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Introduction
Parenchymal renal diseases affect many millions of persons in the United States and worldwide. In 2006 in the United States over 250,000 person were in End Stage Renal Disease Programs largely as a result of renal involvement by parenchymal diseases. One form of glomerular damage alone, diabetic glomerulophropathy, is said to affect many millions of persons in the U.S. with a cost to the government of billions of dollars annually. Worldwide glomerular disease associated with infectious agents such as malaria and schistosomiasis and interstitial diseases such as chronic bacterial pyelonephritis.
Clinical Manifestations of Glomerular Diseases
Several findings are common to many glomerular diseases and focus the differential diagnosis of unknown parenchymal renal diseases towards a glomerular origin. They include the findings of erythrocyte casts and/or dysmorphic erythrocytes in the urinary sediment and the presence of large amounts of albuminuria. In normal man the urinary excretion of albumin is less than 50 mg daily. While increases in urinary protein excretion may come from the filtration of abnormal circulating proteins (such as light chains in multiple myeloma), or from the deficient proximal.
Minimal Change Disease
Minimal change disease, also called "Nil" disease and in the past "lipoid nephrosis," remains the most common pattern of idiopathic nephrotic syndrome in children. It comprises from 10 to 15 percent of idiopathic nephrotic syndrome in adults. The incidence of idiopathic minimal change disease in adults appears to be decreasing as that of FSGS increases independent of any changes in histologic interpretation of renal biopsies. Minimal change disease may present at any age and should be considered in the differential diagnosis of adult idiopathic nephrotic syndrome in all adults no matter how elderly. Patients typically present with sudden onset of the nephrotic syndrome with periorbital and peripheral edema related to the proteinuria.
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is a clinical and histopathologic entity with a pattern of glomerular injury which may be idiopathic or secondary to a number of etiologies . The most common manifestation is proteinuria which may range from minor amounts to nephrotic levels. FSGS accounts for less than 15% of cases of idiopathic nephrotic syndrome in children, but a greater percent in adults. In adults recent studies have documented an increased incidence of FSGS among all biopsies at several large institutions.
Clinical Features
Most patients with idiopathic FSGS present with either asymptomatic proteinuria or the full nephrotic syndrome. The 10 -30% with asymptomatic proteinuria are most commonly detected in children by routine pediatric check-ups, and camp or sports physicals; in adults detection of asymptomatic cases occurs most often at military induction examinations, routine gynecologic or obstetric check-ups, and insurance or employment physicals. Patients with the nephrotic syndrome present.
Therapy and Outcome
Although variable in the individual patient, the course of untreated FSGS is usually one of progressive proteinuria and declining GFR. Patients with asymptomatic proteinuria typically develop the nephrotic syndrome over time. Only a small minority of patients experience a spontaneous remission of proteinuria and/or the nephrotic syndrome. Both children and adults have a similar course, most develop ESRD 5-20 years from presentation. Some patients with the collapsing variant (on so-called malignant FSGS) will have a more rapid course to ESRD in 2-3 years. Several features which have been associated with a more rapid progression to renal failure in idiopathic FSGS include higher grade proteinuria (>10-15 grams daily), a higher serum creatinine.
Membranous Nephropathy
Most patients with idiopathic membranous nephropathy present with the nephrotic syndrome, but isolated proteinuria, hypertension, abnormal GFR, and hematuria may be found as well. Although only a small percentage of patients with membranous nephropathy have an systemic or secondary etiology (eg, underlying tumor) these entities must be excluded prior to instituting therapy. There has been considerable debate about the variable natural history of this disease. In general, most large series show that renal survival is over 75 percent at 10-15 years. There is also a spontaneous remission rate that varies from 20 to 30 percent of patients. Both the slow progression and spontaneous remission rate have confounded clinical treatment trials.
Both a retrospective study and a controlled clinical trial suggested that short term corticosteroid therapy led to a reduction in the number of patients progressing to renal insufficiency. Another study found that prolonged therapy with corticosteroids led to not only preservation of renal function but remissions of the nephrotic syndrome. These studies have been criticized: two of them lacked a control group and the controlled trial had an extremely rapid rate of progression of the control group towards renal insufficiency conferring a favorable advantage upon those patients receiving corticosteroids. Two recent controlled studies have shown no benefit of corticosteroid regimens upon the course of membranous nephropathy in terms of reduction of proteinuria.
