Primary hiperoxaluria diagnosed after kidney transplantation : report of 2 cases and literature review

1 University of Antioquia, Pablo Tobón Uribe Hospital, Department of Nephrology and Renal Transplant, Medellín, Colombia. 2 Universidad Pontificia Bolivariana, Department of Internal Medicine, Medellín, Colombia. 3 Universidade de Eberhard Karls, Instituto de Epidemiologia Clínica e Biometria Aplicada, Tuebingen, Alemanha. 4 Fundación Santafé de Bogotá, Department of Pathology, Medellín, Colombia. 5 Urogine, Department of Nephrology, Medellín, Colombia.

Primary hyperoxaluria (PH) is a very rare genetic disorder; it is characterized by total or partial deficiency of the enzymes related to the metabolism of glyoxylate, with an overproduction of calcium oxalate that is deposited in different organs, mainly the kidney, leading to recurrent lithiasis, nephrocalcinosis and end stage renal disease (ESRD).In patients with ESRD that receive kidney transplantation alone, the disease has a relapse of 100%, with graft loss in a high percentage of patients in the first 5 years of transplantation.Three molecular disorders have been described in PH: mutation of the gene alanin glioxalate aminotransferase (AGXT); glyoxalate reductase/hydroxy pyruvate reductase (GRHPR) and 4-OH-2-oxoglutarate aldolase (HOGA1).We present two cases of patients with a history of renal lithiasis who were diagnosed with primary hyperoxaluria in the post-transplant period, manifested by early graft failure, with evidence of calcium oxalate crystals in renal biopsy, hyperoxaluria, hyperoxalemia, and genetic test compatible; they were managed with proper diet, abundant oral liquids, pyridoxine, hydrochlorothiazide and potassium citrate; however, they had slow but progressive deterioration of their grafts function until they reached end-stage chronic renal disease.

IntRoductIon
Recurrent nephrolithiasis is associated with metabolism disorders of calcium, oxalate, uric acid or cysteine; or with recurrent urinary tract infections that favor struvite stones.Calcium calculi account DOI: 10.5935/0101-2800.20170081for 80% of lithiasis cases, half of which are associated with hyperoxaluria, which is most often secondary to digestive or eating disorders, and which rarely leads to end-stage chronic renal disease (ESRD); however, hyperoxaluria may also be associated with genetic alterations in the metabolism of glyoxylate, which are termed primary hyperoxaluria (PH). 1,2Next we describe two cases of patients with recurrent nephrolithiasis that led to ESRD with subsequent relapse of lithiasis in their transplanted kidneys, and in whom PH was finally diagnosed.

Case 1
A 33-year-old female patient, who first presented ESRD associated with coral calculi (Staghorn calculi) in 2002, requiring bilateral nephrectomy and to start hemodialysis.She was transplanted on February 5, 2004 in another institution, with subsequent graft loss due to unclear cause at 5 years, and to reenter to hemodialysis.Second transplant of cadaveric donor kidney on February 5, 2010 in our institution; she received induction with alentuzumab plus metilprednisolona and maintenance with cyclosporine, mycophenolate and prednisone.
One year after transplantation, she presented a creatinine elevation, with renal biopsy that documented acute rejection of cellular Banff 1A and extensive deposits of oxalate in the interstitial tubule (Figure 1).For this reason, the rejection was treated with steroid boluses and conversion to tacrolimus; and there were performed complementary studies of renal oxalosis (Table 1), which led to the diagnosis of primary type 1 hyperoxaluria.Extension studies found oxalate deposits in the bone marrow.Management was started with a diet low in oxalate, pyridoxine, potassium citrate and hydrochlorothiazide.She remained with graft nephropathy with slow but progressive deterioration; at her last follow-up at 6 years, her creatinine was 4.8 mg/ dl; she is in pre-dialysis stage and being evaluated for combined liver-kidney transplant.

