Detective Nephron

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HenleA case for you, sir!
The detective sits facing the window, awaiting the arrival of his new students.
NephronWhat do you have for us today, my dear apprentice?
HenleA 60-year-old man with proteinuria, microscopic hematuria, and an acute rise in creatinine level.
NephronI see that you have taken a break from the electrolyte disorders and moved to the world of acute kidney injury (AKI). This is why nephrology is so much fun. It has so much variety to offer to us diagnosticians.
HenleHmmm… getting back to the case, the patient was in his usual state of health until a few weeks ago when he was seeing his primary care physician; a creatinine level of 2.2 mg/dL was noted. It was 1.6 mg/dL several months earlier.
NephronWhat was his creatinine level 1 year ago?
HenleIt was 0.7 mg/dL 1 year ago
Nephron(angrily): OK; did you examine his urine?
HenleYes, of course I did. There are a few red blood cells, none dysmorphic, and many white blood cells. I noticed several white cell casts but no red cell casts, and no signs of any granular casts.
NephronIs there any proteinuria?
HenleYes, 2.2 grams in a 24-hour urine collection.
NephronI am sure they did serologies before they called you.
HenleHere are the results: antinuclear antibodies, anti–double-stranded DNA, myeloperoxidase, and proteinase 3—all negative results. His HIV test result is negative. Hepatitis B and C results are negative.
NephronStop right there. Before we go any further, let’s think if this is truly an injury to the glomerulus.
Henle(wondering to himself about quick decision by Nephron): Hmmm. I am not too sure whether this is a glomerular process.
NephronWhy is this not a rapidly progressive glomerular process?
HenleIn this case, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies are negative … and I suppose he could have an immune complex glomerular process.
NephronMy dear apprentice, you have a lot to learn still. First and foremost, can you give me this individual’s medication list? Please go get that while I drink my coffee.
Henle leaves to get the information, and Nephron gets a cup of warm coffee. Henle returns after a few hours.
NephronPlease read out all his medications to me.
HenleHe is receiving only two medications: insulin for his type 2 diabetes mellitus and loperamide for chronic diarrhea because of his episodes of chronic pancreatitis.
Nephron(shocked): Interesting! And boring. It’s likely diabetic nephropathy. Go on to the next case.
Henle(jumps in): Can we go back to his laboratory results? Did I mention that he had a serum immunoglobulin free light chain ratio of 2.2 and a mild IgG κ spike in the serum immunofixation?
Nephron(eyes light up): Of course there is. So you’re telling me there is potentially a monoclonal gammopathy of renal significance (MGRS)? I suppose there are more reports on MGRS than there are cases in nephrology. But a free light chain ratio of 2.2 is not concerning for someone with a creatinine in the range of 2 to 3 g/dL. Remember, both free light chains are cleared by the kidney. I would still continue the workup and not just stop at this immunofixation. Two-thirds of patients with MGRS have non–paraprotein-related findings in the kidney biopsy specimens, but the other third do have MGRS. What is his ethnicity?
NephronHmmm… if we still think this is a glomerular process, could it be MGRS? Or just diabetic nephropathy?
Henle(confused): Hmmm…. so is that the connection? How about we start from a more basic approach? Why are we jumping into the glomerulus without a systematic approach?
Nephron(interrupting): Is there anything on his physical examination?
HenleNothing specific except some trace edema bilaterally in the lower extremities. There was some concern for potential lymph nodes felt in the axillary regions. I think we are jumping around too much. It’s as if I am getting power texts of multiple information.
NephronHaha! As you say, laughing out loud. The social media generation shouldn’t have a problem with overproduction of information. You can handle it. I am assuming you want to go over a systematic approach to rule in and rule out other causes of AKI?
HenleYes. I don’t think it is a prerenal condition, because his urine sodium is high, and I don’t think it’s a postrenal condition, because I personally inserted a Foley catheter, and a bladder sonogram shows no significant residual volume. He is not oliguric.
 That leaves us with intrarenal causes. A tubular cause is still possible, regardless of the hematuria and proteinuria. This could be garden-variety tubular necrosis, but I can’t find any source of low BP or any toxic medications, and the urinalysis showed no granular casts. An interstitial cause still bothers me. He has a lot of white blood cells and casts in his urine, and the result of his urine culture is negative, which suggests a sterile pyuria. He might have an acute interstitial nephritis, and the proteinuria could be of tubular origin.
