GlomCon Nephropathology Essentials

The goal of the GlomCon Teaching Platform is to enable Nephrologists, Nephropathologists, and trainees in Medicine, Nephrology, and Pathology to connect with each other to 1) Discuss challenging cases, 2) Share clinical experiences and 3) Obtain the expertise of participating faculty and invited speakers. Access to this resource is completely free!

Going forward, every Tuesday (same time weekly, 11am EDT) there will be a case-based conference, fellow's interactive conference, or renal pathology seminar.

You are invited to the inaugural session of GlomCon Nephropathology Essentials on Tuesday, June 5th at 11 am EDT. The first session will be led by Dr. Isaac E. Stillman and will focus on the basic principles of renal pathology.

For more on the Nephropathology Essentials webinars, visit: https://glomcon.org/nephropathology-essentials/

To join the meeting go to: https://glomcon.zoom.us/ and select 'Join a Meeting'. Enter the Meeting ID into the web site (or connect directly from your Zoom app).

Meeting ID: 394-801-817

You HAVE to be logged into ZOOM to join the session. You may either create a free ZOOM account, or sign in through a Google or Facebook account (if you have one). 

Alternatively, use your institution's 'Polycom' system, enter IP address:
US West: 162.255.37.11
US East: 162.255.36.11
Europe: 213.19.144.110
Then, enter the Meeting ID: 394-801-817

Lonely Glomeruli

One of the difficulties in doing molecular research on the kidney is the diversity highly specialized cells that exist in the glomerulus. As a result, it is important to be able to isolate glomerular tissue from the surrounding kidney. A recent paper in KI detailing a method for isolated podocytes reminded me of a relatively simple technique that I was taught a few years ago for glomerular isolation in mice.

The technique was first described in this paper from 2002 but in brief, it involves injecting the mouse heart with deactivated magnetic beads (after euthanizing them of course). Some of these beads (which are just 5µm in diameter) get trapped in the glomerular capillaries. The kidneys are then removed, minced, digested and passed through a 100µm strainer to remove any larger particulate matter. Finally, the remaining tissue is suspended and exposed to a magnet to pull the glomeruli (with the beads inside) out of the mixture. The glomeruli are then left stuck to the wall of the tube next to the magnet and they can be easily removed.

The picture below is a low-power view of the glomeruli following isolation. You can see that there is very little non-glomerular tissue present, which is remarkable given that the glomeruli make up such a small proportion of renal tissue.

Below is a higher power view of 3 more glomeruli following isolation. You can clearly see the microbeads trapped in the glomerular capillaries. Cool science. (Click on any image to enlarge)

Pathology Case of the Month

An elderly woman presented for evaluation to the rheumatology service with arthritis and neuropathy. She was hypertensive and had microscopic hematuria with dysmorphic red cells on microscopy. Her creatinine was 1.6 which had not changed in the previous year. She had no history of diabetes. Her serology was notable for a positive ANCA, elevated CRP and ANA 1:640. The sense was that despite the presence of the ANCA, the likelihood of a vasculitis was low due to the indolent course but she went on to have a renal biopsy.

A low power view of the renal cortex revealed an obvious nodular appearance of the glomeruli. The tubules were relatively well-preserved.

High-power view of the glomerulus was characteristic of nodular glomerulosclerosis. Notably, there was no evidence of any crescents and no thickening of the capillary loops.

 IF was completely negative

There were no medullary or BM inclusions on EM

Nodular glomerulosclerosis is classically associated with diabetes and this is the first diagnosis that came to the mind of the pathologist when the slides were processed. However, the patient had no history of diabetes. Alternative diagnoses include chronic MPGN and dysproteinemias. There was no evidence of either in this case. The final diagnosis was "Idiopathic Nodular Glomerulosclerosis". This is somewhat of a misnomer as these days, it is thought that IGN is directly related to smoking. The mechanism is uncertain but is suggested in the flow-chart below from an a review in JASN on the topic.

This is not a benign condition. In the largest case series to date of 23 patients with biopsy-proven IGN, 6 patients reached ESRD in a median of 26 months. Predictors of progression included not quitting smoking, lack of ACEi use and the degree of atrophy, fibrosis and arteriosclerosis on renal biopsy.

