Detective Nephron: A 65-year-old woman with hematuria and a subacute rise in creatinine

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Detective Nephron, world-renowned for expertise in analytical 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 consultant.

NephronWhat do we have today, my dear apprentice?
HenleA 65-year-old woman with hematuria and a subacute rise in creatinine.
NephronI see that you have taken a break from the electrolyte disorders and moved to the glomerular disease world. This is why nephrology is so much fun: it has so much variety to offer diagnosticians.
HenleHmmm getting back to the case, she was in her usual state of health until a few weeks ago, when she started noticing foamy urine and fatigue.
NephronWhat is her creatinine level now?
HenleIt was 0.7 mg/dL 1 year ago and 1.2 mg/dL 2 months ago. Now it is 1.9 mg/dL.
NephronDid you look at her urine?
HenleYes, of course I did. There are many red blood cells and a few white blood cells. The red cells are dysmorphic, but no red cell casts that I could notice, and no signs of any granular casts.
NephronIs there any proteinuria?
HenleYes, there is: 3.5 grams in a 24-hour urine collection.
A knock on the door is heard.
NephronCome on in, Dr. Slit Podocyte. You are just in the nick of time again.
Henle looks at Dr. Nephron as Dr. Podocyte enters the room.
NephronDr. Podocyte helped us solve our last case in glomerular disease. Lets take this one together. Does that sound good, Slit?
PodocyteGood morning, Henle. I am Dr. Slit Podocyte. Nice to meet you.
NephronHenle has a case here of an elderly lady with hematuria, a subacute decline in renal function, and nonspecific complaint of fatigue.
HenleHer anti nuclear antibody, antidoublestranded DNA, and anti neutrophil cytoplasmic antibody titers are negative as well. Her C3 is slightly depressed, and she has a normal C4 value.
NephronStop right there. So you are telling me you already have a diagnosis? Why are you presenting this case, then?
PodocyteSounds as if you have a glomerular disease with low complements. Very few would present in this manner.
HenleGiven the low C3, I would consider postinfectious glomerular process, membranoproliferative glomerulonephritis (MPGN) pattern of injury, or a proliferative pattern such as in lupus nephritis.
PodocyteYou are doing a great job. Given the negative serologic results, lupus nephritis is less likely but is always a possibility. Can you expand on the MPGN pattern of injury and perhaps think more in terms of C3 glomerulopathy?
NephronMy dear apprentice, you still have a lot to learn.
HenleWell, historically, MPGN has been classified as type I, II, or III on the basis of electron microscope (EM) findings. A more useful classification is based on immunofluorescence (IF), which is clinically more useful. And sometimes a persistent postinfectious glomerular nephritis (GN) will also present with low C3 levels. The term atypical postinfectious GN is used for such cases.
NephronPlease continue as I drink my coffee.
PodocyteThe EM approach should likely be replaced by the IF approach.
HenleBut in this patient, we dont even know that its MPGN. It could be postinfectious GN for all you know. The biopsy was done only this morning.
PodocyteExcellent. Lets discuss after the biopsy findings what to do next.
NephronInteresting! Not the approach I usually take.
Henle returns a few hours later. Slit and Nephron enjoy their warm coffee.
PodocyteWhats so interesting? Just because its not an electrolyte case. This is actually fascinating! In glomerular diseases, we need biopsies to make a diagnosis.
HenleIs there a connection of this to the presentation?
PodocyteWhat did it show?
HenleYesand the biopsy confirmed an MPGN pattern of injury on light microscopy.
PodocyteJust as we suspected. Now IF is the next important part of the biopsy. Also, I am glad you use the term MPGN pattern of injury rather than MPGN because this is truly a pattern of injury with most causes being secondary in nature.
HenleHmm IF showed immunoglobulin (Ig) G (3), kappa (3), and C3(3); the other results were all negative. EM showed subendothelial deposits, as one would expect in an MPGN pattern.
NephronI am assuming she has MPGN type 1.
PodocyteLets discuss this in more detail. Not so soonand I dont agree with Dr. Nephron. How about staining for lambda?
HenleNegative for lambda.
PodocyteShe has monoclonal deposits in the IF findings. Isnt that the case?
HenleYes, IgG kappa and C3.
NephronAhh! She has myeloma!
HenleWhere does MPGN fit in all this?
PodocyteGood question. Think of MPGN again as a pattern of injury that results from capillary wall injury. If there is no staining in IF (which also can happen), then such a pattern might be seen in chronic thrombotic microangiopathies from medications, from radiation, after stem cell transplantation, and so forth. If there is IF staining, you move to diseases resulting from deposition of immune complexes or complement factors or both. Now here is the major breakdown: if there is C3 and immunoglobulin staining, one has to consider many secondary causes such as infections, autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), and paraprotein-mediated diseases. The paraprotein-mediated diseases usually have a monoclonal component seen at biopsy. Classically, monoclonal gammopathy of undetermined significance (MGUS) has been noted to be a major cause of the MPGN pattern of injury. The old classification of MPGN type I would fit under this category if no secondary cause is found and would be labeled idiopathic MPGN.
