Pathways Case Record: A Patient With Renal Failure Found to Have Nephrotic Syndrome With Histopathological Findings of Podocyte Effacement

A 63-year-old man with acute myeloid leukemia in remission after remote stem cell transplant, cirrhosis secondary to hereditary hemochromatosis (excess absorption of iron), vitiligo, positive celiac antibody serologies, and type 2 diabetes was admitted to the hospital with kidney injury following removal of fluid from the abdomen (paracentesis). A month prior to the presentation, he noted lower extremity edema and weight gain. He presented to his primary care physician, and it was presumed that his symptoms were secondary to decompensated cirrhosis (i.e., the acute deterioration of liver function), which was treated with paracentesis.

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Labs performed immediately after the procedure revealed an acute kidney injury (AKI) and high potassium levels, and he was admitted to the hospital. He subsequently progressed to renal failure and was started on hemodialysis for volume overload. The cause of his renal failure was initially thought to be ischemic acute tubular necrosis in the setting of fluid shifts from his paracentesis, superimposed on chronic renal insufficiency due to subacute chronic kidney injury of unclear cause.

To better elucidate his renal pathophysiology, a 24-hour urine collection revealed extremely elevated urine protein levels (proteinuria). He underwent a kidney biopsy for a workup of presumed nephrotic syndrome, a kidney disorder characterized by excessive protein in the urine. His renal pathology showed severe podocyte injury with effacement consistent with minimal change disease along with diabetic glomerular changes and evidence of prior AKI.

The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted to elucidate the current mechanism of injury to this patient's podocytes and the pathophysiologic underpinnings of his nephrotic syndrome. The following questions were interrogated:

1. Are there anti-nephrin autoantibodies in this patient's serum that may explain his histologic findings of podocyte effacement?
2. If not anti-nephrin antibodies, are there autoantibodies to any other glomerular proteins that may explain his histologic findings and clinical syndrome?
3. Does the patient exhibit polymorphisms in his kidney proteins by whole exome sequencing compared to his stem cell transplant donor that may have predisposed him to autoimmunity following stem cell transplantation?

Background and Diagnosis

Podocytopathies occur by either direct or indirect damage to the podocyte, a highly specialized cell in the glomerulus of the kidney. Indirect or "secondary" podocytopathies occur when systemic disease causes indirect injury to the podocyte. Examples of these include diabetic nephropathy and depositional disease such as amyloid or plasma cell dyscrasias. Primary podocytopathies are due to direct podocyte injury, examples of which have classically been categorized by their histopathology, some examples including minimal change, focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis, and membranous nephropathy. This classical framework of understanding primary podocytopathies is incomplete, as histological presentations can occur on a spectrum and further do not fully describe the underlying mechanism of disease. Instead, understanding primary podocyte injury from the perspective of genetics, infectious insults, toxins, and immune dysregulation better captures the underlying causes and has implications for targeted therapy.

Primary podocytopathies usually cause nephrotic syndrome (edema, high lipid levels in the blood, hypercoagulability, low albumin levels), while secondary podocytopathies do not (though both can cause nephrotic-range proteinuria). This difference is thought to be due to the diffuse nature of podocyte injury seen in primary compared to secondary podocytopathies, which leads to hyperfiltration and subsequent upregulation of distal tubular sodium channels, increasing sodium uptake and causing edema in conjunction with loss of intravascular pressure.

In general, patients with primary podocytopathies do not have evidence of AKI as net glomerular filtration is only slightly decreased. However, 35% of patients with nephrotic syndrome can develop AKI. Most of these patients have underlying renal vascular incompetence. A leading theory for AKI development in these patients suggests that podocyte injury and hyperfiltration lead to upregulation of endothelin-1 (ET-1), causing vasoconstriction and ischemic acute tubular necrosis in an already at-risk kidney.

The established histopathological evidence of primary podocytopathy in our patient led our team to consider the differential diagnosis of podocyte injury. Sources of injury include toxins, medications, viral infections, hyperfiltration (low nephron number), obesity, genetic syndromes, and immune dysregulation. Our patient has a history of stem cell transplant and evidence of other autoimmune conditions (vitiligo and positive celiac serologies) but no other clear etiological features. Furthermore, recent research suggests that acquired anti-nephrin antibodies are found in a significant subset of patients with minimal change disease (J Am Soc Nephrol). Nephrin is a modified desmosome protein that maintains podocyte inter-cellular interactions and slit diaphragm integrity. Autoantibodies bound to nephrin cause vacuolization, loss of the slit diaphragm, and subsequent loss of the size-restricted filtration barrier. Given this recent data in conjunction with our patient's autoimmune milieu, we propose anti-nephrin antibodies as a likely mechanistic process by which this patient developed a primary podocytopathy.

Summary and Future Steps

Recent evidence suggests that anti-nephrin antibodies may be implicated in a large percentage of adult patients with non-genetic nephrotic syndrome who have histopathological evidence of minimal change disease (J Am Soc Nephrol). Furthermore, our patient's development of renal failure after a relatively low-grade insult (paracentesis) is likely attributable to his nephrotic syndrome, with an underlying susceptibility to ischemic acute tubular necrosis due to multifactorial mechanisms, including ET-1 upregulation (Renal Pathophysiology: The Essentials).

To answer these three questions, the Pathways consult service proposes the following experiments:

1. Check for anti-nephrin antibodies: Patient serum from our patient and others with nephrotic syndrome could be used to measure anti-nephrin antibodies through an ELISA assay compared to age-matched healthy controls.
2. Examine antibodies targeting any glomerular proteins: If we do not observe anti-nephrin antibodies, utilizing a glomerular protein extract, we can determine if there are antibodies to any glomerular protein in patient serum. Antibodies to glomerular proteins, if present, would bind to proteins and be detected with appropriate secondary antibodies.
3. Whole exome sequencing: Lastly, we could perform whole genome sequencing of our patient's native DNA (skin punch) compared to his stem cell donor (serum sample) to identify polymorphisms in key podocyte-expressed proteins that may explain a predisposition for the development of an autoantibody against his kidneys. The patient's exome will be compared to his donor's exome for polymorphisms within nephrin, podocin, and other key glomerular proteins of interest (Nat Rev Dis Primers). If present, these polymorphisms could be assessed for the likelihood of antigen presentation based on the sequences. Polymorphisms may explain why the donor immune system has recognized the patient's native kidney proteins as foreign and led to the development of an autoimmune phenotype.

These experiments would substantiate an autoimmune hypothesis as the pathophysiologic underpinnings of podocyte injury (minimal change disease) and the associated clinical phenotype of nephrotic syndrome that this patient exhibits. These findings would align with trends as the field of nephrology moves away from histopathologic classification of nephrotic syndrome (minimal change, FSGS, and so forth) and towards a description of the molecular underpinnings (anti-nephrin antibodies, genetic syndromes), isolation of the specific underlying etiology will influence treatment course. Additionally, patients with donor immune systems are under-represented in databases. They may be at higher risk than the average patient due to polymorphisms in their exomes compared to their donors.

This case serves as an illustration of how dedicated time to delve into molecular and pathophysiological underpinnings of disease can produce achievable experiments to answer the question of "Why this patient, and why now?" and in doing so, bring the basic sciences into the clinical realm with implications for actual patient care.

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