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.

Understanding nPCR (Normalized Protein Catabolic Rate)

The normalized protein catabolic rate (nPCR) is a formula commonly used to assess dietary protein intake in dialysis patients, as a means towards determining nutritional adequacy, a major problem in many ESRD patients. For example, say you have a patient on dialysis who has a pre-dialysis BUN of 18 mg/dL--reasonably low, right?. This could mean that the patient is a well-nourished individual who is adequately dialyzed. But it could also mean that the patient is malnourished, which is often linked to poor appetite that is linked to inadequate dialysis. The nPCR helps distinguish between these possibilities.

The nPCR is reported in grams of urea nitrogen per kilogram per day, and can be calculated using several methods. One of them is shown here:

nPCR = 0.22 + (.036 * intradialytic rise in BUN * 24)/(intradialytic interval).

For instance, if the pre-dialysis BUN is 70 and the post-dialysis BUN is 18, and the intradialytic interval is 44 hours (e.g., there is an interval of 44 hours from the end of one dialysis until the beginning of the next), then the nPCR is calculated to be 1.24 g/kg/day. As you can see, a large intradialytic rise in BUN is generally indicative of adequate nutrition. Most guidelines specify maintaining the protein intake above 1.0 - 1.2 g/kg/day in dialysis patients, with values less than 0.8 g/kg/day being equated with malnutrition.

If the patient has significant residual renal function, then one must add a term that takes into account endogenous urea clearance. Importantly, these equations are only valid for individuals in steady state, and are not as helpful in the setting of acute illness. Separate equations exist for peritoneal dialysis, since the BUN levels are relatively constant and therefore pre- and post- levels cannot be used to estimate nPCR; rather urea levels in serum and peritoneal filtrate can be compared. Nutritional status can be especially important to assess in patients on peritoneal dialysis, since these patients are at high risk of losing albumin in the peritoneal filtrate. There is a nice discussion of this topic in Up-To-Date ("Protein catabolic rate in maintenance dialysis"), which includes alternative formulas for nPCR that incorporate Kt/V.

Complement Levels & Glomerulonephritis

Although the complement cascade is an essential aspect of the response to infection, it unfortunately can be activated by a variety of means in several types of kidney disease. In common day clinical practice, most of the time we determine complement activity by assessing serum C3 and C4 levels; a decreased C3 level means that the alternative complement pathway has been activated whereas a decreased C4 level means that the classical complement pathway has been activated. This is especially important in the workup of glomerulonephritis of uncertain etiology.

Sometimes, the pattern of C3/C4 levels can give a clue as to the specific diagnosis. Disorders in which C3 is decreased but C4 is not include MPGN and post-infectious glomerulonephritis, indicating a tendency for the alternative pathway to be active moreso than the classical pathway. Activation of the classical pathway will typically result in lowering of both C3 and C4, and therefore disorders in which BOTH C3 and C4 are decreased include lupus nephritis and cryoglobulinemia. These rules may not be perfect, but can potentially give a hint as to the mechanism of inflammation in glomerulonephritis.

Secondary Causes of Membranous Nephropathy

Although the majority of membranous nephropathy falls under the "idiopathic" category, there are a variety of causes of secondary membranous nephropathy. It is quite important to eliminate these entities as possible diagnoses, as the treatment for secondary membranous nephropathy relies primarily on treatment of the underlying cause of disease whereas idiopathic membranous nephropathy often involves the use of steroids and/or cytotoxic agents.

Broadly speaking, the secondary causes of membranous nephropathy can be broken down into 4 general categories:

1. Infection-associated Membranous Nephropathy: hepatitis B and hepatitis C are both associated with membranous nephropathy. Because diseases such as malaria, schistosomiasis, TB, and leprosy are likewise associated with membranous nephropathy, secondary nephrotic syndrome is likely much more common in developing countries subject to these tropical diseases. Syphilis is also on the list.

2. Disease-associated Membranous Nephropathy: it is well-known that MN may be see in lupus ("WHO Type V Lupus Nephritis") either alone or in combination with other lupus-related pathologies. A variety of the other conditions associated with MN are also autoimmune diseases (e.g., rheumatoid arthritis, Sjogren's syndrome). Diabetes mellitus and membranous nephropathy have also been linked, as has sickle cell disease.

3. Drug-induced Membranous Nephropathy: the classic offenders are gold, penicillamine, NSAIDs, and captopril, though there are case reports for many others.

