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1. Past Med Hx: DM type 2 (for a couple of years, most recently started on insulin); Uncontrolled hypertension (160-200/100-130), and hypothyroidism; eye grounds said to be normal
   
   
2. PE: bipedal edema/EKG and labs: no evidence of MI
   
   
3. Labs: BUN/serum Cr: 8/0.9 (on 7/04), and on this admission and next few days (10/25-11/10, 2004) was 26-39/2.2-2.8; 4+ proteinuria; remainder normal or negative
   
   
4. Renal Biopsy: (11/09/04) New onset of renal failure and nephrotic syndrome
   (? thought to be too short a duration of DM as a cause)
   Other lab tests ordered.

Case 1 - Figure 1 -

Case 1 - Figure 2 - Several of the glomeruli appear normal in size and cellularity with patent capillary lumens. PAS reaction.

Case 1 - Figure 3 - Higher magnification showing patent glomerular capillaries. There is one or two very small rounded mesangial nodules. PAS reaction.

Case 1 - Figure 4 - There is a mild to moderate increase in mesangial matrix with a couple of small founded mesangial nodules. PAS reaction.

Case 1 - Figure 5 - Higher magnification of another glomerulus showing a couple of very small rounded mesangial nodules. PAS reaction.

Case 1 - Figure 6 - Another glomerulus showing mild to moderate intracapillary hypercellularity with some closure of the glomerular capillaries. H&E

Case 1 - Figure 7 - Another glomerulus showing more marked intracapillary hypercellularity with closure of the glomerular capillaries. There is also some prominent visceral epithelial cell change, suggestive of proteinuria. H&E

Case 1 - Figure 8 - The glomerulus shows marked closure of the glomerular capillaries with intracapillary hypercellularity and some increase in mesangial matrix. H&E

Case 1 - Figure 9 - The glomerulus show some segmental, but marked prominence of the glomerular epithelial cells. PAS reaction.

Case 1 - Figure 10 - The low magnification of the glomerulus shows a proliferation/hypercellularity within Bowman’s space (and possibly attached to the glomerular tuft). PAS reaction.

Case 1 - Figure 11 - Higher magnification of the glomerulus in slide 1-9. There is a segmental marked hypercellularity (crescent) in Bowman’s Space, apparently attached to the glomerular tuft. PAS reaction.

Case 1 - Figure 12 - Another glomerulus showing several moderate sized mesangial nodules (Kimmelstiel-Wilson nodules). Trichrome stain.

Case 1 - Figure 13 - Another glomerulus showing Kimmelstiel-Wilson mesangial nodules, suggestive of diabetic nephropathy. Trichrome stain.

Case 1 - Figure 14 - Another glomerulus showing Kimmelstiel-Wilson mesangial nodules, suggestive of diabetic nephropathy. Trichrome stain.

Case 1 - Figure 15 - The glomerular tuft is somewhat unremarkable. The glomerular capillaries are patent, and the mesangial/GBM regions appear unremarkable. There is a small segmental hypercellularity in Bowman’s Space (?early crescent formation). Silver methenamine stain.

Case 1 - Figure 16 - Bowman’s space on the right hand side is filled (about 50% of Bowman’s space) by very prominent epithelioid cells (crescent). Silver methenamine stain.

Case 1 - Figure 17 - Another section of the same glomerulus in Slide 1-15 showing what is considered a cellular crescent. Silver Methenamine stain.

Case 1 - Figure 18 - There is segmental tubular thinning/degeneration and a sparse interstitial inflammation (lymphocytes). H&E

Case 1 - Figure 19 - There is no evidence of vascular disease in the few vessels present in the biopsy. H&E

Case 1 - Figure 20 - Electronmicrograph showing patent glomerular capillaries, but a moderate increase in mesangial matrix and especially GBM thickening. No definite electrondense (“immune-type”) deposits were noted anywhere in the glomeruli studied.

Case 1 - Figure 21 - Higher magnification of a glomerulus, showing only increased thickening of the GBM. No electrondense (“immune-type”) deposits were noted anywhere. There are some visceral epithelial changes (segmental “effacement”, etc).

