MO112SYSTEMIC OXALOSIS IN PRIMARY HYPEROXALURIA TYPE 3 – ARE THE PATIENTS AT RISK?

Background and Aims Primary Hyperoxaluria type 3 (PH3) is said to be the less problematic form of PH and with low risk of chronic kidney disease (CKD) and end stage renal disease. However, a recent OxalEurope registry evaluation reported both urine and plasma oxalate levels in a comparable range as in PH1 and PH2 patients. In addition, PH3 patients remain symptomatic with recurrent kidney stones, even in adulthood, and 24% of the 95 patients evaluated were on CKD ≥ 2 at last follow up. Hence, it was speculated, that PH3 patients may also be on risk to develop systemic oxalate deposition. Method We retrospectively analyzed the imaging procedures performed so far in patients regularly seen at the German Hyperoxaluria Center, which included: eye exams; x-rays of the hand; bone MRI (3 Thesla of the left knee and proximal tibia); and Speckle tracking echocardiography using 2D Cardiac Performance Analysis VC (TomTec Imaging Systems GmbH, Germany), which measures changes in global longitudinal strain (GLS), an index of left ventricular contractibility. The normal range for GLS is ≤18%. All patients or parents signed an informed consent. Results From the 49 PH3 patients registered at the German Hyperoxaluria center, 12 pediatric and 4 adult patients are seen on a regular basis, at least twice a year, and the rest are followed in other centers. All the 16 patients were in stable kidney function and in no less than CKD 2. Eye examination was performed in six patients and was normal in all. Four patients received an x-ray of the left hand, which was normal in 3, but in one patient with a problematic clinical course (multiple stone removal procedures, decline in GFR), tiny sclerosing areas, although no true metaphyseal bands, were seen at caput MCP IV and the thumb. Therefore, MRI of the left knee and proximal tibia was performed in this and another patient, which showed no signs of systemic oxalate deposition. Speckle tracking echocardiography was done in 6 patients and was abnormal in one (GLS – 17.3 and left ventricular hypertrophy) and borderline in the twin sibling (GLS – 18.6). The patient with the abnormal GLS also had salivary stones in the parotid gland, as were also found in his other, older sibling in a routine x-ray of the jaw before orthodontic treatment. Conclusion Although this is currently only data of a small cohort of patients, the parameters available so far show, that systemic oxalate deposition may also occur in PH3. Based on our experience on PH1, we regard Speckle tracking echocardiography as the best parameter to detect early systemic calcium-oxalate depositions. Hence the reduction in global longitudinal strain, thus ventricular contractability, is a clear proof of such deposits. Of course, data in more patients are needed to elucidate the true risk of systemic oxalate deposition and we are therefore currently screening all our PH3 patients.

P0173CHRONIC KIDNEY DISEASE IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 3 (PH 3) - A LITERATURE META-ANALYSIS

Background and Aims Primary Hyperoxaluria type 3 (PH3) is considered the most benign phenotype of all forms of primary hyperoxaluria. Being it typical that patients with PH type 1 and 2 develop chronic kidney disease (CKD) or end-stage renal disease (ESRD), it appears to be more or less uncommon that patients with PH3 are on risk of CKD and even do not develop ESRD. We now aimed to determine the number of PH3 patients reported to have any kind of CKD. Method We performed a literature meta-analysis, searching in PubMed with the following keywords: primary hyperoxaluria, PH, primary hyperoxaluria type III, PH III or PH3. Results We found 154 patients in 18 relevant papers published between 2010-2019. The number of patients reported per paper ranged from 1-2 up to 38 patients. Age of diagnosis/disease onset ranged from 1 month to 48 years of life. Most of the patients suffered recurrent urolithiasis, most often during the first years of life, but recurrent kidney stone episodes were also found later in life. In 77 patients no adequate information was provided with regard to renal function. In 14 patients it was only mentioned that they did not have renal failure at time of reporting. Five patients were said to be in stable kidney function without providing eGFR or serum creatinine levels. In 62 patients we were able to assess kidney function at time of paper and only in 41 patients (27%) eGFR values were available (18-232 ml/min/1.73m2). Only one patient in ESRD was reported, however the clear reason for ESRD is not provided in the reference. One patient with CKD stage 4-5 was found with an eGFR of 18 ml/min/ 1.73m2, after heminephrectomy was performed due to renal carcinoma. He was diagnosed at age 78 but has had recurrent kidney stones over a period of 30 years. Other three patients had stage 2-3 kidney disease (eGFR 53-61.8 ml/min/1.73m2). CKD stages 1-2 were found in 17 patients (eGFR from 77-104 ml/min/1.73m2). In six patients follow-up measures were available, as their data were included in two papers (4 years apart from each other). Here, in one patient eGFR significantly declined from 134 to 68.1 ml/min/1.73m2, while in the other 5 it remained stable over time. Conclusion Based on this non-comprehensive dataset, the majority of PH3 patients remain in stable kidney function over time. However, there is a massive bias in the data published, as data on kidney function is mostly not adequately reported. Nevertheless, CKD was observed in 13.7% of PH3 patients, and even one patient with ESRD was described. Also, one PH3 patient had died at age 4 months, but because of respiratory failure and not because of PH. Thus, as true long-term follow-up data is still missing, we nevertheless suspect PH3 not being as benign as currently being reported.

P0172ARE FREQUENT STONE REMOVAL PROCEDURES IN PATIENTS WITH PRIMARY HYPEROXALURIA TYPE 3 (PH 3) RELATED TO DECLINE IN KIDNEY FUNCTION?

Background and Aims PHIII is seen as the less problematic type of autosomal recessive inherited PH. This group of disorders in glyoxylate metabolism is clinically characterized by recurrent urolithiasis and/or progressive nephrocalcinosis, and, in type I and II, end-stage renal failure. The cause of PHIII was identified only in 2010 and unlike in PHI/II a remarkable low prevalence of symptomatic adults was observed, hence long-term clinical data are scarce. This phenomenon is commonly attributed to reduced penetrance of causative hydroxy-oxo-glutarate aldolase 1 gene (HOGA1) variants and a still unexplained tendency for clinical remission with age. Most PHIII patients present in early childhood with recurrent urolithiasis and undergo (repeated) stone removal procedures. We now hypothesized that repeated stone removal procedures may be associated with decline in kidney function. Method We retrospectively analyzed clinical and laboratory data of 41 genetically confirmed PHIII patients (0.5-29.3 years of age, with (20 different) biallelic mutations in the HOGA1 gene). Period of follow-up ranged from just diagnosed to 22 years. Results Recurrent urolithiasis was most prominently found in the first 3 years of life (>25% of patients). Not all patients experienced clinical remission, 3/6 patients > 20 years of age have ongoing kidney stone development. In addition, patients presented with nephrocalcinosis and/or urolithiasis. A high amount of stone removal procedures during the first years, but also later in life was observed. Urinary oxalate excretion is significantly elevated, and within the range of PHI/II. A decline in kidney function was observed, which is related to a decreased clearance of oxalate (figure). Two patients each post multiple stone removal procedures had CKD stages 2 or 3. Seven further patients had CKD stage 2, which was not related to stone removal. Conclusion PHIII is said to be the most favorable PH type, but early diagnosis is mandatory to treat the patients adequately and to avoid repeated stone removal procedures, which may have an influence on decline in kidney function. This decline may also be related to hyperoxaluria per se, as reported for PHI and II.

Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3

4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle.