Not Your Everyday Nephrotic Syndrome
Last week I performed a kidney biopsy on a child whose history read like the textbook description of a certain kidney disease. The parents, worried about the procedure, asked why we needed the biopsy if the history were so clear. First, with any kidney disease you often need to know how advanced it appears in the tissue to guide therapy. Some are mild enough we do not give medications, while others are so advanced that there is little point in treating. Second, any kidney disease can cause almost any clinical presentation, and we may find something completely different in the tissue.
The latter happened. We found a “primary” kidney disease called membranous nephropathy.
My brief summary here draws heavily on a recent review by Menon and Valentini in Pediatric Nephrology 25:1419-428, 2010. DOI 10.1007/s00467-009-1324-5
Primary Kidney Disease
Nephrologists refer to primary kidney diseases when no systemic disorder is producing problems in the kidney. We can see membranous nephropathy on a biopsy in patients with systemic lupus erythematosus, infections such as hepatitis and malaria, cancers, and diabetes. If the patient has no evidence of such a disease, then we call it a primary kidney disease.
Most primary kidney diseases do not start and end in the kidney. Many involve the immune system inappropriately reacting with the kidney in some way, and many disorders get better with treatments that alter the immune system.
Bottom line: we really do not understand why most “primary” kidney diseases occur. The term just means we have excluded all of the known secondary causes in that particular patient.
Why do we call this particular pattern of kidney damage “membranous?” To understand that, you have to know a bit about the filtering units of the kidney, the glomerui (see figure 1). This unit contains clusters of tiny blood vessels called capillaries that surround a supportive area called the mesangium (dark pink areas). Blood flows through the capillary loops and stuff is filtered out into the space around the glomerulus. This filtered fluid must pass through the basement membrane of the loop. The basement membrane includes cells from the blood vessel (endothelial cells), proteins made by the cells, and extensions of the visceral epithelial cells (also called podocytes).
In membranous nephropathy, on light microscopy (done with a regular microscope like you find in a high school science lab) the basement membranes of the glomeruli look thick, so the filtering unit appears “membranous.” A closer look with a special stain shows the cause of this appearance (Figure 2). Silver stain makes the proteins in the basement membrane appear black. The glomerulus in figure 2 shows a fuzzy or spikey appearance to this basement membrane material.With electron microscopy, the reason for these spikes becomes clear (Figure 3). The arrows point to a number of lumps underneath the epithelial (podocyte) cells with basement membrane between them. Those black spikes on the silver stain are the proteins of the basement membrane working their way between these deposits.
What causes these deposits? We really do not know. A variety of immune components compose them, and we suspect that the injury targets the podocyte.
Membranous nephropathy presents with protein in the urine. This proteinuria may not cause any symptoms, or it may be heavy enough to result in nephrotic syndrome. In adults, membranous nephropathy is a common cause of nephrotic syndrome. It accounts for <5% of cases in children overall; from 1-12 years of age, the incidence appears to be 1% of cases, increasing to 22% between ages 13-19. Secondary causes can be identified in 20% of adults and perhaps as many as 35% of children.
Between 40-75% of children with membranous nephropathy present with full-blown nephrotic syndrome. Another 16-38% have proteinuria in the nephrotic range, but no swelling or other symptoms. Most of the others have lower levels of asymptomatic proteinuria. Microscopic hematuria (blood in the urine) is present in most of these children, and gross hematuria, visible with the naked eye, can occur in as manyas 40% of affected children.
Because so few children have this kidney disorder, most of what we know about it comes from adult patients. Approximately 1/3 of patients show spontaneous resolution of their proteinuria, another third have persistent proteinuria but no loss of renal function, and the others progress to permanent kidney failure. In general, younger age predicts a better course, so children probably do better than adults overall. Membranous nephropathy only accounts for 0.5% of children on dialysis in the US. Some findings on biopsy may predict worse outcomes, including glomerular scarring (sclerosis) and tubulointerstitial damage (inflammation and scarring in the non-glomerular parts of the kidney).
Once again, so few children have membranous nephropathy that our treatment guidelines are extrapolated from data in adults. Children with asymptomatic low-grade proteinuria (spot urine protein:creatinine ratio <2) may be managed with observation and anti-angiotensin II medications (ACEi or ARB) to reduce proteinuria. These patients are expected to have a very high rate of spontaneous remission with little risk of progressive loss of kidney function. Children with nephrotic syndrome and a spot urine protein:creatinine ratio >2 would be first treated with prednisone. Those failing to respond to this medication alone would have cyclophosphamide added for 12 weeks. The combination of prednisone and cyclophosphamide has proved most effective in the adult studies.
If the patient continues to spill protein after 12 weeks of combination therapy, the next step would be a calcineurin inhibitor such as cyclosporine or tacrolimus. Other drugs may be effective in patients, but less data support their use.