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.     

Prolonged survival after renal transplantation in primary hyperoxaluria of childhood.

Cadaver renal transplantation was performed in a 14-year-old girl with primary hyperoxaluria. Acute tubular necrosis was present initially, and a moderate rejection crisis occurred at 6 weeks. Renal biopsy performed at 4 months showed considerable deposition of calcium oxalate. Urinary excretion of oxalate varied between 315-371 mg/24 hr per 1.73 m2 (normal less than 50 mg). Despite these unfavourable factors, renal function has remained stable for the last 2 1/2 years; the serum creatinine is 1.5 mg/100 ml at 3 years. This is the longest surviving graft reported so far in documented primary hyperoxaluria. Graft failures in previous reports could in part be explained by additional complicating factors. It is concluded that renal transplantation is not necessarily contraindicated in primary hyperoxaluria.     

Prevention of cardiac complications in peripheral vascular surgery

The prevalence of severe coronary artery disease in peripheral vascular patients exceeds 50 per cent. It is therefore not surprising that complications of coronary artery disease are the most common causes of mortality following peripheral vascular operations. If the incidence of cardiac complications is to be reduced, it is first necessary to identify patients at risk through screening tests that will reliably detect hemodynamically important coronary occlusive disease. The operative risk can then be reduced by modifying the magnitude of the procedure, taking measures that can enhance the tolerance for a specific operation, or employing a combination of both. Screening methods in current use include risk factor analysis, exercise testing, routine coronary angiography, and dipyridamole thallium-201 scintigraphy. The risk factor approach has the advantage of being widely applicable since it makes use of historical, physical, and electrocardiographic findings that are already familiar to surgeons and anesthesiologists. It is also inexpensive. However, it may overlook the patient who has no symptoms of coronary artery disease, possibly as a result of the sedentary lifestyle imposed by complications of peripheral vascular disease. The electrocardiographically monitored stress test will identify the asymptomatic patient with occult coronary disease and is helpful in predicting operative risk. However, a meaningful test is dependent on the patient's ability to exercise--an activity that is frequently limited by claudication, amputation, or arthritis. Exercise testing also suffers from a lack of sensitivity and specificity when compared with coronary arteriography. Routine preoperative coronary angiography overcomes the exercise limitation of treadmill testing but is not widely applicable as a screening test for reasons of cost and inherent risk. Dipyridamole thallium-201 scanning, on the other hand, is safe and of relatively low cost and does not require exercise. Further, it has a high degree of sensitivity and specificity when compared with coronary arteriography. It appears to be an accurate predictor of postoperative cardiac complications.     

Late vascular complications of the subclavian dialysis catheter

The use of the subclavian dialysis catheter is generally regarded as free of long-term sequelae. However, we observed the occurrence of central vein stenosis in three hemodialysis patients following the use of the subclavian dialysis catheter to provide temporary access. In each case, the stenosis became clinically apparent months after the establishment of an ipsilateral arteriovenous fistula that became compromised by the stenosis. The stenoses may be amenable to dilatation by balloon angioplasty. Although the factors predisposing to this complication and its incidence are unknown, the potential for compromising access sites in the ipsilateral arm warrants awareness that use of subclavian dialysis catheters may be associated with significant long-term sequelae.     

Metabolism of pyridoxine in mild metabolic hyperoxaluria and primary hyperoxaluria (type 1).

Plasma pyridoxine metabolites in plasma and 4-pyridoxic acid excretions in urine were measured in normal subjects, in 7 patients with type-1 hyperoxaluria and in 8 patients with mild metabolic hyperoxaluria, while receiving various doses of pyridoxine. Compliance with ingestion of pyridoxine was verified by measuring urinary 4-pyridoxic acid. In the normal subjects the maximum level of pyridoxal phosphate was obtained after only 10 mg/day of pyridoxine. The patients were divided into nonresponders, good responders and poor responders to pyridoxine according to the fall in urinary oxalate and glycollate excretions. In patients taking pyridoxine, the plasma pyridoxal phosphate levels were as for normal subjects in primary hyperoxaluria, lower than for normal subjects in mild metabolic hyperoxaluria (p less than 0.01), and in the latter group lower in partial responders than in good responders (p = 0.04). Hence in mild metabolic hyperoxaluria there may be difficulty in converting pyridoxine to pyridoxal phosphate.     

