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March 2005, Volume 55, Issue 3

Original Article

Impact of Cyclosporin immunosuppression on Serum Magnesium and its Fractional Excretion in Renal Transplant Recipients

Abstract

Objective: To evaluate the effect of cyclosporine (CSA) on serum magnesium and its fractional excretion in renal transplant recipients.

Methods: A cross sectional comparative study on 50 live related renal transplant recipients on CSA therapy with serum creatinine <2.0 mg/dl and 30 healthy controls. Serum creatinine, magnesium and its fractional excretion and CSA levels were monitored. Patients were followed at 6 months.

Results: The mean serum creatinine in patients was 1.41 ± 0.42 mg/dl, cyclosporine 210 ± 66 ng/ml at a dose of 4.8 ± 1.4 mg/kg/day. The serum magnesium was 1.77± 0.32mg/dl vs 1.98 ± 0.17mg/dl in healthy controls (p<0.05).Fractional excretion was 5.05 ± 2.53% in patients vs 2.8 ± 1.05% in controls (p<0.05). No correlation was found between CSA levels (100-400 ng/ml) and serum magnesium (r = 0.053) or FEMg % (r = 0.215). Of the 50 recipients 27 (54%) had FEMg % in the control range. At 6 months follow up no difference in CSA levels was found between recipients with FEMg % in the normal range vs those with FEMg >5%. However, serum creatinine increased from 1.42 ± 0.30 mg/dl to 1.68 ± 0.82mg/dl (p< 0.05).

Conclusion: CSA therapy lowers serum magnesium as compared to healthy controls and there is marked increase in FEMg% in 50% of the patients. Patients with FEMg >5% developed renal function deterioration. FEMg percent can thus be a good follow up marker of CSA chronic toxicity in stable transplant recipients (JPMA 55:98;2005).

Introduction

Renal transplantation has become the therapy of choice for end stage renal failure patients. Success has largely been achieved by immunosuppressive drugs particularly cyclosporine (CSA), which has revolutionized the field of organ transplantation with considerable improvements in graft survival rate by 12 to 20%.1 However, its benefits are countered by its major side effect nephrotoxicity. This is characterized by a reduction of glomerular filtration rate, and renal blood flow, tubular injury and hypomagnesaemia by leakage through tubular cells.2 CSA can cause both acute and chronic nephrotoxicity leading to deterioration in renal allograft function and eventual chronic graft loss.3 Blood levels of CSA have been used as surrogate markers of optimum immunosuppresion and toxicity. However intra and inter patient variation has compromised CSA blood level predictive values.4 Hypomagnesemia isa common finding in CSA-treated patients and has been proposed as both a cause and a consequence of CSA-induced nephrotoxicity.5 This study evaluates the effect of CSA at maintenance doses on the level of serum magnesium and the significance of fractional excretion (FE) of magnesium (Mg) as predictor of CSA nephrotoxicity.

Patients and Methods

A cross-sectional comparative study was conducted on fifty live related renal allograft recipients on maintenance cyclosporine (CSA) therapy with stable renal function for more than three months where serum creatinine value was less than 2.0 mg/dL and compared with thirty healthy normal controls. Patients with creatinine >2.0 mg/dL were excluded from the study. Controls were subjects not taking any medication.

All patients were on maintenance CSA therapy by oral route as primary immunosuppressant, along with azathioprin and steroids orally. None of the participants in the control group were taking any drug or receiving magnesium supplement.

On the first visit, clotted blood from venipuncture was drawn for the analysis of creatinine, and magnesium levels as base line measurement. Spot urine was taken at the same time as blood samples in sterile containers and analyzed for urinary creatinine and magnesium. On the first visit whole blood trough levels of CSA were measured in patients, approximately 12 hours after administration of the last dose.

