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Keywords:

  • oxalate;
  • cystic fibrosis;
  • hyperoxaluria;
  • lung transplant;
  • renal transplant

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically-mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional Basiliximab. Calcium Carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter Formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended.


SUMMARY

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

We present a case of an irreversible oxalate nephropathy following complicated sequential double lung transplant successfully managed with dialysis and subsequently a living related kidney transplant.

CASE

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

A 29-year-old man with cystic fibrosis underwent a sequential bilateral lung transplant for end-stage lung disease. There was a history of recurrent pulmonary infections and pneumothorax requiring regular hospitalizations and he was colonized with Pseudomonas aeruginosa.

At 3 days of age he underwent an ileal resection for meconium ileus and was diagnosed with pancreatic exocrine insufficiency, for which he used enzyme supplements (Creon®, Abbott products, Pymble, NSW, Australia). He had normal renal function, normal endocrine pancreatic function and no prior history of renal calculi. A renal ultrasound, prior to lung transplant, demonstrated normal size of right and left kidneys of 10.9 cm and 11.7 cm respectively. A renal isotope perfusion scan demonstrated bilateral homogenous uptake of the tracer with a GFR (glomerular filtration rate) of 117 mL/min.

Following the lung transplant, his postoperative course was complicated by an anastomotic stricture and severe haemorrhage necessitating a repeat thoracotomy. He required multiple blood transfusions and became coagulopathic and hypotensive requiring intensive inotropic support. At the time of his lung transplant, immunosuppression consisted of Basiliximab and methylprednisolone induction with maintenance tacrolimus and mycophenolate. He received antiviral, bacterial and fungal treatment and prophylaxis with moxifloxacin, co-trimoxazole, voriconazole, amikacin, tazocin, vancomycin and ganciclovir.

He developed acute renal failure and was started on continuous veno-venous haemodiafiltration on the second postoperative day and then intermittent haemodialysis after discharge from the intensive care unit (ICU) on day 10. During the postoperative period he received nasogastric feeds with omission of his pancreatic supplements. He resumed normal diet and Creon® supplements after day 10, but required insulin for new onset diabetes after transplantation. His renal failure was managed expectantly. Routine protocol lung biopsies showed no evidence of rejection.

Six weeks post-transplant, he remained dialysis-dependent and oliguric (urine output <400 mL/day) but was haemodynamically stable. A renal ultrasound showed structurally normal kidneys without obstruction. A radiolabelled isotope scan demonstrated normal, uniform uptake and progressive accumulation of the isotope with complete absence of excretion at 21 min. There was no eosinophilia and the urine sediment was bland consistent with a diagnosis of acute tubular necrosis (ATN). There was no further clinical improvement and at week 8 he underwent a diagnostic renal biopsy (Figs 1,2).

image

Figure 1. Renal biopsy. (A) The renal cortical tubular lumen contains abundant anisotropic calcium oxalate crystals (arrows). There are dilated tubules with hyaline casts and tubular vacuoles (haematoxylin and eosin ×40). (B) Calcium oxalate crystals are present in the tubular epithelial cells (arrow head). There is epithelial cell necrosis and the centre shows tubular atrophy and interstitial fibrosis with mild lymphocytic cell infiltration (haematoxylin and eosin ×40).

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image

Figure 2. Under polarized light microscopy the oxalate crystals are birefringent and show colours of the rainbow. They are present in the tubular lumen and in the epithelial cell cytoplasm (polarized microscopy, haematoxylin and eosin ×40).

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PATHOLOGY

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

The lung transplant biopsy showed lung parenchyma comprised of bronchopulmonary tissue and lymphovascular bundles. There was no evidence of allograft rejection, inflammation or other pathology.

The renal biopsy contained 26 glomeruli and they showed mild mesangiopathic changes and no evidence of a glomerulitis. A few glomeruli showed ischaemic obsolescence. The pathology was seen mainly in the tubules and focally in the interstitium. The tubules showed variable dilatation of the lumina and many of them were expanded by crystals, which were translucent. There were patchy areas of tubular cell degeneration, necrosis and debris in the lumen. Some tubular epithelial cells showed large vacuoles and loss of the brush border. There were focal areas of tubular atrophy and interstitial fibrosis and mild cellular lymphocytic infiltration. Polarized microscopy showed birefringent crystals with some showing all colours of the rainbow. Some crystals were combined with calcium deposits (see Figs 1,2).

