Nierenfunktionsverschlechterung durch Parathyreoidektomie nach Nierentransplantation

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Aus der Abteilung Nephrologie des Zentrums für Innere Medizin der Medizinischen Hochschule Hannover

Nierenfunktionsverschlechterung durch

Parathyreoidektomie nach Nierentransplantation

Dissertation zur Erlangung des Doktorgrades der Medizin In der Medizinischen Hochschule Hannover

Vorgelegt von Gunnar Rustien

aus Haltern Hannover 2007

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Gedruckt mit Genehmigung der Medizinischen Hochschule Hannover Präsident: Prof. Dr. med. Dieter Bitter-Suermann

Betreuer: Prof. Dr. med. Anke Schwarz

Referent: Prof. Dr. med. Georg F. W. Scheumann Korreferent: PD Dr. med. Lars Pape

Tag der Mündlichen Prüfung: 20.09.2007 Promotionsausschussmitglieder:

Prof. Dr. med. Tobias Welte Prof. Dr. med. Carlos Guzman Prof. Dr. med. Frank Gossé

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Meinen Eltern und Geschwistern für ihre Unterstützung gewidmet

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Inhaltsverzeichnis

Inhaltsverzeichniss...I 1. Verwendete Abkürzungen ... II 2. Publikation... III

3. Einleitung... 1

4. Patienten, Material und Methoden... 3

4.1. Patienten... 3

4.1.1. Patienten allgemein... 3

4.1.2. Patienten mit Inulin/PAH-Clearance... 4

4.2. Daten... 5

4.2.1. Datenerhebung... 5

4.2.2. Bewertung der erfassten Daten... 8

4.2.2.1. Laborwerte... 8

4.2.2.2. Medikamente... 8

4.2.2.3 Blutdruck... 9

4.2.2.4. Glomeruläre Filtrationsrate... 9

4.3 Durchführung der Inulin/PAH - Clearance... 10

4.3.1. Grund der Inulin/PAH - Clearance... 10

4.3.2. Ablauf der Clearance-Untersuchung... 11

4.3.3 Messung der Plasma-Inulinkonzentration... 12

4.3.4 Messung der Plasma-PAH-konzentration... 13

4.4 Retrospektive Analyse... 14

4.5 Statistik... 14

5. Ergebnisse... 15

5.1. Inulin/PAH Gruppe... 15

5.1.1. Patientenkollektiv allgemein... 15

5.1.2 Gruppenvergleich... 23

6. Diskussion... 32

7. Zusammenfassung... 36

8. Literatur... 38

Anhang ( Danksagung, Lebenslauf, Erklärung)... 44

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1. Verwendete Abkürzungen

CI Inulinkonzentration in der Infusion Clin Inulin-Clearance

ClPAH PAH-Clearance

CP Inulinkonzentration im Plasma GFR Glomeruläre Filtrationsrate IR Infusionsrate

KIZ Kalte Ischämiezeit NTX Nierentransplantation PAH P-Aminohippursäure PTH Parathormon

PTX Parathyreoidektomie RPF Renaler Plasmafluss

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Original Article

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

Abstract

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, 5721 vs 3817 ml/min, P¼0.001). The patients with decreased creatinine clearance had higher parathyroid hormone (PTH) concentrations before and lower values after PTX compared with those who did not (594392 vs 447234 pg/ml before PTX, P¼0.03;

35vs 123 pg/ml thereafter, P¼0.002). They also had lower serum calcium concentrations after PTX (2.0vs 2.2 mmol/l,P¼0.005) 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%, P¼0.03).

However, in multivariate analysis, only the delta PTH decline (%) after PTX was a significant predictor of deteriorating renal function (P¼0.005) and was correlated with the creatinine clearance decrease (R¼0.369, P¼0.001). 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, P¼0.001; PAH 360 vs 289 ml/min/1.73 m², P¼0.001).

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

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 superim- posed steroid-induced osteopenia may lead to relevant bone mass loss within only a few months [2,4,6–17].

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

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 The authors wish it to be known that, in their opinion, the first two

authors contributed equally to this work.

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@mh-hannover.de doi:10.1093/ndt/gfl583

For Permissions, please email: journals.permissions@oxfordjournals.org

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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^Õ N-tact^TM 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 (meanSD) age, gender, time spent on dialysis before and time after renal transplantation, home systolic and diastolic blood pressures taken 1 h after break- fast, 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 (n¼19), 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. Unpairedt-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

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 aP-value0.1 were removed from the analysis and variables with a P-value0.05 were retained). All results are presented as meanSD. AP-value of<0.05 was considered significant.

