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NDT Advance Access originally published online on June 9, 2006
Nephrology Dialysis Transplantation 2006 21(9):2664-2666; doi:10.1093/ndt/gfl306
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Teaching Point
(Section Editor: A. Meyrier)

A patient with unexplained hyperphosphataemia

Piero Stratta1, Caterina Canavese1, Marco Quaglia1, Elisa Lazzarich1, Veronica Morellini1, Maddalena Brustia1, Beatrice Bardone2 and Giorgio Bellomo2

1 Departments of Nephro-Urology, Nephrology and Transplantation and 2 Department of Biomedical Sciences, Laboratory of Chemistry and Clinical Research, Amedeo Avogadro University, Maggiore Hospital, Novara, Italy

Correspondence and offprint requests to: Prof. Piero Stratta, Transplantation and Nephrology, Department of Nephro-Urology, Amedeo Avogadro University, Novara, Ospedale Maggiore della Carità, Corso Mazzini 18, 28100 Novara, Italy. Email: strattanefro{at}hotmail.com

Keywords: monoclonal gammopathy; myeloma; paraproteinaemia; phosphate



   Introduction
Top
 Introduction
Case report
 Discussion
 Teaching points
 References
 
Hyperphosphataemia is not a common biochemical alteration outside the context of renal failure. In fact, phosphate homeostasis is mainly regulated by kidney function and parathyroid hormone (PTH) activity [1–4]. In the presence of normal renal function and normal PTH activity, serum phosphate values are tightly regulated within a reference range of 0.8–1.5 mmol/l (2.5–4.5 mg/dl). As phosphates are filtered by the glomerular barrier and excreted into the urine with a renal clearance of 15–20 ml/min, serum phosphate levels do increase early from the beginning of renal failure, reaching levels as high as 4–5 mmol/l in the case of end-stage renal failure in patients with poor compliance to therapeutic schedules [1,2]. Furthermore, true hyperphosphataemia can also result from impaired PTH activity, as PTH is the main factor responsible for phosphate secretion by renal tubular cells, eventually leading to the typical picture of hyperphosphataemia and hypocalcaemia in the presence of hypoparathyroidism [3,4]. Lastly, true hyperphosphataemia could be caused by phosphate poisoning, mainly attributed to phosphate enemas in children, even in the absence of renal failure [5,6].

From a clinical point of view, severe hyperphosphataemia stimulates PTH secretion, induces and worsens extra-osseous tissue calcification and can cause acute paralysis, convulsions and cardiac arrest mainly due to complexes with free serum calcium, resulting in hypocalcaemia [7,8].

We report a case of a patient with normal renal function, IgG myeloma and persistent hyperphosphataemia, in whom further laboratory analyses allowed a diagnosis of ‘pseudo-hyperphosphataemia’ caused by interferences of his paraproteinaemia with analytical procedure for phosphate measurement.



   Case report
Top
 Introduction
 Case report
Discussion
 Teaching points
 References
 
A 56-year-old female patient was admitted to our unit because of proteinuria. Her past history included poliomyelitis (1952) and kidney stones (right kidney colic in 1988). In 2000 she was diagnosed with IgG-k multiple myeloma (Salomon Durie stage IA), and she was on a regular haematological follow-up. Due to the absence of end-organ damage, no specific therapy for myeloma was started. Arterial hypertension was also diagnosed and she was put on a carvedilol and doxazosine association.

In 2004, proteinuria was first detected (around 1 g/day) and urinary immunoelectrophoresis showed that monoclonal ‘kappa’ light-chain accounted for most of it (Bence Jones proteinuria), whereas albumin was only minimally represented. Urinary sediment was unremarkable. Renal function was normal [serum creatinine 64 µmol/l (= 0.8 mg/dl) and creatinine clearance 1.77 ml/s (= 106 ml/min)].

Other routine blood exams showed high total protein levels (86 g/l), slight hyperuricaemia (356 µmol/l = 6 mg/dl), normal calcium levels (2.4 mmol/l = 9.6 mg/dl) and constantly elevated phosphate levels (2.22–2.59 mmol/l = 6.9–7.8 mg/dl). Urinary excretion of calcium and phosphate was normal, as was phosphate clearance, PTH and vitamin D values (Table 1).