Case 1 - Figure 22 - IgG

Case 1 - Figure 23 - IgA

Case 1 - Figure 24 - IgM

Case 1 - Figure 25 - kappa

Case 1 - Figure 26 - lambda

Case 1 - Figure 27 - C3

Case 1 - Figure 28 - Albumin

Case 1 - Figure 29 - Fibrinogen

1. Light microscopy: There is a diffuse underlying diabetic glomerulosclerosis which in some areas shows small mesangial nodule formation (Kimmelstiel-Wilson nodules).
   
   In addition, there is some focal intracapillary glomerular hypercellularity, and especially what was interpreted as cellular crescent formation (in 3 of 15 glomeruli: 20% of the glomeruli; 2 large, 1 small); these were not thought to be reactive glomerular epithelial proliferations as one sees in collapsing GN/HIV-associated nephropathy or other conditions. . No glomerular fibrinoid necrosis was noted. There is "associated" tubulointerstitial disease (tubular degeneration/thinning, severe, and interstitial fibrosis, moderately severe, somewhat diffuse by trichrome staining).
   
   
2. Electronmicroscopy: There is diffuse thickening of the GBM's and increase in mesangial matrix. No electrondense deposits are seen anywhere. No other major or diagnostic ultrastructural findings are noted.
   
   
3. Immunofluorescence: Negative for all antisera employed (including IgG, IgA, IgM, C3, kappa and lambda light chains, fibrin and albumin). There was in retrospect mild linear staining for IgG and maybe albumin.

Comment: It is difficult to know with certainty whether we are dealing with one disease (an atypical severe advancing form of diabetic nephropathy) or a proliferative GN (with crescents) superimposed upon an underlying diabetic nephropathy. Although crescents can be seen in virtually any renal disease of some severity, definite multiple cellular crescents are generally not thought to be part-and-parcel of a typical/standard diabetic nephropathy (at least in the recent textbook descriptions). Thus the question as to whether this is a severe form of diabetic nephropathy, or an underlying diabetic nephropathy with superimposed glomerulonephritis. The total lack of EM and IF deposits would certainly be against an overt immune complex GN, and there was no clinical evidence for any underlying condition which would like to immune complex deposition (such as deep-seated abscesses, line-nephritis, endocarditis, etc). There was no clinical evidence of any infection anywhere, and no evidence of a recent viral infection; there was no evidence of "systemic disease" (like rash, pulmonary hemorrhage, arthritis, etc). The anti-GBM antibody and ANCA tests were negative (we thought that the ANCA was likely positive, as has been reported in several patients with underlying diabetes; this was not the case). Thus we are left with the notion that there is likely a superimposed proliferative GN that we cannot easily explain. It must be noted in light of the Haas et al. paper in Human Pathology (2003 Dec; 34 (12): 1225-1227; comment on 1235-41) that no "residual " electrondense deposits were noted (even on the GBMs overlying the mesangial areas which are apparently the last of the "humps" to resolve in postinfectious GN), and no C3 was noted in the glomerular mesangial regions by IF, thought by some to be the IF findings of a resolving postinfectious GN). Thus there was no evidence, clinically or via renal biopsy, of a resolving but superimposed acute proliferative post-streptococcal/post-infectious GN. Also, the cellular proliferation in Bowman's spaces (crescents) looked fairly recent.

1. The Typical (Standard) Histology of Diabetic Nephropathy: [1-41].
   The histology of advancing diabetic nephropathy shows an increase in mesangial matrix and usually subsequent thickening of the GBM [1-41]. There was some discussion in the past as to whether the GBM changes or the mesangial changes were primary and most clinically important [22, 23]. However careful morphometric work by Mauer et al [14, 17] suggest that the mesangial changes (increase in mesangial matrix: probably both increased production and decreased removal) are primary, and occur before the GBM thickening, although the GBM thickening is by routine light microscopy easier to demonstrate. Further studies show that sometimes the GBM thickening, is intersperced with GBM thinning. Also, although the standard model is that nodular diabetic glomerulosclerosis (Kimmelstiel-Wilson mesangial nodules) is superimposed upon the diffuse GBM and mesangial changes (diffuse diabetic glomerulosclerosis) studies of individual cases show that sometimes the nodules are present without marked evidence of underlying diffuse diabetic glomerulosclerosis. Another point not often made in the textbooks, is the variation of the severity (or even presence) of diffuse (and nodular) diabetic glomerulosclerosis between the various glomeruli in the renal biopsy; thus some glomeruli can look virtually normal histologically, yet others show diffuse and/or nodular lesions of diabetic glomerulosclerosis. [1-41]
   