(Click on any image to enlarge)

Image of the Month - GN with a twist

A man in his 30s with no significant medical history presented to the ED following a fainting episode. Routine screening found an abnormal creatinine, hematuria and proteinuria. Serological work-up including complements were negative. In view of a slowly increasing creatinine and 3g of proteinuria, he was referred for a renal biopsy.

A low power view of the renal cortex revealed diffuse fibrosis and interstitial inflammation. There was evidence of focal sclerosis with occasional sclerosed glomeruli.

A high power view of a typical glomerulus revealed mesangial expansion and proliferation with normal-appearing capillary loops. There were no cellular crescents and some glomeruli had evidence of focal sclerosis.

Examination of the renal vasculature revealed severe arterial sclerosis and moderate arteriolar sclerosis.

Not unexpectedly, the EM found extensive mesangial deposits with no sub-endothelial or subepithelial deposits and a normal appearing basement membrane. The podocyte morphology was also well preserved.

Top on the list of differentials in this patient was IgA nephropathy and as expected, the immunofluorescence revealed extensive mesangial staining for IgA. At this point, many pathology labs would leave it at this and make a straightforward diagnosis of IgA. However, our lab can't just leave it alone and generally also routinely stains for immunoglobulin light chains. Typically in IgA nephropathy, lambda light chains are more prominent than kappa light chains on IF but the difference is not marked.

 

In this case, there was almost no staining for kappa and marked lambda staining. This suggests that a monoclonal IgA is present. The serum immunofixation was negative and so far, a bone marrow biopsy has not been done.

Monoclonal IgA is rare and has only been reported in case series in the literature. It is often accompanied by a positive SPEP and is thought, at least in some cases, to be related to a clonal expansion of B-cells. About 20% of myeloma is IgA but this is rarely associated with deposition in the kidney (although this may be due to a lack of biopsies). Anecdotally (speaking to my colleagues), this form of IgA nephropathy is relatively aggressive with rapid progression. This has not been formally studied. The question that arises is how to treat this. Should it be treated with rituximab/steroids/velcade? This is relatively toxic treatment and in the absence of an abnormal bone marrow or serum evidence of a monoclonal gammopathy, it is difficult to make this argument. However, one would wonder about the likelihood of recurrence after renal transplantation. 

In this case, the decision has been made to hold off on aggressive treatment for the moment with regular monitoring of the serum. This is a fascinating case and just goes to show how diverse a condition like IgA can be. 

(Click on any image to enlarge)

Pathology Image of the Month

A 47 year old man with ESRD secondary to a chronic TMA presented 3 months following a renal transplant with a rising creatinine (1.44 mg/dl from a baseline of 0.9 mg/dl). His prograf level had ranged from 5-7. His flow XM was positive although no donor-specific antibody was detectable on a single antigen bead. His H&E stain is seen below.

He has a moderate interstitial infiltrate. (A) marks an enlarged, abnormal nucleus with a Cowdry type B inclusion. These inclusions can be seen both in adenovirus infections and in patients with BK nephropathy. (B) marks a lymphocyte in the proximal tubular epithelium – tubulitis. The absence of significant necrosis makes adenovirus less likely and, given the recent history of a renal transplant, the likeliest diagnosis therefore is BK nephropathy.

This image shows immunohistochemical staining for BK (SV-40) in the renal cortex. There is some cytoplasmic staining in surrounding tubules. However, this is non-specific. There is intense staining in the nuclei of infected cells (which are also enlarged relative to the non-infected cells) and this is highly specific for BK-virus infection.

The final image is a EM image of an infected cell. Because BK-viral infection tends to be focal, it is unusual to actually see this appearance on EM. There is the appearance of a crystalline array of viral inclusions and in BK-virus, these tend to the in the range of 40-50 nm in size. In contrast, the inclusions in patients with adenovirus tend to be larger.

