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					Dr. Laski ICM 2/14/01

Allison & Thornton

Nephrosis and Nephritis Contd.
Scribe note: There where a bunch of slides in this lecture. They are in the handout, but did not copy very well. I found some similar pictures in Robbins, which may help. I. Membranoproliferative GN (mesangioproliferative/mesangiocapillary GN) A. Primary or Secondary: Secondary to infections or dislipidemia B. Etiology: Tends to effect younger patients than membranous GN. Merbranoproliferative, especially primary, is a disease of late youth to early 20’s. C. Clinical: These patients are usually hypertensive. They have swelling, full nephrosis, elevated creatinine, and active urine. Membranous may have a few RBC’s, red cell cast, hyaline casts, etc. However, Mebranoproliferative GN urine will have numerous RBC’s, WBC’s, and a major bridge disease (?). D. Membranoproliferative GN (MPGN) has both a membranous (involving the basement membrane) and a proliferative component. This means the disease falls in the categories of both nephrosis and nephritis. Very destructive disease E. Treatment: VERY IMPORTANT….MPGN does not get better with the usual treatment approaches for nephrotic diseases. For primary kidney disease, try steroids with immunosuppressives, or steroids without immunosuppresives. If that doesn’t work, try cyclosporin. Which largely means, “We don’t know what we are doing…but some of this works some of the time.” However, in MPGN, none of these things work. In the pediatric population some kids will respond to steroids, but very few. F. Patients will have some fibrin clots in glomeruli and possibly a mild platelet abnormality. Thus, anticoagulation has been the treatment of choice. An Aspirin/day and a little Persantin may be helpful. People who are really aggressive put their pts. on Coumadin, and the “criminally insane” put pts. on cobra venom (Ancrod). Slide: (see Robbins fig. 21-23) You don’t see any capillary loops. The loops are all closed off. Inflammatory disease leads to proliferation of PMN’s, endothelial cells, mesangial cells, macrophages, Etc. Slide: MPGN sliver stain that shows basement membrane. Looks like someone has inflated the basement membrane. There is supposed to be one line, but the membrane has “railroad tracking” (splitting of basement membrane). This is diagnostic of MPGN Slide: (see Robbins Fig. 21-24) EM of Type I and Type II MPGN. Type I occurs because mesangial material invades basement membrane from capillary loops. Type II is associated with electron dense deposits within the subendothelial space. NOT IMPORTANT FOR TEST Slide: IF of MPGN “This slide is probably a little advanced, so don’t worry about it.” G. Treatment continued: There is another arm of therapy that is not specific to MPGN, but is aimed at protein loss. Protinuria appears to be toxic. It triggers fibrotic responses in kidney. The aim is do decrease this process. One approach is to aggressively decrease protein intake, which decreases protein loss in urine and increases serum protein. There is a danger of malnutrition and low patient compliance. A modified solution is to decrease protein to 0.6 to 0.8 grams protein per Kg body weight plus urine loss. A more popular method is to use converting enzyme inhibitors and angiotensin II blockers. These drugs alter the renin/ angiotensin arm and shut down filtration. Another option to reduce filtration is to use a NSAID that is not renal protective. The NSAID’s affect the prostaglandin control of renal filtration. A side effect is decreased GFR, but it is a functional effect rather than the more serious loss of tissue. H. This is a disease that re-occurs in transplants.

