<% 'if (Session("Type") <> 1 and Session("Type") <> 5 and Session("Type") <> 28) then Response.Redirect "../Msg.asp?Messaggio1=Restricted access area!!!&Messaggio2=Return to HomePage" 'if Session("UserCount") = "" then Response.Redirect "../Msg.asp?Messaggio1=Error while initialising the quiz!!!&Messaggio2=Return to HomePage" a_capo = chr(13) + chr(10) NumQuestions = 6 RightAnswer1 = "a" RightAnswer2 = "a" RightAnswer3 = "c" RightAnswer4 = "b" RightAnswer5 = "e" RightAnswer6 = "d" currentID = Request("currentID") if currentID = "" then currentID = 1 Answer1 = Request("Question1") if Request("Answer1") <> "" then Answer1 = Request("Answer1") Answer2 = Request("Question2") if Request("Answer2") <> "" then Answer2 = Request("Answer2") Answer3 = Request("Question3") if Request("Answer3") <> "" then Answer3 = Request("Answer3") Answer4 = Request("Question4") if Request("Answer4") <> "" then Answer4 = Request("Answer4") Answer5 = Request("Question5") if Request("Answer5") <> "" then Answer5 = Request("Answer5") Answer6 = Request("Question6") if Request("Answer6") <> "" then Answer6 = Request("Answer6") if currentID = 11 or currentID = 22 or currentID = 33 or currentID = 44 or currentID = 55 then Label = "Continue" elseif currentID = 66 then Label = "Continue" else Label = "Evaluate" end if %> P. Scotto - Case study




Drug abuse and hyperparathyroidism: a poisonous mixture in haemodialysis

scotto

by Patrizia Scotto, MD
Operative Territorial Unit of Nephrology and Dialysis
Azienda USL N.8 - Cagliari - Italy

 

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Introduction:

A 23-year-old male with chronic renal failure, due to unilateral renal agenesis with associated congenital contralateral upper urinary tract chronic obstructive nephropathy started haemodialysis in 1993. After four years on haemodialysis, he received a cadaveric renal allograft with triple immunosuppression consisting of cyclosporine, sirolimus and prednisone. The patient was discharged from hospital with serum creatinine levels averaging 1.8 mg/dL.
The renal graft function progressively deteriorated within twenty-two months after transplantation. (Figure 1)

Figure 1 - Evolution of the renal allograft function




Three biopsies were performed at 12, 17 and 20 months after transplantation to gain an insight into the progressive graft dysfunction. Thickening of the intima in the interlobar and pre-glomerular arteries was present in the first biopsy, while a pattern of chronic allograft nephropathy including tubular atrophy, interstitial fibrosis and glomerular lesions, was found at the third biopsy. (1).
On 2nd February 1999, bicarbonate hemodialysis was resumed on account of end-stage renal failure, using an arteriovenous fistula as hemoaccess.
Although he was treated with ACE inhibitors, Calcium channel blockers and Diuretics, the blood pressure was consistently above 145/90 and left ventricular hypertrophy (LVH) was detected by transthoracic echocardiography.
Severe hyperparathyroidism was diagnosed. Despite serum intact parathyroid hormone (iPTH) levels above 600 pg/mL, calcitriol was discontinuously undertaken because of hyperphosphatemia, largely due to poor dietetic and pharmacological compliance. (Tab.I)

In March 2000, parathyroidectomy was recommended on account of persistent serum levels of iPTH >1000 pg/mL associated with hyperphosphatemia. A scintigraphy with 99m Tc-sestamibi (MIBI) was performed; three parathyroid glands around the thyroid gland and a mediastinal ectopic parathyroid gland were detected. Even though the patient had been informed repeatedly and comprehensively about the necessity of parathyroidectomy (PTx), he refused over and over again.