(Click any image to enlarge)

Image of the Month

A man in his early 60s was being treated for metastatic adenocarcinoma of the lung for 2 years. Recently, he had  been complaining of increasing hemoptysis and a PET CT was performed which showed progression of his disease. He presented to the ED with general malaise, edema and abdominal bloating. His creatinine had increased from a baseline of 1.0 to 1.5mg/dl and he had >10g urinary protein daily. A renal biopsy was performed. Light microscopy revealed thickened basement membranes with some double-contour formation but no definite "spikes" Immunofluorescence showed dense granular staining for IgG along the capillary loops with some minor staining in the mesangium. The diagnosis was early secondary membranous glomerulopathy most likely related to the progression of his malignancy. An EM image is shown below (Click to enlarge)

Subepithelial deposits typical of membranous nephropathy are easily seen in the image (A). The overlying podocytes are damaged and the foot processes are effaced. The lower part of the image (B) shows an area at the junction of the capillary loop and the mesangium. Here, a deposit is also present but it appears that the overlying glomerular epithelium degenerated and is sloughing into the lumen. This is likely due to complement activation and the formation of membrane attack complexes induced by the presence of the deposits and is thought to be the cause of the severe proteinuria seen in this patient. It is important to note that this is not associated with inflammation because the complexes are out of the reach of inflammatory cells which is not the case where subendothelial deposits predominate. This case was not entirely typical because there were occasional subendothelial deposits noted throughout the glomerulus although they were few and their significance was uncertain. 


Thanks to Dr Bijol for the Image

Still mysterious: the elusive circulating factor for FSGS

Important new findings were recently published in relation to proteinuria and FSGS, which are definitely of interest to our community.

First, the punch line:

There is new evidence for a “circulating factor” in recurrent FSGS in a fascinating case of a re-transplanted kidney (here)

BUT

There is growing evidence that suPAR is a non-specific marker of kidney disease and therefore not likely to be the “circulating factor.”(here)

In fact, it appears that it is non-specifically found in CKD, and correlates with a declining GFR.

Now for some details:

The re-transplanted kidney

A letter to the NEJM editor (here) describes an amazing case of resolution of recurrent FSGS after re-transplantation. 

A 27 year old patient with primary FSGS receiving a kidney from his healthy 24 year old sister developed proteinuria in the nephrotic range (up to 25 g/day!) within 2 days of transplantation, and had no improvement after plasmapheresis and standard immunosuppressive treatment. A renal biopsy confirmed foot process effacement, the first hallmark of recurrent podocyte damage heralding recurrent FSGS. Incredibly, with all appropriate consents and institutional approval, the transplant team removed the allograft from Patient 1 and re-transplanted it into another patient who had ESRD due to diabetes. Within 3-4 days, the proteinuria resolved and a repeat biopsy showed resolution of foot process effacement and re-establishment of a normal podocyte architecture. Eight months later, Patient 2 is reported to be doing very well, with good allograft function and no proteinuria.

This case demonstrates in a remarkable way that recurrent FSGS results from an elusive “factor” rapidly produced by the recipient (with primary FSGS), and that the allograft itself can remain fully functional if removed from the influence of this “factor” and placed in another patient.

suPAR is not suPER specific

What may have seemed to be exciting news in 2011, namely the notion that soluble uPAR may be predictive of recurrent FSGS (here), appears to be unfortunately evolving into yet another unsuccessful attempt to identify the ever elusive circulating factor.

Recent work published in Kidney International by Maas et al. (here) confirms that suPAR is not able to distinguish between idiopathic FSGS, secondary FSGS or minimal change disease. 

This is actually not surprising, because a closer look at the clinical data in Wei et al. (here) reveals that the admittedly arbitrary cut-off for separating primary FSGS from all other glomerular disease (3000 pg/ml) did not hold up when tested among their patient cohorts with idiopathic, recurrent versus non-recurrent FSGS (all had suPAR> 3000 pg/ml, thus suPAR could not predict the recurrent from the non-recurrent cases). 

The second figure in the Maas et al. paper may help explain this conundrum: they show a negative correlation between suPAR and eGFR, meaning that as GFR drops, suPAR levels rise, which essentially means that suPAR is simply a marker of CKD.

Future work will no doubt continue to address these issues, but the apparent lack of specificity of suPAR for FSGS casts serious doubt on its proposed role as the circulating factor.

So, the search is still on!!!

FSGS: The Basics

Gearoid did a nice job reviewing the recent exciting findings surrounding primary Focal Segment Glomerulosclerosis (FSGS) and I thought it would be a good opportunity to review some of the sometimes confusing terminology and clinical basics.


