Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. Mackenzie Ula Densa, a budding nephrologist, plans to present a new case to the master consultant.
Nephron: It's been a while, Mac. What do you have for me?
Mac: I have a 58-year-old woman with type 2 diabetes for over 20 years on insulin with worsening proteinuria.
Nephron: (bored) Whoa! Stop right there. This sounds like diabetic nephropathy. I know people are excited about that diagnosis these days due to the rising pharmaceutical interest with so many new drugs—sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1 agonists, and mineralocorticoid receptor antagonists.
Mac: Just trust me. You are going to love this one! It's not your typical diabetic nephropathy. Go with the FLOW.
Nephron: Well, in that case, we may have to put on my “glomerulonephritis [GN] hat,” as we are taking a break from the electrolytes.
Mac: Hmm…oh well. I can totally relate to that one.
Pause as Dr. Slit Nephrin enters
S Nephrin: Dear Nephron and Mac, please continue to discuss the case. The GN King has arrived. Now let's do the “GN chat.” Oh, this is a different forum. My bad!
Mac: As I was saying, this 58-year-old woman with type 2 diabetes has worsening proteinuria. She had nonadherence to her medications, resulting in remaining high hemoglobin A1c (HbA1c) (10%–14%) throughout her clinical course. She now presents to the office with worsening proteinuria. She has the usual: hypertension (HTN) hyperlipidemia, diabetic retinopathy, and neuropathy. Her meds include a nifedipine, doxazosin mesylate, trichlormethiazide, spironolactone, rosuvastatin calcium, and insulin regimen.
Nephron: Stop! Give us the labs, Mac. This is boring so far.
Mac: (laughing out loud) Can we move on? The focus is proteinuria.
The following labs apply to the patient: white blood cell count: 4.59 × 103/μL; hemoglobin: 11.2 g/dL; platelet count: 21.3 × 104/μL; urine protein: 12.0 g/gCr; urine red blood cells: 10–19 per high-power field; serum creatinine: 1.20 mg/dL; estimated glomerular filtration rate (using the 2021 Chronic Kidney Disease [CKD] Epidemiology Collaboration creatinine equation): 53.5 mL/min/1.73 m2; serum albumin: 2.3 g/dL; and HbA1c: 8.0%. No abnormalities were observed in immunoglobulin (Ig)G, IgA, or IgM; C3 or C4 levels; or autoantibodies. Phospholipase A2 receptor neg, antinuclear antibody, double-stranded DNA neg, and antineutrophil cytoplasmic antibody titers were negative. The serum-free light chain ratio was 2, and serum immunofixation electrophoresis was negative.
Nephron: (bored, rolling his eyes) Well, you just confirmed what I said earlier. This is a boring case of diabetic nephropathy with significant proteinuria.
S Nephrin: Interesting. Do you have the trend of the proteinuria?
Nephron: (winking) Dr. Slit Nephrin, I’m glad you asked.
Mac: Let me tell you a little more about this case. A few years ago, proteinuria was 0.3 gm and creatinine, 0.9 mg/dL; 1 year ago, proteinuria was 3 gm and creatinine, 1.2 mg/dL; 5 weeks ago, proteinuria was 10 gm and creatinine, 1.5 mg/dL…. (fading)
Nephron: (laughing) Big deal. Let me guess: You even did a renal biopsy? I mean a kidney biopsy.
S Nephrin: Hmm…. Has the blood pressure been harder to control?
Mac: (trying to remember) Yes. But that's not unusual for people with diabetes with HTN, right?
S Nephrin: (jumping in) I think you should consider a kidney biopsy to rule out thrombotic microangiopathy (TMA).
Silence
Nephron: (shocked) Let me guess. It's SARS-CoV-2 or quinine use? Everything cannot be TMA.
Mac: (smirking) I thought TMA was your favorite diagnosis, Dr. Nephron.
Silence
Mac: (confident) A kidney biopsy was performed, and the puzzle begins after that. It confirmed early diabetic nephropathy but acute on chronic TMA as well.
S Nephrin: Fascinating! But what is causing her TMA?
Mac: To me, TMA is a syndromic process showing hemolysis and endothelial injury. HTN, proteinuria, and, in some cases, systemic hemolysis may be the hallmark indicators. She appears to have more of a “renal-limited” TMA. ADAMTS-13-mediated TMA was ruled out, Shiga toxin was negative, and there were no signs of systemic autoimmune diseases. Certain viral and bacterial infections were ruled out as potential causes of TMA. Pregnancy is not a contender here. She is not a solid organ or stem cell transplant recipient. She may have a complement deficiency, but those results of both the factor levels and genetics will take time to validate. I think this is a potential drug-induced process.
Nephron: (smiling) Nice work flaunting your TMA knowledge. I agree that this is likely a direct endothelial injury or likely an idiosyncratic reaction from the potential culprit drug. What about this just being from the type 2 diabetes?