   
   Insudative (formerly called Exudative changes) include "fibrin caps", "capsular drops", and the ever-present hyaline arteriolosclerosis. None of these changes are pathognomonic for diabetes, and may be seen with hypertension , sclerosing glomerular diseases, and hyaline arteriolosclerosis in aging. They are however most commonly, severely seen in the diabetic; obviously the diabetic often has hypertension and may be older as well. Usually these insudative changes are seen superimposed upon the diffuse and nodular diabetic glomerulosclerosis, although some authors have seen the severe insudative changes, apparently early on in the course of diabetic nephropathy (possibly in those with underlying severe hypertension, dyslipidemias, etc. [19]. Other changes include the interesting (and as yet not completely understood linear staining, not anti-GBM or anti-TBM, of the glomerular and tubular basement membranes for IgG (subclass IgG IV primarily) and albumin. It has been suggested that the IgG subclass IV deposition is secondary to a charge phenomenon, however the difficulty of eluting off the IgG suggests that it is not totally a charge phenomenon.
   
   There are several papers indicating increased, and possibly more rapid progression of glomerular injury in diabetic nephropathy than usual [36, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55] but few of these primarily directed to the course of diabetic nephropathy discuss true cellular crescent formation.
   
   
2. But is it a crescent? (Or just prominent glomerular epithelial cells in Bowman's space?)(?are all cellular "crescents" created equal?) [56, 57, 58]
   
   This patient shows, in about one-fourth of the glomeruli, prominent cells filling much of Bowman's space. The question is whether this represents crescent formation or not. We are all aware that prominent glomerular epithelial cell formation ("reactive capsular hyperplasia") can be seen in certain conditions (e..g, the "cellular cap" around areas of idiopathic focal segmental glomerulosclerosis), or in HIV-associated nephropathy/collapsing glomerulonephropathy. Also certain authors [56, 57, 58] have suggested that prominent glomerular epithelial cell formation ( ?visceral epithelial cells) can be seen in patients with severe and/or advancing glomerular injury/diseases with proteinuria, and that these prominent epithelial cells are a harbinger of a poorer prognosis (than in those cases/biopsies not showing these prominent cells).
   
   Although everyone understands what a well-formed crescent is and how to diagnosis it, it is likely that occasionally experts in renal pathology will disagree what a crescent is and whether it is present in a specific biopsy/glomerular space. The International Committee for Nomenclature and Nosology of Renal Disease (1975) suggests that a crescent is: "A buildup of several cell layers in a crescentic shape, caused by the proliferation of partietal (glomerular capsule) cells and probably also of the visceral epithelial cells (podocytes) of the glomerulus. The cells rest in a framework of fibrin, basement membrane, and collagen". Many investigators now believe that the visceral epithelial cell proliferation ability is quite limited and that these podocytes play little role in actual bonafide crescent formation. Also, the early crescent may not have much framework of demonstrable fibrin (though it is usually thought to be either the initiating factor and/or a "surrogate molecule" for whatever growth factor(s) are present that cause the crescent to form. Advancing crescents (fibrocellular and/or fibrous) certainly show basement membrane and collagen. The most recent short definition of a "crescent" comes from the upcoming Sixth Edition of Heptinstall's Pathology of the Kidney: "Extracapillary (glomerular) hypercellularity other than the epithelial hyperplasia of collapsing variant of focal segmental glomerulosclerosis". After consideration of all these factors, it was interpreted that this renal biopsy did show crescent formation [56, 57, 58].
   
   
3. Do crescents make it a Crescentic Glomerulonephritis [59] ?
   In the past the percentage of glomeruli harboring crescents to be able to give the diagnosis of diffuse extracapillary (crescentic) glomerulonephritis was a bit arbitrary, with some authors calling it a crescentic (or RPGN) GN with as few as 20-30% of glomeruli, whereas others did not think the percentage of glomeruli harboring crescents was clinically meaningful (in terms of prognosis) until 80% of them had crescents. Although still somewhat arbitrary, most authors now require approximately 50% of the glomeruli to harbor crescents in order to diagnosis "crescentic GN". Certainly, if one has less than 50% crescents, there is still room for worry (re: prognosis), and the diagnostic report should indicate what percentage of glomeruli have crescents in the biopsy studied. Thus, in this patient, the lesion(s) was not called "crescentic GN" (with only 20% or so of glomeruli seen having crescents), but the phrase "with crescent formation" was added to the end of the diagnosis (with the percentage of glomeruli involved stated). The "concordance" (agreement) between experienced renal pathologists as to what is indeed "crescentic GN" and what is not, is over 95% in my experience in the Southwest Pediatric Nephrology Study Group [59], once the determination has been made as to what percentage of glomeruli requiring crescents is determined.
   