To start, it's helpful to realize that the term "FSGS" is used both by pathologists and clinicians to describe related but different things.


In the pathology world FSGS is a nonspecific renal biopsy finding (there are multiple pathophysiologies that can lead to it).


A useful way to understand the key light microscopy findings is to break the name down stepwise. Glomerulosclerosis refers to an increased glomerular extracellular matrix with obliteration of the glomerular capillary lumen. You can see this in the image at the top where on the right side of the glomerulus the capillary loops are open and over on the left they're mostly filled in with pink extracellular material.


The pattern of glomerulosclerotic distribution in FSGS is focal and segmental. The term focal (as opposed to diffuse) refers to only some glomeruli displaying changes while the term segmental (as opposed to global) refers to portions of an individual glomeruli being involved rather than the entire glomerulus which again, you can see nicely in the top image.


To make matters more complex there are five recognized FSGS histologic subtypes:


1. Not Otherwise Specified (NOS) variant
2. Collapsing variant
3. Tip variant
4. Cellular variant
5. Perihilar variant


Each of these has pathogenic and prognostic implications which we'll leave for another post.


In the clinician's world the FSGS histologic pattern is seen in the disease states of primary (or idiopathic) FSGS and secondary FSGS which has multiple associated etiologies (genetic, infectious, drug induced, nephron loss from a variety of other renal diseases and so on). Distinguishing between primary and secondary forms is important because while primary disease is treated with immunnosuppressives, secondary disease treatment involves general CKD management and addressing the associated illness.


Clinically primary FSGS often presents with the insidious onset nephrotic syndrome. Microscopic dysmorphic hematuria is found in roughly half of cases. At presentation, around a third have hypertension and a quarter have impaired renal function. Individuals with continued nephrotic syndrome despite therapy often progress to the need for renal replacement therapy. Secondary forms of FSGS are less likely to present with nephrotic syndrome though exceptions do exist (eg HIV associated secondary FSGS with collapsing variant histology).


The image at the top is taken from the July NephSap which, if you haven't seen it yet, is a fantastic must read. For ASN members it's available online here.

Deciphering the pathologists secret code!

I will share with you some of the tips I learned from my pathologist friend Ibrahim Batal.

When evaluating an allograft kidney biopsy for acute changes, you should:

First, scan at low power magnification, look for arteries, check for necrosis or infiltration:

*Fibrinoid necrosis (seen as the red pink color, Figure 1, star) will automatically indicate Banff type 3 T cell mediated rejection TCMR or severe rejection. Compare the Fibrinoid necrosis of this arteriole to the normal arterial tissue seen in Figure 1 marked by the arrow. To review Banff classification review Nate's prior post.

*Infiltrates seen inside the intima of the arteries (Figure 2, star) are lymphocytes and macrophages, which indicate Banff type 2 TCMR. See how the nuclei of those infiltrates look similar to the nuclei of the infiltrates in the interstitium (Figure 2, arrow) but they look different from the tubular epithelial nuclei that are perfectly rounded (Figure 2, circle).

Second, look at the interstitial infiltrates.

*Normally, the tubules should be packed and back-to-back, if infiltrates exist (Figure 3, blue small cells in the circle), we should be looking at the severity of the tubulitis in the most affected tubule. As you all know the more actively functional proximal tubule has a large strong eosinophilic cytoplasm (Figure 3, star) that differentiate it from the less active small cytoplasm of the distal tubules (Figure 3, arrow).

To differentiate between the tubular infiltrates and the tubular epithelium itself, compare those cells to the interstitial infiltrates, they should look similar. In addition the leukocytes in the tubules appears darker, sometimes with a hallow surrounding.

Now back to the most affected tubule (Figure 4, circle).

*If the infiltrating leukocytes are more than 10 in the absence of arteriolar infiltrate or necrosis, the TCMR is considered Banff 1B.

*If the infiltrates are between 5 and 10, the TCMR is considered Banff 1A,

*If the infiltrates are 4 or less, the TCMR is considered borderline cellular rejection.

*So imagine the sampling error in this classification.