Acute Glomerulonephritis
IgA Nephropathy
IgA nephropathy was originally was felt to be an uncommon and benign form of glomerulopathy (Berger's Disease). It is now recognized as the most frequent form of idiopathic glomerulonephritis worldwide (comprising 15 to 40 percent of primary glomerulonephritides in parts of Europe, Asia, and Japan) and clearly can progress to ESRD. In geographic areas where renal biopsies are commonly performed for milder urinary findings a higher incidence of IgA has been noted. In the United States some centers report IgA nephropathy to comprise up to 20 percent of all primary glomerulopathies. While males outnumber females and the peak occurrence is in the second to third decade of life it can occur in patients of both sexes and all ages.
The diagnosis of IgA nephropathy is established by the finding of glomerular immunoglobulin A deposits either as the dominant or codominant immunoglobulin on immunofluorescence microscopy. In addition to IgA deposits of C3 and IgG are found in many patients. The light microscopic picture may vary from minimal change to mesangial proliferation to crescenteric glomerulonephritis. The most common picture is mesangial hypercellularity often in a focal and segmental distribution. By electron microscopy electron dense deposits are typically found.
Idiopathic Membranoproliferative Glomerulonephritis
MPGN, also known as mesangiocapillary GN, is a relatively uncommon glomerular disease which may present in three forms, (MPGN types I, II, and III ) based upon the glomerular ultrastructure. Hypocomplementemia is found in all three types of MPGN but not in all patients at all times. In Type II MPGN an autoantibody to neoantigens of the alternate pathway C3 convertase, C3NeF, is often found. Although continuous alternate complement pathway activation and low C3 levels are typical of MPGN Type II, the exact role of complement components and C3NeF in the pathogenesis of the glomerular lesion is unclear.
Rapidly Progressive Glomerulonephritis
RPGN comprises a group of glomerulonephritides which have in common progression to renal failure in a matter of weeks to months from diagnosis and the presence of extensive extracapillary proliferation, ie, crescent formation, in a large percent of the glomeruli. RPGN, thus, includes renal diseases with different etiologies, pathogeneses, and clinical presentations. Patients with RPGN have been divided into three patterns defined by immunologic pathogenesis: Type I, with anti-GBM disease; Type II, with immune complex deposition (eg, SLE, post-streptococcal, etc.); and Type III, without immune deposits or anti-GBM antibodies, so-called pauci-immune. Many of the latter such patients fall into the category of ANCA positive RPGN. In the past, with the exception of post-infectious RPGN, prognosis was generally poor for most patients regardless of pathogenesis.
Anti-GBM Disease
Anti-GBM disease is caused by circulating antibodies directed against the non-collagenous domain of type 4 collagen and which damage the GBM. This leads to an inflammatory response, breaks in the GBM, and the formation of a proliferative and often crescenteric glomerulonephritis. If the anti-GBM antibodies cross react with and cause damage to the basement membrane of pulmonary capillaries the patient will develop pulmonary hemorrhage and hemoptysis. The association of anti-GBM antibody mediated damage to the kidneys and lungs is called Goodpasture's syndrome. The disease most commonly affects young adults, and males are far more commonly affected than females.
Immune Complex RPGN
Type II RPGN, associated with immune complex mediated damage to the glomeruli, may occur with a spectrum of diseases from primary glomerulopathies such as IgA nephropathy and MPGN to post-infectious GN, to systemic lupus erythematosus.The therapy of IgA nephropathy and MPGN is discussed above. Most cases of post infectious GN resolve with successful treatment of the underlying infection. Here, the potential hazzards of immunosuppressive treatment and the limited data available on its benefit should prompt caution in the use of this therapeutic option.
Pauci-Immune RPGN and Vasculitis-associated RPGN
Pauci-immune Type III RPGN includes patients with and without evidence of systemic vasculitis. A large retrospective analysis from the Mayo Clinic found no difference in prognosis between the patients with small artery or medium sized artery involvement by vasculitis with focal segmental necrotizing GN (polyarteritis-like ) and those with the necrotizing GN alone (RPGN ). Patients often present with progressive renal failure and a nephritic picture with hematuria, oliguria, hypertension. Many patients will have circulating antibodies directed against neutrophil cytoplasmic antigens (ANCA). Patients who are P-ANCA positive more often have a clinical picture akin to polyarteritis (with arthritis, skin involvement with leukocytoclastic angiitis.
