Is It Polydipsia or Diabetes Insipidus? New Less Burdensome Screening Protocol at UPMC Children’s Uses Arginine Stimulation and Copeptin Levels to Guide Diagnosis

For the last few years, the Division of Pediatric Endocrinology at UPMC Children’s Hospital of Pittsburgh has been testing and gaining expertise in a new form of testing to help diagnose and differentiate between conditions causing excessive thirst and urination (also known as “the polyuria-polydipsia syndrome”), which include diabetes insipidus and primary polydipsia. The new testing protocol, which can be performed in the clinic in just a few hours is much less taxing on the patient and their family compared to the traditional water deprivation test that must be done in the hospital with an overnight admission and subjects children to many hours of thirst.

Luigi Garibaldi, MD, professor of pediatrics at the University of Pittsburgh School of Medicine, leads the efforts to implement the new diagnostic protocol for the division.

Diabetes insipidus (DI) is a rare disorder, with the most common form being central DI. Central DI occurs when normal levels of vasopressin (anti-diuretic hormone, also referred to as ADH or AVP) are disrupted, causing polyuria, which leads to polydipsia, and can then lead to dehydration and electrolyte imbalances if free access to large amounts of water is not available. Most cases of central DI are idiopathic in nature, with fewer instances resulting from direct damage to the hypothalamus or the pituitary gland – for example, from a brain tumor or inflammatory condition – and even less from an inherited genetic anomaly. Another type of DI, the nephrogenic form, is even rarer in children. It occurs not because of disruption in the production of vasopressin in the pituitary but because of the inability of the kidneys to respond to AVP, which results in a clinical picture similar to that of central DI, with inability to concentrate the urine appropriately to help regulate the fluid balance in the body.

"And then we have what's known as primary polydipsia (formerly known as psychogenic polydipsia), which is an abnormal consumption of fluids by the individual which leads to polyuria," says Dr. Garibaldi. "Oftentimes in younger children, this can be behaviorally driven and is generally benign, though the frequency of urination can be disruptive. The difficult part has always been the process for distinguishing between benign polydipsia that will likely resolve itself as the patient ages or behavioral factors change, and true DI, which is a serious medical condition requiring prompt investigations to exclude serious pathology such as a brain tumor, as well as medication."

As Dr. Garibaldi explains, for decades, the gold-standard test to help arrive at a diagnosis of DI has been the inpatient water deprivation test. The test requires admission to the hospital and can be significantly taxing and traumatic for the patient and their family, particularly for those with very young children.

"It's a lot to go through for a young child and their family," says Dr. Garibaldi. "The withholding of fluids and food for many hours, typically for 15-18 hours but sometimes longer, in addition to frequent blood, draws (albeit from an indwelling IV line), weight measurements, and other analytical measures, is a lot to endure. Additionally, children, especially the young ones, need to be monitored frequently for the risk of low blood sugar."

In recent years, however, primarily in Europe, a new form of testing for DI has been developed for adults that can supplant the 24-hour water deprivation test with a screening protocol that can be done in the clinic in a couple of hours.

Dr. Garibaldi and colleagues began exploring its use in pediatric patients at UPMC Children's approximately three years ago. Within the last year, it has been moved into the clinic as a new approach for DI diagnosis. UPMC Children's is the first, and currently only, center in the United States to adapt and begin using it in pediatric patients.

What Does the Protocol Entail?

The test that Dr. Garibaldi and colleagues have implemented uses an intravenous infusion of arginine to stimulate vasopressin secretion, which was initially piloted in Europe.

“Unfortunately, arginine is a pretty weak stimulus for the secretion of AVP and copeptin in children,” says Dr. Garibaldi. “However, we have found that it becomes a very powerful stimulus when it is combined with another agent, such as insulin or Levodopa (L-Dopa). We tend not to use insulin unless we need to test other pituitary hormones simultaneously, due to the discomfort and small risk of hypoglycemia, but the L-Dopa works equally well, with the only side effects being nausea in some children.”

First, the testing nurses obtain a baseline measurement of the patient's copeptin (a surrogate marker for AVP) serum levels. They then collect serial blood samples and measure the serum levels of copeptin for a few hours to look for an appropriate copeptin response, which would suggest primary polydipsia, or an abnormally low response, indicative of central DI. Nephrogenic DI can also be diagnosed easily by persistently elevated copeptin levels, even in the absence of stimulation.

"Measuring vasopressin levels in the blood directly is exceedingly difficult," says Dr. Garibaldi. "It's a very small molecule that degrades or is metabolized rapidly. However, when the pituitary is stimulated and releases vasopressin, it also releases the glycopeptide copeptin in similar amounts. Copeptin is much easier and more reliably measured, making it an excellent biomarker for DI testing and differentiation. It was discovered decades ago, but only recently has the copeptin measurement become available commercially. It has changed the diagnostic landscape for the diagnosis of conditions of polyuria and polydipsia."

“We are still conducting water deprivation tests, and we’re continuing to compare those results against the new protocol to evaluate them against each other in terms of reliability, sensitivity, and specificity in order to fully validate this new test,” says Dr. Garibaldi. “For sure, though, the new protocol is much easier to administer and much better tolerated by the patients and their families, time will tell if we make it our new gold-standard at UPMC Children's."

Learn more about Dr. Garibaldi and the Division of Pediatric Endocrinology at UPMC Children’s.