Results

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 4811.3 years; there were 46 men and 30 women. Mean time on dialysis before renal transplantation was 79.437.6 months. Mean time after renal transplantation was 29.428.9 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 (n¼13), cervical computer tomography, magnet resonance imaging tomography or positron-emission tomography with methionine was conducted. PTX was done as a subtotal procedure (n¼29), or as a total procedure with or without re-implantation of gland tissue into a cervical muscle or the forearm (n¼47) 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

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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 (516291 vs 81125 pg/ml, P¼0.0001; 2.650.2 vs 2.070.3 mmol/l, P¼0.0001), while serum phosphorus increased significantly (1.00.3 vs 1.220.4 mmol/l,P¼0.001).

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,

after PTX were not different between the deteriorating and non-deteriorating group (Table 1). The daily dose of prednisolone (8.02.5 vs 7.52.9 mg) and the trough level of ciclosporin (n¼52, 13930 vs 13618 ng/ml) and tacrolimus (n¼15, 7.71.8 vs 9.23.2 ng/ml) before PTX as well as the pulse pressure before (5314 vs 5111) and after PTX (5213 vs 529) 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 (A¼3.940; B¼ 0.270; R¼0.369; P¼0.001).

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, P¼0.001; PAH clearance from 360 to 289 ml/min/1.73 m², P¼0.001). These 19 prospectively evaluated patients were not different in all demographic, clinical and laboratory parameters compared with the other 57 retrospectively evaluated patients.

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 12918vs 13213, NS; diast 7710vs 809 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 1.280.94 vs after PTX 1.530.81, P¼0.038) in contrast to the

Fig. 1.Intrarenal calcification of the transplant, the arrow pointing to intratubular calcium deposits (H&E, magnification 200;

courtesy of Dr Michael Mengel, Department of Pathology, Hannover Medical School).

35 40 45 50 55

60 Creatinine clearance

before PTX Creatinine clearance.

2 weeks after PTX Creatinine clearance.

2 months after PTX Creatinine clearance.

6 months after PTX Creatinine clearance.

12 months after PTX

(n = 40) Non-deteriorating group (n = 36)

Deteriorating group

GFR (ml/min)

P = 0.001 P = 0.001

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

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non-deteriorating group (1.511.01 vs 1.551.01, NS). In the deteriorating group, there was a tendency to receive fewer angiotensin-converting-enzyme inhibi- tors and angiotensin-receptor blockers; however, this

did not reach statistical significance (before PTX: 19vs 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

All patients With Without Univariate

analysis

Multivariate analysis

Age (years) 4811 4812 4711 NS NS

Gender (% women) 39 39 40 NS NS

Time on dialysis (days) 24211148 22701255 25561039 NS NS

Time after transplantation (days) 898881 952974 850796 NS NS

Systolic blood pressure before PTX (mmHg) 13012 13013 13112 NS NS

Diastolic blood pressure (mmHg) before PTX (mmHg) 799 779 808 NS NS

Antihypertensive drugs (n) before PTX 1.410.98 1.280.94 1.531.01 NS NS

Systolic blood pressure after PTX (mmHg) 13115 12918 13113 NS NS

Diastolic blood pressure (mmHg) after PTX (mmHg) 799 7710 809 NS NS

Antihypertensive drugs (n) after PTX (mmHg) 1.540.92 1.530.81 1.551.01 NS NS

Clearance before PTX (ml/min) 5725 5720 5825 NS NS

Clearance 2 months after PTX (ml/min) 4722 3817 5523 P¼0.001 NS

PTH before PTX (pg/ml) 516291 594392 447234 P¼0.03 NS

PTH after PTX (pg/ml) 81125 3446 123156 P¼0.002 NS

Delta PTH decline (%) 81.4125.56 92.879.83 71.1030.65 P¼0.0001 P¼0.005

Ca before PTX (mmol/l) 2.650.19 2.610.17 2.680.20 NS NS

Ca 2 weeks after PTX (mmol/l) 2.070.26 1.980.26 2.150.24 P¼0.005 NS

PO4before PTX (mmol/l) 1.040.3 1.00.3 1.080.3 NS NS

PO42 weeks after PTX (mmol/l) 1.220.4 1.220.3 1.210.4 NS NS

Ca supply (g/day) 2 months after PTX 1.061.5 1.451.6 0.721.3 P¼0.03 NS Vitamin D supply (mg/day) 2 months after PTX 0.680.9 0.90.9 0.40.9 P¼0.01 NS

Total PTX with autotransplantation 64% 75% 50% P¼0.03 NS

PTH, parathyroid hormone; PTX, parathyroidectomy; Ca, calcium (adjusted for s-protein); PO4, phosphate; creatinine clearance is estimated by the Cockroft and Gault formula.

