Pancreatic insufficiency as a complication of type 1 diabetes causing enteric hyperoxaluria in a transplant kidney

Background

Hyperoxaluria, excess oxalate in the urine, is a well-recognised cause of nephropathy.1 Its aetiology can be separated into primary (genetic) hyperoxaluria and secondary hyperoxaluria, which primarily arises from increased absorption of oxalate (dietary) and malabsorptive disorders (known as enteric hyperoxaluria).

The sequence of events leading to enteric hyperoxaluria begins with malabsorption of fat, resulting in excessive excretion of calcium, which is preferentially bound to fat.2 The low enteric calcium leaves unbound oxalate, which is thus free to be absorbed into the blood. Consequences of hyperoxaluria commonly include kidney stones, chronic kidney disease (CKD) and eventual end-stage renal failure (ESRF).

Well-known causes of enteric hyperoxaluria include bariatric surgery, such as Roux-en-Y gastric bypass, inflammatory bowel disease (IBD) and pancreatic insufficiency.1 3 4 Some causes of pancreatic insufficiency include chronic pancreatitis and Whipple’s surgery. Up to 52.4% of those with diabetes mellitus (DM) have some form of exocrine pancreatic insufficiency (EPI), more commonly in those with insulin-dependent DM.5 6

Case presentation

The patient is a caucasian woman in her 40s with type 1 diabetes mellitus (T1DM) and hypothyroidism. She was diagnosed with ESRF secondary to biopsy-confirmed diabetic nephropathy and subsequently had a pre-emptive live donor kidney transplant. Immunosuppression was with basiliximab induction, tacrolimus and prednisolone. The human leucocyte antigen mismatch was 2-2-1 .The donor was cytomegalovirus (CMV) negative and the recipient was CMV positive. After transplant, the patient had excellent and stable kidney function (baseline creatinine 90 μmol/L estimated glomerular filtration rate, eGFR ~55) (figure 1) and was on a maintenance regime of prednisolone 5 mg once daily (OD) and tacrolimus (Prograf) 5 mg twice daily (BD). Her other regular medication included human insulin (Insulatard) BD, insulin aspart (Novorapid) three times a day, levothyroxine 50 mcg OD and nifedipine 60 mg OD.

Seven years later, the patient presented to the transplant clinic with diarrhoea and acute kidney injury (AKI). The patient described type 7, foul smelling pale stools consistent with steatorrhoea gradually worsening over 1 month with no associated weight loss.

It was initially assumed that this transplant AKI was prerenal (hypovolaemia secondary to diarrhoea). Consequently, the patient was admitted to the ward for intravenous fluids and further investigations.

Investigations

On admission, blood showed a rise in creatinine from 90 μmol/L to 191 μmol/L (figure 1). Full blood count, C reactive protein and liver function tests were normal (table 1). The tacrolimus level was mildly elevated but never exceeded 12. The observations were all within normal range and the physical examination of the patient was normal.

A kidney biopsy was performed (figure 2) showing focal features of acute tubular injury with some interstitial inflammation possibly in keeping with acute tubular injury. It also revealed an increase in mesangial matrix with arteriolar hyalinosis, which could represent an early recurrence of diabetic nephropathy or chronic calcineurin inhibitor toxicity. However, most importantly, it showed focal crystals in keeping with oxalate crystals (Von Kossa stain negative). In this case, the finding of oxalate crystals was made based on the shape and colour on light microscopy, without the use of polarised light. However, calcium oxalate crystals can also be identified as showing positive birefringence. The previous 2004 biopsy report confirmed diabetic nephropathy as the cause of CKD with no evidence of oxalate crystals, showing it was not a missed diagnosis of primary hyperoxaluria.

