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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2004  |  Volume : 15  |  Issue : 1  |  Page : 27-33
Post Renal Transplantation Tubulopathies in Children: A 9-Year Experience at a Tertiary Care Centre

1 Department of Pediatrics King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
2 Department of Pediatrics, American University of Beirut Medical Center, Beirut, Lebanon

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To evaluate the incidence of tubulopathies in the long-term follow-up of children post renal transplantation, we reviewed the records of 43 patients from 1987-1996. There were 24 (56%) boys. The age of patients at the time of transplant ranged from 2.7 to 15 years. Eighteen children (78%) had transplantation from cadaver donors (CAD). Thirty-two (74%) patients were transplanted in Saudi Arabia and 11(26%) were transplanted abroad. Significant tubular dysfunction developed in 72% of patients. Renal Tubular Acidosis (RTA) occurred in 23/43 (53%) patients. The patients who received CAD grafts required higher mean dose of bicarbonate and longer duration of therapy compared to living related donors (LRD) recipients ( mean dose of 1.7 Vs 0.5 meq/kg/day and mean duration of 18 Vs 3 ½ months, respectively). Hypophosphatemia of various degrees of severity (0.4-0.8 mmol/1) was detected in 12 (28%) patients. Those who received CAD grafts required higher mean dose of phosphate and longer period of therapy than those who received LRD grafts. Hypomagnesemia requiring supplemental magnesium therapy occurred in 4 (9%) patients, all received tacrolimus therapy. In four patients with hypomagnesemia, this was mild and transient. Hypokalemia was found in 5 (11.5%) patients; all had CAD grafts. We conclude that tubulopathies were a frequent complication post renal transplantation in our population. They were more severe in the patients who received CAD grafts. However, the defects were controllable and transient.

Keywords: Renal Tubular Disorder, Transplant, Saudi Arabia.

How to cite this article:
Al-Ibrahim A, Sanjed S, Al-Abbad A, Al-Sabban E, Al-Shaibani K. Post Renal Transplantation Tubulopathies in Children: A 9-Year Experience at a Tertiary Care Centre. Saudi J Kidney Dis Transpl 2004;15:27-33

How to cite this URL:
Al-Ibrahim A, Sanjed S, Al-Abbad A, Al-Sabban E, Al-Shaibani K. Post Renal Transplantation Tubulopathies in Children: A 9-Year Experience at a Tertiary Care Centre. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2022 Aug 12];15:27-33. Available from: https://www.sjkdt.org/text.asp?2004/15/1/27/32962

   Introduction Top

Although renal tubular disorders after kidney transplantation have been reported in United States, Europe and Canada, in the late sixties, [1] we are not aware of any report that describes the differences between the recipients from cadaver compared to living donors.

There is a paucity of reports from the Arab countries in this field, including the Kingdom of Saudi Arabia.

We attempt in this study to report our experience with the tubulopathies encountered in the children followed up for a long time in our center and the differences according the donor type.

   Subjects and Methods Top

We reviewed records of 60 children who received 64 renal transplants over a 9-year period, from October 1987 to November 1996. Seventeen patients were excluded from this study because of death, graft loss, loss of follow-up and insufficient data. The data obtained included the original renal disease before renal transplantation, age at the time of transplantation, sex, place of transplanta­tion and cold ischemia time. The biochemical status before and after transplantation in­cluded blood glucose, urea (BUN), creatinine, sodium, potassium, chloride, magnesium, phosphorus, calcium, alkaline phosphatase, parathyroid hormone (PTH) and Uric acid. Total proteins, albumin, globulin, liver fun­ction test, and blood gases were performed when appropriate.

Renal tubular acidosis (RTA) was diagnosed if there was persistent hyperchloremic meta­bolic acidosis with pH in the arterial blood gases less than 7.2, serum HCO 3 less than 20 mmol/l, serum chloride more than 112 mmol/l with normal anion gap in the blood. Urine pH by pH meter in the morning fresh urine sample was measured and urine anion gap was calculated in order to identify the type of renal tubular acidosis. Distal RTA (DRTA) was diagnosed when urine pH was more than 6 (alkaline urine) and urine anion gap was positive, while proximal RTA (PRTA) was diagnosed when urine pH was less than 5.5 (acidic urine) and urine anion gap negative. Some patients could not be classified because inadequate laboratory data.