Immunofluorescence microscopy showed no immunoglobulin, complement or light chain deposits.

Electron microscopy showed crystals in tubular epithelial cells and in the lumen. They also showed patchy epithelial cell necrosis.

CONCLUSION

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

The pathology features are those of an oxalate nephropathy with tubular obstruction and epithelial necrosis. There are foci of tubular atrophy and interstitial fibrosis, with mild lymphocytic inflammation.

PROGRESS

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

The diagnosis of an acute oxalate injury was made and was felt most likely to be related to enteric hyperoxaluria. A diagnosis of primary hyperoxaluria was unlikely, as measured urinary precursors of oxalate metabolism, using liquid chromatography, including urine glyoxylate, glycerate and glycolate, were not raised. There was no history of excessive ascorbic acid intake. A 24 h urine collection for oxalate showed an initial value of 367 µmol/day (normal <550 µmol/day). While within the normal range, this was in the setting of renal failure and severely reduced glomerular filtration with a low urine volume, and was likely to be a significant underestimation. Plasma oxalate was not measured.

Given the absence of pretransplant renal injury or evidence for renal calculi or nephrocalcinosis, it was hypothesized that the interruption to pancreatic supplementation during his ICU stay and continuous nasogastric feeding led to lipid malabsorption with enteric calcium sequestration and increased enteric oxalate absorption with a rapid rise in serum oxalate. Severe reduction in glomerular filtration as a consequence of the vasomotor injury at the time of transplant and ATN allowed deposition of calcium oxalate crystals into sites of tissue injury, eliciting an inflammatory response and precluding reversal of tubular injury. Normally, oxalate is freely filtered, but the high single nephron load of any filtered oxalate would maintain high luminal concentration of oxalate and perpetuate tubular injury.

The resultant final diagnosis was enteric hyperoxaluria complicated by an acute irreversible oxalate nephropathy.

MANAGEMENT

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

Management consisted of a low-oxalate diet and intensification of pancreatic enzyme supplements to limit malabsorption. In addition, calcium carbonate and subsequently Sevelamer were added in order to reduce the enteric absorption of oxalate. Reduction in systemic oxalate load was attempted by the use of daily haemodiafiltration via a tunnelled internal jugular catheter and it is notable that he did not suffer any systemic manifestation of oxalate deposition such as heart block, arthropathy or neuropathy. The patient was managed as an outpatient and received tacrolimus, mycophenolate and steroids and remained free of pulmonary rejection with Forced expiratory volume (FEV1) maintained above 3.0 L.

The patient was distressed and angry at the need for regular haemodialysis and the impact it made on his life despite the renewed benefit of his lung transplantation. Options for renal transplantation were considered and his mother was assessed as a potential kidney donor.

Ten months post lung transplant he underwent a renal transplant with Basiliximab and methylprednisolone induction with maintenance of standard tacrolimus and mycophenolate dosing. There was immediate graft function and no complication. Calcium and Sevelamer supplementation were initially ceased, but were recommenced because of early hyperoxaluria with restoration of adequate glomerular filtration and tubular flow. The patient was advised to maintain a urine output of 3 L a day (see Fig. 3). Urinary oxalate excretion was monitored regularly in order to adjust pancreatic supplementation and oral oxalate binders. Initially very high levels may have reflected an elevated systemic burden and it is notable the urinary oxalate declined to the normal range after 3 months.

image

Figure 3. Twenty-four-hour urinary oxalate excretion.

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A 2-week post-transplant renal biopsy showed no evidence of recurrent oxalate deposition. In the months following his renal transplant, intermittent episodes of diarrhoea related to antibiotics or mycophenolate use precipitated episodes of acute renal failure. However, these diarrhoeal episodes improved on switching mycophenolate to azathioprine. At 8 months post renal transplant he has a creatinine of 122 µmol/L with an eGFR of 60 mL/min per 1.73 m2. His lung function remains stable and he is gainfully employed as an electrician.