PTH (pg/ml)

P = 0.0001 P = 0.0001

P = 0.002 P = 0.03

700 600 500 400 300 200 100 0

(n= 40) Non-deteriorating group (n= 36)

Deteriorating group

PTH before PTX PTH after PTX

(a)

S-Ca before Ptx S-Ca 2 weeks after PTX S-Ca 2 months after PTX S-Ca 6 months after PTX S-Ca 12 months after PTX P= 0.00001

P= 0.00001 P= 0.005

S-calcium (mmol/l)

Deteriorating group 2.8

2.6 2.4 2.2 2 1.8

(b)

P = 0.03 P = 0.03 P = 0.06

Deteriorating group

Calcium substitution. g

2.5 2 1.5 1 0.5 0

Ca substitution 2 weeks after PTX Ca substitution 2 months after PTX Ca substitution 6 months after PTX

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0 0.4 0.8 1.2

1.6 Vitamin D

2 weeks after PTX Vitamin D 2 months after PTX Vitamin D 6 months after PTX P = 0.01

P = 0.01

Deteriorating group

Vitamin D-substitution (µg)

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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-Ca¼protein-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).

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tacrolimus trough levels were not different after PTX (ciclosporin 13740vs12333 ng/ml, NS; tacrolimus 8.21.9vs8.92.3 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.

Discussion

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 increas- ing. 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.

Fig. 4. Delta GFR decline (%) at 2 months after parathyroidectomy (PTX) in relation to delta parathyroid hormone (PTH) decline (%) (non-parametric Loess function; P¼0.001, R¼0.369); a PTH decline of>80% mostly corresponds to a significant decline in GFR.

1.0

0.8

0.6

0.4

0.2

0.0

0 1000 2000 3000

Deteriorating group Non-deteriorating group

P = ns PTX

Cumulative survival (%)

Time after PTX (days)

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

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[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

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 Vargheseet 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

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Conflict of interest statement. None declared.

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18. Schwarz A, Mengel M, Gwinner W et al. Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study.Kidney Int2005; 67: 341–348

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20. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.Nephron1976; 16: 31–41

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14: 457–463

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Br J Surg2005; 92: 1282–1287

25. Rostaing L, Moreau-Gaudry X, Baron E, Cisterne JM, Monrozies-Bernadet P, Durand D. Changes in blood pressure and renal function following subtotal Parathyroidectomy in renal transplant patients presenting with persistent hypercalcemic hyperparathyroidism.Clin Nephrol1997; 47: 248–255 26. Lee PP, Schiffmann L, Offermann G, Beige J. Effects of

parathyroidectomy on renal allograft survival. Kidney Blood Press Res2004; 27: 191–196

27. Evenepoel P, Claes K, Kuypers D, Maes B, Vanrenterghem Y.

Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study.Nephrol Dial Transplant2005; 20: 1714–1720 28. Garcia A, Mazuecos A, Garcia T, Gonzalez P, Ceballos M,

Rivero M. Effect of parathyroidectomy on renal graft function.

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29. Jones DB, Jones JH, Lloyd HJ, Lucas PA, Wilkins WE, Walker DA. Changes in blood pressure and renal function after parathyroidectomy in primary hyperparathyroidism. Postgrad Med J1983; 59: 350–353

30. Almirall J, Lopez T, Comerma I, Garcia E, Marques G. Effect of parathyroidectomy on blood pressure in dialysis patients.

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246: 556

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1995–2000

33. Jespersen B, Randlov A, Abrahamsen J, Fogh-Andersen N, Kanstrup IL. Effects of PTH(1-34) on blood pressure, renal function, and hormones in essential hypertension: the altered pattern of reactivity may counteract raised blood pressure.Am J Hypertens1997; 10: 1356–1367

34. David DS, Sakai S, Brennan BLet al.Hypercalcemia after renal transplantation. Long-term follow-up data.N Engl J Med1973;

289: 398–401

35. Parfitt AM. Hypercalcemic hyperparathyroidism following renal transplantation: differential diagnosis, management, and impli- cations for cell population control in the parathyroid gland.