For patients with hypophosphatemia, hypo­magnesemia, hypokalemia, we measured tubular reabsorption of phosphate (normal >80%), fractional excretion of magnesium (significant if > 20%), and magnesium to creatinine ratio.

Medications, doses and duration of treat­ment were also recorded. The post renal transplantation prophylactic triple immuno­suppressive therapy included cyclosporine A 500mg/m 2 immediately after transplantation followed by a maintenance dose of 300mg/ m 2 /day. We applied a single dose pre-trans­plantation methylprednisolone 10 mg/kg followed by oral prednisone 0.5 mg/kg/day post transplantation, tapered every three weeks to 0.25mg/kg at 3 months, 0.13 mg/kg/day at 6 months and finally to a maintenance dose of 0.1-0.12mg/kg/day. Azathioprine (Imuran) was administered orally at 1-2 mg/kg/day.

All the patients received prophylaxis against infection for three months post renal trans­plantation that included acyclovir at 0.5 mg/ kg/day for viral infection such as cytomegalo­virus (CMV), Cotrimexazole at 5mg/kg/day for gram-negative bacilli such as Enteococci and Staphylococcus aureus, and mycostatin at 500,000 international unit (i.u.) four times per day to prevent fungal infection such as Candida.

Immediately after transplantation fluid was administered to replace insensible loss at 400ml/m as 5% dextrose water and urine output was replaced by half normal saline.

Electrolytes and minerals were monitored every four hours in the first post transplant day, then daily or according to the biochemical and clinical status of the patients. The intra­venous fluids were adjusted accordingly.

   Statistical Methods Top

We used the Mann - Whitney test and Fisher's exact probability test. A P-value of less than 0.05 was considered as significant.

   Results Top

Forty-three patients with complete data were enrolled in this study, 24 (56%) were males and 19 (44%) were females, male: female ratio of 1:1.26. Four patients had more than one renal transplant. Seventy percent of the kidneys were from cadaver (CAD) and 30% from living related donors (LRD). Thirty-four (79%) patients were transplanted at King Faisal Specialist Hospital and Research Center and nine (21%) were transplanted outside the Kingdom. The age at time of trans­plantation ranged between 2 ½-15 years. The duration of follow-up was from 1 month - 9 years post transplantation.

Twelve patients (28%) had obstructive uro­pathy as the cause of end-stage renal failure (ESRF), the cause was unknown in 5 (11.6%) patients and two (4.6%) patients had primary hyperoxaluria; both also had liver transplan­tation in addition to kidney transplantation [Table - 1].

Mean pre and post-transplant serum crea­tinine levels were similar in both CAD and LRD groups (7.3 ± 0.7 mg/dl) and (6.9 ± 1.1 mg /dl) respectively.

Renal tubular dysfunction developed in 31/43 (72%) patients. 24/31 (77%) had cadaver graft and 7/31 patients (23 %) had grafts from a living-related donor. [Table - 2].

Renal tubular acidosis (RTA), developed in 23/43 (54%) patients, 18 (60%) had CAD grafts and 5 (38%) had LRD grafts. Plasma HCO 3 ranged from 13-17 mmol/L. The mean plasma bicarbonate level was comparable in both CAD and LRD group, 15 and 17 mmol/L respectively. Nine patients (39%) had distal RTA, seven from CAD and two from LRD grafts. Five (22%) had proximal RTA four of them from CAD and one from LRD. In the remaining eight patients (35%) RTA could not be classified due to insufficient data. These abnormalities developed in the first few days post transplantation and all required alkali therapy of 0.5-4 meq/kg/day; patients with cadaver graft required 1.5 - 4 meq/kg/day (mean 1.7 meq/kg/day and mean duration of therapy was 18 months. Patients with LRD grafts required 0.5-4 meq/kg/day of alkali therapy (mean 0.5 meq/kg/day and mean duration of therapy of 3 ½ months. Half of these patients were still on treatment six months to five years following transplan­tation [Table - 3].

Hypophosphatemia of various degrees of severity (0.4-0.8 mmol/L) was detected in 12/43 (28%) of patients, eight from the CAD and four from the LRD group. Mean serum phosphorus level was significantly lower in the CAD group than in the LRD group (0.57 mmol/l vs. 0.83 mmol/l). Mean tubular reab­sorption of phosphorus (TRP) was 43% in the CAD and 65% in the LRD group. (Normal 80%). The calcium and alkaline phosphatase level pre and post transplantation were normal [Table - 4].