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  		Table 1. Main biochemical data of the patient with normal renal failure, IgG-myeloma and unexplained hyperphosphataemia

 
As it was impossible to find reasonable causes for a true hyperphosphataemia, an interdisciplinary briefing with the head of the biochemical laboratory stimulated further in-depth analyses including two simultaneous assays for phosphate concentration in the patient's plasma, one in a whole sample and the other one in a deproteinized sample. The inorganic phosphate assay used in our laboratory is based on the Daly and Ertinghausen procedure [9], which relies on the formation of a UV-absorbing complex between phosphate and molybdate. In fact, inorganic phosphate reacts with ammonium molybdate in the presence of sulphuric acid to form an unreduced phosphomolybdate complex, which is measured as an end point at 340 nm using a Bayer Advia 1650 Clinical Chemistry Instrument. Reaction curves for phosphate measurement of the two samples from our patient were completely different (Figure 1A), leading to the result of high levels in the whole sample but absolutely normal value in the deproteinized sample. On the contrary, the two patterns of whole and deproteinized samples from a patient with severe renal failure and true hyperphosphataemia were superimposable (Figure 1B). To further confirm the essential role of an abnormal protein component in causing pseudo-hyperphosphataemia, the whole plasma from the patient was filtered through a microcentrifuge filter with a 100.000 Da cut-off. The filtrate was subsequently assayed and showed a phosphate concentration superimposable to that obtained in the deproteinized sample, with a typical reaction curve.


Figure 1
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  		Fig. 1. Reaction curves for phosphate measurement in pseudo-hyperphosphataemia (A) and true hyperphosphataemia (B). Samples (heparin-plasma) were employed as intact (open symbols) or after perchloric acid deproteinization (filled symbols). The vertical lines indicate the timing for spectrophotometric readings.

 
As no indication for renal biopsy was done, the patient was discharged with a diagnosis of IgG myeloma, normal renal function, overflow Bence Jones proteinuria and pseudo-hyperphosphataemia caused by paraproteinaemia.



   Discussion
Top
 Introduction
 Case report
 Discussion
Teaching points
 References
 
Our report focuses on a somewhat overlooked laboratory or clinical problem, the recognition of hyperphosphataemia which is not biologically ‘true hyperphosphataemia’ but ‘spurious hyperphosphataemia’ due to analytical interference by abnormal serum components.

This result depends on an increase in optic density due to interference between monoclonal immunoglobulin and the molybdic reagent used in some automated systems, eventually leading to a proteinaceous suspension in the reaction mixture. On the contrary, deproteinization of the same samples yielded normal phosphate concentrations. In fact, the insolubility of these paraproteins eventually leading to interference in photometric/turbidimetric assay is responsible for artefacts that can cause both falsely increased or decreased results in multiple parameters––bilirubin, creatinine, iron, urea, uric acid, glucose, cholesterol, HDL-cholesterol [9]. Furthermore, even falsely low serum phosphate concentrations have been occasionally described in serum samples of patients with myeloma [10].



   Teaching points
Top
 Introduction
 Case report
 Discussion
 Teaching points
References
 

  1. The literature reports an incidence of up to 8% of pseudo-hyperphosphataemia in patients with paraproteinaemias [11–20], mainly associated with IgG paraproteinaemia, rarely with IgA [21] even up to extreme levels (8 µmol/l) [15] without clinical manifestation attributable to such laboratory abnormalities. In any case, globulin-depleted sera were found to have normal inorganic phosphate levels.
  2. Knowledge of this phenomenon may obviate confusion, unnecessary testing and expenditure.
  3. Another important point is that unexplained hyperphosphataemia may also provide clinicians with a clue as to the presence of a dysproteinaemia
  4. Both laboratory staff and clinicians should be aware of interference in the clinical laboratory since clinical consequences could be serious.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Case report
 Discussion
 Teaching points
 References
 

