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NDT Advance Access originally published online on October 11, 2006
Nephrology Dialysis Transplantation 2007 22(2):584-591; doi:10.1093/ndt/gfl583
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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

Decreased renal transplant function after parathyroidectomy

Anke Schwarz, Gunnar Rustien, Saskia Merkel, Joerg Radermacher and Hermann Haller

Department of Nephrology, Hannover Medical School, Hannover, Germany

Correspondence and offprint requests to: Prof. Dr Anke Schwarz, Department of Nephrology, Hannover Medical School, Carl Neuberg Strasse 1, D-30625 Hannover, Germany. Email: schwarz.anke{at}mh-hannover.de



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Persistent secondary hyperparathyroidism after renal transplantation may require parathyroidectomy (PTX). Clinical experience suggests that these patients commonly develop decreased renal function thereafter.

Methods. To test this notion, we evaluated 76 transplant patients who underwent pararhyroidectomy between 1997 and 2003.

Results. In half the patients (47%), creatinine clearance decreased >20% (before vs after PTX, 57 ± 21 vs 38 ± 17 ml/min, P = 0.001). The patients with decreased creatinine clearance had higher parathyroid hormone (PTH) concentrations before and lower values after PTX compared with those who did not (594 ± 392 vs 447 ± 234 pg/ml before PTX, P = 0.03; 35 vs 123 pg/ml thereafter, P = 0.002). They also had lower serum calcium concentrations after PTX (2.0 vs 2.2 mmol/l, P = 0.005) and they required more calcium and vitamin D analogues. These patients also more commonly underwent total PTX with autotransplantation, compared with subtotal (75 vs 50%, P = 0.03). However, in multivariate analysis, only the delta PTH decline (%) after PTX was a significant predictor of deteriorating renal function (P = 0.005) and was correlated with the creatinine clearance decrease (R = 0.369, P = 0.001). Prospectively measured inulin and para-amino-hippuric acid (PAH) clearance decreased significantly after PTX in a subgroup of 19 patients (inulin before vs after PTX 67 vs 55 ml/min/1.73 m2, P = 0.001; PAH 360 vs 289 ml/min/1.73 m2, P = 0.001). Transplant biopsies revealed calcification in 70% of biopsied cases.

Conclusion. Since PTH has a known positive regulatory effect on renal perfusion and glomerular filtration rate, we conclude that relative hypoparathyroidism after PTX is the main mechanism contributing to decreased renal function in these patients. There was no difference in 10-year-graft survival between the deteriorating and the non-deteriorating group.

Keywords: hypercalcaemia; hyperparathyroidism; parathyroidectomy; parathyroid hormone; renal transplantation



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Hyperparathyroidism should improve after renal transplantation after the patients develop a reasonable level of renal function, although the process may require several months [1–7]. However, in some patients hyperparathyroidism persists after renal transplantation. Hyperparathyroidism and superimposed steroid-induced osteopenia may lead to relevant bone mass loss within only a few months [2,46–17]. Persistent hyperparathyroidism can lead to renal transplant nephrocalcinosis and is associated with early chronic allograft nephropathy in protocol biopsies [18,19]. Therefore, parathyroidectomy (PTX) must be considered in cases of persisting hyperparathyroidism beyond the first months after renal transplantation. We were concerned that this logical consequence is not always followed by improved renal function, but instead may initiate long-lasting deterioration in renal function. We analysed the course of 76 patients who underwent PTX after renal transplantation retrospectively. In a subgroup of 19 patients we performed prospectively inulin- and para-amino-hippuric acid (PAH) clearance before and after PTX.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patient characteristics
In a retrospective analysis, we evaluated the records of all patients with a functioning graft who underwent PTX after transplantation from January 1997 to June 2003. Persisting hyperparathyroidism was defined as a parathyroid hormone (PTH) concentration >200 pg/ml together with serum calcium >2.6 mmol/l at least 6 months after renal transplantation. Indication for PTX was persisting hyperparathyroidism or calciphylaxis (two cases). The records were evaluated regarding the following: (i) creatinine clearance (calculated creatinine clearance using the Cockcroft–Gault formula [20]); PTH; serum calcium (adjusted to s-protein) and phosphate before as well as 2 weeks, 2, 6 and 12 months after PTX; (ii) the amount of calcium and vitamin D supply per day needed at 2 weeks as well as 3 and 6 months after PTX to stabilize the serum calcium concentration; (iii) the operative technique of PTX; (iv) the blood pressure and the number of antihypertensive medicaments before and after PTX; and (v) the calcineurin inhibitor trough level before and after PTX. The time point ‘before PTX’ means for all parameters the median of data taken 2 months before the operation. For the time point ‘2, 6 and 12 months after PTX; data were taken ± 3 weeks of this date. PTH after PTX means the median of data taken during the year after the operation. PTH was measured by an immuno-chemiluminometric assay (Liaison® N-tactTM PTH-Assay).