 I don’t think he has a vascular disease process, although his platelets are low and he has anemia. Perhaps we should check his lactate dehydrogenase and haptoglobin levels, and do a peripheral smear to make sure there is no thrombotic microangiopathy, or perhaps a bone marrow evaluation (which might rule out MGRS and make sure we are not missing other infiltrative process such as a lymphoma)? You already discussed the glomerular causes. I might get complement levels as well.
NephronAmazing thought process, Henle. I am proud of you! Regardless, go ahead, and let’s get some answers with the tests you ordered. Also, do you think a renal sonogram or a CT scan might help, given you have a concern for lymphoma? Also, why is this not diabetic nephropathy? And why do I keep asking that question?
HenleI suppose. Why not? The size of the kidney might give us a clue regarding a differential diagnosis. Alas, diabetic nephropathy is a default diagnosis here. His hemoglobin A1c has been 6% for years, and he has no diabetic retinopathy. In addition, the kidney size might help rule out diabetic nephropathy.
NephronSure, if you say so. Well, how sudden is the rise in proteinuria? That might be a clue if this is not diabetic nephropathy. Go find out more information, my friend.
Henle exits.
NephronFine work by Henle.
A day later
HenleHe is not doing well. His renal function and anemia are worse. His complements are normal. His renal sonogram shows massively enlarged hyperechoic kidneys that are rather large: 17.5 cm bilaterally in the longitudinal axis. To me, the large size suggests HIV-associated nephropathy, amyloidosis, obstruction, or some combination—but he does not have an obstruction. Another possibility is diabetic kidney disease, but a size over 15 cm sounds rather large to me, and sudden proteinuria in just a few months does not fit the picture. A CT scan shows multiple diffuse large areas of patchy decreased enhancement on both kidneys. Differential diagnosis includes vasculitis, with metastases or lymphoma less likely but not entirely excluded. His lactate dehydrogenase was not that elevated at 400 U/L, and this is surprising. His proteinuria is also new—it was normal 1 year ago, and a few months ago it was 1 gram over 24 hours. I think we have to rule out a lymphoma, given the axillary lymph nodes, large kidneys, positive immunofixation, and worsening creatinine level. I think there might be infiltrative disease in the kidney.
NephronPlease also obtain a bone marrow biopsy and a lymph node biopsy.
Henle, puzzled, leaves the room but returns quickly.
HenleBone marrow biopsy result is negative. I scheduled him for a kidney biopsy and lymph node biopsy.
NephronHenle, your initial hunch was correct. You were thinking of causes of sterile pyuria and came up with interstitial nephritis. What else can cause leaking of white blood cells into the urine and interstitial nephritis and large kidneys or masses around the kidney?
HenleInfiltrative disease? Or some other systemic process?
NephronDoes this patient have any other “itis” in the past besides pancreatitis?
Henle(surprised): Yes, pancreatitis, and prostatitis as well. Why?
NephronYes, please get a kidney biopsy as soon as possible. Also, please make sure to look in the lymph node and kidney biopsy specimens for all subtypes of IgG.
Henle leaves the room in a rush and returns a day later.
HenleMore puzzling than I thought. No lymphoma. The lymph node biopsy specimen showed IgG4-positive plasma cells with fibrosis, consistent with IgG4-related disease. The kidney biopsy specimen also showed IgG4-related interstitial nephritis with significant chronic changes.
Nephron(with confidence): Infiltrating lymphoma in the kidney can lead to large kidneys, sterile pyuria, and AKI, but IgG4 disease is a mimicking disease and often missed, as in this case. In addition, the proteinuria might have been tubular in origin, given that the glomeruli appear normal in many cases.
Henle is stunned.
NephronThere were subtle clues here, but clearly this was not diabetic nephropathy. This was not MGRS, either. You went through a systematic process, and a kidney biopsy was essential here.
Henle(puzzled): But presenting only in the kidneys and in no other place? Is that possible?
