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Background
This class of kidney disease centers around the glomerulus. This is where the main filtration of the nephron occurs and is located within the Bowman's capsule. It is comprised of a mass of tiny tubes through which the blood passes. Its semipermeable structure allows water and soluble wastes to pass through and be excreted out of the Bowman's capsule as urine. The filtered blood passes out of the glomerulus into the efferent arteriole to be returned through the medullary plexus to the intralobular vein.
The glomerular diseases may be broadly characterized by the following table.
PRIMARY GLOMERULOPATHIES SYSTEMIC DISEASES HEREDITARY DISEASES OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION HEPATITIS C
Glomerular injury associated with hepatitis C infection: a correlation with blood and tissue HCV-PCR.Hoch B, Juknevicius I, Liapis H.
Department of Pathology and Immunology and Internal Medicine, Washington University, St Louis, MO, USA.
Semin Diagn Pathol 2002 Aug;19(3):175-87 Abstract quote Membranoproliferative glomerulonephritis, with or without cryoglobulinemia, and membranous glomerulonephritis are the best characterized glomerulonephropathies associated with hepatitis C virus (HCV) infection. Other more unusual patterns of glomerular injury, including IgA nephropathy, focal segmental glomerulosclerosis, crescentic glomerulonephritis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, and thrombotic microangiopathy, have also been associated with HCV infection, but primarily on an anecdotal basis.
It remains uncertain whether the patterns of glomerular injury seen in HCV infected patients, particularly the unusual patterns, represent a disease process specifically related to HCV infection or whether they represent nonspecific patterns of injury due to other causes that happen to occur in HCV-infected patients.
We examine this issue by reviewing the epidemiological and pathological evidence in the literature that either supports or refutes a specific relationship between HCV and the pattern of glomerular injury. We also include our experience with 31 HCV-infected patients. In addition, the pathogenesis of HCV-associated glomerulonephropathies is discussed with an emphasis on the significance of detecting HCV in renal biopsies by reverse transcriptase-polymerase chain reaction.
PATHOGENESIS CHARACTERIZATION ANTIBODY MEDIATED INJURY Fixed intrinsic tissue antigens:
Goodpasture antigen (anti-GBM nephritis)
Heymann antigen (membranous glomerulonephritis)
Mesangial antigens
Others
Planted antigens:
Exogenous (infections, drugs)
Endogenous (DNA, immunoglobulins, immune complexes, IgA)Endogenous antigens (DNA, tumor antigens)
Exogenous antigens (infectious products)CELL MEDIATED IMMUNE INJURY ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY
LABORATORY/RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC LABORATORY MARKERS
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GLOMERULAR SYNDROMES Adopted from Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999. Pg. 942. Hematuria, azotemia, variable proteinuria, oliguria, edema, and hypertension Acute nephritis, proteinuria, and acute renal failure >3.5 gram proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria Azotemia to uremia progressing for years Glomerular hematuria; subnephrotic proteinuria SPECIFIC VARIANTS RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS Idiopathic
Goodpasture syndromeIdiopathic
Postinfectious
SLE
Henoch-Schonlein purpura (IgA)
OthersIdiopathic
Wegener granulomatosis
Microscopic polyarteritis nodosa
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL VARIANTS DIABETIC GLOMERULOPATHY
Diabetic glomerulopathy: unusual patterns and dual disease.Foster K, Salinas-Madrigal L, Miller B, Liapis H.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA.
Semin Diagn Pathol 2002 Aug;19(3):160-74 Abstract quote Diabetic glomerulopathy is a well-recognized consequence of both type I and type II diabetes. Occasionally, pathologic diagnosis may be challenging for the pathologist. These circumstances include atypical light microscopy or diabetic change with a second superimposed glomerulopathy (dual disease).
We have compiled a selection of 12 renal biopsies from diabetic patients that show either an unusual pattern of nephropathy or "dual disease," as well as 2 cases in which the patient had no history of diabetes but had renal biopsies exhibiting changes consistent with diabetic nephropathy. The salient diagnostic features are discussed.
To accurately assess these biopsies, immunofluorescence and electron microscopy become essential, and a broadened differential diagnosis must be considered.
FIBRILLARY GLOMERULOPATHY
Severe chronic renal failure in association with oxycodone addiction: A new form of fibrillary glomerulopathy.Hill P, Dwyer K, Kay T, Murphy B.
