Renal Complications in Propionic Acidemia: Not as Rare as Previously Suspected
Oleg A. Shchelochkov, MD, and Charles Venditti, MD, PhD
Propionic acidemia (PA) is a serious metabolic disease which can impact many organs. For example, it has been known for some time, that propionic acidemia can cause poor heart function (cardiomyopathy) and inflammation of pancreas (pancreatitis). But what about other organs? Because PA is relatively rare, its low frequency makes it difficult to spot an uncommon complication or measure how often a complication happens. We are conducting a natural history study of PA at NIH (https://clinicaltrials.gov/ct2/show/NCT02890342 ). With the help of PA community, we were able to gain new insights into how PA can affect kidneys, and recently published a paper summarizing our findings (https://www.ncbi.nlm.nih.gov/pubmed/31249402). Below we share some important questions raised during the study:
Question: What prompted the study of kidney function in propionic acidemia?
Answer: It has been known for many decades that methylmalonic acidemia, a disease in many ways similar to propionic acidemia, can lead to poor kidney function. A loss of kidney function in methylmalonic acidemia (MMA) can significantly impact the quality of life and may require special treatments. In recent years, there have been isolated reports of patients with propionic acidemia who also developed kidney disease later in life. Our European colleagues had noticed that some older PA patients in their studies also had lower kidney function. Although kidney problems in PA were not as severe as in an isolated MMA, the frequency of this complication and the age of onset was not known. It prompted us to examine renal findings in patients, who were seen at NIH as part of the PA natural history study.
Question: What type of kidney problems did we find in PA patients?
Answer: We discovered that when we used the most common way to estimate renal function using blood creatinine, 50% of adult PA patients had some degree of the chronic kidney disease. We also found that a blood chemical called “cystatin C”, can be helpful to spot a renal function decline sooner. Importantly, patients who had chronic kidney disease had a higher chance of having cardiomyopathy. We don’t know yet, how exactly cardiomyopathy and chronic kidney disease are connected to each other. We are conducting additional studies to look into this association.
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Question: What would doctors do if they discover chronic kidney disease in a PA patient?
Answer: Patients with chronic kidney disease will benefit from establishing care with a renal doctor (a nephrologist). Nephrologists will order and review blood and urine labs, which help them come up with a better care plan. Interval renal ultrasounds can be helpful to follow the size and appearance of kidneys. Some patients may need to have their diet adjusted to control for how much water, calcium, phosphorus, vitamin D and other food ingredients they take each day. Doses of some medications will need to be adjusted in more advanced kidney disease. For example, doses of some anti-epileptic drugs may need to be adjusted if the kidney disease becomes severe.
Question: Can chronic kidney disease of PA be prevented?
Answer: At this point, we don’t know how to stop the chronic kidney disease of PA. But we believe that early diagnosis of chronic kidney disease, good control of blood pressure, avoidance of drugs toxic to kidneys, and prevention of chronic metabolic acidosis, may help slow down the progression of kidney disease.
We wanted to thank all families who participated in the study and we are looking forward to meeting new families at NIH. We are grateful for patients’ generous gift of time and efforts to make our protocol a reality. Every patient contributes in an important way. As we carefully study each patient, we gain new knowledge that we can share with patients, families, healthcare providers, and researchers. Please feel free to contact the team with questions or comments. You can email Dr. Oleg at oleg.shchelochkov@nih.gov or contact our research nurse Susan Ferry, RN at susan.ferry@nih.gov.
From the December 2019 OAA Newsletter
Point-of-Care Ammonia Monitoring from a Single Drop of Blood
Thomas R. Veltman, Department of Chemistry, Stanford University, Natalia Gomez-Ospina, and Matthew W. Kanan, Department of Pediatrics – Medical Genetics, Stanford School of Medicine
Hyperammonemia (elevated blood ammonia) frequently occurs secondary to organic acidemia and is responsible for a large portion of brain damage and death in these patients.[1] The underlying cause is thought to be the accumulation of organic acyl-CoA derivatives,[2],[3] which inhibit the enzyme N-Acetylglutamate Synthetase and deplete acetyl CoA. Both of these effects cause a reduction of N-acetylglutamate levels, which results in dysregulation of the normal nitrogen metabolism that is responsible for converting ammonia to urea for subsequent excretion. Timely intervention to reduce ammonia levels is essential to improve neurodevelopmental outcomes,[4],[5],[6] but diagnosing hyperammonemic infants before an acute crisis is extremely challenging with the standard clinical ammonia test. The standard assay requires intravenous access for at least 1 mL of blood and must be performed in specialized clinical labs. Obtaining samples requires an extremely skilled phlebotomist since accurate values can only be obtained from draws performed without a tourniquet, and patient distress or a slow-flowing venipuncture can contribute to inaccuracies. Additionally, blood is unstable and releases ammonia over time, and therefore samples must be transported on ice and processed rapidly to avoid false elevations.
