Simultaneous Liver Kidney Transplantation in a Primary Type 2 Hyperoxaluria With Corrected TOF and Severe Cardiomyopathy: A Case Report

Abstract

Background

Primary type 2 hyperoxaluria is a very rare genetic disorder,^1,2 where in the progression to renal failure was assumed to be insidious and not very common.³ PH2 is due to deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR),^1,2 which was thought to have extra-hepatic production also.⁴ The progression to renal failure in these patient subgroups is well documented in the Literature and the role of SLK (simultaneous liver and kidney transplantation) has not been clearly established.⁸

Method

We present a case report of a young girl with PH2, who successfully underwent SLK, with evidence of reduction in the urine oxalate levels post SLK.

Results

PH2, though a rare genetic disease, has a proven potential to progress to chronic renal failure requiring transplantation, renal transplantation alone has not shown any benefit, these patients can be offered SLK as a primary treatment option, to improve the outcomes, this needs further validation with consensus and studies.

Primary hyperoxaluria (PH) is a group of rare genetic metabolic disorders that are characterized by the endogenous overproduction and accumulation of oxalates in the kidneys and other organ systems of the body.

Three types are described in the literature, Type 1(PH1), the most common, accounts for 80% of cases, while type 2(PH2) and 3(PH3) account for 10% of cases.^{1,2, 4}

Although progression to renal failure is rare in PH2, some patients can express severe form of PH2 and literature review indicates the progression to chronic renal failure as well.^{5, 6, 7, 8}

SLK as primary treatment option for PH2 is vague and unclear,^3,9 whether the liver transplantation would benefit them is not very clear in the literature,^9,10 with the exception of a few case reports.

We present a case report of simultaneous liver and kidney transplantation, in a 12 yrs old child, who was diagnosed with CKD at the age of 11 yrs, with congenital cyanotic heart disease (Tetralogy of Fallot) correction and cardiomyopathy.

Case Report

The child was born at term, of nonconsanguineous marriage, was cyanotic at birth needing resuscitation, she was diagnosed with congenital cyanotic heart disease TOF, with severe pulmonary valvular stenosis, which was subsequently repaired at the age of 10 months. Post repair, she was doing well with no symptoms of TOF repair sequelae, and was not on any medications. She had repeated episodes of urinary tract infection since 5 years of age.

She was apparently well till the age of 11 years, when she presented with low urine output, sudden onset severe uremia, metabolic acidosis and severe anemia, with coincidental detection of bilateral cortico-medullary nephrocalcinosis seen in the radiograph of the chest (Figure 2, Figure 3). She was put on hemodialysis initially, then maintenance dialysis with CAPD (12 cycles per month, every alternate day with 4 cycles per day 3 h apart during the day). Her serum oxalate levels (by colorimetry) tested was high, 351 mcg/L. urinary oxalate/glycerate studies could not be done, as she was Anuric.

Figure 2.

Plain Abdominal CT (computed tomogram), showing nephrocalcinosis, with peritoneal dialysis catheter in situ. Boot-shaped heart can't be missed.

Figure 3.

CT abdomen coronal section, showing bilateral nephrocalcinosis. CT, computed tomogram.

Her genetic testing (PH panel DNA testing) was done, which revealed a heterozygous missense variation in Exon 6 of GRHPR gene, resulting in the substitution of Aspartic Acid for Glycine at codon165, with the observed variation lying in the catalytic domain of the GRHPR protein, consistent with heterozygous primary type 2 hyperoxaluria.¹⁵

She was referred to our center for further evaluation and the feasibility of SLK was explored with a multidisciplinary meeting with all the concerned specialities, her transthoracic echocardiography revealed global left ventricular (LV) hypokinesia with a LVEF of 45%, suggestive of probably uremic/hyperoxaluria-induced cardiomyopathy.

She also had moderate pulmonary valvular regurgitation (PR), and mild pulmonary valvular stenosis (PS), with no (PAH), with ventricular septal patch in situ, no ventricular or atrial septal defects (VSD/ASD) or left ventricular outflow tract obstruction (LVOTO). Her 12 lead electrocardiograph showed normal sinus tachycardia, with bi-atrial enlargement, Right Bundle Branch block with left posterior fascicular block, Left ventricular hypertrophy and T wave inversion in the anterolateral chest leads. Her fundus examination of the eye was normal, and there was nothing to suggest systemic manifestation of oxalate deposition. Her developmental milestones were adequate, she was severely sarcopenic, and her weight was less than 3rd percentile as per Indian recommended growth standards with a BMI of 13.2 kg/m².

A Combined simultaneous liver and kidney, ABO compatible, living donor transplantation was planned with two related donors.

She was placed on hemodialysis initially twice weekly sessions and daily intensive high flux hemodialysis for 4 h 3 weeks prior to transplantation.

She developed acute congestive heart failure and worsening cardiomyopathy a week prior to transplantation, most likely due to stress-induced/uremic cardiomyopathy, her transthoracic echocardiograph revealed, global hypokinesia, moderate to severe PR, mild PS, moderate to severe left ventricular dysfunction (LVD) with EF of 25%, no PAH, with no LVOTO.

She was put on digoxin and nitrates, and underwent intensive high flux hemodialysis sessions, she became symptomatically better and after a week her echocardiography showed slight improvement with an EF of 32%, mild PR, no PAH and severe LV dysfunction with persisting global hypokinesia.

She was taken up for surgery, with standard right lobe liver graft with adequate size and left renal graft transplantation simultaneously. Intraoperatively CRRT (continuous renal replacement therapy) Continuous veno-venous hemodiafilteration (CVVHDF) was done, which was continued till postoperative day 3 to reduce the oxalate load. Intraoperative parameters like cold/warm ischemia times were under acceptable limits for both the grafts. She was extubated on POD 0, within 12 h following transplant with good graft functions (liver and Kidney).

Immunosuppression with Tacrolimus (started preoperatively a week before transplant with a low dose tacrolimus, with preoperative TAC trough levels-2ng/ml) and steroids (low dose methyleprednisolone 5–7 mg/kg, was given intraoperatively before liver graft reperfusion), postoperatively Tacrolimus was restarted on POD 0, and methyleprednisolone as per protocol, maintaining adequate Tacrolimus trough levels. She was switched to oral prednisolone on POD 4. She had an uneventful recovery, with good graft liver and kidney functions, with improving biochemical parameters (Figure 1) and was subsequently discharged after 20 days of transplantation.

Figure 1.

Showing, from pre-operative serum AST, ALT (Primary Axis), bilirubin Total, INR, Creatinine (Secondary Axis) till postoperative day (POD) 20. AST, Aspartate Amino transferase; ALT, Alanine Amino-transferase; INR, International Normalised Ratio.

Her serial echocardiography done postoperatively, showed gradual improvement in her LV function, which at the time of discharge showed marked improvement, with an EF of 58%, and no regional wall motion abnormality, digoxin and nitrates were subsequently tapered off and stopped.

Her serum oxalate levels were done only twice in the postoperative period, (POD 20:190 mcg/L, and POD 35:169 mcg/L) and 24 h urine oxalate levels (POD 20: 48.60 mg/day, urine creatinine 18.28 mg/kg/day, urine volume: 1800 ml) and were remarkably better by the end of the first month.

Discussion

Literature reviews for Type 2 primary hyperoxaluria, though a very rare genetic disorder has shown to progress to nephrocalcinosis and chronic renal failure.^{1, 2, 3}

PH2 is caused by a deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase, with its majority of activity in the liver, but some activity is also demonstrated in leukocytes and the kidney. GRHPR enzyme is primarily found in the cytosol but can also be seen in the mitochondria. The enzyme plays a role in the gluconeogenic pathway from serine and in the detoxification of cytosolic glyoxylate. Deficiency of GRHPR leads to an accumulation of glyoxylate and hydroxypyruvate, which are both metabolized by lactate dehydrogenase to oxalate and l-glycerate, respectively (Figure 4).

Figure 4.