Frequency and causes of vascular complications requiring surgery in patients without primary vascular disease

Arterial and venous vascular injuries are known but rare complications of severe multiple traumatised patients but are meanwhile more frequently induced iatrogenically. However there are only few reports about incidence, causes, surgical techniques and prognosis of these vascular emergencies. We have therefore analysed the causes, type of therapy, localisation of injury, primary dis-ease, morbidity and mortality of all vascular emergencies in patients without preexisting vascular disease. 2.9?% of all vascular repairs in our unit had to be performed for cases of iatrogenic (87?%) and non-iatrogenic (13?%) vascular complications. The overall mortality and major complication rate of these intrahospital iatrogenically aquired lesions were 4.8?% and 5?%, respectively, which are clearly below those of extrahospital vascular injuries. Thereby the observed increase of iatrogenic vascular injuries seems to be due to the increase in complex and even catheter-based techniques in modern therapy. The iliacofemoral region was affected in 45?% of the cases, in 50?% complex reconstructions and specific surgical skills were needed for the repair. This article on the incidence of and reasons for vascular iatrogenic lesions shows the importance of a planned management for the prognosis of these injuries.     

Surgically treated primary cardiac tumors in early infancy and childhood

OBJECTIVE: Primary heart tumors in childhood are rare and mostly benign. Surgical treatment is advocated when symptoms or hemodynamic impairment is present. MATERIALS AND METHODS: Between 1986 and 2003, 8 children (3 males and 5 females, age ranging 5 days to 6.7 years, median 78 days) with a clinical diagnosis of cardiac mass were treated with surgery. Diagnosis was made by prenatal echocardiography in 3 patients and by 2-dimensional Doppler echocardiography in 5 patients. RESULTS: Complete surgical excision of the cardiac mass was feasible in all but 1 patient who underwent orthotopic heart transplantation. Surgical pathology examination revealed myxoma in 2 patients, fibroma in 2 patients, rhabdomyoma in 2 patients (multiple in 1), hamartoma in 1 patient, and teratoma in 1 patient. One patient died of cerebral malignancy 38 months after cardiac transplantation. At a mean follow-up of 69.2 months (range 3-190 months), all the remaining patients are asymptomatic, with good ventricular function on 2-dimensional echocardiography and no signs of residual or recurrent tumor. CONCLUSION: Surgical excision of obstructive cardiac tumors in childhood is safely feasible. Heart transplantation may represent the only therapeutic option when the tumor extensively invades the ventricular walls. Although 2-dimensional echocardiography remains a reliable diagnostic tool, a definite diagnosis of tumor histotype requires a thorough histopathologic characterization.     

Changing pattern of primary hyperoxaluria in Switzerland

BACKGROUND: The clinical course of primary hyperoxaluria (PH) is greatlyvariable and diagnosis is often delayed. Little is known aboutthe overall occurrence and current prognosis. METHODS: We evaluated all known patients with PH residing and observedin Switzerland during the last 15 years with the help of a surveyamong Swiss nephrologists. RESULTS: Of the 25 patients observed between 7/79 and 6/94 in Switzerland,18 were alive in 1994—14 on conservative therapy and fouron renal replacement therapy (RRT). Twenty-two patients hadPH type 1; the exact type was not determined in three. The estimatedprevalence of PH (type 1) is 2 per million population; the minimalincidence is 1 per 100000 live births. Diagnosis was delayedby 8 years (median) except in infants. Five patients were pyridoxinesensitive. According to life table analysis, 20% of patientswere in end-stage renal failure (ESRF) and 10% had died by theage of 15 years, and 50% were in ESRF and 20% dead at 25 years.Prognosis has improved: Five of 13 patients died during thefirst half of the observation period as opposed to two of 20in the second part. CONCLUSIONS: Overall prognosis appears better than hitherto believed consideringthe large clinical spectrum of PH. Greater awareness of PH isneeded to improve further long-term prognosis.     

Molecular and clinical heterogeneity in primary hyperoxaluria type 1

The autosomal recessive disease primary hyperoxaluria type 1 (PH1) is caused by a functional deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). An analysis of liver samples from 59 PH1 patients showed considerable heterogeneity at the enzymic level. Approximately two thirds of patients had zero AGT catalytic activity, whereas the remaining one third had activities that ranged from 3% to 48% of the mean normal level. Two thirds of patients with zero AGT activity also had zero immunoreactive AGT protein, while the other one third, together with all the patients with detectable AGT catalytic activity, had levels of immunoreactive AGT protein that varied from normal to only a few percent of normal. All patients with AGT catalytic activity had their enzyme in the wrong intracellular compartment (ie, mitochondria). On the other hand, in all but one of the patients with immunoreactive AGT protein, but zero catalytic activity, the inactive AGT was correctly located within the peroxisomes. This enzymic heterogeneity was matched by considerable heterogeneity at the clinical level (eg, age at onset, rate of progression, age at renal failure, etc). No simple relationship was found between the level of hepatic AGT and the severity of the disease. It is suggested that a lack of AGT might be responsible for a broader pathological phenotype than classically associated with PH1. The possibility is advanced that some patients with idiopathic oxalate stone disease might owe their predisposition to stone formation to a functional deficiency of AGT.     