Patients diagnosed with acidemia require lifelong management to minimize hyperammonemic crises. Current clinical guidelines indicate that suspected patients should be sent to a metabolic treatment center as soon as possible, and transport teams should be equipped with ammonia scavengers and Carbaglu to continue management.[7] Thus, any suspected hyperammonemic crisis may result in transport to a metabolic center. Frequently, patient families may be hours away from such a center. Finally, uncertainty in a patient’s ammonia status is a source of significant stress for parents. The symptoms of hyperammonemia are non-specific, and caloric management can be difficult when children are physically active. Illness can also be a trigger for hyperammonemia, and parents frequently report concern over the uncertainty of the wellbeing of their children.
Our work has focused on addressing all of the above issues through the development of a point-of-care ammonia testing device. The availability of a user-friendly and accurate ammonia monitor is of longstanding interest to the organic acidemia community, but technical challenges have heretofore kept other proposed devices from achieving success. Our breakthrough came with the recognition that ammonia could be measured in small volumes of whole blood simply by alkalizing the blood sample and monitoring the concentration of ammonia released from the sample. We have built a series of prototypes to validate this detection scheme, culminating in a handheld device that produces accurate ammonia readings in less than a minute from a single drop of blood. The device is as easy to use as a blood glucose meter, and because we are detecting ammonia in the gas phase, typical interferents in the blood that can cause inaccurate readings with the conventional plasma ammonia test do not influence our results. Furthermore, the immediate readout eliminates complications from sample handling and permits the immediate evaluation of the patient’s status with respect to their ammonia treatment regimen. With the device in hand, we were further motivated to devise a measurement protocol that would provide the easiest access to patient samples with a minimum of effort and as little discomfort as possible, as routine venipuncture can be challenging and traumatic for acidemia patients. Fortunately, we discovered that sampling with a skin prick from the underside of the patient’s earlobe is completely painless and produces ammonia values that match those measured from a concurrent venous draw. For patients who have an indwelling line placed, access is not as significant of a barrier, however indwelling lines come with an increased risk of infection, and therefore their use is not appropriate in all settings. In the future, we envision shifting the treatment paradigm to closer monitoring of ammonia levels in acidemia patients with the objective of reducing hospitalization frequency and parent stress while improving the quality of life for affected families.
[1] Filipowicz, Heather R.; Ernst, Sharon L.; Ashurst, Carrie L.; Pasquali, Marzia; Longo, Nicola. Metabolic changes associated with hyperammonemia in patients with propionic acidemia. Molecular Genetics and Metabolism. 88 (2006) 123-130.
[2] Coude, Francois X.; Sweetman, Lawrence; Nyhan, William L. Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. J. Clin. Invest. 64 (1979) 1544-1551.
[3] Stewart, Peter M.; Walser, Mackenzie. Failure of the normal ureagenic response to amino acids in organic acid-loaded rats: proposed mechanism for the hyperammonemia of propionic and methylmalonic acidemia. J. Clin. Invest. 66 (1980) 484-492.
[4] Msall, Michael; Batshaw, Mark L.; Suss, Richard; Brushlow, Saul W.; Mellits, E. David. Neurologic outcome in children with inborn errors of urea synthesis. N. Engl. J. Med. 310 (1984) 1500-1505.
[5] Picca, Stefano; Dionisi-Vici, Carlo; Abeni, Damiano; Pastore, Anna; Rizzo, Cristiano; Orzalesi, Marcello; Sabetta, Gaetano; Rizzoni, Gianfranco; Bartuli, Andrea. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr. Nephrol. 16 (2001) 862-867.
[6] Vergano, Samantha A.; Crossette, Jonathan M.; Cusick, Frederick C.; Desai, Bimal R.; Deardorff, Matthew A.; Sondheimer, Neal. Improving surveillance for hyperammonemia in the newborn. Mol. Genet. Metab. 110 (2013) 102-105.
[7] Chapman, Kimberly A.; Gropman, Andrea; MacLeod, Erin; Stagni, Kathy; Summar, Marshall L.; Ueda, Keiko; Mew, Nicholas Ah; Franks, Jill; Island, Eddie; Matern, Dietrich; Pena, Loren; Smith, Brittany; Sutton, V. Reid; Urv, Tiina; Venditti, Charles; Chakrapani, Anupam. Acute management of propionic acidemia. Mol. Genet. Metab. 105 (2012) 16-25.
From the Spring, 2019 OAA Newsletter