Two groups were established and compared. The first group showed deterioration in creatinine clearance >20% at 2 months after PTX (deteriorating group), the second group exhibited no such decrease (non-deteriorating group). The two groups were compared using univariate and multivariate analysis according to the development of renal function as well as parameters of calcium homeostasis.

The following clinical parameters were entered in the multivariate analysis (mean ± SD) age, gender, time spent on dialysis before and time after renal transplantation, home systolic and diastolic blood pressures taken 1 h after breakfast, number of antihypertensive drugs, calculated creatinine clearance before and 2 months after PTX [20], PTH concentration before and after PTX, the delta PTH decline (%) after PTX, protein-adapted serum calcium and serum phosphate levels before and 2 weeks after PTX, the amount of daily calcium supply, and amount of vitamin D analogues needed to stabilize calcium homoeostasis 2 months after PTX, as well as the surgical method of PTX (total or subtotal).

In a subgroup of patients (n = 19), prospectively inulin and para-aminohippurate (PAH) clearance was measured before and 8 weeks after PTX (steady-state inulin and PAH infusion techniques are described elsewhere in detail [21]). For this purpose, after an overnight fast the patients were examined in supine position. An inulin and PAH bolus was given; after an equilibration period of 90 min, blood samples were taken at regular intervals during continuous infusion of inulin (10 mg/m2/min) and PAH (8 mg/m2/min). Blood pressure was monitored oscillometrically by Dinamap.

Statistics
For statistical evaluation, the SPSS statistical package (Version 11.0.1, SPSS Inc., Chicago, IL, USA) was used for all analyses. Unpaired t-tests with Bonferroni adjustment for multiple comparisons or chi-square analysis were used as appropriate to assess the differences between groups. Non-parametric analysis was done by the Mann–Whitney test. Odds ratios for the primary end point (deterioration of renal function by >20% or 2 months after PTX) were calculated from two-by-two contingency tables (Fisher's exact test). Graft survival was compared between the deteriorating and the non-deteriorating group using Kaplan–Meier survival curves. For multivariate analysis the effect of multiple parameters (see above) on the primary end point was analysed in all 76 cases with stepwise forward logistical regression analysis (variables with a P-value ≥ 0.1 were removed from the analysis and variables with a P-value ≤ 0.05 were retained). All results are presented as mean ± SD. A P-value of <0.05 was considered significant.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Between January 1997 and June 2003, 78 out of 2192 renal transplant patients of our transplant out-patient clinic underwent PTX because of persisting hyperparathyroidism, which means a period prevalence of 3.6%. Two patients had to be excluded from evaluation since they were lost to observation. Mean patient age was 48 ± 11.3 years; there were 46 men and 30 women. Mean time on dialysis before renal transplantation was 79.4 ± 37.6 months. Mean time after renal transplantation was 29.4 ± 28.9 months (range 2.5–154.8 months). Five patients had the PTX before 6 months post-transplant (one because of calciphylaxia, two because of severe hypercalcaemia and two because of pronounced nephrocalcinosis in the transplant biopsy). The immunosuppression was based on ciclosporin in 52 patients (26 in each group). Thirty-three patients received ciclosporin combined with prednisolone, 18 were given ciclosporin combined with mycophenolate mofetil and prednisolone, and one received ciclosporin combined with azathioprine and prednisolone. Fifteen patients received a tacrolimus-based regimen (6 in the deteriorating and 15 in the non-deteriorating group). Nine patients were given tacrolimus combined with prednisolone, and six received tacrolimus plus mycophenolate mofetil and prednisolone. Six patients received a mycophenolate mofetil-based treatment with prednisolone. One patient was given only azathioprine and prednisolone, while two received a sirolimus-based treatment, one with prednisolone and one with mycophenolate mofetil and prednisolone.

