Nailing down the nephrotic syndrome

Blood and urine composition provide key clues.

LaTonya J. Hickson, MD, began her session “Case-Based Inpatient Nephrology” at Internal Medicine 2013 in April by showing attendees a photo of a patient with marked periorbital edema.

“This is a bad sign. Things are going in the wrong direction,” she said. “When these patients come into the hospital with you, you are now stuck with helping us manage…nephrotic syndrome and complications related to nephrotic syndrome.”

Dr. Hickson, assistant professor of medicine at the Mayo Clinic's Division of Nephrology and Hypertension in Rochester, Minn., offered her audience tips on managing this disorder in the hospital. She said she recalls the key features of nephrotic syndrome this way: “Protein in urine, protein in blood, lipids in urine, lipids in blood, and edema. If you just think about it that way instead of the medical terms such as hypercholesterolemia, hypoalbuminemia, it's so much simpler.”

Initially, hospitalists need to consider the differential for total-body volume excess, she said. The heart and the liver are common culprits that are assessed, but the kidneys are often overlooked. “We'll do a million-dollar workup, including echocardiogram and beyond, only to find out that someone forgot to order a simple urine dipstick to check to see if they're losing protein in the urine,” she said.

One other way to determine the severity of edema, especially in nephrotic syndrome, is to look at its location, Dr. Hickson said, such as the scrotum or the abdominal wall.

“One of the consistent exam things that I tend to do…is to take a peek underneath, especially for the men,” she said. “When we find scrotal edema in patients, we tend to think beyond that of the usual bread-and-butter lower-extremity lymphedema. Once these gentlemen start developing scrotal edema and abdominal-wall edema, it is reflective of a more advanced process.”

Urine studies

For patients who do have abnormal protein on a urine dipstick, Dr. Hickson recommended that hospitalists avoid following up with a total 24-hour urine protein as the initial test.

“We see that someone's got a lot of protein on the dipstick, we're not going to rush off and get them to do a 24-hour urine collection,” she said. “But we can easily do a random urine albumin-to-creatinine. We can certainly, and I really suggest that we consider this strongly, do a urinalysis with microscopy.”

Hospitalists can always repeat the urine dipstick, too, but if it's positive it's just going to be confirmed with a formal urinalysis, she said.

A 24-hour urine collection is appropriate, however, when formal documentation of actual protein excretion rate, not a “predicted” rate, is needed, Dr. Hickson said. “When do we most formally need to do that? When we have nephrotic-range proteinuria,” she said, or a value over 3,500 mg/24 h.

Random urine studies correlate less well with measured protein excretion rates beyond the nephrotic range, she noted. To demonstrate, she showed a comparison of urine protein studies in a patient from her institution, which found a protein/ osmolality ratio of 53.72 with predicted protein of 41,950 mg/24 h, an albumin/creatinine ratio above 4,384 mg/g, and a 24-hour total protein of 12,168 mg/24 h.

The last value (24-hour total protein) is the most accurate, Dr. Hickson pointed out. The protein/osmolality ratio has a very wide reference range, she said, and for albumin/creatinine, the laboratory doesn't obtain precise values once the ratio is over a certain level. “When you finally do a 24-hour urine collection, you find that they really were excreting 12 grams of protein per day, which of course is very high,” she said.

Causes and management

Hospitalists caring for patients with the nephrotic syndrome should consider the whole person, Dr. Hickson said. Several glomerular diseases associated with nephrotic syndrome are primary diseases, including minimal-change disease, focal segmental glomerulosclerosis, membranous nephropathy, amyloidosis, light-chain deposition disease and diabetic glomerulosclerosis.

A main secondary cause of nephrotic syndrome, Dr. Hickson stressed, is malignancy. “Membranous nephropathy is unfortunately highly associated with malignancy,” she said, “and if a nephrologist diagnoses someone with this, we need to do appropriate cancer screening.” Hospitalists should also think about systemic problems that could be contributing to glomerular diseases, such as lupus, hepatitis and HIV.

“If patients have an underlying malignancy, or if they have a monoclonal protein disorder, all of these things could have an impact on what we're seeing in the kidney itself,” Dr. Hickson said. She also noted that certain drug exposures can secondarily lead to a glomerular process.

Dr. Hickson recommended using loop diuretics to treat volume overload in patients with the nephrotic syndrome, but, she said, “you also want to block something a little more distally.” The kidney will sense that sodium is being depleted in that loop of Henle, she said, and will ramp up the epithelial sodium channel (ENaC) receptors more distally in the tubule to reabsorb sodium. “If you block both, you tend to excrete more sodium and lose more fluid that way,” she said.

Compression stockings, low-sodium diet and supine positioning can also help, but the efficacy of albumin infusions is debatable, she noted.

“It's at the discretion of the provider,” she said. “Every now and then when I've got a tough challenge I will go ahead and utilize some albumin. Of course, it's expensive, and if you don't need it, and the patient's doing just fine mobilizing fluid, then it's not necessary at all that you add this.”

Hospitalists should also keep an eye out for thromboembolism, since patients with nephrotic syndrome, especially those with membranous nephropathy, are at higher risk than the general population, Dr. Hickson said. Generally, it is accepted that patients with thrombosis in the setting of membranous nephropathy should continue anticoagulation until the nephrotic syndrome is resolved, Dr. Hickson said, rather than the usual duration of three to six months.

When to refer

Dr. Hickson recommended referring to a nephrologist patients with progressive renal dysfunction (e.g., decline in estimated glomerular filtration rate >4 mL/min/year), progressive proteinuria that isn't responding to first-line therapy, uncontrolled hypertension, or estimated glomerular filtration rate less than or equal to 45 mL/min/1.73 m2.

“Certainly [involve a nephrologist] if there's evidence for nephrotic-range proteinuria, because that is an indication for kidney biopsy,” she said.

Dr. Hickson also discussed referrals for persistent hematuria, which recent studies have addressed. Although a workup should be done at the primary clinicians' discretion, she said, gross and microscopic hematuria are also seen with relatively benign glomerular processes such as thin-basement membrane disease or with IgA nephropathy, which may have variable prognoses.

“Glomerular diseases can be the cause of your hematuria, and we could certainly figure that out with a kidney biopsy if we think it's necessary,” she said.

Another important point Dr. Hickson reminded the audience to consider in referring a patient with suspicion for glomerular disease is to remember to stop the patient's aspirin in advance of the nephrology consultation.

“We get called many times to see patients for nephrotic syndrome or glomerular diseases and we may not see them until the end of the day. Oops, by the way, they took aspirin the night before, or they took aspirin the day of, and unfortunately, we now have to wait around three to five days before we can more safely perform an ultrasound-guided kidney biopsy,” she said.

Risk factors for bleeding after kidney biopsy include inpatient status, thrombocytopenia, use of antiplatelet therapy, younger age, and female sex. “Patients that bleed the most, in my opinion, are those that we're working up in the hospital that are more sick,” Dr. Hickson said. “It just makes sense.”