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Impaired phosphate handling of renal allografts is aggravated under rapamycin-based immunosuppression. Nephrol Dial Transplant2001; 16: 378–382

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Bone metabolism in patients with functioning kidney

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39. Dumoulin G, Hory B, Nguyen NUet al.No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients.Am J Kidney Dis1997; 29: 746–753

40. Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH. High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation.J Am Soc Nephrol2000; 11: 1093–1099

41. Geis WP, Popovtzer MM, Corman JL, Halgrimson CG, Groth CG, Starzi TE. The diagnosis and treatment of hyperparathyroidism after renal homotransplantation. Surg Gynecol Obstet1973; 137: 997–1010

42. Diethelm AG, Edwards RP, Whelchel JD. The natural history and surgical treatment of hypercalcemia before and after renal transplantation. Surg Gynecol Obstet 1982; 154:

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Effects of parathyroid hormone on delayed renal allograft function.Br Med J1991; 303: 287–288

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Successful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparathyroidism.

Nephrol Dial Transplant2005; 20: 1315–1319 Received for publication: 13.8.06

Accepted in revised form: 30.8.06

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3. Einleitung

Störungen des Kalzium/Phosphat-Haushalts und des Knochenmetabolismus finden sich häufig bei Patienten mit chronischer Niereninsuffizienz. Diese Störungen beginnen bereits in der Frühphase der Niereninsuffizienz und nehmen progredient mit Verlust der exkretorischen Nierenfunktion zu. Es kommt bereits sehr früh zu einer Phosphatretention, die wahrscheinlich zum einen durch den Verlust der GFR, zum anderen durch einen relativen Vitamin-D-Mangel bedingt ist, denn in der Urämie kann Vitamin D3 nicht in das aktive hydroxylierte Vitamin D (1,25-Dihydroxycholecalciferol) umgewandelt werden. Infolge des relativen Mangels an aktivem Vitamin-D wird im Darm Kalzium weniger resorbiert und sinkt das S-Kalzium ab. Die Hyperphosphatämie mit komplementär absinkendem Kalzium verstärkt die Hypokalzämie, die zunächst physiologisch eine vermehrte PTH-Sekretion bedingt. Dies nennt man sekundären Hyperparathyreoidismus, das Kalzium ist niedrig. Mit der Zeit hypertrophiert die Nebenschilddrüse und kann Adenome bilden, die dem physiologischen Regelkreis nicht mehr unterliegen; das Kalzium steigt an, es kommt zur Hyperkalzämie (56, 57)

Nach erfolgreicher Nierentransplantation bildet sich der Hyperparathyreoidismus in den meisten Fällen innerhalb der ersten 6-12 Monate zurück (1-7). In einigen Fällen kommt es jedoch zu anhaltend hohen Parathormonspiegeln. Dieser persistierende Hyperparathyreoidismus führt zu einer Verminderung der Knochenmasse, Muskelschwäche und Müdigkeit (2, 4, 6- 17). Zusätzlich kann es zu einer Nephrokalzinose mit nachfolgender Verschlechterung der Transplantatfunktion kommen (18, 19).

Aus diesem Grund sollte in Fällen von persistierendem Hyperparathyreoidismus, welcher länger als 6 Monate nach Nierentransplantation anhält, eine chirurgische Intervention mittels Parathyreoidektomie erfolgen (14).

Es gibt drei Arten der Parathyreoidektomie. Bei einer totalen Parathyreoidektomie werden alle vier Nebenschilddrüsen entfernt; anschließend wird der Kalziumhaushalt durch Vitamin D-Analoga geregelt. Bei totaler Parathyreoidektomie mit Autotransplantation wird Nebenschilddrüsengewebe

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vorzugsweise in den Bereich des M. sternocleidomastoideus, alternativ in den nicht-dominanten Unterarm autotransplantiert. Bei subtotaler Parathyreoidektomie werden in der Regel nur dreieinhalb Nebenschilddrüsen entfernt und der belassene Rest mit einem Clip markiert (14).

Nach Parathyreoidektomie sollte sich der Knochenstoffwechsel normalisieren, wodurch eigentlich auch die Transplantatfunktion profitieren sollte.

Stattdessen ist in vielen Fällen bei Patienten mit Parathyreoidektomie nach Nierentransplantation eine anhaltende Verschlechterung der Nierenfunktion zu beobachten. Ausmaß der Verschlechterung, Risiko- und Cofaktoren hierfür und Einfluss auf das Transplantatüberleben waren bisher nicht bekannt.