HenleThen how do you define C3 glomerulopathy?
NephronGood question. Now, as we already noted, IF was positive for C3 and immunoglobulins, so we should be thinking infections, autoimmune diseases, and paraprotein deposition. If the IF is positive only for C3 strongly, you get an MPGN pattern resulting from deposition of complement factors. This is defined as C3 glomerulopathy. What the C3 glomerulopathy is trying to tell us is that the injury is due to a problem in the alternative pathway complement cascade and hence leads to deposition of complement factors that ultimately might lead to double contouring and MPGN-like lesions. One needs to keep in mind that other patterns such as mesangial proliferative, diffuse proliferative, and even crescentic GN can result from all these causes of MPGN.What constitutes C3 glomerulopathy is glomerular deposits of complement C3 (and other complement factors of the alternative and terminal pathway) and absence of immunoglobulin within the glomeruli or just pauci immunoglobin deposition. C3 glomerulopathy is further classified into dense deposit disease and C3 glomerulonephritis, both of which result from alternative pathway abnormalities. Why one results in dense deposit disease and another in C3 glomerulonephritis is not known. However, this may have to do with where the alternative pathway is disrupted, allele variants, and severity of disruption.
HenleWhy is this classification important?
NephronPerhaps we can look for these causes in specific cases and tailor the treatment accordingly. Medications affecting the complement system such as eczulimab might be of benefit in some of these disease entities in the near future. With regard to Ig-positive MPGN, for example, MPGN associated with monoclonal gammopathy is likely to recur after transplantation, whereas MPGN due to infections is less likely to recur. There are few data about recurrent MPGN causes by alternative pathway abnormalities, although early studies suggest that these also recur. If one suspects C3 glomerulopathies, it’s worth checking the complement cascade function: C3 and C4 levels. Check also for C3 nephritic factor, factor H antibodies, and serum membrane attack complex levels. Tests of genetic mutations for CFH, CFI, and allele variants are also available.
PodocyteGood work, Dr. Nephron. You have done well!
HenleThis is very revealing. In other words, in this case, she likely has MGUS that hasn’t been diagnosed.
Henle leaves, and returns a few days later.
NephronFine work, Detective!
PodocyteIt’s always nice to drop in and discuss a good case of glomerular disease.
HenleHer serum free light chains suggested an elevated free kappa-to-lambda ratio of 5. Her bone marrow biopsy specimen showed 5 percent plasma cells, which is consistent with MGUS. Greater than 10 percent and she would have a myeloma. So now we are left with MGUS and MPGN. Do we treat or not? And what do we treat with?
NephronThis is a tough question you are asking, Henle.
PodocyteTo me it seems that if damage is happening in an organ, particularly in the kidney, because of the monoclonal nature of this light chain kappa, how can we call this “undetermined significance”? It is clear to me that it is significant. Unfortunately, the hematology community needs to learn more about this entity and perhaps not call it MGUS when there is end-organ damage. Some cases of this have been successfully treated with anti–B cell agents such as rituximab. However, it makes more sense to treat this entity as a paraprotein, targeting agents such as those used in multiple myeloma. But, until we have more data, we might not be able to do anything.
NephronWe prescribe medications all the time, and we have to be careful regarding the potential drastic effects they can have on the body. My dear apprentice, MGUS is a chronic entity, and so is MPGN, and it is possible that she might not need treatment for now. Conservative management is reasonable, given the lack of data.
PodocyteI disagree. I would give her rituximab if B lymphocytes were responsible for the monoclonal gammopathy. Rituximab would not be effective if plasma cells were responsible for the monoclonal gammopathy. This raises the question whether drugs such as bortezomib would be of benefit in such cases.
Henle watches them argue.
NephronHenle, as you can see, we don’t have a final answer for you. That is perfectly reasonable and the main reason why ongoing research in nephrology is critical. The current status of nephrology research is grim. It needs more energy and enthusiasm from residents, students, and fellows to move the field forward. Nevertheless, from a single entity of MPGN, you diagnosed a potential premalignancy state in this patient. Never underestimate the power of the nephrologist.
Detective Nephron was developed by Kenar Jhaveri, MD, assistant professor of medicine at Hofstra Medical School and an attending nephrologist at North Shore University and Long Island Jewish Medical Center in Great Neck, New York. Thanks to Dr. Rimda Wanchoo of the Weill Cornell Medical Center, New York, and Dr. Sanjeev Sethi of the Mayo Clinic, Minnesota, for their editorial assistance. Send correspondence regarding this section to kjhaveri@nshs.edu or kdj200@gmail.com.
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