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InternalMed_Harrison. Calcineurin inhibitors (cyclosporine and tacrolimus) have an afferent arteriolar constrictor effect on the kidney and may produce permanent vascular and interstitial injury after sustained high-dose therapy. This action will lead to a deterioration in renal function difficult to distinguish from rejection without a renal biopsy. Interstitial fibrosis, isometric tubular vacuolization, and thickening of arteriolar walls are suggestive of this side effect, but not diagnostic. Hence, if no rejection is detected on the biopsy, serum creatinine may respond to a reduction in dose. However, if rejection activity is present in the biopsy, appropriate therapy is indicated. The first rejection episode is usually treated with IV administration of methylprednisolone, 500–1000 mg daily for 3 days. Failure to respond is an indication for antibody therapy, usually with antithymocyte globulin.


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InternalMed_Harrison. Evidence of antibody-mediated injury is present when endothelial injury and deposition of complement component c4d is detected by fluorescence labeling. This is usually accompanied by detection of the antibody in the recipient blood. The prognosis is poor, and aggressive use of plasmapheresis, immunoglobulin infusions, anti-CD20 monoclonal antibody (rituximab) to target B lymphocytes, bortezomib to target antibody-producing plasma cells, and eculizumab to inhibit complement is indicated. The typical times after transplantation when the most common opportunistic infections occur are shown in Table 337-4. Prophylaxis for cytomegalovirus (CMV) and Pneumocystis jiroveci pneumonia is given for 6–12 months after transplantation.


InternalMed_Harrison

InternalMed_Harrison. The signs and symptoms of infection may be masked or distorted. Fever without obvious cause is common, and only after days or weeks may it become apparent that it has a viral or fungal origin. Bacterial infections are most common during the first month after transplantation. Recipient High % PRA (sensitization level) Recipient PRA <10%, and


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InternalMed_Harrison. No response Empirical IV steroid “pulse” therapy (methylprednisolone 0.2–1.0 g/d x 3 days) Low calcineurin inhibitor level Adequate calcineurin inhibitor level Transplant dysfunction* “High risk” Antilymphocyte globulin “induction” therapy Avoid calcineurin inhibitor until kidney function is established Steroids Calcineurin inhibitor Mycophenolic acid mofetil No response Acute rejection Renal biopsy Empirical IV steroid “pulse” therapy (methylprednisolone 0.2–1 g/d x 3 days) “Low risk” Persistent renal dysfunction orDe novo transplant dysfunction* with adequate calcineurin inhibitor levels Steroids Calcineurin inhibitor Mycophenolic acid mofetil Anti-CD3 monoclonal antibody (OKT3 5 g/d x 7–10 days) FIGuRE 337-2 A typical algorithm for early posttransplant care of a kidney recipient. If any of the recipient or donor “high-risk” factors exist, more aggressive management is called for. Low-risk patients can be treated with a standard immunosuppressive regimen. Patients at higher risk of


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InternalMed_Harrison. of the recipient or donor “high-risk” factors exist, more aggressive management is called for. Low-risk patients can be treated with a standard immunosuppressive regimen. Patients at higher risk of rejection or early ischemic and nephrotoxic transplant dysfunction are often induced with an antilymphocyte globulin to provide more potent early immunosuppression or to spare calcineurin nephrotoxicity. *When there is early transplant dysfunction, prerenal, obstructive, and vascular causes must be ruled out by ultrasonographic examination. The panel reactive antibody (PRA) is a quantitation of how much anti-body is present in a candidate against a panel of cells representing the distribution of antigens in the donor pool.


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InternalMed_Harrison. the MOst COMMOn OppOrtunIstIC InFeCtIOns In renaL transpLant reCIpIents The importance of blood cultures in such patients cannot be overemphasized because systemic infection without obvious foci is common. Particularly ominous are rapidly occurring pulmonary lesions, which may result in death within 5 days of onset. When these lesions become apparent, immunosuppressive agents should be discontinued, except for maintenance doses of prednisone.


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InternalMed_Harrison. Aggressive diagnostic procedures, including transbronchial and open-lung biopsy, are frequently indicated. In the case of P. jiroveci (Chap. 244) infection, trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice; amphotericin B has been used effectively in systemic fungal infections. Prophylaxis against P. jiroveci with daily or alternate-day low-dose TMP-SMX is very effective. Involvement of the oropharynx with Candida (Chap. 240) may be treated with local nystatin. Tissue-invasive fungal infections require treatment with systemic agents such as fluconazole. Small doses (a total of 300 mg) of amphotericin given over a period of 2 weeks may be effective in fungal infections refractory to fluconazole. Macrolide antibiotics, especially ketoconazole and erythromycin, and some calcium channel blockers (diltiazem, verapamil) compete with calcineurin inhibitors for P450 catabolism and cause elevated levels of these immunosuppressive drugs. Analeptics, such as phenytoin and


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InternalMed_Harrison. calcium channel blockers (diltiazem, verapamil) compete with calcineurin inhibitors for P450 catabolism and cause elevated levels of these immunosuppressive drugs. Analeptics, such as phenytoin and carbamazepine, will increase catabolism to result in low levels. Aspergillus (Chap. 241), Nocardia (Chap. 199), and especially CMV (Chap. 219) infections also occur.


InternalMed_Harrison

InternalMed_Harrison. CMV is a common and dangerous DNA virus in transplant recipients. It does not generally appear until the end of the first post-transplant month. Active CMV infection is sometimes associated, or occasionally confused, with rejection episodes. Patients at highest risk for severe CMV disease are those without anti-CMV antibodies who receive a graft from a CMV antibody–positive donor (15% mortality). Valganciclovir is a cost-effective and bioavailable oral form of ganciclovir that has been proved effective in both prophylaxis and treatment of CMV disease. Early diagnosis in a febrile patient with clinical suspicion of CMV disease can be made by determining CMV viral load in the blood. A rise in IgM antibodies to CMV is also diagnostic. Culture of CMV from blood may be less sensitive. Tissue invasion of CMV is common in the gastrointestinal tract and lungs. CMV retinopathy occurs late in the course, if untreated. Treatment of active CMV disease with valganciclovir is always indicated. In


InternalMed_Harrison

InternalMed_Harrison. invasion of CMV is common in the gastrointestinal tract and lungs. CMV retinopathy occurs late in the course, if untreated. Treatment of active CMV disease with valganciclovir is always indicated. In many patients immune to CMV, viral activation can occur with major immunosuppressive regimens.


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InternalMed_Harrison. The polyoma group (BK, JC, SV40) is another class of DNA viruses that can become dormant in kidneys and can be activated by immunosuppression. When reactivation occurs with BK, there is a 50% chance of progressive fibrosis and loss of the graft within 1 year by the activated virus. Risk of infection is associated with the overall degree of immunosuppression rather than the individual immunosuppressive drugs used. Renal biopsy is necessary for the diagnosis. There have been variable results with leflunomide, cidofovir, and quinolone antibiotics (which are effective against polyoma helicase), but it is most important to reduce the immunosuppressive load.


