This is the story of a 64 year old male mason with past medical history notable for hypertension and hyperlipidemia who was referred to me for evaluation of proteinuria.
The patient noted onset of lower extremity edema nine months prior to the clinic visit. At the time, he was admitted to the hospital due to increasing complaints of lower extremity edema and shortness of breath, and received the presumptive diagnosis of congestive heart failure. He had an echocardiogram showing preserved ejection fraction and no valvular abnormalities. A chest CTA was negative for pulmonary embolism and imaging of the lower extremities was negative for deep venous thromboses. His serum albumin at the time was 2.5 g/dl down from his baseline of 4.0 g/dl a few months prior. No urinalysis data was available from that admission. He was treated with furosemide to which he responded with resolution of his shortness of breath, but with no effect on his notable 3+ pitting edema. He was discharged from the hospital with cardiology follow up as an outpatient.
Teaching point: not all edema is heart failure! A simple urinalysis would have been revealing.
Now back to the case…
During this time period, the patient’s lower extremity edema and exertional dyspnea had not improved in spite of escalating doses of furosemide. He was admitted to the hospital again two months prior to the renal clinic visit, this time for hypertensive emergency treated with intravenous labetalol followed by escalation in his anti-hypertensive regimen which included beta blocker, calcium channel blocker and a small amount of ACE inhibitor. A urinalysis sent at this time showed 3+ protein. He was also subsequently noted to have a serum albumin of 1.3 g/dl. Of note, his renal function was normal at his baseline of 1.0 mg/dl on presentation to renal clinic. Quantification of his proteinuria revealed 13 gms/day.
The patient denied a family history of kidney disease or any known past episodes of kidney problems. He denied fever, headache, chest pain, visual problems, rashes, joint pain, muscle pain, abdominal pain, nausea, vomiting, dysuria, hematuria, or hemoptysis. He had noticed foamy urine over the past few months. He also complained of occasional dyspnea on exertion, which was markedly different from his baseline a year prior. Renal ultrasound was notable for kidneys measuring 14 cm bilaterally with no hydronephrosis and no masses. Ultrasound evaluation of the renal arteries revealed no renal artery stenosis.
He underwent a renal biopsy which revealed membranous glomerulonephritis.
The patient was initially managed with angiotensin converting enzyme inhibitor, angiotensin receptor blocker and diuretics. After a six month period — fifteen months since the onset of symptoms — during which there was no sign of spontaneous remission, we initiated treatment with Cyclophosphamide and high dose Prednisone
The patient developed severe leukopenia, so Cyclophosphamide was discontinued. While we have some experience with Rituximab at our institution, this patient had normal renal function and therefore appeared to be a good candidate for a trial of Cyclosporine. We therefore initiated treatment with Cyclosporine at a dose of 3 mg/kg/day.
He responded well with reduction of his proteinuria to less than 2 gms/day. However, due to an episode of VZV/shingles, the Cyclosporine dose had to be decreased to 1 mg/kg/day, which resulted in trough levels less than 40 ng/ml. In spite of Cyclosporine levels well below these known to have a significant immunomodulatory effect, the patient achieved a surprising partial remission. It is of course conceivable that his remission was spontaneous, but this is not supported by the fact that he had been persistently nephrotic for 1.5 years prior to initiation of Cyclosporine treatment. Furthermore, the fact that the patient continues to be in remission 3 years later suggests that Cyclosporine may continue to exert a beneficial effect.
It is not surprising that Cyclosporine
can be successfully used to achieve remission in patients with IMN. However, past experience has shown that many patients with IMN have recurrence of proteinuria once Cyclosporine is removed. On the other hand, the chronic use of Cyclosporine is known to result in a decline of renal function, and nephrologists have been reluctant to use it for a prolonged period of time in the nontransplant setting. It would therefore seem advantageous to devise therapeutic strategies for the use of low dose Cyclosporine to prevent recurrence of nephrosis.
Intriguingly, a 2008 study by the Mundel group
suggests that Cyclosporine may have a new target: the glomerular podocyte. The authors present data in mouse models of acquired proteinuria, and specifically in mice that have been genetically modified to express calcineurin in a constitutive fashion. Interestingly, these mice develop severe albuminuria. Through a series of experiments, the authors subsequently determine that Cyclosporine confers an anti-proteinuric benefit through its protective effect on a critical, podocyte-specific molecule called synaptopodin. The preservation of synaptopodin ensures that the podocyte cytoskeleton remains intact, preventing the disruption of the glomerular filtration barrier.
These findings challenge our understanding of Cyclosporine as an immune modulatory agent for proteinuric kidney disease, and our long held belief that Cyclosporine puts patients in remission through its effects on T-cell activity. These data necessitate a closer look at the effects of traditional “immune modulatory” agents on the podocyte cytoskeleton.
Extrapolating from these data, is it possible to maintain podocyte health – and keep nephrotic patients in remission – by using Cyclosporine, or preferably targeted agents with similar podocyte-specific effects?
My patient enjoys a partial remission (currently proteinuria is less than 0.8 gm/day) on what would be considered “subtherapeutic” levels of Cyclosporine. However, if we begin to think of Cyclosporine as a podocyte-modulating agent, perhaps we also need to redefine what levels are “therapeutic.” This case suggests that lower doses may allow us to use Cyclosporine to maintain patients in remission with less concern for its nephrotoxicity. We have now employed this approach in a few other patients with IMN, with encouraging results thus far. Moreover, the use of low dose Prograf in some of our patients with FSGS has also proven to be effective in maintaining remission. Future clinical studies on these questions will be revealing. In the meantime, we are hard at work in the lab to identify new podocyte-specific anti-proteinuric agents.