Departments of Anatomical Pathology and Nephrology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Hum Pathol 2002 Aug;33(8):783-7 Abstract quote A number of well-documented renal lesions have been associated with intravenous drug use. Recently, investigators reported three cases of granulomatous glomerulonephritis in association with intravenous injection of oxycodone suppositories.
We report 2 patients with similar glomerular pathology who presented with chronic renal failure. However, we also highlight the widespread tubulointerstitial involvement in this renal lesion. The fibrillar deposits seen within the glomeruli and extensively within tubular basement membranes on electron microscopy do not have the staining characteristics of amyloid and are not associated with immunoglobulin (Ig) deposition.
Is this a new form of non-Ig-associated fibrillary glomerulopathy with its pathogenesis linked to some component of the oxycodone suppositories? One of the patients had a history of narcotic addiction but denied intravenous injection of suppositories. In both patients there was progressive deterioration of renal function with 1 patient requiring dialysis within 3 months of initial presentation.
IDIOPATHIC NODULAR GLOMERULOSCLEROSIS
Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking.Markowitz GS, Lin J, Valeri AM, Avila C, Nasr SH, D'agati VD.
Departments of Pathology, Medicine, and Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, NY.
Hum Pathol 2002 Aug;33(8):826-35 Abstract quote Idiopathic nodular glomerulosclerosis (ING) is an enigmatic condition that resembles nodular diabetic glomerulosclerosis but occurs in nondiabetic patients.
We reviewed clinicopathologic features, immunohistochemical profiles, and outcomes in 23 patients with ING diagnosed from among 5,073 native renal biopsy samples (0.45%) at Columbia University from January 1996 to March 2001. This cohort, in which diabetes mellitus was excluded, consisted predominantly of older (mean age, 68.2 years) white (73.9%) men (78.3%). Clinical findings at presentation included renal insufficiency in 82.6% (mean serum creatinine = 2.4 mg/dL), proteinuria (> 3 g/d in 69.6%; mean 24-hour urine protein = 4.7 g/d), and-less frequently-full nephrotic syndrome (21.7%). There was a high prevalence of hypertension (95.7%; mean = 15.1 +/- 3.4 years), smoking (91.3%; mean = 52.9 +/- 6.9 pack-years), hypercholesterolemia (90%), and extrarenal vascular disease (43.5%).
All 23 patients had prominent diffuse and nodular mesangial sclerosis, glomerular basement membrane thickening, arteriosclerosis, and arteriolosclerosis. Immunohistochemical staining for CD34, a marker of endothelial cells, showed an increased number of vascular channels within ING glomeruli compared with normal controls. Follow-up data were available for 17 patients, 6 of whom reached end-stage renal disease (ESRD) (35.3%). By Kaplan-Meier estimates, the median time after biopsy to ESRD was 26 months.
Predictors of progression to ESRD included continuation of smoking (P =.0165), lack of angiotensin II blockade (P =.0007), degree of tubular atrophy and interstitial fibrosis (P =.0517), and degree of arteriosclerosis (P =.0096). In conclusion, ING is a progressive vasculopathic lesion linked to hypertension and cigarette smoking.
LIGHT CHAIN DISEASE
- Expanding the pathologic spectrum of light chain deposition disease: a rare variant with clinical follow-up of 7 years.
Chang A, Peutz-Kootstra CJ, Richardson CA, Alpers CE.
1Department of Pathology, University of Washington Medical Center, Seattle, WA, USA.
Mod Pathol. 2005 Jul;18(7):998-1004. Abstract quote
We report an unusual histologic manifestation of light chain deposition disease in a 69-year-old female patient, who presented with nephrotic syndrome and an increased serum creatinine.
The renal biopsy findings by light and electron microscopy suggested a glomerulonephritis with massive immune-complex deposition, such as lupus nephritis. However, the overall clinical scenario was inconsistent with lupus. Subsequent tests revealed multiple myeloma confirmed by bone marrow biopsy and identification of a monoclonal kappa light chain immunoglobulin by serum and urine immunoelectrophoresis and immunofixation.