TABLE I. Outcome of mineral metabolism and related therapy (Phase 1)




Dialysis, severe hyperparathyroidism and LVH were not his only problems. He often suffered from headaches, vomiting and loss of balance, which the patient correlated with his alcohol abuse. Changes of behaviour were also noticed: on Thursday and Saturday morning he was quite sleepy on dialysis, on Tuesday morning he was euphoric. In February 2000 on suspicion that alcohol was being used in conjunction with drugs, some samples of the outflow dialysate were collected in the early minutes of the dialysis to measure benzodiazepine, cannabis, cocaine and opiate levels. The tests repeatedly resulted positive for cocaine (2), whereas they occasionally resulted positive for heroin and cannabis too.
In October 2000, the patient complained of general fatigue, a dry cough, diarrhoea and fever accompanied by shivers and night sweats. Although physical examination was normal, some tests were performed and cefazidime was prescribed. (Tab. II)

TABLE II. Signs, symptoms and tests before his admission to hospital.





References:

  1. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions. Transplantation 2006 March 15; 81(5): 643-54.
  2. Loper KA. Clinical toxicology of cocaine. Med Toxicol Adverse Drug Exp. 1989 May-Jun; 4(3):174-85.
  3. Doulton T, Sabharwal N, Cairns HS, Schelenz S, Eykyn S, O'Donnell P, Chambers J, Austen C, Goldsmith DJ. Infective endocarditis in dialysis patients: new challenges and old. Kidney Int. 2003 Aug; 64(2): 720-7.
  4. Brawn PD, Levine DP. Infective endocarditis in the injection drug user. Infect Dis Clin North Am. 2002 Sept; 16(3): 645-65.
  5. Bashore TM, Cabell C, Fowler V Jr. Update on infective endocarditis. Curr Probl Cardiol. 2006 Apr; 31(4): 274-352.
  6. McDonald JR, Olaison L, Anderson DJ, Hoen B, Miro JM, Eykyn S, Abrutyn E, Fowler VG Jr, Habib G, Selton-Suty C, Pappas PA, Cabell CH, Corey GR, Marco F, Sexton DJ. Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database. Am J Med. 2005 Jul; 118(7): 759-66.
  7. Reynolds HR, Jagen MA, Tunick PA, Kronzon I. Sensitivity of tansthoracic versus transesophageal echocardiography for the detection of native valve vegetations in the modern era. J Am Soc Echocardiogr. 2003 Jan; 16(1): 67-70.
  8. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey GR. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000; 30:633-8.
  9. Saleh A, Dawkins K, Monro J. Surgical treatment of infective endocarditis. Acta Cardiol. 2004 Dec; 59(6): 658-62.
  10. Greub G, Lepidi H, Rovery C, Casalta JP, Habib G, Collard F, Fournier PE, Raoult D. Diagnosis of infectious endocarditis in patients undergoing valve surgery. Am J Med. 2005 Mar; 118(3): 230-8.
  11. Brezina B, Qunibi WY, Nolan CR. Acid loading during treatment with sevelamer hidrochloride: mechanisms and clinical implications. Kidney Int Suppl. 2004 Sep; (90): S39-45.
  12. National Kidney Foundation. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003 Oct; 42 (Supp 3): S1-202.
  13. Brancaccio D, Zoccali C. The continuous challenge of cardiovascular and bone disease in uremic patients: Clinical consequences of hyperphosphatemia and advanced therapeutic approaches. J Nephrol. 2006 Jan-Feb; 19(1): 12-20.
  14. Qunibi WY. Consequences of hyperphosphatemia in patients with end-stage renal disease (ESRD). Kidney Int Suppl. 2004 Sep; (90): S8-12.
  15. Nolan CR. Phosphate binder therapy for attainment of K/DOQITM bone metabolism guidelines. Kidney Int Suppl. 2005 Jul; (96): S7-14.
  16. Zucchelli P, Santoro A. Inorganic phosphate removal during different dialytic procedures. Int J Artif Organs. 1987 May; 10(3): 173-8.