S Nephrin: (interrupting) TMA has been reported with diabetic nephropathy. Patients with diabetic nephropathy and TMA usually have higher blood pressure and proteinuria and a lower rate of glomerular filtration at baseline. Vascular endothelial growth factor (VEGF) assessments obtained in such patients showed lower arteriolar and glomerular expression with diabetic nephropathy plus TMA. The VEGF expression levels had an inverse relationship with proteinuria. There is also a higher probability of kidney failure in patients with diabetic nephropathy plus TMA.
Mac: (proclaiming) Fascinating. But she started intravitreal injection of aflibercept (2 mg every 4 weeks) for the treatment of retinopathy 2 years ago. Fourteen months after the first injection, she reported bilateral leg edema and HTN (159/87 mm Hg) with a urine protein level of 4.9 g/gCr, urine red blood cells of 0–1 per high-power field, and a serum creatinine of 0.65 mg/dL; thus, amlodipine, telmisartan, and furosemide were added to the therapy. Nevertheless, urine protein continued to increase to 10.0 g/gCr at 2 years after the first injection, and she was referred. A total dose of 40 mg of aflibercept was administered in 20 injections during the 2 years following the first injection, which stabilized her retinopathy and vision.
S Nephrin: Yes, this is important and the likely culprit. Despite being intravitreal, anti-VEGF therapy has been known to cause TMA (systemic or renal limited). I think we must ask her to stop this agent.
Mac: (nodding) So, what do we do here…let her go blind and protect the kidney?
Nephron: (puzzled) Seriously?! I don't believe this! Can you enlighten me regarding this small intravitreal dose and TMA?
Mac: So dramatic, you are!
S Nephrin: Since the 1990s, systemic inhibition of angiogenesis has revolutionized cancer treatment. The discovery of the VEGF receptor led to bevacizumab's clinical application, effectively targeting various malignancies like lung, renal, breast, and colorectal cancers; gliomas; and retinal neovascularization. Aflibercept and ranibizumab, newer inhibitors, offer increased potency and duration compared with bevacizumab.
Nephron: We know this stuff already, and systemic anti-VEGF therapy for cancer can lead to renal-limited TMA. Bevacizumab has been used intravitreally for age-related macular degeneration and proliferative diabetic retinopathy/diabetic macular edema. Many retina specialists also use aflibercept and ranibizumab. Pegaptanib, a multimer nonmonoclonal aptamer anti-VEGF agent, was also approved with an indication for intravitreal use for proliferative diabetic retinopathy.
S Nephrin: (confident) US Food and Drug Administration data on aflibercept and ranibizumab revealed detectable serum levels after intravitreal injections, with aflibercept levels approximately 200-fold lower than needed for systemic VEGF inhibition. Systemic absorption varied among ocular pathologies. Some studies later found that systemic levels after injections exceeded inhibitory concentrations, persisting for weeks. Aflibercept showed prolonged systemic presence, whereas ranibizumab had quicker clearance. Multiple injections maintained detectable serum levels, with aflibercept displaying potent systemic VEGF inhibition compared with bevacizumab and ranibizumab.
Of course, there are several case reports and series showing this association of intravitreal anti-VEGF and renal injury.
Mac: (jumping in) I also found some retrospective and observational data that patients with CKD and diabetes who received these agents were more likely to progress to kidney failure faster with a higher need for renal replacement therapy.
Nephron: Although I am still skeptical, I will go along to see what happens once we hold this agent.
Mac: (surprised) Well, we may have to wait a few months to see any improvement.
Nephron: Fantastic! Let's do that. What about anticomplement therapy?
Mac: For now, I am not sure but wouldn't want to do that, as I am confident this is the offending agent.
S Nephrin: Good question, Detective Nephron. Of course, as with any rare disease, such as drug-induced TMA, there are no data to support anything.
Silence
Nephron You sound like a true GN doctor, needing more data on GN. IgA nephropathy seems to be gathering some momentum.
Mac winks.
5 Months later
Mac: I have an update for you, Detective Nephron and Dr. Slit Nephrin! Intravitreal aflibercept injection was discontinued after the biopsy, and both urinary protein and serum albumin gradually improved. Four months after withdrawal of aflibercept, the patient no longer has nephrotic syndrome. She has improvement in her leg edema with disappearance of the bilateral pleural effusion and ascites. After ceasing aflibercept, her laboratory parameters (serum creatinine: 1.49 mg/dL, serum albumin: 4.0 g/dL, and urine protein: 0.6 g/gCr) and blood pressure (123/54 mm Hg) have improved. Her eyesight has remained stable even after aflibercept discontinuation.
Nephron: (laughing) There you go again! Fascinating diagnosis and treatment, Mac. Special thanks to our GN specialist, Dr. Slit Nephrin, in helping us with this tough case. I must say, GN nephrologists are truly the best detectives on the planet.
Dr. Slit Nephrin takes a bow and winks.