Additional immunohistochemistry of the first biopsy also demonstrated strong kappa light chain staining of the glomerular capillary walls and mesangium but not lambda light chain or IgG staining. The patient responded well to therapy and was asymptomatic until nearly 7 years later. A repeat biopsy revealed similar findings to the first biopsy with the addition of immunofluorescence microscopy, which confirmed the prominent kappa light chain staining of the glomeruli, tubular basement membranes, and interstitium with corresponding electron-dense deposits visualized by electron microscopy.
This case represents an unusual histologic variant of light chain deposition disease, which to our knowledge has not been previously described and further expands the wide clinicopathologic spectrum within the diagnostic entity of light chain deposition disease.POSTINFECTIOUS
Incidental healed postinfectious glomerulonephritis: A study of 1012 renal biopsy specimens examined by electron microscopy.Haas M.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
Hum Pathol 2003 Jan;34(1):3-10 Abstract quote Glomerulonephritis (GN) characterized by immune complex deposits typical of postinfectious GN but with a paucity or absence of overt clinical symptoms and/or urinary abnormalities may occur after a group A streptococcus infection. The overall incidence of this type of subclinical GN is not known.
To address this question, electron microscopy findings in 1012 consecutive renal biopsy specimens (952 native kidney, 60 transplant) examined by a single renal pathologist from August 1999 to April 2002 were retrospectively reviewed for the presence of distinct subepithelial and intramembranous deposits indicative of postinfectious GN.
Such deposits were noted in 83 biopsy sspecimens, including 26 with a primary diagnosis of postinfectious GN (acute, persistent, or latent) and 57 in which these deposits were an incidental finding. In each of the latter 57 cases, some or all of the deposits showed partial or extensive loss of electron density typical of partially or largely resorbed deposits.
A diagnosis of incidental postinfectious GN was not made in any biopsy specimen exhibiting another immune complex-related glomerular disease that could possibly account for the deposits, composing 443 of the 1012 biopsy specimens examined. Thirty of the 57 biopsy specimens with incidental postinfectious GN showed mesangial hypercellularity, although this was focal and segmental in all but 3 cases and was not accompanied by the endocapillary hypercellularity typical of acute postinfectious lesions. Immunofluorescence microscopy revealed glomerular deposits of C3 in >90% of these biopsy specimens and IgM deposits in 66%, but only rare IgG, IgA, and Cq deposits. Twenty-three (40%) of these 57 biopsy specimens exhibited diabetic nephropathy, either alone or in combination with another lesion; for perspective, only 128 (13%) of the 1012 biopsy specimens examined showed evidence of diabetic nephropathy.
In summary, incidental evidence of resolving or largely healed postinfectious GN was noted in up to 10.5% of renal biopsy specimens (57 of 543, not including specimens with a primary diagnosis of an immune complex-related glomerular disease). The recognition of such lesions is potentially important in the interpretation of certain renal biopsy specimens.
THIN GLOMERULAR BASEMENT MEMBRANE DISEASE
Histopathology, ultrastructure, and clinical phenotypes in thin glomerular basement membrane disease variants.Liapis H, Gokden N, Hmiel P, Miner JH.
Departments of Pathology and Immunology, Pediatrics, and Medicine, Renal Division and Cell Biology, Washington University School of Medicine, St. Louis, MO.
Hum Pathol 2002 Aug;33(8):836-45 Abstract quote Recent genetic studies indicate that Alport syndrome and thin glomerular basement membrane disease (TMD) may both be due to COL4A3, COL4A4, and COL4A5 mutations, but there is continuing uncertainty concerning the diagnosis and management of patients without classic family history and symptoms.
We examined kidney pathology and collagen alpha 3 to alpha 5(IV) expression in a series of 16 patients who presented with overlapping signs between TMD and Alport nephritis. All patients presented with hematuria, and 11 also had proteinuria, of whom 5 had nephrotic range proteinuria. Only 9 had family history of hematuria. In 9 of 16 (60%) we found premature glomerulosclerosis in the renal biopsies. Three of 16 had predominantly wide, lamellated glomerullar basement membranes (GBM), and in these, alpha 3 to alpha 5(IV) was absent in glomeruli or skin, diagnostic of Alport nephritis. One patient (12) had a very wide GBM with intramembranous lucencies but no lamellation. Skin biopsy was collagen alpha 5(IV) positive. Nine of 16 patients had predominantly thin GBM by electron microscopy, and 3 had thin and slightly lamellated GBM. Collagen alpha 3 to alpha 5(IV) expression in the kidney or skin biopsy was present in all of the latter 12 patients. Three patients had end-stage renal disease, 7 patients had hypertension, and 1 patient had chronic renal failure.