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InternalMed_Harrison. The complications of glucocorticoid therapy are well known and include gastrointestinal bleeding, impairment of wound healing, osteoporosis, diabetes mellitus, cataract formation, and hemorrhagic pancreatitis. The treatment of unexplained jaundice in transplant patients should include cessation or reduction of immunosuppressive drugs if hepatitis or drug toxicity is suspected. Therapy in such circumstances often does not result in rejection of a graft, at least for several weeks. Acyclovir is effective in therapy for herpes simplex virus infections.


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InternalMed_Harrison. Although 1-year transplant survival is excellent, most recipients experience progressive decline in kidney function over time thereafter. Chronic renal transplant dysfunction can be caused by recurrent disease, hypertension, cyclosporine or tacrolimus nephrotoxicity, chronic immunologic rejection, secondary focal glomerulosclerosis, or a combination of these pathophysiologies. Chronic vascular changes with intimal proliferation and medial hypertrophy are commonly found. Control of systemic and intrarenal hypertension with angiotensinconverting enzyme (ACE) inhibitors is thought to have a beneficial influence on the rate of progression of chronic renal transplant dysfunction. Renal biopsy can distinguish subacute cellular rejection from recurrent disease or secondary focal sclerosis.


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InternalMed_Harrison. The incidence of tumors in patients on immunosuppressive therapy is 5–6%, or approximately 100 times greater than that in the general population in the same age range. The most common lesions are cancer of the skin and lips and carcinoma in situ of the cervix, as well as lymphomas such as non-Hodgkin’s lymphoma. The risks are increased in proportion to the total immunosuppressive load administered and the time elapsed since transplantation. Surveillance for skin and cervical cancers is necessary. Both chronic dialysis and renal transplant patients have a higher incidence of death from myocardial infarction and stroke than does the population at large, and this is particularly true in diabetic patients. 1831


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InternalMed_Harrison. Contributing factors are the use of glucocorticoids and sirolimus and hypertension. Recipients of renal transplants have a high prevalence of coronary artery and peripheral vascular diseases. The percentage of deaths from these causes has been slowly rising as the numbers of transplanted diabetic patients and the average age of all recipients increase. More than 50% of renal recipient mortality is attributable to cardiovascular disease. In addition to strict control of blood pressure and blood lipid levels, close monitoring of patients for indications of further medical or surgical intervention is an important part of management.


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InternalMed_Harrison. Hypertension may be caused by (1) native kidney disease, (2) rejection activity in the transplant, (3) renal artery stenosis if an end-to-end anastomosis was constructed with an iliac artery branch, and (4) renal calcineurin inhibitor toxicity, which may improve with reduction in dose. Whereas ACE inhibitors may be useful, calcium channel blockers are more frequently used initially. Amelioration of hypertension to the range of 120–130/70–80 mmHg should be the goal in all patients. Hypercalcemia after transplantation may indicate failure of hyper-plastic parathyroid glands to regress. Aseptic necrosis of the head of the femur is probably due to preexisting hyperparathyroidism, with aggravation by glucocorticoid treatment. With improved management of calcium and phosphorus metabolism during chronic dialysis, the incidence of parathyroid-related complications has fallen dramatically. Persistent hyperparathyroid activity may require subtotal parathyroidectomy.


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InternalMed_Harrison. Although most transplant patients have robust production of erythropoietin and normalization of hemoglobin, anemia is commonly seen in the posttransplant period. Often the anemia is attributable to bone marrow–suppressant immunosuppressive medications such as azathioprine, mycophenolic acid, and sirolimus. Gastrointestinal bleeding is a common side effect of high-dose and long-term steroid administration. Many transplant patients have creatinine clearances of 30–50 mL/min and can be considered in the same way as other patients with chronic renal insufficiency for anemia management, including supplemental erythropoietin. Chronic hepatitis, particularly when due to hepatitis B virus, can be a progressive, fatal disease over a decade or so. Patients who are persistently hepatitis B surface antigen–positive are at higher risk, according to some studies, but the presence of hepatitis C virus is also a concern when one embarks on a course of immunosuppression in a transplant recipient.


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Julia B. Lewis, Eric G. Neilson

InternalMed_Harrison. Julia B. Lewis, Eric G. Neilson


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InternalMed_Harrison. Two human kidneys harbor nearly 1.8 million glomerular capillary tufts. Each glomerular tuft resides within Bowman’s space. The capsule circumscribing this space is lined by parietal epithelial cells that transition into tubular epithelia forming the proximal nephron or migrate into the tuft to replenish podocytes. The glomerular capillary tuft derives from an afferent arteriole that forms a branching capillary bed embedded in mesangial matrix (Fig. 338-1). This capillary network funnels into an efferent arteriole, which passes filtered blood into cortical peritubular capillaries or medullary vasa recta that supply and exchange with a folded tubular architecture. Hence the glomerular capillary tuft, fed and drained by arterioles, represents an arteriolar portal system. Fenestrated endothelial cells resting on a glomerular basement membrane (GBM) line glomerular capillaries. Delicate foot processes extending from epithelial podocytes shroud the outer surface of these capillaries, and


InternalMed_Harrison

InternalMed_Harrison. cells resting on a glomerular basement membrane (GBM) line glomerular capillaries. Delicate foot processes extending from epithelial podocytes shroud the outer surface of these capillaries, and podocytes interconnect to each other by slit-pore membranes forming a selective filtration barrier.


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InternalMed_Harrison. The glomerular capillaries filter 120–180 L/d of plasma water containing various solutes for reclamation or discharge by downstream FIGuRE 338-1 Glomerular architecture. A. The glomerular capillaries form from a branching network of renal arteries, arterioles, leading to an afferent arteriole, glomerular capillary bed (tuft), and a draining efferent arteriole. (From VH Gattone II et al: Hypertension 5:8, 1983.) B. Scanning electron micrograph of podocytes that line the outer surface of the glomerular capillaries (arrow shows foot process). C. Scanning electron micrograph of the fenestrated endothelia lining the glomerular capillary. D. The various normal regions of the glomerulus on light microscopy.


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InternalMed_Harrison. (A–C: Courtesy of Dr. Vincent Gattone, Indiana University; with permission.) tubules. Most large proteins and all cells are excluded from filtration by a physicochemical barrier governed by pore size and negative electrostatic charge. The mechanics of filtration and reclamation are quite complicated for many solutes (Chap. 325). For example, in the case of serum albumin, the glomerulus is an imperfect barrier. Although albumin has a negative charge, which would tend to repel the negatively charged GBM, it only has a physical radius of 3.6 nm, while pores in the GBM and slit-pore membranes have a radius of 4 nm. Consequently, variable amounts of albumin inevitably cross the filtration barrier to be reclaimed by megalin and cubilin receptors along the proximal tubule. Remarkably, humans with normal nephrons excrete on average 8–10 mg of albumin in daily voided urine, approximately 20–60% of total excreted protein. This amount of albumin, and other proteins, can rise to gram quantities


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InternalMed_Harrison. normal nephrons excrete on average 8–10 mg of albumin in daily voided urine, approximately 20–60% of total excreted protein. This amount of albumin, and other proteins, can rise to gram quantities following glomerular injury.


