Podocyturia: Is there any clinical utility?

Constant efforts are ongoing to identify reliable and reproducible noninvasive biomarkers for acute and chronic kidney injury targeted toward identifying kidney injury not only in its early stages, but also in classifying kidney disease according to severity, predict disease outcomes, and monitor response to therapeutic interventions. Podocyturia has not reached mainstream clinical testing in the field of glomerular diseases. The authors in the previous issue of the Journal present a small, but interesting study.[1] Along with biopsy samples and urinary podocyte quantification, the authors show that in class III and IV lupus nephritis, levels of podocyte marker Wilm's tumor (WT)-1 expression are lower than control normal subjects. They also conclude that the cumulative excretion of urinary podocytes and proteinuria was significantly higher in the lupus nephritis patients.

The podocytes are the largest cell in the glomerulus and have a highly specialized three-dimensional structure with a unique molecular profile closely linked to the critical functions it performs.[2] The molecular signature of podocytes is unique among epithelial cells of the kidney and are the only cells in the adult kidney to express intranuclear WT-1 and are the only glomerular cells to express the C3b receptor.[2] Podocytes are normally absent or seen in small numbers in urine of normal individuals or those with inactive kidney disease. Although not visible utilizing a microscope, it is possible to visualize these podocytes in urine with immunofluoresence staining and after incubation with antihuman podocalyxin monoclonal antibody PHM-5 (Australian Monoclonal Development, Artarmon, New South Wales, Australia). The number of podocytes in urine or podocyturia increases with active kidney disease even before proteinuria appears and seems to improve with treatment.[2] Also, podocyturia seems to be confined to active disease, in contrast to proteinuria, which is present during both active and chronic phases of glomerular damage.[3] It will be particularly interesting to explore podocyturia, as a marker of subclinical early renal damage, which may be a detectable way before the occurrence of overt proteinuria and development of full blown glomerular disease.

The role of podocyturia in lupus nephritis (LN) has a short history in the literature. Li et al.(Chinese study) showed that the degree of podocyturia correlated well with LN disease activity in class III, IV patients. The podocyturia disappeared after treatment in their group of patients.[4] Another study on pediatric patients showed similar findings in class III and IV LN flares.[3] In the current study, the authors elegantly show that a lupus class III and IV flare was associated with podocytopenia on kidney biopsy and podocyturia. The authors suggest that this could be an early marker for lupus activity. It is also interesting to note that all three studies could not show this correlation with LN class V. The first study by Li et al. included class V patients but the podocyturia was not evident as much as one noticed in active flare of classes III and IV. The current study did not evaluate class V patients.

In many of the primary or secondary glomerular diseases, including focal segmental glomerular sclerosis(FSGS), membranous nephropathy, membranoproliferative glomerulonephritis, amyloid nephropathy, and diabetic nephropathy,[5] podocytes are injured which then completely detach from their basement membrane and are shed into the urinary space. Podocyte injury has been verified by electron microscopic examination of renal biopsies in all of the above-mentioned glomerular diseases. Since the loss of podocytes associates well with glomerulosclerosis, monitoring podocyte loss by measuring podocytes or their products in urine has potential to become a clinically useful tool in years to come. Hara and colleagues[6-8] detected podocytes and their fragments in the urine of humans with a variety of glomerular diseases using antibodies to the podocyte proteins: podocalyxin, podocin, nephrin, and synaptopodin.

In diabetic nephropathy, podocyte detachment is associated with the degree of proteinuria. Nakamura et al.[9] has described podocyturia as a useful marker of disease activity in diabetic nephropathy, and Vogelmann et al.[10] went on to show the viability of the majority of urinary podocytes. Petermann et al.[11] were able to demonstrate cells that express podocyte-specific antigens by immunostaining and RT-PCR in the urine of rats with the PHN (passive Heymann nephritis) model of membranous nephropathy, but not in that of controls. Garovic et al.[12] reported urinary podocytes in association with toxemia of pregnancy. These podocytes retained the ability to attach to tissue culture plates in vitro, again indicating their viability in urine. Podocyturia was shown to be present in patients with preeclampsia even at the time of delivery. Women with normotensive pregnancies and women with either hypertension or proteinuria, but in the absence of the clinical syndrome of preeclampsia, did not have podocyturia suggesting that podocyturia is not merely a result of hypertensive kidney damage or a marker of proteinuria.

Noninvasive methods to quantify podocyte damage are emerging, such as detection of podocyturia in the urinary sediment. Podocyturia may serve as the first noninvasive marker of “active” glomerular damage and might thus drive therapeutic interventions in the future. However, urinary podocytes are difficult to quantify for technical reasons.[13] Given the current study on LN, and others as mentioned above, podocyturia is becoming a common tool to study the severity and nature of glomerular disease, only in the research setting so far. While the authors link podocyturia to LN flare, one must keep in mind that the loss of podocytes in the urine could be a common pathway for many glomerular diseases and not specific to LN.

At present technical issues and nonspecificity still prevent a broad clinical application of podocyturia detection in clinical practice.