Aus diesem Grund untersuchten wir 76 Patienten nach Nierentransplantation retrospektiv und zusätzlich eine Untergruppe bestehend aus 19 Patienten prospektiv mittels Inulin- und p-Aminohippursäure- (PAH) Clearance vor und nach Parathyreoidektomie. Zusätzlich werteten wir die Akten dieser Patienten aus bezüglich der klinischen Begleitumstände und bezüglich des weiteren Transplantatüberlebens.

Die Ergebnisse der retrospektiven Untersuchung für das Gesamt-Kollektiv werden in der beigelegten Originalarbeit wiedergegeben. Im Ergebnissteil der hier geschilderten Arbeit wird ausschließlich auf die Untergruppe aus 19 Patienten eingegangen, die mittels Inulin- und PAH-Clearance prospektiv vor und nach Parathyreoidektomie untersucht wurde.

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4. Patienten, Material und Methoden

4.1. Patienten

4.1.1. Patienten allgemein

Es wurden in die Untersuchung alle nierentransplantierten Patienten der Nierenambulanz aufgenommen, bei denen zwischen dem 01.01.1997 und dem 30.06.2003 ein chirurgischer Eingriff unter der Indikation eines Hyperparathyreoidismus durchgeführt wurde. Dies waren 78 Patienten. Bei zwei Patienten gab es zur Auswertung nicht genügend Unterlagen, da sie nur vorübergehend von uns betreut worden waren. Also wurden im beschriebenen Zeitraum die Daten von 76 Patienten erfasst, wobei im Verlauf des Untersuchungszeitraums die Anzahl der Eingriffe pro Jahr leicht zunahm (Abb. 1).

Anzahl der Parathyreoidektomien

15

17 20

7 7

12

8

0 5 10 15 20 25

1997 1998 1999 2000 2001 2002 2003

Kalenderjahr

Anzahl

Abb. 1: Zahl der Parathyreoidektomien bei Hyperparathyreoidismus nach Nierentransplantation pro Kalenderjahr (n=76) von 1997-2003. Für 2003 Hochrechnung aufs ganze Jahr.

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4.1.2. Patienten mit Inulin/PAH-Clearance

Von den 76 Patienten wurden insgesamt 20 Patienten im Zeitraum vom 01.03.2002 bis 30.06.2003 (16 Monate) in der MHH parathyreoidektomiert, diese wurden prospektiv mit einer Inulin/PAH-Clearance untersucht. Die Clearance- Untersuchungen wurden 1 Tag präoperativ und 8-12 Wochen postoperativ durchgeführt. Eine Patientin lehnte die postoperative Clearance-Untersuchung ab, so dass insgesamt 19 Patienten prospektiv untersucht wurden.

Vor Beginn der prospektiven Untersuchung mit Inulin- und PAH-Clearance holten wir das Einverständnis der Ethik-Kommission ein (Nr. 3160).

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4.2. Daten

4.2.1. Datenerhebung

Quellen der Datenerhebung waren neben dem Zentralarchiv für Patientenakten ( ALIDA ), die Archive der Transplantationsambulanz der MHH und aller betreuenden Dialyseärzte. Zunächst wurde aus dem Archiv der Transplantationsambulanz Name, Geburtsdatum und Parathyreoidektomiedatum aller Patienten ermittelt, die im Untersuchungszeitraum wegen eines sekundären Hyperparathyreoidismus nach Nierentransplantation operativ behandelt worden waren.

Aus den Krankenakten der 76 ermittelten Patienten wurden folgende Rohdaten erfasst:

1) Allgemeine Informationen

• Alter der Patienten

• Geschlecht

• Diagnosen

• Datum der Nierentransplantation (NTX)

• Datum der Parathyreoidektomie (PTX)

• Dialysebeginn

• Wartezeit auf die Niere

• Zeitspanne zwischen NTX und PTX

• Art der Parathyreoidektomie

• Ort der Parathyreoidektomie

• Vorhergehende Parathyreoidektomien

• Spenderalter

• Akute Rejektionen

• Kalte Ischämiezeit

• Missmatch der Nierentransplantation

(19)

2) Präoperative Daten

• Art der Immunsupression

• Anzahl und Art der Antihypertonika

• Blutdruck und Pulse Pressure

• der maximale Parathormonwert

• der Median aller präoperativen Parathormonwerten

• der Median aller Kreatininwerte der Monate 2-6 nach Nierentransplantation (so genannter Krea-Bestwert)

• der Median aller Kreatininwerte 2 Monate präoperativ

• der Median aller Serum-Kalziumwerte 2 Monate präoperativ

• der Median aller Serum-Phosphatwerte 2 Monate präoperativ

• der Median aller Serum-Harnstoffwerte 2 Monate präoperativ

• der Median des Körpergewichts 2 Monate präoperativ

3) Daten während des stationären Aufenthaltes

• S-Kreatinin, S-Kalzium, S-Phosphat, S-Harnstoff der Tage 1 bis 10 postoperativ

• Kalziumsubstitution i.v.