Following the biopsy, a 24-hour urine oxalate level was carried out demonstrating a markedly elevated level of 1142 μmol (normal <460). As such, causes of hyperoxaluria were examined, which include primary, enteric and dietary hyperoxaluria. The patient had no prior history of bowel surgery, inflammatory bowel disorders or malabsorptive disorders, and her diet was not high in oxalate. Moreover, the patient was not taking vitamin C supplementation, which is a risk factor as oxalate is formed from the breakdown of ascorbic acid.7 A faecal elastase was performed, which was 81 mcg/g, demonstrating severe pancreatic exocrine insufficiency, a common cause of enteric hyperoxaluria (<100).

Differential diagnosis

There are lots of causes of AKI to consider in this case. First, it is important to recognise that those with renal transplants are at risk of the same causes of AKI as those with native kidneys. This can be easily split into prerenal, renal and postrenal causes.

Prerenal AKI, specifically hypovolaemia, was thought to be the most likely cause of this patient’s AKI. Her history of diarrhoea suggests dehydration and can be reversed with intravenous fluids if treated early enough.8 Postrenal causes can be readily identified using ultrasound and include renal calculi, obstructing tumours and an enlarged prostate. Typically, these present with symptoms that suggest obstruction such as pain, haematuria and lower urinary tract symptoms, making them less likely in the patient’s case. However, a renal ultrasound is indicated in most patients with AKI to ensure they have been ruled out.9

Once the more common and rapidly identifiable causes of an AKI have been ruled out, we can begin considering those causes that are specific to renal transplant recipients. Rejection, drug toxicity, infections and recurrence of primary disease are all investigated and are common culprits of transplant dysfunction.

Rejection is often the first thing that patients ask about, and has a long list of causes that is out of the scope of this case review. Acute rejection affects roughly 8% of transplant recipients in the first year,10 and can be antibody or T cell mediated. It is diagnosed on renal biopsy and can be managed with steroids (for T cell-mediated rejection) and plasma exchange/monoclonal antibodies for antibody mediated rejection.10

The main pharmacological cause of transplant dysfunction is tacrolimus (FK506) toxicity. Tacrolimus levels are affected by acute infections, liver dysfunction and other medications, and thus was considered quite high on the list of differentials for the patient, with diarrhoeal illnesses putting you at increased risk of toxicity.11 A predose level of tacrolimus can be easily obtained using a blood test. However, as individual factors including genetics also influence at what level a person becomes toxic, tacrolimus toxicity can only be completely ruled out using biopsy. Additionally, infections like the BK virus have previously been recognised to cause graft dysfunction in 30%–60% of infected patients,12 although with better diagnosis and treatment, this percentage is improving.

Finally, renal biopsy in acute transplant dysfunction can also diagnose recurrences of the primary disease. Although diabetic nephropathy is considered a long-term complication of diabetes, recurrence of disease post-transplant can occur quite rapidly.13 A study of renal biopsies in the first 5 years post transplant showed that structural changes to the allograft such as mesangial expansion often occur within 2 years of transplantation, arising independently of glycaemic control post transplant, and can result in deterioration in graft function.13

It is clear there are a large number of differential diagnoses to consider in acute transplant dysfunction. Investigations include drug concentrations, renal ultrasound and renal biopsy, which allow almost all of the aforementioned differentials to be ruled out and, in the patient’s case, also allow the identification of less common causes of allograft dysfunction.

Treatment

Consequently, given the biopsy report, the urine oxalate findings and the faecal elastase, the patient was diagnosed with acute oxalate nephropathy (AON) secondary to enteric hyperoxaluria as a result of pancreatic insufficiency. The most likely cause in this case is T1DM.

The patient was initiated on pancreatin (Creon) and calcium carbonate. The patient was also advised on a low oxalate diet and referred to gastroenterology for management of pancreatic insufficiency.

Outcome and follow-up

Renal replacement therapy was not required, and within 8 weeks, the creatinine returned to baseline of 90 μmol/L. She has had a stable kidney transplant function since (figure 1). The repeat 24-hour urinary oxalate 3 months after treatment was 641, which has remained low since. She did not require dialysis during this acute episode. The lowest reported eGFR was 19, and she never developed fluid overload, hyperkalaemia or refractory hypertension.