NephronThis is a systemic process and has been in this man’s body for years. Pancreatitis might have been the first “itis” that this presented with. This disease causes inflammation and formation of fibrosis at several sites. Autoimmune pancreatitis was one of the first states in which IgG4 disease was discovered in 2003. IgG4-related kidney disease can have any pattern of renal involvement: the glomeruli, tubules, and interstitial vessels, and also the renal pelvis, may all be affected. The most frequent renal manifestations are IgG4-related tubulointerstitial disease (most common), membranous GN, obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis, prostatitis, or ureteral inflammation. The role of IgG4 in the pathophysiology of IgG4-related kidney disease is still controversial. Cellular immunity, particularly T cell–mediated immunity, might be playing a major role.
HenleCan’t you just diagnose using IgG4 levels in the serum?
Nephron(angrily): Life is always not that simple, Henle. A diagnosis should not be made solely on the basis of serum IgG4 levels because there are both false positives and false negatives in serum IgG4 testing. Elevated IgG4 does not equate to IgG4-related kidney disease. A serum IgG4 level >1350 mg/L is a suggested cutoff value for the diagnosis of IgG4-related kidney disease; however, that is to be used as a useful screening tool, not a standalone diagnostic marker. A tissue diagnosis is indeed important as a differential diagnosis in lymphoma or a paraprotein disorder.
NephronIn addition, often in this disease the complements might be low. In your case, they were normal.
HenleI am still confused regarding this disease. Is this a precancerous condition, an autoimmune disease, or an allergic reaction?
Nephron(smiling): Glad you asked, my friend. Always ask! The current hypothesis is that this is a combination of autoimmune and allergic diseases. CD4+ cytotoxic T cells orchestrating the disease are sustained by continuous antigen presentation by B cells and plasmablasts. And if you are an onconephrologist, think of the patient being on a checkpoint inhibitor. The immune system is constantly activated and causing all forms of “itis.” In IgG4 disease, there is also a lot of “itis” and inflammation of similar sorts. A T-follicular helper cell response that is separate from the CD4+ cytotoxic T lymphocytes is likely to be responsible for the development of germinal centers within lymph nodes (and involved organs) and the production of cytokines that drive the IgG4 class-switch, culminating in the creation of IgG4-secreting plasmablasts and long-lived plasma cells. B cell depletion often does not lead to the complete normalization of serum IgG4 concentrations even after clinical remission, implying that long-lived plasma cells continue to make this immunoglobulin.
HenleI assume treatment with steroids or immunosuppression will help this process?
NephronHigh-dose prednisone can help with tapering over weeks and then maintenance over 1 to 4 years. In refractory or frequently recurrent cases, immunosuppressive medications including mycophenolate, cyclophosphamide, and azathioprine can be combined with steroids. I am sure “Vitamin R,” or rituximab, has been used in many tough cases. Seems like the renal world is in love with that agent. Regardless, in IgG4 disease, with appropriate immunosuppressive treatment, kidney function can be preserved in most patients.
NephronWhat are you waiting for?
Henle leaves to discuss the case with his hematology colleagues.
A few weeks later
HenleWhat a dramatic response. After steroids were initiated, the patient’s renal function improved, and his proteinuria resolved. In addition, I repeated a sonogram, and the kidneys are now 10 cm bilaterally. This is amazing!
NephronWell done, apprentice. Keep an open mind. Again, with a renal disorder you diagnosed a systemic disease that saved this patient’s life. This was a complex disease and a complex case—although I recently read that nephrologists treat the most complex patients. That is a true statement. Complexity creates curiosity, and for a detective, it creates a venue for solving tough cases! Henle, let’s get a cup of my favorite coffee.
Detective Nephron was developed by Kenar D. Jhaveri, MD, professor of medicine at Zucker School of Medicine at Hofstra/Northwell. Special thanks to Dr. Rimda Wanchoo, associate professor of medicine at Zucker School of Medicine at Hofstra/Northwell, for her editorial assistance. This case was provided by Smitha Anam, MD, fellow, and Enrica Fung, MD, assistant professor, both from Loma Linda University, Southern California. Send correspondence regarding this section to or

Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. L.O. Henle, a budding nephrologist, presents a new case to the master consultant.