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InternalMed_Harrison. The breadth of diseases affecting the glomerulus is expansive because the glomerular capillaries can be injured in a variety of ways, producing many different lesions. Some order to this vast subject is brought by grouping all of these diseases into a smaller number of clinical syndromes. There are many forms of glomerular disease with pathogenesis variably linked to the presence of genetic mutations, infection, toxin exposure, autoimmunity, atherosclerosis, hypertension, emboli, thrombosis, or diabetes mellitus. Even after careful study, however, the cause often remains unknown, and the lesion is called idiopathic. Specific or unique features of pathogenesis are mentioned with the description of each of the glomerular diseases later in this chapter.


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InternalMed_Harrison. ing familial disease or a founder effect: congenital nephrotic syn drome from mutations in NPHS1 (nephrin) and NPHS2 (podocin) affect the slit-pore membrane at birth, and TRPC6 cation channel mutations produce focal segmental glomerulosclerosis (FSGS) in adulthood; polymorphisms in the gene encoding apolipoprotein L1, APOL1, are a major risk for nearly 70% of African Americans with nondiabetic end-stage renal disease, particularly FSGS; mutations in complement factor H associate with membranoproliferative glomerulonephritis (MPGN) or atypical hemolytic uremic syndrome (aHUS), type II partial lipodystrophy from mutations in genes encoding lamin A/C, or PPARγ cause a metabolic syndrome associated with MPGN, which is sometimes accompanied by dense deposits and C3 nephritic factor; Alport’s syndrome, from mutations in the genes encoding for the α3, α4, or α5 chains of type IV collagen, produces split-basement membranes with glomerulosclerosis; and lysosomal storage diseases, such as


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InternalMed_Harrison. syndrome, from mutations in the genes encoding for the α3, α4, or α5 chains of type IV collagen, produces split-basement membranes with glomerulosclerosis; and lysosomal storage diseases, such as α-galactosidase A deficiency causing Fabry’s disease and N -acetylneuraminic acid hydrolase deficiency causing nephrosialidosis, produce FSGS.


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InternalMed_Harrison. Systemic hypertension and atherosclerosis can produce pressure stress, ischemia, or lipid oxidants that lead to chronic glomerulosclerosis. Malignant hypertension can quickly complicate glomerulosclerosis with fibrinoid necrosis of arterioles and glomeruli, thrombotic microangiopathy, and acute renal failure. Diabetic nephropathy is an acquired sclerotic injury associated with thickening of the GBM secondary to the long-standing effects of hyperglycemia, advanced glycosylation end products, and reactive oxygen species.


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InternalMed_Harrison. Inflammation of the glomerular capillaries is called glomerulonephritis. Most glomerular or mesangial antigens involved in immune-mediated glomerulonephritis are unknown (Fig. 338-2). Glomerular epithelial or mesangial cells may shed or express epitopes that mimic other immunogenic proteins made elsewhere in the body. Bacteria, fungi, and viruses can directly infect the kidney producing their own antigens. Autoimmune diseases like idiopathic membranous glomerulonephritis (MGN) or MPGN are confined to the kidney, whereas systemic inflammatory diseases like lupus nephritis or granulomatosis with polyangiitis (Wegener’s) spread to the kidney, causing secondary glomerular injury. Antiglomerular basement membrane disease producing Goodpasture’s syndrome primarily injures both the lung and kidney because of the narrow distribution of the α3 NC1 domain of type IV collagen that is the target antigen.


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InternalMed_Harrison. Local activation of Toll-like receptors on glomerular cells, deposition of immune complexes, or complement injury to glomerular structures induces mononuclear cell infiltration, which subsequently leads to an adaptive immune response attracted to the kidney by local release of chemokines. Neutrophils, macrophages, and T cells are drawn by chemokines into the glomerular tuft, where they react with antigens 1833 and epitopes on or near somatic cells or their structures, producing more cytokines and proteases that damage the mesangium, capillaries, and/or the GBM. While the adaptive immune response is similar to that of other tissues, early T cell activation plays an important role in the mechanism of glomerulonephritis. Antigens presented by class II major histocompatibility complex (MHC) molecules on macrophages and dendritic cells in conjunction with associative recognition molecules engage the CD4/8 T cell repertoire.


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InternalMed_Harrison. Mononuclear cells by themselves can injure the kidney, but auto immune events that damage glomeruli classically produce a humoral immune response. Poststreptococcal glomerulonephritis, lupus nephritis, and idiopathic membranous nephritis typically are associated with immune deposits along the GBM, while anti-GBM antibodies produce the linear binding of anti-GBM disease. Preformed circulating FIGuRE 338-2 The glomerulus is injured by a variety of mechanisms. A. Preformed immune deposits can precipitate from the circulation and collect along the glomerular basement membrane (GBM) in the subendothelial space or can form in situ along the subepithelial space.


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InternalMed_Harrison. B. Immunofluorescent staining of glomeruli with labeled anti-IgG demonstrating linear staining from a patient with anti-GBM disease or immune deposits from a patient with membranous glomerulonephritis. C. The mechanisms of glomerular injury have a complicated pathogenesis. Immune deposits and complement deposition classically draw macrophages and neutrophils into the glomerulus. T lymphocytes may follow to participate in the injury pattern as well. D. Amplification mediators as locally derived oxidants and proteases expand this inflammation, and, depending on the location of the target antigen and the genetic polymorphisms of the host, basement membranes are damaged with either endocapillary or extracapillary proliferation.


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InternalMed_Harrison. 1834 immune complexes can precipitate along the subendothelial side of the GBM, while other immune deposits form in situ on the subepithelial side. These latter deposits accumulate when circulating autoantibodies find their antigen trapped along the subepithelial edge of the GBM. Immune deposits in the glomerular mesangium may result from the deposition of preformed circulating complexes or in situ antigen-antibody interactions. Immune deposits stimulate the release of local proteases and activate the complement cascade, producing C5–9 attack complexes. In addition, local oxidants damage glomerular structures, producing proteinuria and effacement of the podocytes. Overlapping etiologies or pathophysiologic mechanisms can produce similar glomerular lesions, suggesting that downstream molecular and cellular responses often converge toward common patterns of injury.


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InternalMed_Harrison. Persistent glomerulonephritis that worsens renal function is always accompanied by interstitial nephritis, renal fibrosis, and tubular atrophy (see Fig. 62e-27). What is not so obvious, however, is that renal failure in glomerulonephritis best correlates histologically with the appearance of tubulointerstitial nephritis rather than with the type of inciting glomerular injury.