  1. Indridason OS, Quarles LD. Hyperphosphatemia in end-stage renal disease. Adv Ren Replace Ther 2002; 9: 184–192[CrossRef][Web of Science][Medline]
  2. Malluche HH, Monier-Faugere MC. Understanding and managing hyperphosphatemia in patients with chronic renal disease. Clin Nephrol 1999; 52: 267–277[Web of Science][Medline]
  3. Kempson SA, Lotscher M, Kaissling B, Biber J, Murer H, Levi M. Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules. Am J Physiol 1995; [4 Pt 2]: F784–F791
  4. Pfister MF, Lederer E, Forgo J et al. Parathyroid hormone-dependent degradation of type II Na+/Pi cotransporters. J Biol Chem 1997; 272: 20125–20130[Abstract/Free Full Text]
  5. Ismail EAR, Al-Mutairi G, Al-Anzy H. A fatal small dose of phosphate enema in a young child with no renal or gastrointestinal abnormality. J Pediatr Gastroenterol Nutr 2000; 30: 220–221[CrossRef][Web of Science][Medline]
  6. Marraffa JM, Hui A, Stork CM. DABAT Severe hyperphosphatemia and hypocalcemia following the rectal administration of a phosphate-containing fleet(R) pediatric enema. Pediatr Emerg Care 2004; 20: 453–456[CrossRef][Web of Science][Medline]
  7. Prie D, Blanchet FB, Essig M, Jourdain JP, Friedlander G. Dipyridamole decreases renal phosphate leak and augments serum phosphorus in patients with low renal phosphate threshold. J Am Soc Nephrol 1998; 9: 1264–1269[Abstract]
  8. Shiber JR, Mattu A. Serum phosphate abnormalities in the emergency. J Emerg Med 2002; 23: 395–400[CrossRef][Web of Science][Medline]
  9. Berth M, Delanghe J. Protein precipitation as a possible important pitfall in the clinical chemistry analysis of blood samples containing monoclonal immunoglobulins: 2 case reports and a review of the literature. Acta Clin Belg 2004; 59: 263–273[Web of Science][Medline]
  10. Caras JA. Spurious hypophosphatemia associated with multiple myeloma. Endocr Pract 1997; 3: 135–136[Medline]
  11. Lacher DA, Nally JV. Falsely elevated values for serum phosphorus in multiple myeloma. Clin Chem 1986; 32: 1232[Medline]
  12. Busse JC, Gelbard MA, Byrnes JJ, Hellman R, Vaamonde CA. Pseudohyperphosphatemia and dysproteinemia. Arch Intern Med 1987; 147: 2045–2046[Abstract/Free Full Text]
  13. Pettersson T, Hortling L, Teppo AM, Totterman KJ, Fyhrquist F. Phosphate binding by a myeloma protein. Acta Med Scand 1987; 222: 89–91[Web of Science][Medline]
  14. Puechal X, Mariette X, Bennet P, Dugre V, Bisson M. False hyperphosphoremia in multiple myeloma. Presse Med 1989; 18: 494[Web of Science][Medline]
  15. Jarchovsky I, Beitner H, Plavnick L. Spurious hyperphosphatemia in multiple myeloma (Article in Hebrew). Harefuah 1991; 121: 515–516[Medline]
  16. Lorcerie B, Besancenot JF, Maillefert F et al. False hyperphosphoremia in multiple myeloma. Interference of monoclonal immunoglobulin G with the determination of blood phosphorus level (Article in French). Rev Med Interne 1991; 12: 262–264[Web of Science][Medline]
  17. Hawkins RC. Pseudohyperphosphataemia in multiple myeloma. Ann Clin Biochem 1991; 28 [Pt 3]: 226–228
  18. McClure D, Lai LC, Cornell C. Pseudohyperphosphataemia in patients with multiple myeloma. J Clin Pathol 1992; 45: 731–732[Abstract/Free Full Text]
  19. Cohen AM, Magazanik A, van-der Lijn E, Shaked P, Levinsky H. Pseudohyperphosphataemia incidence in an automatic analyzer. Eur J Clin Chem Clin Biochem 1994; 32: 559–561[Web of Science][Medline]
  20. Barutcuoglu B, Parildar Z, Mutaf I, Habif S, Bayindir O. Spuriously elevated inorganic phosphate level in a multiple myeloma patient. Clin Lab Haematol 2003; 25: 271–274[CrossRef][Web of Science][Medline]
  21. Sinclair D, Smith H, Woodhead P. Spurious hyperphosphataemia caused by an IgA paraprotein: a topic revisited. Ann Clin Biochem 2004; 41 [Pt 2]: 119–124
Received for publication: 22.10.05
Accepted in revised form: 2. 5.06


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This Article
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