The mean serum level of parathyroid hormone (IPTH) pre- and post-transplant were not significantly different in both groups. In LRD patients, the PTH level was 1178 pg/L pre and 1151 pg/L post transplant, while it was 1232pg/L pre and 1194 pg./L post transplant in the CAD patients, (Normal PTH C-terminal range 416-1760pg/L) [Table - 4]. There was a marked difference between the CAD and LRD groups in regard to the dose of phos­phate supplement required to correct the defect and duration of treatment, 90 mg/kg/day for a mean period of 8 months, vs. 20 mg/kg/day for a mean period of 2 ½ months [Table - 2].

Significant hypomagnesemia (mean 0.4 mmol/L) was detected in five patients; the fractional excretion of magnesium was > 30%; four had CAD grafts. All the patients received tacrolimus and three patients also had proximal RTA. All patients required supplemental magnesium therapy; the average dose 63 mg/kg/day and the duration of treatment ranged between 5 - 45 months.

Moderate hypokalemia (2.4-2.8 mmol/L) was detected in seven (16%) patients; five had CAD grafts. Five patients had also RTA that was mild and transient and lasted from 2-7 days in three patients. Four patients required potassium supplement for 6-8 weeks; one patient required potassium supplement of 2 meq/kg/day for 8 months.

Cold ischemia time in patients with tubulo­pathies was 15.6 hours Vs 11.5 hours in patients without tubulopathies.

   Discussion Top

Renal tubulopathies such as renal tubular acidosis (RTA), hypomagnesemia, hypophos­phatemia, hypercalcemia, hyperkalemia may follow successful kidney transplantation.

Renal tubular acidosis was first reported in 1967 by Massry and associates, [1] and sub­sequently described by several authors. [1],[2],[3],[4],[5],[6],[7] Revusova et al described more than one tubular disorder (ie.hypomagnesemia, hypophosphatemia and hypocalcemia) in one patient. [6] In addition, hypophosphatemia secondary to hyperparathyroidism or inde­pendent of PTH was described by the same group. [6]

It has been also described before that the grafts survival rate from living donors is superior to those of cadaver grafts. [13]

In our study renal tubular acidosis was the most frequent renal tubulopathy (53%) observed, similar observation was reported in other studies, but the exact incidence is not really known. [1],[2],[8]

Several factors may be responsible for these disorders, such as the ischemic injury during transplantation, and the reduced renal mass for few months post transplant that might result in a decrease of ammonia excretion, bicarbonate wasting (proximal RTA) and inability to lower urine pH (distal RTA). Patients with secondary hyperparathyroidism before transplantation may develop RTA post transplantation because high PTH activity may result in a leak of bicarbonate from the proximal tubules that may affect urine acidification. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15]

Immunosuppressive drugs such as cyclo­sporine A and tacrolimus, and cold ischemia time can be implicated as an explanation for RTA in the present study, except for the PTH that was under control.

In the present study, the majority of the patients who developed RTA post kidney transplant had CAD kidneys; the mean cold ischemia time was longer in CAD patients but the difference was not significant.

The requirement for a longer period of treatment with alkali and larger dose in CAD patients might be explained by the longer period of recovery from the effect of acute tubular necrosis. Distal and proximal RTA was reported to occur in transplanted kidneys. However, the relation between the duration of treatment and dose of alkali therapy and type of RTA could not be ascertained in this study because of inadequate data.

Patients with some original diseases such as obstructive uropathy, autoimmune diseases such as systemic lupus erythematosis (SLE) have been reported before to continue to have RTA post successful kidney transplantation if they had it prior to transplantation. [1] However, this was not the case in this study, since none of our patients had RTA pre transplantation.

Hypophosphatemia with normal calcium was observed in 12 of our patients post successful kidney transplant.

Hypophosphatemia may result from a leak of phosphate from the proximal tubule secondary to the effect of the high level of PTH enhanced by cortisol intake Furthermore, phosphate leak may result from the hypersensitivity of the transplanted kidney to normal PTH level. Hypophosphatemia may persist for several years post transplantation despite achieving normal graft function, because the involution of parathyroid gland to normal size and function may take a long time. [3],[5],[13]

In the present study, the PTH activity level was under control pre transplantation and the calcium level was also normal. Accordingly, PTH-independent hypophosphatemia may be considered. Although hypophosphatemia occurred with similar frequency among CAD and LRD recipients, the degree of phospha­turia was higher in CAD than LRD patients suggested by the TRP. This may explain the requirement of the CAD patients for a larger dose of phosphate supplementation and for a longer period than the LRD patients.