II. Diabetic Nephropathy A. Clinical: 1. Usually the pts. have been diabetic for over 8 yrs. The course is easy to trace in type I Diabetics, but a Type II may have had diabetes for many years prior to seeing a physician. 2. Bland urinalysis with protein. 3. May be hypertensive and most people have retinopathy (concordance rate of 85%). Even if he can’t see eye damage, he will send the pts. to an eye doc. It is necessary to catch retinopathy early because its progress can be stopped or at least delayed 4. Diabetic nephropathy is not biopsied. It is strictly a clinical diagnosis. 5. Dialysis is usually need within 3 years of protinuria B. Types: 1. Nodular sclerosis: (Kimmelstiel-Wilson’s disease) Slide: (See Robbins fig 21-32) very bland, pink, eosinophilic, 2. Diffuse thickening of basement membrane with pink “amorphous gunk” (slide shown). You should study with EM to distinguish thickening from amyloidosis. C. Treatment: 1. The best treatment is prevention. A type I diabetic should have microalbumin checked every year after the 5-year mark. Type II diabetics should be checked every year after diagnosis. Measure microalbumin versus urinary creatinine excretion. 2. Monitor blood pressure. Must be NORMAL. If the pt. has any hint of protinuria he wants 125/75. Use converting enzyme inhibitors or angiotensin II blockers for control. If the pt. is hypertensive, give the amt. that normalizes. If the patient is normal, give an amt. that they can tolerate. 3. Measure glucose: The hemoglobin A1C (3 month measure of overall control) should be under 8 or even 7 if the pt. can handle it. 4. How far do you push treatment? Doctors used to not give these meds to pts with renal failure, but now they are even giving to pts. with creatinine levels as low as 3. Aim is to slow down progression and reduce protinuria. III. Amyloidosis A. Clinical: 1. This disease is often associated with chronic infections. Examples are paraplegics with urinary tract infections, familial Mediterranean fever ( most treatable), and primary amyloidosis. 2. Pts. have large kidneys, low BP, poor prognosis, and are not treatable. B. Diagnosis: 1. Biopsy is made away from they kidney. 3. Slide: Vascular lesions and nodular sclerosis that look similar to Diabetes. Diagnosis has to be made by EM using Apple green birefringence (Congo red) stain. NOT IMPORTANT IV. Summary of nephritic diseases: If they are young enough for you to suspect Nill’s disease watch and treat them. If they are “strong for” diabetes or amyloidosis follow them ant treat conservatively. Anything else you can make and argument to biopsy or give a trial of steroids with or without immunosuppression. Monitor the blood pressure and lower GFR. The role of biopsy is to determine diagnosis, prognosis and treatment. Protinuria is a “bad thing.” More protinuria equals more scaring, which equals more progression. If you are not a diabetic you want to keep the protein loss to less that 4 grams per day. This seems to be the critical point where disease seems to be more progressive. For diabetics it should be around 2grams. Nephritic Syndrome I. General characteristics A. Clinical: 1. Pts. may present with edema and hypertension. 2. Hematuria will be present with large numbers of red cells and red cell casts. Membranoproliferative falls here, even if it is often grouped with the nephritic diseases.

Glomerular injury results in decreased GFR and primary salt retention. Everything is expanded…extracellular volume, intravascular volume…blood pressure goes up. The elevated blood pressure actually helps the GFR by having a higher hydrostatic pressure against diminished filtration. When blood pressure is controlled, GFR will decrease. 4. Pts. will also have pulmonary edema and difficulty breathing 5. There is progression towards azotemia and elevated BUN with decreased function. 6. Diffuse vs. Focal: Diffuse (involving more that 50% of the countable glomeruli) includes proliferative GN, PSGN and SLE. Focal involves less than 50% of the countable glomeruli. Focal has better prognosis than diffuse and is not commonly treated. 7. Global vs. Segmental: Global involves the entire glomeruli and segmental only a portion. B. Most of these diseases are immune-complex in origin with one exception. II. Proliferative Glomerulonephritis A. Clinical: Occur in response to immune complexes which can be either formed in the circulation and trapped in the basement membrane, or the antigen is trapped in the basement membrane and the complex is formed when the antibody finds it there. This also happens in membranous GN. The difference is that Proliferative GN complexes trigger the complement cascade, recruit inflammatory cells and induce proliferation. Immune damage decreases filtration. Slide: (see Robbins Fig. 21-16) Glomerulus with no open loops and a multitude of cells which included proliferated endothelial cells and proliferated PMN’s and other inflammatory cells. Slide: IF lights up. You will see IgG and IgM as well as complement components C3 and C4. Slide: EM. (Robbins Fig. 21-16) You will see dense deposits in the subepithelial space called “humps,” which are characteristic or infectious types. B. Post Streptococcal glomerulonephritis 1. A child will present with edema, hypertension, dark urine (oliguria), and occasionally with seizures (hypertension related). Urine will have red cells, red cell casts, and a dark “tea color.” Slide: tea colored urine and a great slide of red cells casts which tell you there is inflammation in the kidney. To find cell casts you need and early morning urine and pretty much have to “do it yourself.” 2. The GN follows a week to ten days after infection. Above the equator, you are talking about a 5-day strep infection. Only certain strep stains cause the infection. If you have an GN that develops 2-3 days into an infection think more about IgA nephropathy, which flares with infection. 3. LAB: GFR will be slightly decreased. But, you will not know that a serum creatine of 1 was .7 two weeks ago. This is a BIG change in function because it is a reciprocal. You have probably lost 30-40% of filtration. Get an ASO titer. Complement will be low, but it is an expensive test. 4. Do not go around biopsing children…It is a clinical diagnosis. 5. Treatment: There is no specific treatment because it is an immune complex disease and a one-shot serum sickness. Overtime it resolves. While waiting give a diuretic and do salt retention. Treat blood pressure aggressively. 6. Outcome: Adults with childhood PSGN may have and increased chance of protinuria and hypertension. C. Other infections that cause GN: 1. Endocarditis, vascular infections, deep-seeded abscesses, prolonged cellulites, osteomyelitis, 2. Diagnosis is made by biopsy. Caution should be taken with bacteremia because the hematoma resulting from the biopsy is prime for an abscess. 3. Treat the underlying disease.