We found that of the 16 patients with presumed TMD, 3 had X-linked Alport nephritis, 2 appeared to have autosomal recessive Alport nephritis, and the remaining patients had either an Alport or a TMD variant. The latter had histologic and/or clinical evidence of progressive renal disease, including premature glomerulosclerosis, hypertension, sustained proteinuria, and either thin or slight GBM lamellation focally, and preserved alpha 3 to alpha 5(IV) expression. These patients have a TMD variant, but an Alport variant with a potentially transmissible severe defect different from benign hematuria cannot be excluded.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
Demonstration of Immune Complex Deposits Using Fluorescence Microscopy of Hematoxylin and Eosin-Stained Sections of Hollande's Fixed Renal Biopsies.McMahon JT, Myles JL, Tubbs RR.
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
Mod Pathol 2002 Sep;15(9):988-97 Abstract quote A new method that may be useful in the evaluation of renal biopsies is described using fluorescence microscopy on standard hematoxylin and eosin-stained sections of kidney tissue fixed in Hollande's fixative. We describe brightly fluorescing immune complex deposits within glomerular basement membranes and mesangial matrices that correlate well with the results of standard direct immunofluorescence on frozen tissue and electron microscopy.
In a blind analysis of 261 consecutive renal biopsies, we determine that this method has diagnostic utility for identification of immune complex glomerulonephritis and significantly extends the usefulness of standard histologic preparations before the use of special stains or procedures.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS TREATMENT KIDNEY BIOPSY INDICATIONS
Do current recommendations for kidney biopsy in nephrotic syndrome need modifications?Gulati S, Sharma AP, Sharma RK, Gupta A, Gupta RK.
Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, India.
Pediatr Nephrol 2002 Jun;17(6):404-8 Abstract quote The current recommendations of kidney biopsy in childhood idiopathic nephrotic syndrome (CINS) were put forward to minimize unnecessary kidney biopsies in underlying minimal change disease (MCD). However, there remains a diversity of opinion about the criteria for biopsying children with idiopathic nephrotic syndrome.
This study was conducted to prospectively study their usefulness in avoiding biopsies in MCD and to evaluate further modifications for minimizing biopsies in CINS. Of 400 consecutive CINS patients, 222 patients were subjected to kidney biopsy according to the current recommendations. The histopathology spectrum of these selectively biopsied children revealed focal segmental glomerulosclerosis (FSGS) in 39%, MCD in 34.2%, membranoproliferative glomerulonephritis (MPGN) in 16.2%, mesangioproliferative glomerulonephritis (MesPGN) in 7.6%, membranous nephropathy (MN) in 1.8%, and diffuse mesangial sclerosis (DMS) in 0.9%. We observed that despite the current recommendations and efforts to minimize biopsy, 34% of children had MCD on histopathology. Two or more clinical (hematuria and hypertension) or biochemical (renal insufficiency) parameters were present in all children with MPGN. Low C3 was present only in children with MPGN. All the steroid responders were found to have MCD, FSGS, or MesPGN on biopsy. Cyclophosphamide response correlated better with steroid responsiveness ( P=0.02) than with histo- pathology ( P=0.80) in MCD, FSGS, and MesPGN.
Based on these observations, we suggest some modifications in current recommendations for kidney biopsy to minimize biopsying children with MCD. These are (1) biopsies in children (age 1-16 years) should be restricted (a) to a subgroup with two or more clinical and biochemical parameters and (b) in steroid non-responders, (2) the decision to administer cyclophosphamide should be based on steroid response pattern without requiring a prior routine biopsy.
RITUXIMAB
Rituximab for idiopathic membranous nephropathy.Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P.
Ospedali Riuniti Di Bergam, unit of Nephrology and Dialysis, Via Gavazzeni 1124125, Bergamo, Italy
Lancet 2002 Sep 21;360(9337):923 Abstract quote Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic.
In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m2)- the monoclonal antibody to B-cell antigen CD20-in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end.
The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.
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Last Updated July 16, 2005
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