   The glomerular intracapillary hypercellularity (seen best in the H&E) in this case ranged from glomerulus to glomerulus, and frankly made the exact categorization of this biopsy difficult at best (especially in the absence of frank immune complex disease).
   
   
4. What about non-antiGBM, non-Immune Complex, ANCA-negative pauci-immune GN with crescents? What is that? How common is that? Could this be that? [60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76]
   It is well known that in addition to the three "streams that lead into the lake of crescentic GN" (immune-complex deposition disease; anti-GBM; pauci-immune ANCA GN) that there is another "wilderbeast" out there (look-out! There may actually be several as of yet undefined ones)!; that is, a pauci-immune ANCA-negative (also negative for anti-GBM and Immune Complex Deposition) crescentic GN whose nature (and cause} is of yet uncertain. [63, 67, 68, 69]. Indeed, in large series of pauci-immune crescentic glomerulonephritis, up to 20% of patients are ANCA-negative (despite indirect IF and multiple negative Elisa studies) [63, 69]. Many of the patients presented by Eisenberger et al. found that the histological findings and prognosis in ANCA-negative patients are comparable with those found in ANCA-positive patients [63]. Extra-renal signs of skin, joint and muscle vasculitis was common, as was glomerular infiltrating inflammatory cells (i.e., neutrophils) , non of which was seen in our patient presented here. It is not known whether ANCA-negative pauci-immune crescentic GN is the result of ANCA's below the threshold of the sensitivity of indirect IF/ELISA, or whether the ANCA levels can wax and wane (i.e., be positive in the past, or the future, but not the present test).
   
   Of course these studies deal with patients with usually at least 50% of the glomeruli present showing crescents.
   
   The mechanism(s) leading to the occurrence of ANCA-negative vasculitis/glomerulonephritis are unclear. We'll know what it is, when we know what it is! It is even possible (?probable) that there are several causes (?T cell defect) that lead to this pattern.
   
   
5. Diseases superimposed upon Diabetic Nephropathy: [77-150]
   What does the literature say? The question in this patient is whether there is one disease (diabetes) or two diseases (with a renal disorder superimposed upon a diabetic nephropathy, or alternatively noted in a patient with diabetes mellitus but without prominent diabetic nephropathy).
   As noted above, any glomerular disease, if severe enough, seems to be able to lead to crescent formation. So many diseases can be superimposed upon a diabetic nephropathy or patients with diabetes. However, typically (and in our standard mental model), crescents are not generally cited in the textbooks and reviews [1, 5, 8, 20] as part-and-parcel of diabetic nephropathy. Elfenbein et al [45] did write an article about crescents in diabetes, but little subsequent literature quote this association in the typical patient with diabetic nephropathy. Indeed many or most of his illustrations show what other investigators might call "adhesions", or "capsular reactions", or something other than standard definite cellular crescents. The question arises, could a severe/rapidly advancing diabetic nephropathy be demonstrated by crescent formation? Should crescents be considered part-and-parcel of diabetic nephropathy? Should Occam's Razor (The Law of Parsimony: Entities are not to be multiplied beyond necessity) be followed here: or will it cut you?
   
   Alternatively, thus, the question is could this be a second, superimposed renal (glomerular) disease superimposed upon a diabetic nephropathy, and what does that do for (to) the patient.
   