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InternalMed_Harrison. Loss of renal function due to interstitial damage is explained hypothetically by several mechanisms. The simplest explanation is that urine flow is impeded by tubular obstruction as a result of interstitial inflammation and fibrosis. Thus, obstruction of the tubules with debris or by extrinsic compression results in aglomerular nephrons. A second mechanism suggests that interstitial changes, including interstitial edema or fibrosis, alter tubular and vascular architecture and thereby compromise the normal tubular transport of solutes and water from tubular lumen to vascular space. This failure increases the solute and water content of the tubule fluid, resulting in isosthenuria and polyuria. Adaptive mechanisms related to tubuloglomerular feedback also fail, resulting in a reduction of renin output from the juxtaglomerular apparatus trapped by interstitial inflammation. Consequently, the local vasoconstrictive influence of angiotensin II on the glomerular arterioles decreases, and


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InternalMed_Harrison. renin output from the juxtaglomerular apparatus trapped by interstitial inflammation. Consequently, the local vasoconstrictive influence of angiotensin II on the glomerular arterioles decreases, and filtration drops owing to a generalized decrease in arteriolar tone. A third mechanism involves changes in vascular resistance due to damage of peritubular capillaries. The cross-sectional volume of these capillaries is decreased by interstitial inflammation, edema, or fibrosis. These structural alterations in vascular resistance affect renal function through two mechanisms. First, tubular cells are very metabolically active, and, as a result, decreased perfusion leads to ischemic injury. Second, impairment of glomerular arteriolar outflow leads to increased intraglomerular hypertension in less-involved glomeruli; this selective intraglomerular hypertension aggravates and extends mesangial sclerosis and glomerulosclerosis to less-involved glomeruli. Regardless of the exact mechanism, early


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InternalMed_Harrison. glomeruli; this selective intraglomerular hypertension aggravates and extends mesangial sclerosis and glomerulosclerosis to less-involved glomeruli. Regardless of the exact mechanism, early acute tubulointerstitial nephritis (see Fig. 62e-27) suggests potentially recoverable renal function, whereas the development of chronic interstitial fibrosis prognosticates permanent loss (see Fig. 62e-30).


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InternalMed_Harrison. Persistent damage to glomerular capillaries spreads to the tubulointerstitium in association with proteinuria. There is a hypothesis that efferent arterioles leading from inflamed glomeruli carry forward inflammatory mediators, which induces downstream interstitial nephritis, resulting in fibrosis. Glomerular filtrate from injured glomerular capillaries adherent to Bowman’s capsule may also be misdirected to the periglomerular interstitium. Most nephrologists believe, however, that proteinuric glomerular filtrate forming tubular fluid is the primary route to downstream tubulointerstitial injury, although none of these hypotheses are mutually exclusive.


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InternalMed_Harrison. The simplest explanation for the effect of proteinuria on the development of interstitial nephritis is that increasingly severe proteinuria, carrying activated cytokines and lipoproteins producing reactive oxygen species, triggers a downstream inflammatory cascade in and around epithelial cells lining the tubular nephron. These effects induce T lymphocyte and macrophage infiltrates in the interstitial spaces along with fibrosis and tubular atrophy.


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InternalMed_Harrison. Tubules disaggregate following direct damage to their basement membranes, leading to epithelial-mesenchymal transitions forming more interstitial fibroblasts at the site of injury. Transforming growth factor β (TGF-β), fibroblast growth factor 2 (FGF-2), hypoxemiainducible factor 1α (HIF-1α), and platelet-derived growth factor (PDGF) are particularly active in this transition. With persistent nephritis, fibroblasts multiply and lay down tenascin and a fibronectin scaffold for the polymerization of new interstitial collagen types I/III. These events form scar tissue through a process called fibrogenesis. In experimental studies, bone morphogenetic protein 7 and hepatocyte growth factor can reverse early fibrogenesis and preserve tubular architecture. When fibroblasts outdistance their survival factors, apoptoses occurs, and the permanent renal scar becomes acellular, leading to irreversible renal failure. APPROACH TO THE PATIENT: HEMATuRIA, PROTEINuRIA, AND PYuRIA


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InternalMed_Harrison. Patients with glomerular disease usually have some hematuria with varying degrees of proteinuria. Hematuria is typically asymptomatic. As few as three to five red blood cells in the spun sediment from first-voided morning urine is suspicious. The diagnosis of glomerular injury can be delayed because patients will not realize they have microscopic hematuria, and only rarely with the exception of IgA nephropathy and sickle cell disease is gross hematuria present. When working up microscopic hematuria, perhaps accompanied by minimal proteinuria (<500 mg/24 h), it is important to exclude anatomic lesions, such as malignancy of the urinary tract, particularly in older men. Microscopic hematuria may also appear with the onset of benign prostatic hypertrophy, interstitial nephritis, papillary necrosis, hypercalciuria, renal stones, cystic kidney diseases, or renal vascular injury. However, when red blood cell casts (see Fig. 62e-34) or dysmorphic red blood cells are found in the sediment,


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InternalMed_Harrison. necrosis, hypercalciuria, renal stones, cystic kidney diseases, or renal vascular injury. However, when red blood cell casts (see Fig. 62e-34) or dysmorphic red blood cells are found in the sediment, glomerulonephritis is likely.


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InternalMed_Harrison. Sustained proteinuria >1–2 g/24 h is also commonly associated with glomerular disease. Patients often will not know they have proteinuria unless they become edematous or notice foaming urine on voiding. Sustained proteinuria has to be distinguished from lesser amounts of so-called benign proteinuria in the normal population (Table 338-1). This latter class of proteinuria is nonsustained, generally <1 g/24 h, and is sometimes called functional or transient proteinuria. Fever, exercise, obesity, sleep apnea, emotional stress, and congestive heart failure can explain transient proteinuria. Proteinuria only seen with upright posture is called orthostatic proteinuria and has a benign prognosis. Isolated proteinuria sustained over multiple clinic visits is found in many glomerular lesions. Proteinuria in most adults with glomerular disease is nonselective, containing albumin and a mixture of other serum proteins, whereas in children with minimal change disease, the proteinuria is selective


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InternalMed_Harrison. in most adults with glomerular disease is nonselective, containing albumin and a mixture of other serum proteins, whereas in children with minimal change disease, the proteinuria is selective and composed largely of albumin.


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InternalMed_Harrison. Some patients with inflammatory glomerular disease, such as CLINICAL SYNDROMES acute poststreptococcal glomerulonephritis or MPGN, have pyuria Various forms of glomerular injury can also be parsed into sevcharacterized by the presence of considerable numbers of leuko-eral distinct syndromes on clinical grounds (Table 338-2). These cytes. This latter finding has to be distinguished from urine infected syndromes, however, are not always mutually exclusive. There is with bacteria. an acute nephritic syndrome producing 1–2 g/24 h of proteinuria, aCan present as rapidly progressive glomerulonephritis (RPGN); sometimes called crescentic glomerulonephritis. bCan present as a malignant hypertensive crisis producing an aggressive fibrinoid necrosis in arterioles and small arteries with microangiopathic hemolytic anemia. cCan present with gross hematuria. Abbreviations: AA, amyloid A; AL, amyloid L; ANCA, antineutrophil cytoplasmic antibodies; GBM, glomerular basement membrane.