  17. Man NK, Chauveau P, Kuno T, Poignet JL, Yanai M. Phosphate removal during hemodialysis, hemodiafiltration, and hemofiltration. A reappraisal. ASAIO Trans.1991 Jul-Sep; 37(3): M463-5.
  18. Zehnder C, Gutzwiller JP, Renggli K. Hemodiafiltration - a new treatment option for hyperphosphatemia in hemodialysis patients. Clin Nephrol. 1999 Sep; 52(3): 152-9.
  19. Ahrenholz P, Winkler RE, Ramlow W, Tiess M, Muller W. On-line hemodiafiltration with pre- and postdilution: a comparison of efficacy. Int J Artif Organs. 1997 Feb; 20(2): 81-90.
  20. Bolasco P, Ghezzi PM, Ferrara R, Cogoni G, Cadinu F, Casu D, Murtas S. New method for phosphate kinetics estimation during hemodialysis and on-line hemodiafiltration with endogenous reinfusion. Blood Purif. 2006; 24(3): 301-8.
  21. Rufino M, Garcia S, Jimenez A, Alvarez A, Miquel R, Delgado P, Marrero D, Torres A, Hernandez D, Lorenzo V. Heart valve calcification and calcium x phosphorus product in hemodialysis patients: analysis of optimum values for its prevention. Kidney Int Suppl. 2003 Jun; (85): S115-8.
  22. Ventura JE, Tavella N, Romero C, Petraglia A, Báez A, Muñoz L. Aortic valve calcification is an indipendent factor of left ventricular hypertrophy in patients on maintenance haemodialysis. Nephrol Dial Transplant. 2002 Oct; 17(10):1795-801.
  23. Panuccio V, Tripepi R, Tripepi G, Mallamaci F, Benedetto FA, Cataliotti A, Bellanuova I, Giacone G, Malattino LS, Zoccali C. Heart valve calcifications, survival, and cardiovascular risk in hemodialysis patients. Am J Kidney Dis 2004 Mar; 43(3): 479-84.
  24. Seliger SL. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int. 2003 Aug; 64(2): 603-9.
  25. Barnes B, Cawley CM, Barrow DL. Intracerebral hemorrhage secondary to vascular lesions. Neurosurg Clin N Am. 2002 Jul; 13(3): 289-97.
  26. McEvoy AW, Kitchen ND, Thomas DG. Lesson of the week. Intracerebral haemorrhage in young adult: the emerging importance of drug misuse. BMJ 2000 May 13;320: 1322-4.
  27. Carpentier AF, Pellerin M, Fuzellier JF, Relland JY. Extensive calcification of the mitral valve anulus: pathology and surgical management. J Thorac Cardiovasc Surg. 1996 Apr; 111(4): 718-29.
  28. Tsuneyoshi H, Komeda M. Update on mitral valve surgery. J Artif Organs. 2005; 8(4): 222-7.
  29. Piga M, Bolasco PG, Satta L, Altieri P, Loi G, Nicolosi A, Tarquini A, Mariotti S. Double-Phase Parathyroid Technetium-99m-MIBI Scintigraphy to identify functional autonomy in secondary hyperparathyroidism. J Nucl Med 1996 Apr(4); 37: 565-9.
  30. Lindberg J, Martin KJ, Gonzalez EA, Acchiardo SR, Valdin JR, Soltanek C. A long-term , multincenter study of the efficacy and safety of paricalcitol in end-stage renal disease. Clin Nephrol 2001 Oct; 56(4): 315-23.
  31. Robinson DM, Scott LJ. Paricalcitol: a review of its use in the management of secondary hyperparathyroidism. Drugs 2005; 65(4): 559-76.
  32. Moe SM, Cunningham J, Bommer J, Adler S, Rosansky SJ, Urena-Torres P, Albizem MB, Guo MD, Zani VJ, Goodman WG, Sprague SM. Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant. 2005 Oct; 20(10):2186-93.
  33. Dong BJ. Cinacalcet: an oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov; 27(11): 1725-51.
  34. Drueke TB. Calcimimetics versus vitamin D: what are their relative roles? Blood Purif. 2004; 22(1):38-43.
  35. Chertow GM, Blumenthal S, Turner S, Roppolo M, Stern L, Chi EM, Reed J. Cinacalcet Hydrochloride (Sensipar) in Hemodialysis patients on active vitamin D derivates with controlled PTH and elevated Calcium x Phosphate. Clin J Am Soc Nephrol. 2006; 1: 305-12.
  36. Torres PU, Prie D, Beck L, Friedlander G. New therapies for uremic secondary hyperparathyroidism. J Ren Nutr. 2006 Apr; 16(2): 87-99.
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Question 1) - Which tests do you think are suitable for this patient?