D. SLE 1. The antigen-antibody complexes are double stranded DNA, which you don’t want to get rid off. It is a continuous serum sickness. They key is to change the antigenantibody complex characteristics, by altering the antibody response…Immunotherapy. 2. Type III lupus is focal proliferative GN and the diffuse is Type IV. Type II looks like Berger’s. Type V looks like membranous. Type IV is treatable. E. Mesangial GN 1. Inflammation is away from the capillary loop and towards the stalk. 2. IgA nephropathy (Berger’s)---the single most common primary kidney disease in the world. Can present with GN, or even nephritic syndrome, asymptomatic urinary abnormalities including red cell casts. Diagnosis is made by biopsy and finding IgA on IF. There is really no treatment unless you are one of the rare cases with nephritic syndrome in which steroids my help. 20% will go on to kidney failure. The disease will flare after infections. Slide: (see robins fig. 21-26) more pink, more cells, and thicker that normal. 3. IgG mesangial disease means Lupus. III. Rapidly Progressive GN A. Primary or Secondary: B. Clinical: There is less hypertension, edema, and protinuria, and the pt. doesn’t look that bad. However, GFR goes to “Hell in a few months.” Creatine rises a milligram every week to ten days. There is proliferation not only in the glomerulus but also in the capsule. This creates what looks like a crescent moon in the capsule. The crescents can be cellular or fibrous and indicate that, “you are in deep trouble.” D. Slide: crescent surrounds the glomerular tuft. (Robbins Fig. 21-17) E. Slide: There are three kind are IF. These are liner, granular, or none at all. The smooth or linear IF is a sign of Goodpasture’s disease. The “lumpy-Bumpy” is immune complex with low complements and is often post-infectious. The Pauci-immune staining is related to ANCA, which is anti-MPO, anti-proteinase 3 (these are components of vacuoles in WBC). F. Slide: P-ANCA is perinuclear. When the white cells are fixed to the slide with methanol, proteins become soluble and positively charged particles migrate toward the nucleus. In CANCA the proteins did not migrate. P-ANCA is against myloperoxidase and is associated with primary renal disease and PAN. C-ANCA is associated with antiproteinase 3 and Wegener’s granulomatosis or primary renal disease. G. These diseases have a very bad prognosis. Treatment is aggressive. Plasmapheresis is necessary to pull antibodies off the basement membrane. Treat infections and steroids or cyclophosphamide. …. “Now we are out of time…The rest of this stuff is pretty straightforward. The one specific point here is this slide right here (second to last one). It is key, key, key key…If you have hematuria in a patient and you don’t know where it is from RULE OUT BLADDER AS A SOURCE ESPECIALL IF THE PATIENT IS OVER 50.”

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