Three Tesla magnetic resonance imaging detects oxalate osteopathy in patients with primary hyperoxaluria type I.

BACKGROUND: With declining kidney function and therefore increasing plasma oxalate, patients with primary hyperoxaluria type I (PHI) are at risk to systemically deposit calcium-oxalate crystals. This systemic oxalosis may occur even at early stages of chronic kidney failure (CKD) but is difficult to detect with non-invasive imaging procedures. METHODS: We tested if magnetic resonance imaging (MRI) is sensitive to detect oxalate deposition in bone. A 3 Tesla MRI of the left knee/tibial metaphysis was performed in 46 patients with PHI and in 12 healthy controls. In addition to the investigator's interpretation, signal intensities (SI) within a region of interest (ROI, transverse images below the level of the physis in the proximal tibial metaphysis) were measured pixelwise, and statistical parameters of their distribution were calculated. In addition, 52 parameters of texture analysis were evaluated. Plasma oxalate and CKD status were correlated to MRI findings. MRI was then implemented in routine practice. RESULTS: Independent interpretation by investigators was consistent in most cases and clearly differentiated patients from controls. Statistically significant differences were seen between patients and controls (p < 0.05). No correlation/relation between the MRI parameters and CKD stages or Pox levels was found. However, MR imaging of oxalate osteopathy revealed changes attributed to clinical status which differed clearly to that in secondary hyperparathyroidism. CONCLUSIONS: MRI is able to visually detect (early) oxalate osteopathy in PHI. It can be used for its monitoring and is distinguished from renal osteodystrophy. In the future, machine learning algorithms may aid in the objective assessment of oxalate deposition in bone. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review.

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

[Primary hyperoxaluria: case report and therapeutic perspectives].

Primary hyperoxaluria (PH) is a rare genetic disorder with autosomal recessive transmission, characterized by high endogenous production and markedly excessive urinary excretion of oxalate (Ox). It causes the accumulation of calcium oxide crystals in organs and tissues including bones, heart, arteries, skin and kidneys, where it may cause oxalo-calcic nephrolithiasis, nephrocalcinosis and chronic renal failure. Some forms are secondary to enteric diseases, drugs or dietetic substances, while three primitive forms, caused by various enzymatic defects, are currently known: PH1, PH2 and PH3. An early diagnosis, with the aid of biochemical and genetic investigations, helps prevent complications and establish a therapeutic strategy that often includes liver and liver-kidney transplantation, improving the prognosis of these patients. In this work we describe the clinical case of a patient with PH1 undergoing extracorporeal hemodialysis treatment and we report the latest research results that could change the life of patients with PH.

Late diagnosis of primary hyperoxaluria type III.

We report the case of a 78-year-old patient with late diagnosis of hyperoxaluria type III (PH3). He developed renal failure after nephrectomy for clear cell papillary renal carcinoma and complained of recurrent urolithiasis for some 30 years, whose aetiology was never identified. Biochemical laboratory investigations of urine and urolithiasis composition revealed marked hyperoxaluria but normal concentrations of urinary glyceric and glycolic acid as well as stones of idiopathic calcium-oxalate appearance. Furthermore, the dietary survey showed excessive consumption of food supplements containing massive amounts of oxalate precursors. However, the persistence of excessive hyperoxaluria after his eating habits was changed leading us to perform molecular genetic testing. We found heterozygous mutations of the recently PH3-associated HOGA1 gene when sequencing PH genes. This is the first description of late diagnosis primary PH3 in a patient with several additional pro-lithogenic factors. This case illustrates the importance of undertaking a complete biological work-up to determine the aetiology of hyperoxaluria. This may reveal underdiagnosed primary hyperoxaluria, even in older patients.

[Oxalate: a poorly soluble organic waste with consequences]. / L'oxalate: un déchet organique peu soluble, avec conséquences.

Oxalate is a highly insoluble metabolic waste excreted by the kidneys. Disturbances of oxalate metabolism are encountered in enteric hyperoxaluria (secondary to malabsorption, gastric bypass or in case of insufficient Oxalobacter colonization), in hereditary hyperoxaluria and in intoxication (ethylene glycol, vitamin C). Hyperoxaluria causes a large spectrum of diseases, from isolated hyperoxaluria to kidney stones and nephrocalcinosis formation, eventually leading to kidney failure and systemic oxalosis with life-threatening deposits in vital organs. New causes of hyperoxaluria are arising recently, in particular after gastric bypass surgery, which requires regular and preemptive monitoring. The treatment of hyperoxaluria involves reduction in oxalate intake and increase in calcium intake. Optimal urine dilution and supplementation with inhibitors of kidney stone formation (citrate) are required. Some conditions may need vitamin B6 supplementation, and the addition of probiotics might be useful in the future. Primary care physicians should identify cases of recurrent calcium oxalate stones and severe hyperoxaluria. Further management of hyperoxaluria requires specialized care.