Case 2 dIscussIon
We present two cases of patients with a history of recurrent nephrolithiasis with progression to ESRD, with subsequent graft failure associated with extensive tubulo-interstitial infiltration by calcium oxalate crystals, which led us to investigate the cause, finally diagnosing PH.
PH is an autosomal recessive genetic disorder, characterized by total or partial deficiency of the enzymes related to the metabolism of glyoxylate, with an excessive production of calcium oxalate that is deposited in different organs, mainly the kidney, leading to recurrent lithiasis, nephrocalcinosis and ESRD. 1,2 (AGXT) in 80% of cases; glyoxalate reductase/hydroxy pyruvate reductase (GRHPR) and 4-OH-2oxoglutarate aldolase (HOGA1), each one in 10% of cases. 1,2,6he most affected in PH is the urinary system, manifesting as recurrent nephrolithiasis and progressive deterioration of renal function.However, as the glomerular filtration rate falls below 40 ml/min, the compensation for serum oxalate levels is lost, reaching concentrations that exceed the threshold value of 30 micromoles/L, which triggers the accumulation of calcium oxalate in tissues such as the myocardium, retina, blood vessels, joints, skin, nerve tissue and bone.
This can lead to arrhythmias, loss of visual acuity, ischemic phenomena, synovitis, livedo reticularis, calciphylaxis, neuropathy and bone deformities. 2In the case of our patients, the initial commitment was exclusively renal, with progression to ESRD, which needed dialysis and later transplantation.
][10][11][12][13][14] In fact, frequently (30-60%, depending on the series), the diagnosis of PH is made after the relapse of oxalate deposits in renal transplantation, as it was described by Lorenzo et al. 15 in a recent review on this topic.
The major question is why the patients who had a mild clinical course during the years prior to dialysis developed a more severe manifestation with graft failure after transplantation.It's been suggested that the burden of serum and tissue oxalate migrates early in the graft; however, there are still doubts about the factors that influence on this, since the diagnosis of PH has only been described after a second renal transplant, as it was the case of our first patient. 13im et al. 14 described the case of a woman with ESRD secondary to chronic interstitial nephritis, in whom the initial biopsy showed no crystals of calcium oxalate, nor did she have symptoms of renal lithiasis or systemic oxalosis, but she had deterioration of her renal function in the first 5 days post-transplant, evidencing deposits of calcium oxalate crystals in the tubules, and whose diagnosis of PH was later confirmed as due to a decrease in the enzymatic activity in the liver biopsy.
In addition, there is a post-transplant diagnosis of this condition without progression to graft failure, which is explained by a partial enzymatic defect with response to pyridoxine (cofactor of the enzyme AGXT); it has also been described the disappearance of renal oxalate deposits and their systemic values 18 months after therapy. 16orenz et al. 17 reported 5 cases of patients with homozygous post-transplant hyperoxalosis for the G170R mutation of the AGXT gene, who had a sustained response to pyridoxine following isolated renal transplantation; only one presented graft failure, but after 13.9 years of follow-up.In the cases reported here, the patients had a progressive deterioration of their renal function, despite treatment with pyridoxine, which we associated with a late diagnosis.
The diagnosis is finally confirmed with oxaluria greater than 45 mg/day, 24 hour urine glycolate greater than 45 mg/day and oxalemia greater than 50 micromoles/L.Additional images can be obtained and a histological study be performed to evaluate the commitment of other organs, plus a genetic analysis of the AGXT, GRHPR, HOGA1 through sampling of peripheral blood DNA, in order to determine the specific mutation.
If the results are negative, it can be measured the activity of the enzyme in the hepatic tissue. 2,6,8In the first case described, two mutations of the AGXT gene were found, one of them was a classical mutation with clear pathological significance (compatible with PH type 1); the other one was of uncertain meaning, probably pathological, never reported before.In the second case, two GRHPR gene mutations were found with uncertain meaning, but according to the literature, they were probably pathological, and taking into account the clinical context of the patient, there's no doubt that they were really pathological (compatible with PH type 2).
Treatment should be initiated immediately to decrease the deposit of urinary calcium oxalate, by increasing the fluid intake to more than 3L/m 2 /day; and avoiding crystallization by maintaining urinary pH between 6.2 and 6.8, with the use of potassium citrate at a dose of 0.1-0.15g/kg a day; and using thiazide diuretics that decrease calciuria and increase urine volume. 6he only therapeutic strategy that impacts oxalate production, but only in PH type 1, is pyridoxine, starting with a dose of 5 mg/k/day, which is titrated to a maximum of 20 mg/k day.It is considered as adequate a decrease of oxaluria higher than 30% in three months of treatment with the maximum doses. 1,6,11Intermittent dialysis therapy is insufficient to purify all the oxalate produced.Similarly, isolated renal transplantation is a transient measure, because there is recurrence of the disease in the graft, and the only curative therapy is the combined liver and kidney transplantation, with reported survival rates of 80% at 5 years. 2,6,16n accordance with the above, we consider that in all patients with a history of recurrent urolithiasis and nephrocalcinosis, a complete metabolic study in blood and urine should be performed, in order to determine the cause; in case of hyperoxaluria, a PH study must be included in the initial screening prior to renal transplantation, to establish early therapeutic measures that prevent the loss of renal graft.

conclusIon
PH is a genetic disorder of glyoxylate metabolism, which can lead to recurrent nephrolithiasis, with progression to ESRD and to early relapse of the graft, with damage to the graft itself.An early and timely diagnosis in the early stages of the disease may lead to the introduction of measures that may delay the progression of renal disease and avoid multisystemic compromise.

Figure 2 .
Figure 2. Case 2 -Histopathologic study of kidney biopsy, deposits of oxalate crystals and microcalcifications can be seen (4X polarized light).