Glomerular Involvement in Systemic Diseases
Diabetes Mellitus
Diabetic nephropathy is the most common cause of ESRD in the United States with up to one-third of all new ESRD patients being diabetic. From 25-40 percent of Type I, insulin dependent diabetics, will develop nephropathy. The course is characterized initially by glomerular hyperfiltration with a normal serum creatinine but with microalbuminuria, and then progressively increasing proteinuria and the nephrotic syndrome, and a slow decrease in glomerular filtration rate. Recent evidence supports a similar renal course for noninsulin dependent Type II diabetics. The glomerular histopathologic changes in both are similar with thickening of the GBM, mesangial sclerosis, nodular intercapillary glomerulosclerosis (Kimmelsteil-Wilson nodules ).
Systemic Lupus Erythematosus
Renal involvement greatly influences the course and choice of treatment of lupus patients. The incidence of clinically detectable renal disease varies from 15 to 75% of patients with SLE. Histologic evidence of renal involvement in SLE is found in the vast majority of biopsies when studied by LM, IF, and EM even in the absence of clinical renal disease.
The WHO classification of LN has been used successfully for both clinical and research activities. It has the advantages of using LM, IF, and EM to classify each biopsy rather than only one form of microscopy; of separating the milder mesangial forms of LN from the true focal and diffuse proliferative forms; and of utilizing well defined criteria allowing different groups to compare results. The WHO classes correlate well with the clinical picture of the patients at biopsy.
Amyloidosis
Amyloidosis is a generic term for a group of diseases in which there is extracellular deposition of one of a number of insoluble fibrillar proteins in a characteristic beta-pleated sheet configuration. Although the proteins may be very different all have this configurational structure on X-ray diffraction leading to the defining tentorial properties such as Congo red binding with apple-green birefringence on polarization microscopy. They also have amyloid P component (AP), (a glycoprotein composed of 10 identical subunits each of molecular weight 25,000 D). One of the two most common forms of the amyloidosis is primary amyloidosis, now called AL amyloidosis, due to a plasma cell dyscrasia with over-production of a monoclonal immunoglobulin
HIV Nephropathy
There have now been over 200,000 cases of AIDS in the United States and over 40,000 deaths due to this disease. Some cities such as New York have reported over 10,000 cases of AIDS, and up to 500,000 persons in the New York Metropolitan area have been reported to be infected with the virus. Many studies have found populations of IV drug abusers (IVDA) to have a 60-85% carriage rate for HIV. Infection with this virus has been associated with a number of patterns of renal disease including acute renal failure and a unique form of glomerulopathy now called HIV nephropathy.
Acute Renal Failure
The course of patients with acute renal failure and AIDS has been described by a number of investigators. Rao et al at Downstate Medical Center have described the course of 23 such patients and Valeri, et al reviewed 88 episodes of acute renal failure in 449 AIDS patients at Bellevue Hospital in New York City. The most common precipitating factors for acute renal failure in both studies included medications (pentamidine, aminoglycosides, TMP-SMX, NSAIDs), and pyrexia and dehydration superimposed on sepsis-hypotension-respiratory failure. In Rao's study all six patients with mild renal failure regained renal function. Of those 17 with severe renal failure (serum creatinine >6mg/dL), eight of the eleven who did not undergo dialysis died in renal failure
HIV Nephropathy
Several histologic patterns of glomerulopathy have been seen in patients with AIDS or HIV infection. These include minimal change pattern, mesangial hyperplasia, glomerulopathies associated with immune complex deposition and/or IgA deposition, and most important HIV nephropathy. HIV nephropathy is a unique pattern of glomerulopathy in HIV infected patients characterized by heavy proteinuria and rapid progression to renal failure and with characteristic USG and renal biopsy findings. HIV nephropathy is a better term than AIDS nephropathy since this glomerulopathy may occur in patients with AIDS, ARC, as well as in asymptomatic HIV carriers. While HIV nephropathy has a prevalence of only three to seven percent of unselected autopsy series, it is by far the most common lesion found in HIV infected patients undergoing renal biopsy. For example, of 37 consecutive renal biopsies in HIV infected patients at
Hepatitis C Virus and the Kidney
Although the existence of "non-A, non-B" hepatitis virus as a major cause of mortality and morbidity was known by the late 1970's, it was the cloning and expression of portions of the Hepatitis C virus (HCV) RNA in 1989 that allowed the full spectrum of disease caused by this agent to be appreciated. HCV is a major cause of transfusion associated and sporadic hepatitis world-wide, and is a major cause of chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. The chronic indolent nature of HCV infection despite a vigorous humoral response with antibody production allows for the production of chronic immune complex disease. HCV is also a significant cause of immune complex mediated glomerular damage. The incidence of HCV infection varies in different geographic locations from 0.3% in Canada and Northern Europe, to 0.6% in the USA, to 1.2-1.5 % in Japan and Southern Europe, to 3.5 to 7.0% in parts of Africa. In high risk groups the incidence is much higher: 60-90 % of hemophiliacs, 60-70% of IV drug abusers, and as high as 15-25% of certain dialysis populations.