Routine pre-operative examinations included cervical ultrasonography and scintigraphy with 99-mTc MIBI. When re-operation was necessary (n = 13), cervical computer tomography, magnet resonance imaging tomography or positron-emission tomography with methionine was conducted. PTX was done as a subtotal procedure (n = 29), or as a total procedure with or without re-implantation of gland tissue into a cervical muscle or the forearm (n = 47) according to the surgeon's preference.

Forty-six of 76 patients had renal biopsies performed at least 2 years before or 3 years after PTX (21 patients with 25 biopsies before and 34 with 37 after PTX; nine patients had both and thus were counted twice). Some of the patients participated in our protocol biopsy programme and had biopsies routinely [18]. In 32 of these 46 biopsied patients (70%), intratubular or interstitial calcium deposits were seen in at least one transplant biopsy (Figure 1), and 20 of 32 biopsied patients with nephrocalcinosis (63%) belonged to the group with deteriorating renal function after PTX. In 14 patients, nephrocalcinosis was one of the arguments favouring PTX. Twenty biopsies were performed because of the observed renal function decline after PTX. Only one of these patients had rejection. The other 19 biopsies showed calcium deposition in tubules or interstitium. PTH and serum calcium levels decreased significantly after PTX (516 ± 291 vs 81 ± 125 pg/ml, P = 0.0001; 2.65 ± 0.2 vs 2.07 ± 0.3 mmol/l, P = 0.0001), while serum phosphorus increased significantly (1.0 ± 0.3 vs 1.22 ± 0.4 mmol/l, P = 0.001).


Figure 1
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  		Fig. 1. Intrarenal calcification of the transplant, the arrow pointing to intratubular calcium deposits (H&E, magnification x200; courtesy of Dr Michael Mengel, Department of Pathology, Hannover Medical School).

 
Thirty-six patients (47%) developed a permanent >20% deterioration in their renal function measured up to 1 year (Figure 2, Table 1). Age, gender, time on dialysis and after transplantation, creatinine clearance before PTX, calcium and phosphate levels before PTX, systolic as well as diastolic blood pressure and the number of antihypertensive medicaments before and after PTX were not different between the deteriorating and non-deteriorating group (Table 1). The daily dose of prednisolone (8.0 ± 2.5 vs 7.5 ± 2.9 mg) and the trough level of ciclosporin (n = 52, 139 ± 30 vs 136 ± 18 ng/ml) and tacrolimus (n = 15, 7.7 ± 1.8 vs 9.2 ± 3.2 ng/ml) before PTX as well as the pulse pressure before (53 ± 14 vs 51 ± 11) and after PTX (52 ± 13 vs 52 ± 9) were not significantly different between the groups. Deteriorating patients had higher PTH concentrations before and a lower after PTX, compared with patients with a stable renal function (Table 1, Figure 3). They also had lower calcium levels 2 weeks after PTX and required more calcium and vitamin D analogues at several time points after PTX (Table 1, Figure 3). They more commonly had undergone total PTX (Table 1). However, only the delta PTH decline (%) after PTX was statistically significant in the multivariate analysis (Table 1, Figure 4). In regression analysis, delta PTH decline (%) correlated to delta creatinine clearance decline (%) 2 months after PTX (A = 3.940; B = –0.270; R = 0.369; P = 0.001). Finally, inulin and PAH clearance decreased significantly in the 19 patients studied prospectively before and after PTX (inulin clearance from 67 to 55 ml/min/1.73 m2, P = 0.001; PAH clearance from 360 to 289 ml/min/1.73 m2, P = 0.001). These 19 prospectively evaluated patients were not different in all demographic, clinical and laboratory parameters compared with the other 57 retrospectively evaluated patients.


Figure 2
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  		Fig. 2. Thirty-six of 76 renal transplant patients (47%, deteriorating patients, left columns) developed deteriorating GFR after parathyroidectomy (PTX).

 

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  		Table 1. Comparison is made between 36 patients with deterioration and 40 patients without deterioration in renal function (mean ± SD)

 

Figure 3
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  		Fig. 3. (a) Group with deteriorating GFR had higher parathyroid hormone concentrations before parathyroidectomy (PTX), but lower values thereafter. (b) Group with deteriorating GFR had lower serum calcium concentrations after parathyroidectomy (PTX) (s-Ca = protein-adapted). (c) Group with deteriorating GFR required more calcium substitution after parathyroidectomy (PTX). (d) Group with deteriorating GFR required more vitamin D-analogues after parathyroidectomy (PTX).