The samples were processed and analyzed on Hitachi 911 auto-analyzer for serum and urinary creatinine and magnesium. Magnesium was analyzed by xylidyle Blue Method.6 Creatinine was analyzed by Jaffe-Kinetic method.7 Cyclosporine blood levels in ng/ml were monitored on whole blood by monoclonal anti body assay (TDX-Abbot).8

The patients were followed up at 6-months when serum creatinine, and CSA levels were estimated. The fractional excretion of magnesium was calculated by the formula:

FE solute = U/P solute ÷ U/P creatinine X 100 where U is for urine and P for plasma magnesium.The result was expressed as a percentage and as mean ±1SD. The statistical analysis was performed by statistical package SPSS version 8.0. Comparisons between variables were done by t-test and correlation was estimated by Pearson test. P-values less than 0.05 were considered statistically significant.

Results

Of the 50 renal transplant recipients 30 were males and 20 females. The mean age was 28.8 ± 8.7 with a range of 16 - 55 years. The post transplant period ranged from 260 to 1870 days with a mean of 338 days. The mean baseline creatinine was 1.41 ± 0.42 with a range of 0.64 - 2.0 mg/dl. The mean dose of cyclosporine was 4.8 ± 1.4 mg / kg / day orally with a range of 1.9 - 6.5 and the mean level was 210±66 ng/ml. Of the 30 healthy controls, 20 were males and 10 females with a mean age of 33 ± 6.7 years range 22 - 50 years. The mean serum creatinine in control group was 0.76 ± 0.14 mg/dl. The mean serum magnesium in recipients was 1.77 ± 0.32 vs 1.98 ± 0.17 mg/dL in controls (Table 1). The difference was statistically significant. Fractional excretion of magnesium in recipient was higher than controls with a maximum of 13% in recipients and 5% in controls. The correlation of serum magnesium and FEMg% were evaluated with CSA blood levels in recipients. No correlation was found for serum Mg (r= 0.053) and FEMg% (r = 0.215) (Figure).

Table 1. Comparison of Mg in blood and its fractional excretion (FE) in stable recipients and healthy controls.
  Stable recipients Healthy controls P value
  n = 50 n = 30
  mean+SD mean+SD
  (range) (range)
Serum magnesium 1.77± 0.32 (1.1-2.3) 1.98 ± 0.17 (1.6-2.3) <0.05
mg/dl      
       
Fractional excretion 5.05±2.53 (1.7-13.0) 2.8 ± 1.05 (1.6-5.0) <0.05
of magnesium %
     

[(0)]

Of the 50 recipients with mean FEMg% of 5.04 ± 2.53, 27(54%) had FEMg% less than 5% (group 1) similar to the healthy controls and the rest 46% had more than 5% (group 2) (Table 2). The mean FEMg% in group 1 was 3.5 ± 1.06 and in group 2 was 7.45 ± 2.0. There was no difference in creatinine level between group 1 and 2 at baseline. However at 6-months follow-up there was a significant increase in creatinine in group 2 as compared to group 1. The mean creatinine in group 1 was 1.42 ± 0.30 mg/dL vs 1.68 ± 0.82 mg/dL (P<0.05) in group 2. There was also a significant increase in creatinine within group 2 from an initial creatinine of 1.47 ± 0.40 mg/dL to 1.68 ± 0.82

Table 2. Follow-up serum creatinine and CSA in patients with FeMg <5% vs FeMg >5%.
  Group I (FeMg <5%) Group II (FeMg>5%) P value
  n - 27 n = 23
 
  mean+SD mean+SD
 
Initial Creatinine 1.33 ± 0.42 1.47 ± 0.40 0.25
mg/dL      
Creatinine after 1.28 ± 0.30 1.68 ± 0.82 <0.05
6-months mg/dL      
Initial CSAng/ml 213 ± 60 198 ± 77 0.16
CSA after 6-months 219 ± 75 228 ± 132 0.57
ng/ml      

mg/dL (p<0.05). There was no difference in CyA blood levels in the two groups at initial baseline and 6-months (Table 2).