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InternalMed_Harrison. hematuria with red blood cell casts, pyuria, hypertension, fluid retention, and a rise in serum creatinine associated with a reduction in glomerular filtration. If glomerular inflammation develops slowly, the serum creatinine will rise gradually over many weeks, but if the serum creatinine rises quickly, particularly over a few days, acute nephritis is sometimes called rapidly progressive glomerulonephritis (RPGN); the histopathologic term crescentic glomerulonephritis is the pathologic equivalent of the clinical presentation of RPGN. When patients with RPGN present with lung hemorrhage from Goodpasture’s syndrome, antineutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis, lupus erythematosus, or cryoglobulinemia, they are often diagnosed as having a pulmonary-renal syndrome. Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large


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InternalMed_Harrison. syndrome. Nephrotic syndrome describes the onset of heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia, hypoalbuminemia, edema/anasarca, and microscopic hematuria; if only large amounts of proteinuria are present without clinical manifestations, the condition is sometimes called nephrotic-range proteinuria. The glomerular filtration rate (GFR) in these patients may initially be normal or, rarely, higher than normal, but with persistent hyperfiltration and continued nephron loss, it typically declines over months to years. Patients with a basement membrane syndrome either have genetically abnormal basement membranes (Alport’s syndrome) or an autoimmune response to basement membrane collagen IV (Goodpasture’s syndrome) associated with microscopic hematuria, mild to heavy proteinuria, and hypertension with variable elevations in serum creatinine. Glomerular–vascular syndrome describes patients with vascular injury producing hematuria and moderate proteinuria. Affected


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InternalMed_Harrison. proteinuria, and hypertension with variable elevations in serum creatinine. Glomerular–vascular syndrome describes patients with vascular injury producing hematuria and moderate proteinuria. Affected individuals can have vasculitis, thrombotic microangiopathy, antiphospholipid syndrome, or, more commonly, a systemic disease such as atherosclerosis, cholesterol emboli, hypertension, sickle cell anemia, and autoimmunity. Infectious disease–associated syndrome is most important if one has a global perspective. Save for subacute bacterial endocarditis in the Western Hemisphere, malaria and schistosomiasis may be the most common causes of glomerulonephritis throughout the world, closely followed by HIV and chronic hepatitis B and C. These infectious diseases produce a variety of inflammatory reactions in glomerular capillaries, ranging from nephrotic syndrome to acute nephritic injury, and urinalyses that demonstrate a combination of hematuria and proteinuria.


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InternalMed_Harrison. These six general categories of syndromes are usually determined at the bedside with the help of a history and physical examination, blood chemistries, renal ultrasound, and urinalysis. These initial studies help frame further diagnostic workup that typically involves testing of the serum for the presence of various proteins (HIV and hepatitis B and C antigens), antibodies (anti-GBM, antiphospholipid, antistreptolysin O [ASO], anti-DNAse, antihyaluronidase, ANCA, anti-DNA, cryoglobulins, anti-HIV, and anti-hepatitis B and C antibodies) or depletion of complement components (C3 and C4). The bedside history and physical examination can also help determine whether the glomerulonephritis is isolated to the kidney (primary glomerulonephritis) or is part of a systemic disease (secondary glomerulonephritis).


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InternalMed_Harrison. When confronted with an abnormal urinalysis and elevated serum creatinine, with or without edema or congestive heart failure, one must consider whether the glomerulonephritis is acute or chronic. This assessment is best made by careful history (last known urinalysis or serum creatinine during pregnancy or insurance physical, evidence of infection, or use of medication or recreational drugs); the size of the kidneys on renal ultrasound examination; and how the patient feels at presentation. Chronic glomerular disease often presents with decreased kidney size. Patients who quickly develop renal failure are fatigued and weak and often have uremic symptoms associated with nausea, vomiting, fluid retention, and somnolence. Primary glomerulonephritis presenting with renal failure that has progressed slowly, however, can be remarkably asymptomatic, as are patients with acute glomerulonephritis without much loss in renal function. Once this initial information is collected, selected patients


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InternalMed_Harrison. slowly, however, can be remarkably asymptomatic, as are patients with acute glomerulonephritis without much loss in renal function. Once this initial information is collected, selected patients who are clinically stable, have adequate blood clotting parameters, and are willing and able to receive treatment are encouraged to have a renal biopsy.


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InternalMed_Harrison. A renal biopsy in the setting of glomerulonephritis quickly identifies the type of glomerular injury and often suggests a course of treatment. The biopsy is processed for light microscopy using stains for hematoxylin and eosin (H&E) to assess cellularity and architecture, periodic acid–Schiff (PAS) to stain carbohydrate moieties in the membranes of the glomerular tuft and tubules, Jones-methenamine silver to enhance basement membrane structure, Congo red for amyloid deposits, and Masson’s trichrome to identify collagen deposition and assess the degree of glomerulosclerosis and interstitial fibrosis. Biopsies are also processed for direct immunofluorescence using conjugated antibodies against IgG, IgM, and IgA to detect the presence of “lumpy-bumpy” immune deposits or “linear” IgG or IgA antibodies bound to GBM, antibodies against trapped complement proteins (C3 and C4), or specific antibodies against a relevant antigen. High-resolution electron microscopy can clarify the principal


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InternalMed_Harrison. antibodies bound to GBM, antibodies against trapped complement proteins (C3 and C4), or specific antibodies against a relevant antigen. High-resolution electron microscopy can clarify the principal location of immune deposits and the status of the basement membrane.


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InternalMed_Harrison. Each region of a renal biopsy is assessed separately. By light microscopy, glomeruli (at least 10 and ideally 20) are reviewed individually for discrete lesions; <50% involvement is considered focal, and >50% is diffuse. Injury in each glomerular tuft can be segmental, involving a portion of the tuft, or global, involving most of the glomerulus. Glomeruli having proliferative characteristics show increased cellularity. When cells in the capillary tuft proliferate, it is called endocapillary, and when cellular proliferation extends into Bowman’s space, it is called extracapillary. Synechiae are formed when epithelial podocytes attach to Bowman’s capsule in the setting of glomerular injury; crescents, which in some cases may be the extension of synechiae, develop when fibrocellular/fibrin collections fill all or part of Bowman’s space; and sclerotic glomeruli show acellular, amorphous accumulations of proteinaceous material throughout the tuft with loss of functional capillaries and


InternalMed_Harrison

InternalMed_Harrison. collections fill all or part of Bowman’s space; and sclerotic glomeruli show acellular, amorphous accumulations of proteinaceous material throughout the tuft with loss of functional capillaries and normal mesangium. Since age-related glomerulosclerosis is common in adults, one can estimate the background percentage of sclerosis by dividing the patient’s age in half and subtracting 10. Immunofluorescent and electron microscopy can detect the presence and location of subepithelial, subendothelial, or mesangial immune deposits, or reduplication or splitting of the basement membrane. In the other regions of the biopsy, the vasculature surrounding glomeruli and tubules can show angiopathy, vasculitis, the presence of fibrils, or thrombi. The tubules can be assessed for adjacency to one another; separation can be the result of edema, tubular dropout, or collagen deposition resulting from interstitial fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and progression to


InternalMed_Harrison

InternalMed_Harrison. separation can be the result of edema, tubular dropout, or collagen deposition resulting from interstitial fibrosis. Interstitial fibrosis is an ominous sign of irreversibility and progression to renal failure.