   The literature is replete with cases of diabetic nephropathy complicated by other non-diabetic glomerular diseases. The following diseases leading to a second renal (usually) glomerular disease (in addition to diabetic nephropathy) include:
   1. Acute proliferative GN
      
      
   2. Cyroglobulinemic GN
      
      
   3. Crescentic GN
      
      
   4. MPGN 1, 3, and 2 (i.e., dense deposit disease)
      
      
   5. IgA Nephropathy or HSP
      
      
   6. Membranous GN (including focal/seg. MGN)
      
      
   7. Minimal Change Nephrotic Syndrome/Nil Disease
      
      
   8. Focal segmental sclerosis
      
      
   9. SLE
      
      
   10. Amyloidosis
       
       
   11. Mesangial proliferative glomerulonephropathy
       
       
   12. Sarcoidosis
       
       
   13. Immune complex GN (including Focal GN) - not otherwise specified and incidental healed postinfectious GN
       
       
   14. Anti-GBM disease
       
       
   15. Churg-Strauss Crescentic GN
       
       
   16. Fibrillary or Immunotactoid GN
       
       
   17. Microscopic polyangiitis
       
       
   18. Pre-eclampsia
       
       
   19. Monoclonal immunoglobulin deposition disease and Heavy (immunoglobulin) Chain Nodular Glomerulosclerosis, and not to leave out the other components of the kidney -
       
       
   20. A tubulointerstitial nephritis/nephropathy!
   (This list is not complete, as I'm sure someone out there has published additional types of superimposed diseases on diabetes; this list is probably not complete!)
   
   
6. Diseases superimposed upon Diabetic Nephropathy: [77-150]
   As with any study or group of studies, by the time a series has been generated, it must have gone through multiple steps in order to be published: i.e., the patient and their physician identify a nephrologic problem, the patient is referred to a nephrologist, the nephrologist deems it necessary to perform a renal biopsy, tissue is obtain, a diagnosis (correct one) is obtained, and the cases are assembled for study and publication. Thus, there are several steps in the process from patient to literature, and any one can show "entry bias" (i.e., not be truly representative of the groups at large). And of course there is always the comment that "correlation does not equal causation" (or as sometimes said in the test: "true, true, related" or "true, true, unrelated"!) It is always difficult, if not impossible, to know for certain in a single case study whether the association is causal or not (e..g, bee sting and the subsequent development of a membranous GN). Thus, the next question from the literature above:
   
   
7. Why biopsy diabetic patients in the first place, and what is found? [151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164]
   Most patients with diabetes mellitus thought to have a typical diabetic nephropathy (i.e. without unusual clinical features) are not usually biopsied in the United States. This may change in the future with better therapies for diabetes (such as combined kidney-pancreas transplantation; islet cell or stem cell transplantation) and the need to decide when to transplant (earlier may be more effective). Thus, when a series of patients with diabetes is biopsied and published in the literature, it is important to know why they were biopsied; this is usually because of an atypical clinical features/course for diabetes such as sudden onset of severe proteinuria or nephrotic syndrome early in the course of diabetes, or other findings not thought to be typical for diabetic nephropathy, such as hematuria, acute renal failure, etc. They are biopsied in an effort to identify a second, treatable form of renal disease according to Alpers [1]. All of the common glomerular and tubulointerstitial lesions have been documented to occur in diabetic patients [1]. There is a "particularly noteworthy but currently unexplained association between diabetes and the development of idiopathic membranous nephropathy in biopsied diabetic patients" [1].
   
   A number of studies demonstrate this point. Although a number of authors [9] state that so-called Type 1 (insulin dependent; juvenile-onset) diabetes and Type 2 diabetes (adult onset; non-insulin dependent) have the very same morphology and comparable clinical severity, some authors have noted that there is a greater heterogeneity in glomerular structure in Type 2 patients. A study of 52 microalbuminuric and proteinuric northern Italian type 2 diabetic patients showed three general groups of abnormalities: 1.) About one-third had changes of diabetic nephropathy similar to typical type 2 diabetes, 2.) About one-third had a marked increase in the percentage of globally sclerosed glomeruli associated with severe tubulointerstitial lesions, whereas non-sclerosed glomeruli showed only mild diabetic changes, and 3.) Changes typical of diabetic nephropathy with superimposed changes of proliferative GN, Membranous GN, and other superimposed diseases [154].
   
   Another Danish study showed that three-fourths of the proteinuric Type 2 diabetic patients had a diabetic nephropathy; however, one fourth had a variety of non-diabetic lesions including minimal change nephrotic syndrome, glomerulonephritis, mixed diabetic and GN lesions, or chronic GN. All patients with proteinuria and diabetic retinopathy had diabetic nephropathy; only about 40% of patients without retinopathy had a diabetic nephropathy. [27].
   