Now will shift to the acute antibody mediated rejection where the tissue injury is mainly manifested in the microcirculation mainly peritubular capillaries and or glomerular capillaries in its typical form.

*First, We look at the peritubular capilarities, you have to “imagine” a capillary (Figure 5, circled) between the different surrounding tubules (Figure 5 stars). The “imaginary capillary” is infiltrated by neutrophils (appreciate the multilobular appearance of the nuclei) and macrophages (Figure 5 arrows).

*Second, Because those pathologic manifestations are not sensitive, we always stain for C4d either by immunofluorescence or immunoperoxidase according to the institutions preference, Immunoperoxidase being less sensitive but easier to perform. C4d should be evaluated in the peritubular capillaries (Figure 6, arrow).

*In contrast to antibody-mediated rejection, when neutrophils are mainly concentrated within the tubular lumen rather than peritubular capillaries (Figure 7, star), then bacterial urinary infection should be high on our differential.

Conclusion: It is always good to have a pathologist as a friend. However, this review should be helpful in trying to interpret renal pathology.

Did you know your endothelium is hairy?

Just heard an interesting talk on endothelial dysfunction and its relation to nephrology.  One thing I learned is that the vascular endothelium is actually "hairy", as demonstrated from this electron micrograph (taken from this website). These little hairs are the endothelial glycocalyx, a gel-like layer of negatively charged proteoglycans and membrane glycoproteins which helps serve as a protective barrier from blood flow for the endothelial cells. You can't see it on standard light microscopy since it apparently requires special preservation techniques not normally used.  There is some data to suggest that vasculopaths and diabetics have a less developed and overall thinner endothelial glycocalyx compared to healthy controls, suggesting the importance of this structure in maintaining a healthy vasculature. 

In the kidney, the glomerular endothelium is a little different than most other endothelia in that they contain fenestrae:  actual pores in the endothelial cells which are large enough to let most proteins pass through, but small enough to exclude circulating blood cells. The glomerular fenestrated endothelium makes up a component of the glomerular filtration barrier (along with the glomerular basement membrane and the podocyte layers), and the classic teaching is that the negatively charged proteoglycans on this layer help form part of the charge barrier keeping albumin from getting filtered (though this is now being debated by some). Here are some pretty pictures of the glomerular fenestrated endothelium:

Classification of Cryoglobulins and MPGN

Cryoglobulinemia is characterized by the presence of circulating antibodies which precipitate at cooler temperatures, and not infrequently leads to renal failure/glomerulonephritis. The stereotypical histologic lesion of cryoglobulinemia is membranoproliferative glomerulonephritis, which takes the appearance on light microscopy of this heavily lobulated glomerulus.

While cryoglobulinemia and MPGN display this link, it is important to realize that each term has its own classification scheme--this can be confusing since both cryoglobulinemia and MPGN each have 3 "Types".

Cryoglobulinemia is classified based on the type of immunoglobulin present in the cryocrit:

Type I cryoglobulinemia is comprised simply of monoclonal immunoglobulins, typically IgM but less frequently IgG, IgA, or serum light chains. Not surprisingly, individuals with Type I cryos typically have a paraproteinemia (e.g., myeloma, Waldenstrom's macroglobulinemia).

Type II cryoglobulinemia is when a monoclonal IgM recognizes and binds to polyclonal IgG's, explaining why Type II cryos are IgM-IgG complexes.

Type III cryoglobulinemia is when a polyclonal Ig recognizes polyclonal Ig. Together, Type II & III cryoglobulinemia are referred to as "Mixed Cryoglobulinemia", and these are the types most commonly associated with hepatitis C.

The MPGN Classification system is as follows:

Type I MPGN is a pattern which can be associated with many different diseases, of which cryoglobulinemia is one. Histologic findings include "tram tracking"/double contours of the GBM, hypercellularity of the glomerular tuft, and a lobulated appearance of the glomerulus. EM may show mesangial and subendothelial immune complex deposits.

Type II MPGN is also known as "dense deposit disease", usually caused by the presence of C3 nephritic factor, and on EM shows ribbon-like electron-dense deposits within the glomerular and tubular basement membranes.

Type III MPGN, which is very rare, apparently includes a many of the features of Type I MPGN along with subepithelial deposits.