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InternalMed_Harrison. Acute nephritic syndromes classically present with hypertension, hematuria, red blood cell casts, pyuria, and mild to moderate proteinuria. Extensive inflammatory damage to glomeruli causes a fall in GFR and eventually produces uremic symptoms with salt and water retention, leading to edema and hypertension.


InternalMed_Harrison

InternalMed_Harrison. Poststreptococcal glomerulonephritis is prototypical for acute endocapillary proliferative glomerulonephritis. The incidence of poststreptococcal glomerulonephritis has dramatically decreased in developed countries and in these locations is typically sporadic. Acute poststreptococcal glomerulonephritis in underdeveloped countries is epidemic and usually affects children between the ages of 2 and 14 years, but in developed countries is more typical in the elderly, especially in association with debilitating conditions. It is more common in males, and the familial or cohabitant incidence is as high as 40%. Skin and throat infections with particular M types of streptococci (nephritogenic strains) antedate glomerular disease; M types 47, 49, 55, 2, 60, and 57 are seen following impetigo and M types 1, 2, 4, 3, 25, 49, and 12 with pharyngitis. Poststreptococcal glomerulonephritis due to impetigo develops 2–6 weeks after skin infection and 1–3 weeks after streptococcal pharyngitis.


InternalMed_Harrison

InternalMed_Harrison. The renal biopsy in poststreptococcal glomerulonephritis demonstrates hypercellularity of mesangial and endothelial cells, glomerular infiltrates of polymorphonuclear leukocytes, granular subendothelial immune deposits of IgG, IgM, C3, C4, and C5–9, and subepithelial deposits (which appear as “humps”) (see Fig. 62e-6). (See Glomerular Schematic 1.) Poststreptococcal glomerulonephritis is an immune-mediated disease involving putative streptococcal antigens, circulating immune complexes, and activation of complement in association with 1837 cell-mediated injury. Many candidate antigens have been proposed over the years; candidates from nephritogenic streptococci of interest at the moment are: a cationic cysteine proteinase known as streptococcal pyrogenic exotoxin B (SPEB) that is generated by proteolysis of a zymogen precursor (zSPEB), and NAPlr, the nephritis-associated plasmin receptor. These two antigens have biochemical affinity for plasmin, bind as complexes facilitated by this


InternalMed_Harrison

InternalMed_Harrison. by proteolysis of a zymogen precursor (zSPEB), and NAPlr, the nephritis-associated plasmin receptor. These two antigens have biochemical affinity for plasmin, bind as complexes facilitated by this relationship, and activate the alternate complement pathway. The nephritogenic antigen, SPEB, has been demonstrated inside the subepithelial “humps” on biopsy.


InternalMed_Harrison

InternalMed_Harrison. The classic presentation is an acute nephritic picture with hematuria, pyuria, red blood cell casts, edema, hypertension, and oliguric renal failure, which may be severe enough to appear as RPGN. Systemic symptoms of headache, malaise, anorexia, and flank pain (due to swelling of the renal capsule) are reported in as many as 50% of cases. Five percent of children and 20% of adults have proteinuria in the nephrotic range. In the first week of symptoms, 90% of patients will have a depressed CH50 and decreased levels of C3 with normal levels of C4. Positive rheumatoid factor (30–40%), cryoglobulins and circulating immune complexes (60–70%), and ANCA against myeloperoxidase (10%) are also reported. Positive cultures for streptococcal infection are inconsistently present (10–70%), but increased titers of ASO (30%), anti-DNAse, (70%), or antihyaluronidase antibodies (40%) can help confirm the diagnosis. Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a


InternalMed_Harrison

InternalMed_Harrison. titers of ASO (30%), anti-DNAse, (70%), or antihyaluronidase antibodies (40%) can help confirm the diagnosis. Consequently, the diagnosis of poststreptococcal glomerulonephritis rarely requires a renal biopsy. A subclinical disease is reported in some series to be four to five times as common as clinical nephritis, and these latter cases are characterized by asymptomatic microscopic hematuria with low serum C3 complement levels.


InternalMed_Harrison

InternalMed_Harrison. Treatment is supportive, with control of hypertension, edema, and dialysis as needed. Antibiotic treatment for streptococcal infection should be given to all patients and their cohabitants. There is no role for immunosuppressive therapy, even in the setting of crescents. Recurrent poststreptococcal glomerulonephritis is rare despite repeated streptococcal infections. Early death is rare in children but does occur in the elderly. Overall, the prognosis is good, with permanent renal failure being very uncommon, less than 1% in children. Complete resolution of the hematuria and proteinuria in the majority of children occurs within 3–6 weeks of the onset of nephritis but 3–10% of children may have persistent microscopic hematuria, nonnephrotic proteinuria, or hypertension. The prognosis in elderly patients is worse with a high incidence of azotemia (up to 60%), nephrotic-range proteinuria, and end-stage renal disease.


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InternalMed_Harrison. Endocarditis-associated glomerulonephritis is typically a complication of subacute bacterial endocarditis, particularly in patients who remain untreated for a long time, have negative blood cultures, or have right-sided endocarditis. Glomerulonephritis is unusual in acute bacterial endocarditis because it takes 10–14 days to develop immune complex–mediated injury, by which time the patient has been treated, often with emergent surgery. Grossly, the kidneys in subacute bacterial endocarditis have subcapsular hemorrhages with a “flea-bitten” appearance, and microscopy on renal biopsy reveals focal proliferation around foci of necrosis associated with abundant mesangial, subendothelial, and subepithelial immune deposits of IgG, IgM, and C3. Patients who present with a clinical picture of RPGN have crescents. Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation.


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InternalMed_Harrison. have crescents. Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation. Patients present with gross or microscopic hematuria, pyuria, and mild proteinuria or, less commonly, RPGN with rapid loss of renal function. A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia, high titers of rheumatoid factor, type III cryoglobulins, circulating immune complexes, and ANCAs may be present. Levels of serum creatinine may be elevated at diagnosis, but with modern therapy there is little progression to chronic renal failure. Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for renal recovery is good. ANCA-associated vasculitis sometimes accompanies or is confused 1838 with subacute bacterial endocarditis (SBE) and should be ruled out, as the treatment is different. As


InternalMed_Harrison

InternalMed_Harrison. for renal recovery is good. ANCA-associated vasculitis sometimes accompanies or is confused 1838 with subacute bacterial endocarditis (SBE) and should be ruled out, as the treatment is different. As variants of persistent bacterial infection in blood-associated glomerulonephritis, postinfectious glomerulonephritis can occur in patients with ventriculoatrial and ventriculoperitoneal shunts; pulmonary, intraabdominal, pelvic, or cutaneous infections; and infected vascular prostheses. In developed countries, a significant proportion of cases afflict adults, especially the immunocompromised, and the predominant organism is Staphylococcus. The clinical presentation of these conditions is variable and includes proteinuria, microscopic hematuria, acute renal failure, and hypertension. Serum complement levels are low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal lesions include membranoproliferative


InternalMed_Harrison

InternalMed_Harrison. Serum complement levels are low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal lesions include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative and exudative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis, sometimes leading to RPGN. Treatment focuses on eradicating the infection, with most patients treated as if they have endocarditis. The prognosis is guarded.