GRHPR enzyme in the cytosol of the hepatocyte, its role in glyoxalate metabolism. In the absence of GRHPR, lactate dehydrogenase (LDH) catalyzes the metabolism of hydroxypyruvate to l-glycerate and glyoxylate to oxalate, leading to oxalate accumulation in PH2. AGT, alanine glyoxylate aminotransferase; GRHPR, Glyoxylate reductase/hydroxypyruvate reductase.²

With progressive decline in the renal function, systemic oxalosis with calcium oxalate getting deposited in the bones, skin, retina, heart, arterial media, peripheral nerves to name a few, is frequently seen. Oxalates deposition in the conduction bundles can cause serious arrhythmias, though defined serum oxalate levels, the frequency and severity of cardiac complications are not well known and there are case reports of cardiomyopathy, valvular and conduction abnormalities with PH2.^14,15

Despite the predominant production of GRHPR enzyme in the liver, the earlier assumptions of extrahepatic enzyme production compensating the progression to chronic renal failure are not entirely accurate.²

In fact, many patients have severe form of PH2 manifestations with high mortality, the role of liver transplantation is not clear, despite being evident that renal transplantation alone is not curative.²

There are isolated case reports of renal allograft dysfunction with hyperoxaluria setting early in the graft kidney, in patients subjected to purely renal transplantation, leading to graft loss.^5,12,13 and some of them have been subjected successfully to liver transplantation with a second renal transplantation.

Simultaneous liver and kidney transplantation has not only benefitted these subsets of patients,^8,13,16 but has also shown to prevent early reoccurrence of the disease.^2,8,11,12

General measures of treatment for PH1, which has been used with some benefit, like increased hydration, alkalinization of the urine with potassium citrate and other inhibitors of calcium oxalate crystallization, and pyridoxine supplementation has not shown any beneficial effects in PH2.

Recently the RNAi (RNA interference) therapeutic agents which target glycolate oxydase resulting in depletion of substrate for oxalate synthesis, has been tried with limited success in PH1, but none so far in PH2.

Hence offering SLK as a treatment option looks promising in treating these patients who already have progressed to CKD, rather than offering them renal transplant alone.^8,12

Our patient had surgical TOF repair in infancy, even though long-term clinical and late functional status is generally good following surgical repair. Nevertheless, some of them might progress to severe pulmonary valvular regurgitation, stenosis and right heart failure. Her pulmonary stenosis was only mild with no PAH with no right heart failure, in fact she was asymptomatic following repair of her congenital heart disease, which suggests stable and good long-term outcomes.

The renal failure was due to nephrocalcinosis and with a high serum oxalate value. She did not have any systemic manifestations of hyperoxaluria (retinal fundus examination was normal, no radiological signs and pathological fractures). With a genetic testing validating the diagnosis of PH2, further urinary oxalate and glycerate estimations were not done, as she was anuric.

The deterioration in her LV function was thought to be predominantly related to uremic cardiomyopathy or probably stress cardiomyopathy, but definitely not due to hyperoxaluria, which was not a contraindication for proceeding with transplantation, considering the fact that she had normal liver functions and no liver disease related pathophysiological changes. She was started on digoxin, nitrates and aggressive CRRT pretransplant, which improved her LV function, though only marginally. Post SLK, her cardiac functions improved dramatically, to the extent that the LVEF increased to 58% with no regional wall motion abnormality, which authenticated our theory of uremic/stress cardiomyopathy as the reason for her sudden deterioration preoperatively.

Primary type 2 hyperoxaluria, a rare genetic disorder with severe disease manifestations, progressing to chronic renal failure, offering renal transplantation alone has not shown any benefit. A combined simultaneous Liver and Kidney transplantation looks promising as a primary treatment option, which needs to be validated with further studies.

Credit authorship contribution statement

Dr. Navaneethan Subramanian: Conceptualization, Writing - Original Draft, Visualization.

Dr Abhishek Yadav: Conceptualization, Supervision.

Dr Jithin S Kumar: Supervision.

Dr. George P Abraham: Supervision.

Conflicts of interest

No conflict of interest.

Funding

No funding.