4) Postoperative Daten zum Entlassungzeitpunkt

• S-Kreatinin, S-Kalzium, S-Phosphat, S-Harnstoff

• Körpergewicht

• Kalzium- und Vitamin D-Menge die substituiert wird

• Anzahl und Art der Antihypertonika

• HMG-CoA-Reduktasehemmer

(20)

5) Postoperative Daten 2 Monate nach Entlassung

• Körpergewicht

• Anzahl und Art der Antihypertensiva

• Blutdruck und Pulse Pressure

• Körpergewicht

• der Median aller Parathormonwerte postoperativ

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4.2.2. Bewertung der erfassten Daten

4.2.2.1. Laborwerte

Die Laborwerte wurden in den gängigen Einheiten der Medizinischen Hochschule Hannover erfasst. Bei auswärtigen Laborwerten wurden diese auf die MHH Einheiten umgerechnet. Tabelle 1 zeigt einen Überblick.

Laborwert Einheit Umrechnungsfaktor

S-Kreatinin µmol/l µmol/l x 0,0113= mg/100ml S-Kalzium mmol/l mmol/l x 4,008 = mg/100ml S-Phosphat mmol/l mmol/l x 9,497= mg/100ml S-Harnstoff mmol/l mmol/l x 6,006= mg/100ml

Tabelle 1: Übersicht über die Einheiten der Laborwerte

4.2.2.2. Medikamente

Die Kalziumsubstitution wurde zu verschiedenen postoperativen Zeitpunkten ermittelt. Hierzu wurden alle Kalziumpräparate erfasst und daraus der gesamte Kalziumgehalt errechnet. Dieser Wert ging in die statistische Berechnung ein.

Kalzium-Brausetabletten entsprechen 500 mg Ca²⁺

Frubiase Trinkampullen entsprechen 90 mg Ca²⁺

Kalziumacetat entspricht 126,7 mg Ca²⁺

Vitamin D-Analoge werden in µg angegeben. Ein Umrechnungsfaktor zwischen den verschieden Wirkstoffgruppen wird in der einschlägigen Fachliteratur nicht beschrieben. Die Hersteller der gängigen Medikamente geben an, dass die angegebene Wirkstoffmenge äquivalent sei. In der prospektiven Untersuchung wurde ausschließlich der Wirkstoff Calcitriol verabreicht (s.Tab.8).

In der retrospektiven Untersuchung wurden die Wirkstoffe Calcitriol und Alfacalcidol verwendet.

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4.2.2.3 Blutdruck

Als Nachweis eines manifesten Hypertonus wurde das Vorhandensein einer antihypertensiven Therapie herangezogen, Diuretika wurden nicht als Blutdruckmittel gezählt, weil deren Einsatz nach Nierentransplantation mehrdeutig ist.

Keine antihypertensive Therapie = kein manifester Hypertonus Gabe eines Medikament = leichter Hypertonus

Gabe zweier Medikamente = Hypertonus mittleren Grades Gabe dreier Medikamente = schwerer Hypertonus

und mehr

4.2.2.4. Glomeruläre Filtrationsrate (GFR)

Mit der Berechnung der GFR mittels der von Cockroft und Gault erstellten Formel (20), wurde eine Methode benutzt, die aufgrund ihrer schnellen und handlichen Durchführbarkeit im klinischen Alltag häufig Anwendung findet. Die GFR nach Cockroft und Gault wird nach Geschlechtern getrennt errechnet.

Männer:

ClKrea[ml/min]=

] / [

* 82 , 0

] [

* ]) [

140 (

l µmol Kreatinin S

kg cht Körpergewi Jahren

Alter

−

Frauen:

ClKrea[ml/min]=

] / [

* 82 , 0

] [

* ]) [

140 (

l µmol Kreatinin S

kg cht Körpergewi Jahren

Alter

−

− -15%