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
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.
Keywords: hyperoxaluria, primary; kidney failure, chronic; kidney transplantation; lithiasis; nephrocalcinosis.
A hiperoxalúria primária (HP) é um distúrbio genético muito raro, caracterizado
por deficiência total ou parcial das enzimas relacionadas ao metabolismo do
glioxilato, superprodução de oxalato de cálcio que se deposita em vários órgãos
(principalmente os rins) resultando em litíase recorrente, nefrocalcinose e
doença renal terminal (DRT). Nos pacientes com DRT que recebem transplante
renal, a doença apresenta recidiva em 100% dos casos, com perda do enxerto nos
primeiros cinco anos após o transplante num elevado percentual de pacientes.
Três distúrbios moleculares foram descritos na HP: mutação dos genes da
alanina-glioxilato aminotransferase (AGXT), glioxilato redutase/hidroxipiruvato
redutase (GRHPR) e 4-OH-2-oxoglutarato aldolase (HOGA1). Apresentamos dois casos
de pacientes com histórico de litíase renal diagnosticados com hiperoxalúria
primária no período pós-transplante, manifestada na forma de perda precoce do
enxerto com evidências de cristais de oxalato de cálcio na biópsia renal,
hiperoxalúria, hiperoxalemia e testes genéticos compatíveis. Os pacientes foram
tratados com abordagem nutricional, líquidos orais em abundância, piridoxina,
hidroclorotiazida e citrato de potássio. Contudo, os pacientes apresentaram
deterioração lenta e gradual da função do enxerto e evoluíram para doença renal
Palavras-chave: falência renal crônica; hiperoxalúria primária; litíase; nefrocalcinose; transplante de rim.
|Citation: Rios Nieto JF, Zuluaga M, Higuita LMS, Florez A, Bello-Marquez DC, Aristizábal A, et al. Primary hiperoxaluria diagnosed after kidney transplantation: report of 2 cases and literature review. Braz. J. Nephrol. (J. Bras. Nefrol.) 39(4):462. doi:10.5935/0101-2800.20170081|
|Financial support: Funding source Pablo Tobón Uribe Hospital, Medellín-Colombia.|
|Received: March 14 2017; Accepted: May 18 2017|
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 for 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).1,2 Next 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.
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.
|Patient||Oxalate in blood||Oxalate in 24-hour urine||Genetic Study|
|(RV: lower than 30 um/L)||(RV: 3.6-38 mg)|
|Number 1||38 um/L||102.6 mg||Heterozygote for 2 variants of the gene|
|-c.731T > C (p.lle244Thr): Variant with clear pathological meaning3|
|-c.307G > A (p.Gly103Arg): Variant of unclear meaning, probably pathological,|
|which had not been described.|
|Number 2||42 um/L||150 mg||Gen GRHPR positive|
|Heterozygote for 2 variants of the gene|
|-c.478G > A (p.Gly160Arg)4|
|-c.626C > T (p.Ser209Phe)5|
RV: reference value, umL: micromoles per liter, AGXT: alanine glyoxalate aminotransferase, GRHPR: glyoxalate reductase/hydroxy pyruvate reductase.
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.
A 53-year-old patient with a history of recurrent untreated nephrolithiasis who progressed to ESRD, which required to initiate dialysis in May 2008. A cadaveric donor kidney transplant was performed on July 9, 2010; the patient received induction with alentuzumab plus methylprednisolone, maintenance with cyclosporine, mycophenolate and prednisone. In November 2010, the patient presented renal function impairment, and a graft biopsy showed Banff 2A acute cell rejection and extensive tubular damage, with presence of calcium oxalate crystals and microcalcifications (Figure 2).
The rejection was handled with pulses of methylprednisolone, thymoglobulin and conversion to tacrolimus; it was carried out a study of oxalosis with measurements of oxalate in urine and blood, which were elevated; and a genetic study, which was positive for the GRHPR gene. For this reason, it was diagnosed primary hyperoxaluria type 2 (Table 1).
|Paciente||Oxalato no sangue||Oxalato na urina de 24 horas||Estudo genético|
|(VR: abaixo de 30 um/L)||(RV: 3.6-38 mg)|
|Número 1||38 um/L||102.6 mg||Heterozigoto para 2 variantes do gene|
|-c.731T > C (p.lle244Thr): Variante com claro significado patológico3|
|-c.307G > A (p.Gly103Arg): Variante de significado não claro, provavelmente patológico,|
|que não havia sido descrito.|
|Número 2||42 um/L||150 mg||Gene GRHPR positivo|
|Heterozigoto para 2 variantes do gene|
|-c.478G > A (p.Gly160Arg)4|
|-c.626C > T (p.Ser209Phe)5|
VR: valor de referência, umL: micromoles por litro, AGXT: glioxalato de alanina aminotransferase, GRHPR: glioxalato redutase /hidroxi-piruvato redutase.
In a study of extension for lower-limb chronic pain, it was diagnosed sensitive peripheral polyneuropathy, which is associated with this pathology. It was started management with diet low in oxalate, pyridoxine, potassium citrate and hydrochlorothiazide. The patient remained with creatinine of 1.9 mg/dl; at follow-up, the renal function became progressively deteriorated until a terminal stage, with reentry to dialysis in May 2015.
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 Three molecular disorders are described: mutation of the enzyme gene alanin glioxalate aminotransferase (AGXT) in 80% of cases; glyoxalate reductase/hydroxy pyruvate reductase (GRHPR) and 4-OH-2-oxoglutarate aldolase (HOGA1), each one in 10% of cases.1,2,6
The 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.2 In the case of our patients, the initial commitment was exclusively renal, with progression to ESRD, which needed dialysis and later transplantation.
External factors that promote or inhibit the crystallization of oxalate influence on the phenotype, from hyperoxaluria without other changes in the urine, recurrent nephrolithiasis in adulthood, nephrocalcinosis, hematuria, urinary tract infection or progressive involvement, until it leads to ESRD; this explains that usually many of the patients with this disease remain undiagnosed, given the mild clinical presentation, with reports of its suspicion only when it is reached an ESRD;7 or after transplantation, when there is early graft dysfunction and evidence of birefringent oxalate crystals in the renal biopsy, as it was the case of our patients.8-14 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.13
Kim 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.16
Lorenz 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.2,6,8 In 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/m2/day; and avoiding crystallization by maintaining urinary pH between 6.2 and 6.8, with the use of potassium citrate at a dose of 0.1-0.15 g/kg a day; and using thiazide diuretics that decrease calciuria and increase urine volume.6
The 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.1,6,11 Intermittent 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.2,6,16
In 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.
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.