Early onset of stone diseases and primary hyperoxaluria

A case of primary hyperoxaluria is presented. In a product of consanguinous marriage recurrent stone formation, nephrocalcinosis and increased urinary oxalate excretion revealed the diagnosis of hyperoxaluria. Diagnosis and treatment of primary hyperoxaluria are briefly reviewed and the importance of elevated urinary oxalate level in diagnosis is emphasized.     

Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria

BACKGROUND: Primary hyperoxaluria is a rare genetic disorder of glyoxylate metabolism that results in overproduction of oxalate. The disease is characterized by severe calcium oxalate nephrolithiasis and nephrocalcinosis, resulting in end-stage renal disease (ESRD) early in life. Most patients eventually require dialysis and kidney transplantation, usually in combination with the replacement of the liver. Reduction of urinary oxalate levels can efficiently decrease calcium oxalate depositions; yet, no treatment is available that targets oxalate biosynthesis. In previous in vitro studies, we demonstrated that pyridoxamine can trap reactive carbonyl compounds, including intermediates of oxalate biosynthesis. METHODS: The effect of PM on urinary oxalate excretion and kidney crystal formation was determined using the ethylene glycol rat model of hyperoxaluria. Animals were given 0.75% to 0.8% ethylene glycol in drinking water to establish and maintain hyperoxaluria. After 2 weeks, pyridoxamine treatment (180 mg/day/kg body weight) started and continued for an additional 2 weeks. Urinary creatinine, glycolate, oxalate, and calcium were measured along with the microscopic analysis of kidney tissues for the presence of calcium oxalate crystals. RESULTS: Pyridoxamine treatment resulted in significantly lower (by approximately 50%) levels of urinary glycolate and oxalate excretion compared to untreated hyperoxaluric animals. This was accompanied by a significant reduction in calcium oxalate crystal formation in papillary and medullary areas of the kidney. CONCLUSION: These results, coupled with favorable toxicity profiles of pyridoxamine in humans, show promise for therapeutic use of pyridoxamine in primary hyperoxaluria and other kidney stone diseases.     

Potential mechanisms of marked hyperoxaluria not due to primary hyperoxaluria I or II

BACKGROUND: Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria. METHODS: Six children were identified with marked hyperoxaluria, urolithiasis, and normal hepatic AGT (N = 5) and GR/HPR (N = 4). HPR was below normal and GR not measured in one. Of an affected sibling pair, only one underwent biopsy. GO mutation screening was performed, and dietary oxalate (Diet(ox)), enteric oxalate absorption (EOA) measured using [13C2] oxalate, renal clearance (GFR), fractional oxalate excretion (FE(ox)) in the children, and urine oxalate in first-degree relatives (FDR) to understand the etiology of the hyperoxaluria. RESULTS: Mean presenting age was 19.2 months and urine oxalate 1.3 +/- 0.5 mmol/1.73 m2/24 h (mean +/- SD). Two GO sequence changes (T754C, IVS3 - 49 C>G) were detected which were not linked to the hyperoxaluria. Diet(ox) was 42 +/- 31 mg/day. EOA was 9.4 +/- 3.6%, compared with 7.6 +/- 1.2% in age-matched controls (P = 0.33). GFR was 90 +/- 19 mL/min/1.73 m2 and FE(ox) 4.2 +/- 1.4. Aside from the two brothers, hyperoxaluria was not found in FDR. CONCLUSIONS: These patients illustrate a novel form of hyperoxaluria and urolithiasis, without excess Diet(ox), enteric hyper-absorption, or hepatic AGT, GR/HPR deficiency. Alterations in pathways of oxalate synthesis, in liver or kidney, or in renal tubular oxalate handling are possible explanations. The affected sibling pair suggests an inherited basis.     

Genetic basis of primary hyperoxaluria type II

Primary hyperoxaluria Type II (PH2) is a rare monogenic disease characterized by excessive urinary oxalate and L-glycerate excretion. The severity of clinical complications in PH2 patients can range from none to end-stage renal failure secondary to massive deposits of calcium oxalate crystals in the kidney. The disease is a result of the absence of an enzyme with glyoxylate reductase and hydroxypyruvate reductase activities (GRHPR). Recent breakthroughs have occurred in our understanding of the molecular basis of PH2. In this article, we briefly review the literature concerning the clinical and biochemical characteristics of the disease and the enzyme associated with it. We describe the identification of the cDNA for the GRHPR enzyme using the expressed sequence tag database, the characterization of the human GRHPR gene, and the identification of mutations in patients with PH2. Insights gained from the molecular biology underlying this disease as they relate to relevant clinical issues such as potential therapeutic strategies are discussed.