Osmotic Nephrosis

"Osmotic nephrosis" is a term which describes a common form of renal tubular injury in response to hyperosmolar substances. It is especially relevant to iv contrast nephropathy, and was first observed in animals and human patients infused with hypertonic sucrose. The pattern of injury is shown below (images from a 2008 AJKD review by Dickenmann et al): by both light microscopy and electron microscopy, there is vacuolization and swelling, predominantly along the apical membrane of proximal tubular cells.

In addition to iv contrast nephropathy, the osmotic nephrosis pattern of injury can also occur in response to IVIG, mannitol, and hydroxyethyl-starch ("hetastarch"). It is useful a reversible injury, but not always. Vacuolated cells can be seen in other forms of renal injury (e.g., calcineurin inhibitor toxicity, renal clear cell carcinoma, foam cells) which must be differentiated from osmotic nephrosis.

Pathology of BK Nephropathy

BK Nephropathy refers to damage suffered to a renal allograft as a result of the polyomavirus BK virus.   It is named based on the fact that it was originally isolated in the urine of a kidney transplant patient with the initials "B.K." in 1971.  Infection with BK virus rarely causes problems in immunocompetent individuals; however, the increased use of potent immunosuppressives such as tacrolimus and MMF have increased the risk of BK nephropathy.

While BK nephropathy is often suspected based on monitoring of either serum or urine BK virus levels, the allograft biopsy is presently an essential aspect of its diagnosis.  A few of the key characteristics of BK nephropathy worth noting:

1.  interstitial fibrosis:  there is a staging system for BK Nephropathy (see this article)--it lists three stages (A, B, and C) which vary according to the degree of interstitial fibrosis and, not surprisingly, is associated with prognosis. 

2.  intranuclear inclusion bodies:  renal epithelial cells may contain large nuclei indicative of viral infection.  Viral infection may also occur in transitional epithelium of the bladder, and when shed into the urine show up as decoy cells, another non-invasive means of helping obtain a diagnosis of BK Nephropathy.

3.  Immunohistochemical staining against the SV-40 T-antigen.  These special stains will often clinch the diagnosis of BK Nephropathy, as it is highly specific for all polymaviruses (the most common of which is BK virus, but on occasion is JC virus).  Staining should be restricted to the nucleus and is a sign of active viral replication.

4.  Electron microscopy demonstrating viral particles:  the viral particles are typically intranuclear, 30-50nm in diameter, and have a icosahedral capsid structure (see below).

the von Kossa Stain for Acute Phosphate Nephropathy

One of the hot topics in Nephrology over the past few years has been the epidemiologic and histopathologic studies suggesting oral sodium phosphate colonoscopy preparations as a cause of acute phosphate nephropathy. As evidence continued to mount, the FDA in December 2008 forbade the over-the-counter sale of oral sodium phosphate products; however, they are still available by prescription under the names "Visicol" and "Osmoprep." These preps are still favored by many gastroenterologists (and patients) based on the fact that it is much easier to take than the more traditional polyethylene glycol-based colonoscopy prep (e.g., "Go-Lytely").

Biopsies of patients with acute phosphate nephropathy tend to show abundant calcium phosphate crystal deposition, mostly within the distal convoluted tubules and collecting ducts, but sometimes also in the interstitium. A good detection method is the use of the von Kossa stain, which stains certain calcium-containing salts such as calcium phosphate a brownish-blackish color.

Banff '07 Criteria Reviewed

Trick question:  where was the 9th Banff Conference on Allograft Pathology in 2007 held?  Hint:  it wasn't Banff (the beautiful national park in western Canada).  Answer:  La Coruna, Spain.  At this conference a consensus regarding the histopathologic classification of renal transplant biopsies was made and exists as an updated form of the so-called "Banff Criteria."  It is currently the most widely-used scoring system for describing renal allograft biopsies.  

The full scoring system along with commentary can be found in this paper published in a 2008 issue of the American Journal of Transplantation.  As I wanted to review this prior to taking my ASN in-service exam tomorrow, I'll write out the salient details of the Classification system.

Class 1 is a "normal biopsy." 