Hypokalemia was detected in five CAD patients and two patients from LRD group. Distal RTA and hypomagnesemia could have contributed to hypokalemia. [9]

Hypomagnesemia might have been due to tacrolimus therapy or proximal RTA through renal tubular wasting of magnesium. [6],[14]

We conclude that renal tubulopathies are common following renal transplantation. Although the defects are usually mild to moderate and transient in many patients, they may be severe or permanent in some cases. In our study, tubulopathies were more frequent in CAD compared to LRD recipient. The etiology of the tubular dysfunction is probably multifactorial. The roles of anti-rejection drugs, acute tubular necrosis, cold ischemia time, singly or in combination may be contri­buting factors. Further prospective studies may confirm the exact etiological factors.

   References Top

1.Wilson DR, Siddiqui AA, Renal tubular acidosis after kidney transplantation. Natural history and significance. Ann Infern Med 1973;79:352-61.  Back to cited text no. 1    
2.Ladefoged J. Tubular reabsorption of bicarbo­nate in transplanted cadaver kidneys. Nephron 1973;10:216-21.  Back to cited text no. 2  [PUBMED]  
3.Pabico RC, McKenna BA. Metabolic problems in Renal transplant patients. Persistent hyperparathyroidism and hypophos­phatemia: effects of intravenous calcium infusion. Transplant Proc 1988;20:438-42.  Back to cited text no. 3    
4.Batlle DC, Mozes MF, Manaligod J, Arruda JA, Kurtzman NA. The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation. Am J Med 1981;70(4);786-96.  Back to cited text no. 4    
5.Chan JC. Acid-base disorders and the kidney. Adv Pediatr 1983;30:401-71.  Back to cited text no. 5  [PUBMED]  
6.Revusova V, Zvara V. Gratzlova J, et al Magnesium deficit after renal transplantation with secondary post transplantation hypo­calcemia and hypophosphatemia. Urol Int 1975;30(4):313-20.  Back to cited text no. 6    
7.Ochavan-Coveura J. Renal tubular acidosis in the kidney transplant Ann Med Intern 1995;12(2): 65-8.  Back to cited text no. 7    
8.Feld LG, Stablein D, Fivush B, Harmon W, Tejani A. Renal transplantation in children from 1987-1996: the 1996 Annual Report of the North American Pediatric Transplant Co-operative Study. Pediatric Transplant 1997;1:146-62.  Back to cited text no. 8    
9.Yang CW, Kim YS, Yang KH, et al. Primary aldosteronism detected after renal trans­plantation. Am J Nephrol 1994;14(3):220-2.  Back to cited text no. 9    
10.Heering P. Ivens K. Akers S, et al, Distal tubular acidosis induced by FK506. Clin Transplant 1988;12(5): 465-71.  Back to cited text no. 10    
11.Heering P. Degenhardt S. Grabensee B. Tubular dysfunction following kidney transplantation. Nephron 1966;74(3):501-11.  Back to cited text no. 11    
12.Al-Uzri A , Sullivan EK, Fine RN, Harmon WE. Living -unrelated renal transplant­ation in children: a report of the North American Pediatric renal transplant Cooperative study (NAPRTCS). Pediatr Transplant 2(2):139-44.  Back to cited text no. 12    
13.Farrington K, Varghese Z, Newman SP et al. Dissociation of absorptions of calcium and phosphate after successful cadaveric renal transplantation. Br Med J 1979;1: 712-4.  Back to cited text no. 13    
14.Mazzaferro S, Barberi S, Scarda A , et al. Ionized and total serum magnesium in renal transplant patients. J Nephrol 2002;15(3): 275-80.  Back to cited text no. 14    
15.Hansen JM, Fogh-Andersen N, Leyssac PP, Standgaard S. Glomerular and tubular function in renal transplant patients treated with and without ciclosporin A. Nephron 1998;80(4): 450-7.  Back to cited text no. 15    

Correspondence Address:
Alia Al-Ibrahim
Pediatric Nephrology, Sulaimania Children's Hospital, P.O. Box 59046, Riyadh 11525
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 18202463

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