Orthostatic proteinuria is a benign condition first recognized in the middle of the last century. For some reason, as yet unidentified, some youth develop asymptomatic proteinuria when they are up and about during the daytime that normalizes when they lie down and sleep. Serum protein and albumin levels remain normal. The diagnosis can be confirmed in an asymptomatic patient with an elevated protein:creatinine ratio during the day but a normal study on first-morning void. The main reason to make the diagnosis is to keep these patients from undergoing invasive studies; orthostatic proteinuria usually disappears as these children mature into young adults.
When this condition was recognized, measuring total protein in the urine was state of the art; today we know that lower levels of proteinuria may herald the onset of kidney diseases. So-called microalbuminuria first became a diagnostic test for type 1 diabetes mellitus. Chronic kidney disease staging now includes the presence of microalbuminuria as an indicator of kidney damage. Natural history studies have now shown that approximately half of diabetic patients with microalbuminuria will normalize their excretion over time, lessening its value as a disease marker. We still measure it, in part because we do not have anything else besides loss of glomerular filtration rate.
My question for several years: do normal kids get orthostatic microalbuminuria as they mature? If some children get orthostatic proteinuria, it stands to reason that many more might have lower-grade orthostatic microalbuminuria.
I propose the Orthostatic Microalbuminuria in Youth (O-My) Study. I am cheating a bit here; this will be an observational study, not a trial, but we need these data to design the next logical step. This study would measure microalbuminuria in first morning voids and after school voids in normal healthy children with no proteinuria by standard dipstick. Measurements would be performed annually for 6 years from 10 through 15 years of age. Other data would include height, weight, blood pressure, and Tanner stage of sexual maturity.
If we document orthostatic microalbuminuria in normal adolescents (and I suspect we would), the next step would be a study in children with diabetes. Patients with orthostatic microalbuminuria would be randomized to anti-angiotensin II therapy or placebo. After 5 years medications would be stopped to see if microalbuminuria was still present or not. A lot of the adolescents we see with type 1 diabetes and microalbuminuria normalize very quickly with small doses of anti-angiotensin II medications. I wonder if these teens have orthostatic microalbuminuria that really does not warrant treatment. Without knowing if orthostatic microalbuminuria is a “thing” in non diabetic kids, I am hesitant to withhold treatment in someone with diabetes.
So why could this be important? Anti-angiotensin II drugs have few serious side effects, unless you are a fetus. Adolescent pregnancies are usually unplanned, so this presents a risk in this age group. These drugs have been around a long time and generic forms are readily available, so the cost-benefit ratio for these drugs generally favors treatment. However, there are adverse events, even with a class of drugs this safe, and saving patients unnecessary exposure can be a good thing.
Of course, the most important part of a clinical trial is a clever name; I propose Normal Orthostatic MicroAlbuminuria in Diabetes (NOMAD) for this component.
Would rule out left renal vein compression in all of these children first. I think that that problem explains the majority of orthostatic proteinuria and why one grows out of it.
That is the leading theory about orthostatic proteinuria; intermittent renal vein compression causes venous congestion in the upright position. As linear growth occurs through puberty and the periaortic fat pad enlarges, this tendency becomes suppressed and the proteinuria resolves.
First, are we really going to do the US studies needed to confirm this etiology for a benign, self-limited condition? Doubtful.
Second, it doesn't answer my question, namely do a lot of "normal" teens have lower-grade orthostasis that we pick up in diabetic kids because we measure microalbuminuria and we typically don't outside of the diabetic population.
I would love to do O-My, but is anyone really going to fund such a study of an even more benign, self-limited condition????