4. Malignancy-associated Membranous Nephropathy: although there appears to be a increased relative risk of solid tumors and lymphomas in patients with membranous nephropathy as compared to the general population, this association is still somewhat poorly defined and remains controversial. Many would simply recommend age-appropriate cancer screening (e.g., mammogram, screening colonoscopy, etc) in the patient with newly-diagnosed nephrotic syndrome without any other evidence for malignancy rather than a large-scale imaging workup.

Serum Amyloid P prevents renal fibrosis

Congratulations to my colleague at the Brigham, Jeremy Duffield, who made the cover of Science this week for demonstrating human Serum Amyloid P (hSAP) potently inhibits fibrosis in two independent models of renal fibrosis. hSAP is a naturally circulating soluble pattern recognition receptor, and radio-labelled SAP is used clinically to identify sites of amyloid deposition in systemic amyloidosis. In the studies, hSAP was given to mice with either unilateral ureteric obstruction or unilateral ischemia reperfusion mediated kidney injury. In both cases, hSAP potently suppressed fibrotic collagen protein and collagen gene expression in a sustained fashion, preventing the development of interstitial fibrosis. hSAP acts by binding danger molecules at sites of tissue injury, causing the complexes to be cleared by the Fcγ family of receptors on macrophages. This results in suppression of inflammatory and fibrotic gene and protein expression in monocyte-derived cells, via an interleukin-10 dependant mechanism.

These findings raise the possibility of using hSAP as a therapy for kidney diseases with a prominent fibrotic component, such as diabetic nephropathy or chronic allograft nephropathy. A recombinant form of human Serum Amyloid P, PRM-151 (rhSAP), is already in phase 1 trials.

Results of Kidney Biopsy Poll

The results from last week's Poll of the Week are in, and in general, a majority of individuals (64%) felt that their training programs  did a good job of teaching them the art of the renal biopsy, while a significant minority (36%) felt that they were ill-equipped to perform biopsies at the end of their fellowship experience. Interestingly, there was an identical breakdown of those who felt that nephrologists' renal biopsy skills are still relevant (64%) compared to those who felt that it's okay to leave the biopsies up to the interventional radiologists (36%).  Here is another way to look at the results:

 

A 2008 CJASN article by Drs. Berns and O'Neill ("Performance of procedures by nephrologists and nephrology fellows at U.S. nephrology training programs") states that virtually all nephrology fellowship programs provide training in renal biopsies, with about half of those training programs providing the fellow with instruction in hands-on renal ultrasonography.  Interestingly, the number of biopsies required for "certification" in each program varies widely, from only two to up to fifteen, and very few professional guidelines exist which specifically address what should constitute adequate training for kidney biopsy.  

Check out the latest Renal Fellow Poll of the Week on the left, which has to do with the newly-proposed Kidney Allocation System (KAS).  Because the Poll widget only allows the question to be rather short, I had to radically simplify what the plan proposes--I openly acknowledge that the plan is more complex than making it "easier for younger patients to get transplants, but harder for older ones", so to read a more detailed description of precisely what the KAS plan is, you can click here.  

TREAT Trial

The TREAT trial was one of the bigger stories to emerge from this years ASN. This was a large, multicenter trial of darbepoeitin (Aranesp) vs. placebo in 4000 predialysis CKD patients with type 2 diabetes and anemia. The two groups did not differ in the two primary endpoints of all-cause death or cardiovascular event and death or end-stage renal disease and on the plus side, compared with placebo, treatment with Aranesp did result in some improvement in fatigue, less need for red-cell transfusions and a reduction in cardiac revascularization. However, there was also a significantly increased risk of fatal or nonfatal stroke (5% versus 2.6%; HR 1.92, 95% CI 1.38 to 2.68), which was not explained by systolic blood pressure.

The Aranesp group was treated to achieve a target hemoglobin of 13 g/dL, which is higher than I generally aim for, and it may be that a more restrictive dosing strategy could mitigate the risk of stroke. Even still, these findings create a lot of uncertainty and unease as to how best manage anemic CKD patients in the clinic.

As a footnote, this study also lends fuel to the growing literature on ESA’s driving the progression of cancer. In patients with a history of malignancy at baseline, cancer death was an order of magnitude more common in the darbepoetin group (7.4% versus 0.06%, P=0.002).