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InternalMed_Harrison. Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE) and most severe in African-American female adolescents. Thirty to 50% of patients will have clinical manifestations of renal disease at the time of diagnosis, and 60% of adults and 80% of children develop renal abnormalities at some point in the course of their disease. Lupus nephritis results from the deposition of circulating immune complexes, which activate the complement cascade leading to complement-mediated damage, leukocyte infiltration, activation of procoagulant factors, and release of various cytokines. In situ immune complex formation following glomerular binding of nuclear antigens, particularly necrotic nucleosomes, also plays a role in renal injury. The presence of antiphospholipid antibodies may also trigger a thrombotic microangiopathy in a minority of patients.


InternalMed_Harrison

InternalMed_Harrison. The clinical manifestations, course of disease, and treatment of lupus nephritis are closely linked to renal pathology. The most common clinical sign of renal disease is proteinuria, but hematuria, hypertension, varying degrees of renal failure, and active urine sediment with red blood cell casts can all be present. Although significant renal pathology can be found on biopsy even in the absence of major abnormalities in the urinalysis, most nephrologists do not biopsy patients until the urinalysis is convincingly abnormal. The extrarenal manifestations of lupus are important in establishing a firm diagnosis of systemic lupus because, while serologic abnormalities are common in lupus nephritis, they are not diagnostic. Anti-dsDNA antibodies that fix complement correlate best with the presence of renal disease. Hypocomplementemia is common in patients with acute lupus nephritis (70–90%) and declining complement levels may herald a flare. Although urinary biomarkers of lupus nephritis


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InternalMed_Harrison. of renal disease. Hypocomplementemia is common in patients with acute lupus nephritis (70–90%) and declining complement levels may herald a flare. Although urinary biomarkers of lupus nephritis are being identified to assist in predicting renal flares, renal biopsy is the only reliable method of identifying the morphologic variants of lupus nephritis.


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InternalMed_Harrison. The World Health Organization (WHO) workshop in 1974 first outlined several distinct patterns of lupus-related glomerular injury; these were modified in 1982. In 2004 the International Society of Nephrology in conjunction with the Renal Pathology Society again updated the classification. This latest version of lesions seen on biopsy (Table 338-3) best defines clinicopathologic correlations, provides valuable prognostic information, and forms the basis for modern treatment recommendations. Class I nephritis describes normal glomerular histology by any technique or normal light microscopy with minimal mesangial deposits on immunofluorescent or electron microscopy. Class II designates mesangial immune complexes with mesangial proliferation. Both class I and II lesions are typically associated with minimal renal manifestation and normal renal function; nephrotic syndrome is rare. Patients with lesions limited to the renal mesangium have an excellent prognosis and generally do not need


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InternalMed_Harrison. with minimal renal manifestation and normal renal function; nephrotic syndrome is rare. Patients with lesions limited to the renal mesangium have an excellent prognosis and generally do not need therapy for their lupus nephritis.


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InternalMed_Harrison. The subject of lupus nephritis is presented under acute nephritic syndromes because of the aggressive and important proliferative lesions seen in class III–V renal disease. Class III describes focal lesions Note: Revised in 2004 by the International Society of Nephrology-Renal Pathology Society Study Group.


InternalMed_Harrison

InternalMed_Harrison. with proliferation or scarring, often involving only a segment of the glomerulus (see Fig. 62e-12). Class III lesions have the most varied course. Hypertension, an active urinary sediment, and proteinuria are common with nephrotic-range proteinuria in 25–33% of patients. Elevated serum creatinine is present in 25% of patients. Patients with mild proliferation involving a small percentage of glomeruli respond well to therapy with steroids alone, and fewer than 5% progress to renal failure over 5 years. Patients with more severe proliferation involving a greater percentage of glomeruli have a far worse prognosis and lower remission rates. Treatment of those patients is the same as that for class IV lesions. Many nephrologists believe that class III lesions are simply an early presentation of class IV disease. Others believe severe class III disease is a discrete lesion requiring aggressive therapy. Class IV describes global, diffuse proliferative lesions involving the vast majority of


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InternalMed_Harrison. of class IV disease. Others believe severe class III disease is a discrete lesion requiring aggressive therapy. Class IV describes global, diffuse proliferative lesions involving the vast majority of glomeruli. Patients with class IV lesions commonly have high anti-DNA antibody titers, low serum complement, hematuria, red blood cell casts, proteinuria, hypertension, and decreased renal function; 50% of patients have nephrotic-range proteinuria. Patients with crescents on biopsy often have a rapidly progressive decline in renal function (see Fig. 62e-12). Without treatment, this aggressive lesion has the worst renal prognosis. However, if a remission—defined as a return to near-normal renal function and proteinuria ≤330 mg/dL per day—is achieved with treatment, renal outcomes are excellent. Current evidence suggests that inducing a remission with administration of high-dose steroids and either cyclophosphamide or mycophenolate mofetil for 2–6 months, followed by maintenance therapy


InternalMed_Harrison

InternalMed_Harrison. Current evidence suggests that inducing a remission with administration of high-dose steroids and either cyclophosphamide or mycophenolate mofetil for 2–6 months, followed by maintenance therapy with lower doses of steroids and mycophenolate mofetil or azathioprine, best balances the likelihood of successful remission with the side effects of therapy. There is no consensus on use of high-dose intravenous methylprednisolone versus oral prednisone, monthly intravenous cyclophosphamide versus daily oral cyclophosphamide, or other immunosuppressants such as cyclosporine, tacrolimus, rituximab, or belimumab. Nephrologists tend to avoid prolonged use of cyclophosphamide in patients of childbearing age without first banking eggs or sperm.


InternalMed_Harrison

InternalMed_Harrison. The class V lesion describes subepithelial immune deposits producing a membranous pattern; a subcategory of class V lesions is associated with proliferative lesions and is sometimes called mixed membranous and proliferative disease (see Fig. 62e-11); this category of injury is treated like class IV glomerulonephritis. Sixty percent of patients present with nephrotic syndrome or lesser amounts of proteinuria. Patients with lupus nephritis class V, like patients with idiopathic membranous nephropathy, are predisposed to renal-vein thrombosis and other thrombotic complications. A minority of patients with class V will present with hypertension and renal dysfunction. There are conflicting data on the clinical course, prognosis, and appropriate therapy for patients with class V disease, which may reflect the heterogeneity of this group of patients. Patients with severe nephrotic syndrome, elevated serum creatinine, and a progressive course will probably benefit from therapy with steroids


InternalMed_Harrison

InternalMed_Harrison. may reflect the heterogeneity of this group of patients. Patients with severe nephrotic syndrome, elevated serum creatinine, and a progressive course will probably benefit from therapy with steroids in combination with other immunosuppressive agents. Therapy with inhibitors of the renin-angiotensin system also may attenuate the proteinuria. Antiphospholipid antibodies present in lupus may result in glomerular microthromboses and complicate the course in up to 20% of lupus nephritis patients. The renal prognosis is worse even with anticoagulant therapy.