 

Figure 4
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  		Fig. 4. Delta GFR decline (%) at 2 months after parathyroidectomy (PTX) in relation to delta parathyroid hormone (PTH) decline (%) (non-parametric Loess function; P = 0.001, R = 0.369); a PTH decline of >80% mostly corresponds to a significant decline in GFR.

 
There was no significant difference in blood pressure, number of antihypertensive drugs, ciclosporin and tacrolimus trough levels before PTX (Table 1). After PTX, the blood pressure was not different between the groups (syst 129 ± 18 vs 132 ± 13, NS; diast 77 ± 10 vs 80 ± 9 mmHg, NS) and had not significantly changed compared with before PTX; however, the number of antihypertensive drugs had increased in the deteriorating group after PTX (before 1.28 ± 0.94 vs after PTX 1.53 ± 0.81, P = 0.038) in contrast to the non-deteriorating group (1.51 ± 1.01 vs 1.55 ± 1.01, NS). In the deteriorating group, there was a tendency to receive fewer angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers; however, this did not reach statistical significance (before PTX: 19 vs 40%, NS; after PTX: 28 vs 40%, NS). There was no difference in the use of calcium channel blockers between the groups. The ciclosporin as well as tacrolimus trough levels were not different after PTX (ciclosporin 137 ± 40 vs 123 ± 33 ng/ml, NS; tacrolimus 8.2 ± 1.9 vs 8.9 ± 2.3 ng/ml, NS).

Cumulative graft survival up to 10 years was not different between the groups (Figure 5); 78 vs 50% after 3000 days, NS.


Figure 5
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  		Fig. 5. Comparison of graft survival between the deteriorating and non-deteriorating patient group after parathyroidectomy (PTX).

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our study draws attention to the fact that renal function commonly decreases following PTX in patients with renal transplants. Furthermore, the decrease cannot be explained by rejection. We believe our observations are important because refractory hyperparathyroidism in transplant patients is increasing. The mean waiting time for a renal transplant in Germany is currently about 6–7 years from beginning dialysis. This state of affairs is in part the consequence of the Eurotransplant waiting list policies since 1996. The Germans are particularly poor in terms of organ donation and organ procurement compared with other Eurotransplant countries [22]. Consequently, they receive fewer grafts. In Hannover, the median time on dialysis has increased from 3.7 years in 1996 to 6.2 years in 2004. Hyperparathyroidism after renal transplantation depends essentially on the dialysis time [2,4,7,23].

We found that half our patients developed a permanent decrease in their renal function after PTX. The most significant difference between patients with and without deteriorating renal function was the delta PTH decline (%) after PTX compared with the level before PTX (Figure 4). That change in PTH concentration appears to be an important factor influencing subsequent renal function; a decline of >80% seems to be followed by a significant fall in creatinine clearance (Figure 4). This is supported by the direct correlation found between the delta parathyroid decline (%) after PTX and the decline in creatinine clearance. All other parameters such as decreased serum calcium, increased serum phosphorus, and the calcium and vitamin D requirements postoperatively, may be regarded as secondary events depending upon the extent of PTH decline by PTX. The operative procedure employed is also relevant since total PTX results in a lower post-operative PTH concentration.

Other investigators have reported deteriorating renal function following PTX in renal transplant patients [24–28]. Three groups, the largest sample included 34 patients, compared their patients who had undergone PTX with patients who had not [25–27]. Thus, these investigators were unable to explore the phenomenon from a mechanistic standpoint. In two briefer reports, the investigators made the observation, but were unable to include a control group [24,28]. We made before and after PTX measurements in 76 patients, and took the trouble to study a subgroup of 19 of these patients prospectively with inulin and PAH clearance.

In contrast to others, we did not observe a decline in blood pressure after PTX [25,27], but observed an even higher need of antihypertensive drugs in the deteriorating group. However, the decline in blood pressure observed by others partly was seen only temporarily [25], and may be explained by a different number of patients treated with angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonists [27]. The patients in these reports may have been operated on at a different stage of hyperparathyroidism. In both reports, deteriorating and non-deteriorating patients were not compared. There are other reports in the literature observing deterioration of blood pressure after PTX [29,30]. The influence of PTH on blood pressure seems to be complex, and in experimental studies, PTH has a vasodilatory effect [31–33]. This may be counteracted either by a permissive role of PTH for the hypertensive action of hypercalcaemia, or other pressor substances, or arterial wall properties [27].