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES

Oxalate is a ubiquitous molecule found in the soil and taken up by plants and vegetables such as spinach, rhubarb and nuts. Concentrations in foods vary widely depending on the soil and water conditions they were grown in, making quantification in feeds difficult. Approximately2 20–40% of oxalate is obtained from the diet where it is absorbed in the colon. Endogenous production is primarily from the liver where glyoxylate derived from animal protein can be metabolized to glycine, glycolate or oxalate. Deficiencies of the enzymes catalysing the former two products are responsible for the primary hyperoxalurias. Erythrocyte metabolism and ascorbic acid catabolism can also contribute to the oxalate load.

Only free oxalate can be absorbed by the intestinal epithelium. The amount of free oxalate is dependent on the concentration of other ions in the intestine, mainly calcium, and the bioavailability in the food consumed. Normally calcium will bind oxalate preventing its absorption.

In patients with cystic fibrosis, lipid malabsorption, associated with pancreatic insufficiency and prior intestinal surgery, would result in undigested lipids preferentially binding calcium, leaving unbound oxalate free to be absorbed in large quantities. Lipid malabsorption increases the exposure of the colonic mucosa to bile and free fatty acids, increasing mucosal permeability for oxalate. Oxalobacter formigenes, a gut anaerobe capable of metabolizing oxalate, can be eradicated by multiple antibiotics, further increasing oxalate absorption.

Cystic fibrosis is now one of the commonest reasons for lung transplantation and postoperative renal failure is common. In a case series published by Lefaucheur et al.,1 in 2008, 77 patients with cystic fibrosis were followed up post lung transplant. Twenty-five patients developed accelerated renal function loss, 15 of whom underwent a renal biopsy. Oxalate crystals were present in the tubular epithelium of nine of these patients. Three of these patients progressed to end-stage renal disease.

Oxalate is freely filtered by the glomerulus and secreted by the proximal tubules and is minimally protein bound. The diagnosis of hyperoxaluria can be made by demonstrating an elevated 24 h urine oxalate excretion (normal <550 µmol/day). However, levels >2000 µmol/L are often noted in the primary hyperoxalurias together with elevated levels of glycolate and glyoxylate.

In our patient, tubular epithelium damage, because of various drug and haemodynamic insults, would have provided the perfect nidus for oxalate deposition. Oxalate crystals can aggregate and obstruct the tubular lumen or be internalized into the tubular cells where they can lead to further tubular injury.

The rationale for the use of calcium carbonate and addition of Sevelamer to the diet was to bind intestinal oxalate directly and to also bind intestinal phosphate thus freeing up intestinal calcium to then bind oxalate.

Systemic oxalate deposition can result in retinopathy, arthropathy, conduction defects and peripheral neuropathy. Cases have also been reported of patients with an occult diagnosis of primary hyperoxaluria who received a renal transplant with prompt graft failure because of severe renal oxalate deposition. Therefore in addition to enzyme replacement and dietary supplementation, intensive dialysis was initiated to prevent systemic complications of oxalosis.

A cadaveric kidney with any degree of cold ischaemia and high risk of tubular necrosis increased the possibility of recurrent oxalate deposition and renal injury. Therefore a live related well matched donor was considered optimal to minimize the risk of recurrent ATN and further oxalate injury. In addition, post-transplant high tubular flow rates were maintained to prevent oxalate deposition with the subsequent reintroduction of oral oxalate binders to reduce systemic absorption.

An acute oxalate nephropathy is potentially preventable but unlikely to respond to medical measures once developed. To our knowledge this is the first published case of an acute irreversible oxalate nephropathy complicating a lung transplant that was successfully treated with a renal transplant.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. SUMMARY
  4. CASE
  5. PATHOLOGY
  6. CONCLUSION
  7. PROGRESS
  8. MANAGEMENT
  9. DISCUSSION
  10. Conflict of interests
  11. REFERENCES