The HCV is a single stranded RNA virus in the same flavovirus family with yellow fever and dengue. It is transmitted most often through blood products and shared needles with infrequent
Cryoglobulinemia and HCV
HCV infection has been associated with arthritis, sicca symptoms, corneal ulcerations, porphyria, autoimmune thyroiditis, polyarteritis, as well as mixed cryoglobulinemia associated with immune complex glomerulonephritis. Cryoglobulinemia refers to a pathologic condition caused by the production of circulating warming. Cryoglobulinemia are associated with a variety of infections, as well as collagen-vascular disease, and lymphoproliferative diseases. Cryoglobulins have been divided into three major groups based upon the nature of the circulating immunoglobulins. In type I cryoglobulinemia the cryoglobulin is a single monoclonal immunoglobulin, usually without associated antibody activity. This is found most often in patients with
Pathogenesis and Pathology_ of HCV Cryoglobulin GN and MPGN
In cryoglobulinemia immunoglobulin complexes deposit in the glomeruli binding complement and inciting a proliferative response. The serum cryoglobulin has been clearly shown to participate in the formation of the glomerular immune complex. Although by light microscopy glomerular lesions vary from diffuse proliferative to membranoproliferative forms, and to those with focal sclerosing lesions, D'Amico et al. have delineated four features to distinguish the proliferative GN of essential mixed cryoglobulinemia from other proliferative GNs. These include: massive exudation of cells mainly monocytic in nature; amorphous eosinophilic PAS positive, Congo red negative deposits on the inner side of the glomerular capillary wall and sometimes filling the
A. The normal Glomerulus
B. Histopathologic Terms
C. Clinical Manifestations
D. The Primary Nephrotic Syndrome
1. Minimal Change Disease
2. Focal Segmental Sclerosis
3. Membranous Nephropathy
E. Acute Glomerulonephritis
1. IgA Nephropathy
2. Membranoproliferative GN
3. Rapidly Progressive GN
F. Glomerular Involvement in Systemic Diseases
1. Diabetes mellitus
2. Post-Infectious GN
3. Amyloidosis
4. Systemic Lupus
5. HIV Nephropathy
Incidence of Idiopathic Nephrotic Syndrome in Adults
Minimal Change Disease 10%
Focal Segmental Glomerulosclerosis 20-30%
Membranous Nephropathy 25-30%
Membranoproliferative Glomerulonephritis <5%
Other Proliferative and Sclerosing GNs 15-20%
Serum Complement Levels in Glomerular Disease
Diseases with Reduced Complement Level
-Postinfectious GN (PSGN, SBE, visceral abscesses)
-Systemic Lupus Erythematosus
-Cryoglobulinemia
-Idiopathic Membranoproliferative GN
Diseases Associated with a Normal Serum Complement -Minimal Change NS - FSGS - Membranous Nephropathy
-IgA Nephropathy
- Henoch-Schönlein Purpura
-Anti-GBM disease
-Pauci-immune RPGN-Polyarteritis Nodosa-Wegener's Granulomatosis