   Thus, morphologic renal changes in type 2 diabetes are relatively heterogeneous; approximately 25- 40% (depending on "entry criteria") of the patients show a superimposed renal disease, or another renal disease than diabetic nephropathy. (See Powerpoint slides for summary table of 16 reports).
   
   In some cases (diabetic and/or non-diabetic patients), renal pathologic diagnoses have gotten so precise that three renal diseases/glomerulopathies can be diagnosed in the same patient.
   
   In a recent e-mail survey by the NEPHNPPT, most responders considered a recent case of apparent initial IgA nephropathy, with the subsequent development of Class IV SLE, to be one disease . Many made the point that the entire clinical history, labs, LM, EM, and IF (and followup) had to be synthesized into a "Gestalt" (Holistic) diagnosis. Most favored "Occam's razor" (i.e, the Law of Parsimony-one disease) in this case.
   
   
8. Dual Glomerulonephropathies [165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186]
   There are many other examples where there is continuing discussion about whether certain associations are one disease or two diseases, such as IgA and minimal change nephrotic syndrome occurring together, or IgA nephropathy and membranous glomerulonephropathy occurring together. There are many other examples (see Powerpoint presentation). ?One disease (with some nosological drift/expansion?) or two superimposed (collision) diseases? In the absence of more complete knowledge about the etiology/pathogenesis of these conditions, it is difficult to know for sure. [165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186]. Why are there superimposed (multiple) renal diseases? Does one lead to the other? Is it a sign of Autoimmunity?
   
   Drs. Conrad Pirani and Tullio Bertani (among others) were very interested in those patients whose biopsies showed multiple specific patterns of injury. Dr. Pirani always wondered if one pre-existing renal disease could predispose (for a number of reasons) to subsequent, superimposed renal disease.
   
   There early reports of a renal infarction apparently leading to a glomerulonephropathy, and Klassen et al report [172] of a membranous GN with subsequent development of anti-GBM crescentic disease. Suggested pathogenetic mechanisms include: the release of previously "sequestered" antigens and/or alteration of normal, native self-antigens with subsequent molecular mimicry/cross reactions.
   
   At this stage the literature is preliminary. Maybe there is a "forme-fruste" of autoimmunity in these patients that has yet to be detected. In general, we still don't know but maybe should be studied in these patients with "dual glomerulonephropathies".
   
   
9. But can crescents be part-and-parcel of diabetic glomerulosclerosis?
   In a recent review on Rapidly Progressive Crescentic Glomerulonephritis by J.Charles Jennette [69], he included a table describing the frequency of crescents in a variety of diseases from the University of North Carolina database. Of 648 renal biopsy specimens with diabetic glomerulosclerosis (and no other known disease), 3.2% (n=21) had some degree of crescent formation. When crescents were present, on average only 20% of the glomeruli present had crescents. Only 0.3% (n=2) patients had more than 50% crescents ( 69). Thus, crescents in diabetic nephropathy are not at all common, but no unheard of. Their true "meaning" (with regards to diagnosis, prognosis, and therapy) remain unclear (at least to this author).
   
   
10. Fuzzy thinking:
    Diagnostic missteps: Heuristics and Biases: Selected Errors in Clinical Reasoning. There is an evolving literature on diagnostic missteps, and hopefully how to understand them thus preventing them [187, 188, 189, 190, 191, 192].
    
    
11. Why present this case:
    1. There is an epidemic of Diabetes, which will certainly increase in the world; we are likely to see many more renal biopsies in patients with diabetes mellitus.
       
       
    2. Is the Diagnosis one or two diseases? We must always understand that the clinician is at present not performing a renal biopsy on a patient with typical clinical diabetic nephropathy and we must always consider a Differential Dx: if we don't think of it, we won't make the diagnosis.
       
       
    3. We must always consider Dual GN's (one of Dr. Pirani's favorite themes/questions): Are we getting better at that? And what does it say about possible subclinical autoimmunity? Is this a diagnosis of "exclusion" (least objectionable diagnosis)?
       
       
    4. Maybe all "crescents" are not created equal?
       
       
    5. We must always wonder about Heurism/Missteps/Errors/Getting it Right (and how will we know?)

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