hypercalcemia with suppressed parathormone concentration in Pneumocystis jiroveci pneumonia after kidney transplantation. Transplant Proc 2009; 41: 3320^3322. 9. Jacobs MB. The acquired immunode¢ciency syndrome and hypercalcemia.West J Med 1986; 144: 469^471. 10. Ahmed B, Jaspan JB. Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia. Am J Med Sci 1993; 306: 313^316. 11. Mills AK,Wright SJ,Taylor KM, McCormack JG. Hypercalcaemia caused by Pneumocystis carinii pneumonia while in leukaemic remission. Aust N Z J Med 1999; 29: 102^103. 12. Bushinsky DA, Monk RD. Electrolyte quintet: calcium. Lancet 1998; 352: 306^311. 13. Lionakis MS, Samonis G, Kontoyiannis DP. Endocrine and metabolic manifestations of invasive fungal infections and systemic antifungal treatment. Mayo Clin Proc 2008; 83: 1046^1060. 14. Holick MF. Vitamin D de¢ciency. N Engl J Med 2007; 357: 266^281. 15. Stavroulopoulos A, Cassidy MJ, Porter CJ, Hosking DJ, Roe SD. Vitamin D status in renal transplant recipients. Am J Transplant 2007; 7: 2546^2552. 16. Doorenbos CR, van den Born J, Navis G, de Borst MH. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nat Rev Nephrol 2009; 5: 691^700. 17. Courbebaisse M,Thervet E, Souberbielle JC, et al. E¡ects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients. Kidney Int 2009; 75: 646^651. 18. Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996; 109: 535^539.