Calcium and phosphate homoeostasis after transplantation is complicated by the fact that the renal transplant itself shows tubular abnormalities, and is further influenced by the tubular effects of immunosuppressive drugs. Hypercalcaemia is found in more than 20% of patients in the first year after renal transplantation, which in some reports without protein-adapted calcium measurements is partly explained by the low albumin concentrations after long-term dialysis treatments and high post-transplant steroid treatment [2]. Mobilization of soft-tissue calcifications may also play a role [2,8,34,35]. Phosphaturia and hypophosphataemia are frequent during the first year after transplantation perhaps related to high phosphatonin activity [6,36] as well as from the hyperphosphaturic effects of PTH and different immunosuppressive drugs, especially steroids [36,37]. High PTH levels after renal transplantation occur in more than 20% of the cases [4,7,17,23,35,38–40]. PTX is necessary in 3.2% of renal transplant patients, as reported as a mean value from the literature [3,7,8,12,14,24,34,41–47].

Evidence from experimental studies suggests that PTH has a regulatory influence on renal perfusion, glomerular filtration rate and mesangial cell function [31–33,48]. PTH infusions in rats and humans had a dose-related stimulatory effect on the effective renal plasma flow and the glomerular filtration rate, perhaps through a dilatory effect on the renal vascular system [32,33,49]. From the clinical point of view, patients with low plasma PTH values more commonly have delayed allograft function after renal transplantation than patients with high values [19,50]; this contrasts with a retrospective study by Varghese et al. [51], who found an association of delayed graft function with a high parathyroid function in a group of patients with a generally high prevalence of delayed graft function (46%). The prospective part of our analysis, measuring inulin and PAH clearance before and after PTX, supports the observation that effective renal plasma flow and glomerular filtration rate are reduced after PTX, and this early haemodynamic effect of the low PTH after PTX certainly is the main cause for the early renal function deterioration. The high calcium and vitamin D requirements after PTX likely also contribute to nephrocalcinosis and decreased renal function as a late effect, since we know that nephrocalcinosis influences chronic allograft nephropathy [18,19].

Since PTX often induces a rapid fall in glomerular filtration rate, the question arises, if in the long run is there a benefit doing it? However, the haemodynamic effect of PTH seems to be the afferent vasodilation and the efferent vasoconstriction of the glomerulum like or via angiotensin II, which results in hyperfiltration and consequently may lead to progressive renal function deterioration. And we know from protocol biopsy studies that persisting hyperparathyroidism is associated with nephrocalcinosis which promotes renal function deterioration [18,19].

Graft survival, in the long run, did not differ between the deteriorating and the non-deteriorating patient group. Additionally, renal transplantation offers the opportunity to mobilize extrarenal calcifications including vascular calcification. Therefore, we should adequately address hyperparathyroidism in our patients. This goal could be achieved by early or pre-emptive transplantation. A more generous policy regarding PTX while patients are still on dialysis might be considered. If PTX is necessary after renal transplantation, subtotal PTX may be preferred. Vitamin D analogues should perhaps be given before the operation to avoid severe serum calcium decreases postoperatively.

Finally, calcimemetics may offer an interesting alternative [52,53]. Their prophylactic early use during dialysis treatment, or even before, may prevent the hypertrophic growth of the gland and thus hyperparathyroidism. Their therapeutic use after renal transplantation in established hyperparathyroidism seems to be well tolerated, to be effective in lowering serum calcium levels and has the advantage of flexibility. To discover if an effective lowering of PTH by calcimimetics has the same worsening effect on renal function as surgical PTX will require careful clinical studies, since the dosage of calcimimetics in the early studies so far, has been adapted to serum calcium and thus has lowered PTH not more than 25–80% [52,53]. At least in that moderate dosage no significant decline in renal function has been observed in the two published patient groups.

Conflict of interest statement. None declared.



   Notes
 
The authors wish it to be known that, in their opinion, the first two authors contributed equally to this work.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 8.06
Accepted in revised form: 30. 8.06


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