Discussion

Cyclosporin (CSA) is known to impair renal function where a single dose has been shown to cause significant renal vasoconstriction, hypoperfusion and a decline in glomerular filtration rate in both healthy volunteers and renal transplant recipients.6,7 The effects of CSA have been reported to be dose dependent8 and at low doses no tubular dysfunction was found between transplant recipients who were taking CSA in a triple drug regime and those on azathioprin and steroid alone.9 The presented study included patients who had stable renal function in chronically administered CSA and excluded those patients who had compromised renal function i.e. serum creatinine >2.0 mg/dl. As compared to healthy controls the nephrotoxic effects of CSA were apparent by lower serum magnesium levels and increased magnesium excretion in more than half of the patients. However within the transplant recipient group we did not observe any correlation between serum magnesium or FEMg% at different CSA blood levels in the range 100 - 400 ng/ml. This confirms others findings that low dose range of CSA is not correlated with tubular dysfunction markers.9 The important observation in our study was increased serum creatinine at 6 months follow-up in recipients with FEMg% of more than 5. This is of particular importance since CSA level in both groups of patients did not change significantly at 6 months follow-up. It appears that magnesium leak is not dose dependant at lower CSA levels as reported by others.9 Clearly other factors may be prevalent which give susceptibility to CSA toxicity. It is known that polymorphism of high producers of cytokine TGF-Beta are more susceptible to the toxic effects of CSA, resulting in chronic allograft nephropathy.10 Fractional excretion of magnesium thus appears to be a useful marker of CSA toxicity in stable renal transplant recipients on maintenance CSA immunosuppression with acceptable drug levels. This evaluation can therefore be a useful monitor for CSA toxicity where dose adjustments can be undertaken in stable renal transplant recipients.

References

1. Kahan BD. Cyclosporin. New Engl J Med 1998;321:1725-38.

2. Bennett WM, Demattos A, Meyer MM, Andoh T, Barry JM. Chronic cyclosporine nephropathy. Kidney Int 1996;50:1089-1100.

3. Bennett WM, Burdmann EA, Andoh TF, Honghton DC, Lindsley J, Elzinga LW. Nephrotoxicity of immunosuppressive drug. Nephrol Dial Transplant 1994;9:141-45.

4. Zafar MN, Abbass K, Naqvi A,Rizvi A. Pharmacokinetics of abbreviated AUC of cyclosporine in renal allograft recipients in a Pakistani population. Transplant proceed. 1999;31:3304.

5. Kim HJ, Ahn YH, Kee CS, Lee KS. Kwak JY. Early short-term profile of serum magnesium in living donor renal transplant recipient on cyclosporin. Transplant Proceed 1994;26:2178-80.

6. Hansen JM, Fogh-Andersen N, Christensen NJ, Strandgaard S. Cyclosporine-induced hypertension and decline in renal function in healthy volunteers. J Hypertension 1997;15:319-26.

7. Hansen JM, Christensen NJ, Fough-Andersen N, Strandgaard S. Effects of the prostacyclin analogue iloprost on cyclosporine-induced renal hypoperfusion in stable renal transplant recipients. Nephrol Dial Transplant 1996;11:340-6.

8. Forre O, Dijkmans BA, Tugwell P, Rodriques F, Krayenbuhl JC, Harrison WB. Renal biopsy findings and follow-up of renal function in rheumatoid arthritis patients treatd with cyclosporin A: An update from the International Kidney Biopsy Registry. Arthritis Rheum 1996;39:1491-8.

9. Hansen JM. Fogh-Andersen N, Leyssac PP, Strandgaart S. Glomerular and tubular function in renal transplant patients treated with and without ciclosporin A. Nephron. 1998;80:450-7.

10. Khanna AK, Cairns VR, Becker CG, Hosenpud JD. TGF-beta: a link between immunosuppression, nephrotoxicity and CsA. Transplant Proc 1998;30:944-5.

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