Class 2 is "antibody-mediated changes."  Ideally, both positive C4d staining and circulating donor-specific antibodies are present in the setting of a rising creatinine to make this diagnosis.  In acute antibody-mediated rejection, there are three variants:  (i) an ATN-like picture, (ii) capillary involvement, or (iii) arterial involvement.  In chronic antibody-mediated rejection, there is evidence of chronic tissue injury such as glomerular double contours, peritubular capillary basement membrane multilayering, interstitial fibrosis/tubular atrophy (IFTA), or fibrous intimal thickening in arteries.

Class 3 refers to "Borderline Changes" which is essentially a mild form of T-cell-mediated rejection.  This category is used when there is no intimal arteritis present, but there are foci of tubulitis or minor interstitial infiltration.

Class 4 is a more full-blown form of T-cell mediated rejection.  As with humoral rejection, there are both acute & chronic forms:

The acute form of T-cell mediated rejection is furthermore subclassified as follows.  Since this is the most common form of rejection, it is useful to know:

Class IA: there is at least 25% of parenchymal showing interestitial infiltration and foci of moderate tubulitis (defined as a certain number of immune cells present in tubular cross-sections).  

Class IB:  just like Class IA except there is more severe tubulitis.

Class IIA:  there is mild-to-moderate intimal arteritis.

Class IIB:  there is severe intimal arteritis comprising at least 25% of the lumenal area.

Class III:  there is transmural (e.g. the full vessel wall thickness) arteritis.

Class 5 refers to interstitial fibrosis and tubular atrophy (IFTA), which is the new preferred term for "chronic allograft nephropathy."  Grade I refers to <25%>50% of cortical area involved.

Class 6 is a catch-all term describing changes not considered to be due to rejection--for example, recurrent FSGS or CNI toxicity.  

Differential Diagnosis of Nodular Glomerulosclerosis

I recently had to look up the differential diagnosis of nodular glomerulosclerosis: we had recently sent a clinic patient to undergo a renal biopsy based on a history of nephrotic-range proteinuria (urine protein to creatinine ratio of about 4) and a gradually rising serum creatinine last measured at 1.7 mg/dL. The pathologist was eager to ascribe a diagnosis of diabetic nephropathy upon describing nodular glomerulosclerosis in the biopsy specimen; however, there was one big problem with this diagnosis: the patient did not have diabetes!

So: what else causes nodular glomerulosclerosis besides diabetic nephropathy? Chronic MPGN is part of the differential diagnosis, as are dysproteinemias such as amyloidosis or monoclonal Ig deposition disease. Organized glomerular deposition diseases such as immunotactoid GN, fibrillary GN, or fibronectin glomerulopathy can also result in nodular glomerulosclerosis. Chronic hypoxic or ischemic conditions--as might be found in individuals with congenital cyanotic heart disease or cystic fibrosis, for instance--can also result in nodular glomerulosclerosis. The diagnosis we are entertaining in our patient is an entity termed "idiopathic nodular glomerulosclerosis" (ING), which appears to be associated with a long-standing history of smoking and hypertension. There are several case series of ING which describe biopsy findings as would be expected in diabetic nephropathy in non-diabetic patients, including this review by members of the Pathology Dept of Columbia University.

atheroembolic renal disease

I heard a lecture not too long ago on atheroembolic renal disease which claimed that atheroembolic renal disease is to nephrology as sarcoidosis is to internal medicine. That is to say, it can present in a myriad of fashions, ends up being the diagnosis in a surprising number of complex cases, and pops up an inordinate number of times on tests.

Although spontaneous atheroembolic can occur, much more commonly it is the result of iatrogenesis, with cardiac catheterization being probably the most common offender. Mechanical disruption of atherosclerotic plaques results in a showering of cholesterol emboli to downstream organs, where they are likely to lodge in small arterioles. The crystals induce an inflammatory reaction, resulting in adventitial fibrosis that eventually obliterates the vessel lumen. The crystals of cholesterol are dissolved during fixation, leaving biconvex "ghosts" within the affected arterioles, as demonstrated on this biopsy section.

Other physical & laboratory findings that can tip you off to a diagnosis of atheroembolic disease include livedo reticularis, amaurosis fugax, bluish discoloration of the distal extremities (often in an asymmetric pattern), peripheral and/or urine eosinophilia, and an elevated ESR/CRP.