L'oxalate est un déchet métabolique peu soluble excrété par les reins, et les hyperoxaluries peuvent être distinguées en hyperoxaluries entériques, hyperoxaluries héréditaires et les intoxications (éthylène glycol, vitamine C). L'hyperoxalurie induit un large spectre de maladies allant de l'hyperoxalurie isolée, formation de calculs rénaux, voire d'une néphrocalcinose, à l'insuffisance rénale et l'oxalose systémique avec des dépôts s'accumulant dans de nombreux organes. De nouvelles causes d'hyperoxalurie sont apparues ces dernières années, en particulier les hyperoxaluries survenant à la suite d'un bypass gastrique. Le traitement des hyperoxaluries fait intervenir, d'une part, une diminution contrôlée des apports en oxalate et une augmentation des apports en calcium et, d'autre part, une dilution des urines et l'ajout d'inhibiteurs de la lithogenèse (citrate). Dans certaines conditions particulières, une supplémentation en vitamine B6 ou l'utilisation de probiotiques peuvent être envisagées. Le praticien doit rester attentif aux cas de calculs d'oxalate de calcium récidivants ou d'hyperoxalurie sévère et les adresser pour une prise en charge spécialisée et multidisciplinaire.

Late diagnosis of primary hyperoxaluria after failed kidney transplantation.

Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive inborn error of the glyoxylate metabolism that is based on absence, deficiency or mislocalization of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase. Hyperoxaluria leads to recurrent formation of calculi and/or nephrocalcinosis and often early end-stage renal disease (ESRD) accompanied by systemic calcium oxalate crystal deposition. In this report, we describe an adult female patient with only one stone passage before development of ESRD. With unknown diagnosis of PH, the patient received an isolated kidney graft and developed an early onset of graft failure. Although initially presumed as an acute rejection, the biopsy revealed calcium oxalate crystals, which then raised a suspicion of primary hyperoxaluria. The diagnosis was later confirmed by hyperoxaluria, elevated plasma oxalate levels and mutation of the AGXT gene, showing the patient to be compound heterozygous for the c.33_34InsC and c.508G > A mutations. Plasma oxalate levels did not decrease after high-dose pyridoxine treatment. Based on this case report, we would recommend in all patients even with a minor history of nephrolithiasis but progression to chronic renal failure to exclude primary hyperoxaluria before isolated kidney transplantation is considered.

The primary hyperoxalurias.

The primary hyperoxalurias (PHs) are rare autosomal-recessive inborn errors of metabolism. In the most severe form (type 1), recurrent kidney stones and progressive nephrocalcinosis lead to the loss of kidney function, accompanied by systemic oxalosis, and often requires dialysis and/or transplantation. The variety of genetic mutations leading to PH increasingly are being defined, resulting in the ability to diagnose most patients accurately via minimally invasive means. During and after definitive diagnosis, supportive therapies with pyridoxine supplementation, urinary crystallization inhibitors, and hydration should be used, but have varying success. Emerging information about the renal tubular and intestinal transport of oxalate is leading to increasing evidence to support the use of oxalate-degrading bacteria (probiotics) and enzymes in the treatment of PH. Organ transplantation historically has offered the only potential cure for PH, and may include kidney-alone, combined liver-kidney, or pre-emptive liver-alone transplantation. Exciting new approaches in the treatment of type 1 PH, however, are under investigation. These include the restoration of defective enzymatic activity through the use of chemical chaperones, hepatocyte cell transplantation, or enzyme replacement by recombinant gene therapy. These novel approaches illustrate the goal for the ideal treatment of PH: correcting the genetic defect without exposing patients to the life-long risks associated with organ transplantation.

Primary hyperoxaluria type-1: an unprecedented presentation at birth.

This report describes a male baby with primary hyperoxaluria type-1, presenting at 5 hours of age with cyanotic episodes, hypotonia, unexplained techypnea and tachycardia. This infant also had renal calcinosis, and middle cerebral arterial infarct with unilateral enlargement of ventricle and left porencephalic cyst on CT scan. The infant improved with diuretics, water supplementation, pyridoxine, and Albright solution.

Diagnosis and management of primary hyperoxaluria type 1 in infancy.

We report a case of a 6-month-old infant who presented with failure to thrive due to end-stage renal disease as a result of primary hyperoxaluria type 1. The infant was managed with a combined daily hemodialysis and peritoneal dialysis prescription in order to manage the total body oxalate burden. Medical management included oral pyridoxine, aggressive hydration and nutritional supplementation via an enteral feeding tube. At one year of age the infant underwent a combined liver/kidney transplantation with intra- and daily post-operative hemodialysis to prevent oxalate deposition in the newly transplanted organs. The post-operative course was complicated by gross hematuria and increased hyperoxaluria, requiring an increase in hydration and thiazide diuretics. This infant received a combination of dialysis modalities which was designed to lower the potential oxalate burden prior to transplantation. This case illustrates the difficulty in medical management of an infant pre- and post-combined liver/kidney transplantation.