> a) Blood Cultures and Echocardiography
> b) Echocardiography
> c) Chest x-ray and Blood Cultures
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Patients undergoing chronic haemodialysis (3) and intravenous drug abusers (4) are at increased risk of infective endocarditis. This is why infective endocarditis (IE) (5) should have been suspected in presence of fever over 38°C.
On arrival in the ward he underwent blood cultures, transthoracic and transesophageal echocardiography, he also received antibiotic treatment with cefazidime and vancomycin.
- Four separate blood cultures resulted positive for enterococcus faecalis (6).
- Transthoracic echocardiography (TTE) detected severe aortic regurgitation and an oscillating intracardiac mass.
- Transesophageal echocardiography (TEE) revealed a tear in the left coronary cusp of the aortic valve causing severe regurgitation. TEE also demonstrated an extensive vegetation, which from the left coronary cusp prolapsed in the left ventricle (7).
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Question 2) - At that point, what was the diagnosis according to the modified Duke criteria (8)?

> a) Definite Infective Endocarditis
> b) Possible Infective Endocarditis
> c) Rejected Infective Endocarditis
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The correct answer is A. The clinical criteria to make diagnosis of definite IE, according to the modified Duke criteria, are:
- 2 major criteria or
- 1 major criterion and 3 minor criteria or
- 5 minor criteria
The correct answer is A because two major criteria were present, in fact TEE was positive for IE and more than two separate blood cultures were positive for Enterococcus faecalis in the absence of a primary focus. However, two minor criteria were also present: injection drug use and body temperature over 38° C.
On 2nd November 2000, the aortic valve was replaced (9) with a mechanical heart valve (Mira).
The vegetation and features of active endocarditis were confirmed by histologic examination (figure 2) (10).

Figure 2 ((by courtesy of Dr. Pierfelice Todde -Department of Pathology, S. Michele Hospital, Cagliari, Italy)


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The postoperative course was uneventful and acenocoumarol was started (target INR 3-4).
On 27th November, the patient was discharged.
Six months later, TTE showed a normally functioning aortic valve and furthermore, only minimal mitral regurgitation . In March 2002, the same diagnosis was confirmed by another TTE.


- With reference to cocaine addiction, psychological support was suggested but the patient refused it.
- Hyperparathyroidism has been one of the biggest challenges in this patient's history. On the one hand, pharmacological treatment with calcitriol was often discontinued or reduced on account of severe hyperphosphatemia, which was very difficult to treat due to poor dietetic compliance and the side effects of the phosphate binders: hypercalcemia during therapy with calcium carbonate, acidosis and abdominal discomfort during therapy with sevelamer (11) (Tab. III). On the other hand, any medical advice about PTx was firmly rejected by the patient.

TABLE III : Outcome of mineral metabolism and related therapy (Phase 2)





In this patient, the elemental calcium provided by the calcium-based phosphate binders had often exceeded the maximum daily intake of elemental calcium suggested by the K/DOQI guidelines (12).



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Question 3) - Which maximum daily intake of elemental calcium is recommended by the K/DOQI guidelines in CKD patients on dialysis?

> a) 4,000 mg/day
> b) 3,000 mg/day
> c) 2,000 mg/day
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The correct answer is C.
In CKD patients on dialysis, the daily dosage of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg (opinion), and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day (opinion) according to the K/DOQI guidelines.
In order to avoid high levels of calcium-phosphorus product (Ca x P) and further complications (13,14), calcium carbonate was reduced and sevelamer was prescribed (15); but in March 2003, Sevelamer and calcium carbonate were self-discontinued because of gastroenteric intolerance and poor compliance. <% newID = 4 else newID = 33 %>


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Question 4) - Which, among the following treatments, should have been preferred in order to achieve a higher phosphorus removal?
> a) High-efficiency and high-flux Hemodialysis (HD)
> b) Hemodiafiltration (HDF)
> c) Hemofiltration (HF)
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The correct answer is B.
HDF should be preferred and considered as an additional option in the treatment of hyperphosphatemia in dialysis patients. Several studies have been conducted to compare the dialytic removal of phosphate with different dialytic techniques (16,17): some studies have compared high-flux haemodialysis (HD) to on-line high-volume haemodiafiltration (HDF) (18), others have compared on-line predilution HDF to on-line postdilution HDF(19). Furthermore, other interesting studies have monitored phosphate kinetics in HFR (20), a new extra corporeal method, which combines diffusion, convection and absorbance. <% newID = 5 else newID = 44 %>


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In February 2003, the patient started HFR, but during the early minutes of the session he complained of dyspnoea, tachycardia and malaise, which disappeared after the session was discontinued and hydrocortisone was administered. In the following session the same symptoms as the year before appeared during several unsuccessful attempts to administer HDF. Afterwards the patient started HD again. His treatment was bicarbonate haemodialysis (HD) 4 hour thrice-weekly, using a synthetically modified cellulose (SMC) dialyser 1.7 m2. The blood flow was 330 ml/min and the dialysate flow was 500 ml/min. The composition of the dialysate was Na 139 mmol/L, K 2 mmol/L, HCO3 34 mmol/L, and Ca 1.25 mmol/L. eKt/V values were between 1.4 and 1.5.

On 22nd April 2003, he complained of fever up to 40° C accompanied by shivers, tachycardia (rate 114 bpm). Admission to hospital was arranged immediately because of a history of a prosthetic aortic valve, previous infective endocarditis and injective drug abuse. On arrival in the ward, a transthoracic echocardiography (TEE) was performed. The TEE detected an extensively calcified mitral valve annulus with severe mitral regurgitation, and calcified aortic annulus (21, 22, 23).
During his first day in hospital, other assessments were performed which highlighted an increased CRP, negative blood cultures and a slightly increased WBC. Although physical examination was normal, he received teicoplanin and gentamicin. After four days in hospital, while he was undergoing haemodialysis, he developed a devastating headache and a left hemiparesis occurred (24).


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Question 5) - At that point, intracerebral haemorrhage was suspected. Which, among the following factors, should have been considered as the possible etiological factors of intracerebral haemorrhage?

> a) Vascular malformations
> b) Hypertension
> c) Treatment with acenocoumarol
ID="Radio1"> d) Cocaine abuse
ID="Radio2"> e) All the above
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The correct answer is: E.
A history of severe headache and hemiparesis, in a drug abuser on treatment with acenocoumarol, alerted doctors to the possibility of intracerebral haemorrhage. Immediately the dialytic session was interrupted and the patient was seen by a neurologist.
A cerebral CT was performed and a cortico-subcortical haemorrhage, localised in the right occipital-parietal region, was shown. After this diagnosis, acenocoumarol was discontinued.
More than one etiological factor were considered:
- Vascular malformations were not found by further investigations, even though nowadays drug related intracerebral haemorrhage usually seems to be the sign of an underlying vascular malformation (25, 26)
- Blood pressure was 130/85
- INR resulted 4.8
- The patient admitted he had used cocaine while he had been in hospital.
However, the patient did not require surgical treatment and he was discharged after 45 days. <% newID = 6 else newID = 55 %>


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In January 2004, he started treatment with oxcarbazepine for epilepsy due to the previous haemorrhage. Three months later he felt better and underwent mitral valve repair (27, 28).
On 9th April 2004 he underwent parathyroidectomy .
Both mitral valve repair and parathyroidectomy were unsuccessful. Residual mitral insufficiency was shown by TTE and a residual retrosternal ectopic parathyroid gland was detected by Double-Phase Parathyroid Technetium-99m-MIBI Scintigraphy with SPECT and TC (Figure 3) (29).

Figure 3 - retrosternal ectopic parathyroid (by courtesy of Prof. Mario Piga - Department of Nuclear Medicine, University of Cagliari, Italy)




In December 2004 iPTH was 2075 pg/mL.


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Question 6) - Because of his valvular disease, the anaesthetist refused to authorise the patient for parathyroidectomy. Which treatment could be used for his severe hyperparathyroidism?

> a) Paricalcitol
> b) Cinacalcet
> c) Combined therapy with Paricalcitol and Cinacalcet
> d) All the above
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The correct answer is: D.
On the grounds of the recent literature either paricalcitol or cinacalcet can be used in haemodialysis patients with severe hyperparathyroidism and combined therapy is also possible (30 - 36).
The case shows further interesting problems. If you are interested in its developments, it will be continued on request with a second report.


Acknowledgements:
I would like to thank Dr. Piergiorgio Bolasco (Operative Territorial Unit of Nephrology and Dialysis, Cagliari - Italy) for his excellent support. <% newID = 7 else newID = 66 %>


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