InternalMed_Harrison

InternalMed_Harrison. Patients with any of the above lesions also can transform to another lesion; hence patients often require reevaluation, including repeat renal biopsy. Lupus patients with class VI lesions have greater than 90% sclerotic glomeruli and end-stage renal disease with interstitial fibrosis. As a group, approximately 20% of patients with lupus nephritis will reach end-stage disease, requiring dialysis or transplantation. Systemic lupus tends to become quiescent once there is renal failure, perhaps due to the immunosuppressant effects of uremia. However, patients with lupus nephritis have a markedly increased mortality compared with the general population. Renal transplantation in renal failure from lupus, usually performed after approximately 6 months of inactive disease, results in allograft survival rates comparable to patients transplanted for other reasons.


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InternalMed_Harrison. Patients who develop autoantibodies directed against glomerular basement antigens frequently develop a glomerulonephritis termed antiglomerular basement membrane (anti-GBM) disease. When they present with lung hemorrhage and glomerulonephritis, they have a pulmonary-renal syndrome called Goodpasture’s syndrome. The target epitopes for this autoimmune disease lie in the quaternary structure of α3 NC1 domain of collagen IV. Indeed, anti-GBM disease may be considered an autoimmune “conformeropathy” that involves the perturbation of quaternary structure of the α 345NC1 hexamer. MHC-restricted T cells initiate the autoantibody response because humans are not tolerant to the epitopes created by this quaternary structure. The epitopes are normally sequestered in the collagen IV hexamer and can be exposed by infection, smoking, oxidants, or solvents. Goodpasture’s syndrome appears in two age groups: in young men in their late twenties and in men and women in their sixties and seventies.


InternalMed_Harrison

InternalMed_Harrison. can be exposed by infection, smoking, oxidants, or solvents. Goodpasture’s syndrome appears in two age groups: in young men in their late twenties and in men and women in their sixties and seventies. Disease in the younger age group is usually explosive, with hemoptysis, a sudden fall in hemoglobin, fever, dyspnea, and hematuria. Hemoptysis is largely confined to smokers, and those who present with lung hemorrhage as a group do better than older populations who have prolonged, asymptomatic renal injury; presentation with oliguria is often associated with a particularly bad outcome. The performance of an urgent kidney biopsy is important in suspected cases of Goodpasture’s syndrome to confirm the diagnosis and assess prognosis. Renal biopsies typically show focal or segmental necrosis that later, with aggressive destruction of the capillaries by cellular proliferation, leads to crescent formation in Bowman’s space (see Fig. 62e-14). As these lesions progress, there is concomitant


InternalMed_Harrison

InternalMed_Harrison. that later, with aggressive destruction of the capillaries by cellular proliferation, leads to crescent formation in Bowman’s space (see Fig. 62e-14). As these lesions progress, there is concomitant interstitial nephritis with fibrosis and tubular atrophy.


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InternalMed_Harrison. The presence of anti-GBM antibodies and complement is recognized on biopsy by linear immunofluorescent staining for IgG (rarely IgA). In testing serum for anti-GBM antibodies, it is particularly important that the α3 NC1 domain of collagen IV alone be used as the target. This is because nonnephritic antibodies against the α1 NC1 domain are seen in paraneoplastic syndromes and cannot be discerned from assays that use whole basement membrane fragments as the binding target. Between 10 and 15% of sera from patients with Goodpasture’s syndrome also contain ANCA antibodies against myeloperoxidase. This subset of patients has a vasculitis-associated variant, which has a surprisingly good prognosis with treatment. Prognosis at presentation is worse if there are >50% crescents on renal biopsy with advanced fibrosis, if serum creatinine is >5–6 mg/dL, if oliguria is present, or if there is a need for acute dialysis. Although frequently attempted, most of these latter patients will not respond


InternalMed_Harrison

InternalMed_Harrison. advanced fibrosis, if serum creatinine is >5–6 mg/dL, if oliguria is present, or if there is a need for acute dialysis. Although frequently attempted, most of these latter patients will not respond to plasmapheresis and steroids. Patients with advanced renal failure who present with hemoptysis should still be treated for their lung hemorrhage, as it responds to plasmapheresis and can be lifesaving. Treated patients with less severe 1839 disease typically respond to 8–10 treatments of plasmapheresis accompanied by oral prednisone and cyclophosphamide in the first 2 weeks. Kidney transplantation is possible, but because there is risk of recurrence, experience suggests that patients should wait for 6 months and until serum antibodies are undetectable.


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InternalMed_Harrison. Berger first described the glomerulonephritis now termed IgA nephropathy. It is classically characterized by episodic hematuria asso ciated with the deposition of IgA in the mesangium. IgA nephropathy is one of the most common forms of glomerulonephritis worldwide. There is a male preponderance, a peak incidence in the second and third decades of life, and rare familial clustering. There are geographic differences in the prevalence of IgA nephropathy, with 30% prevalence along the Asian and Pacific Rim and 20% in southern Europe, compared to a much lower prevalence in northern Europe and North America. It was initially hypothesized that variation in detection, in part, accounted for regional differences. With clinical care in nephrology becoming more uniform, this variation in prevalence more likely reflects true differences among racial and ethnic groups.


InternalMed_Harrison

InternalMed_Harrison. IgA nephropathy is predominantly a sporadic disease but susceptibility to it has been shown uncommonly to have a genetic component depending on geography and the existence of “founder effects.” Familial forms of IgA nephropathy are more common in northern Italy and eastern Kentucky. No single causal gene has been identified. Clinical and laboratory evidence suggests close similarities between Henoch-Schönlein purpura and IgA nephropathy. Henoch-Schönlein purpura is distinguished clinically from IgA nephropathy by prominent systemic symptoms, a younger age (<20 years old), preceding infection, and abdominal complaints. Deposits of IgA are also found in the glomerular mesangium in a variety of systemic diseases, including chronic liver disease, Crohn’s disease, gastrointestinal adenocarcinoma, chronic bronchiectasis, idiopathic interstitial pneumonia, dermatitis herpetiformis, mycosis fungoides, leprosy, ankylosing spondylitis, relapsing polychondritis, and Sjögren’s syndrome. IgA


InternalMed_Harrison

InternalMed_Harrison. chronic bronchiectasis, idiopathic interstitial pneumonia, dermatitis herpetiformis, mycosis fungoides, leprosy, ankylosing spondylitis, relapsing polychondritis, and Sjögren’s syndrome. IgA deposition in these entities is not usually associated with clinically significant glomerular inflammation or renal dysfunction and thus is not called IgA nephropathy.


InternalMed_Harrison

InternalMed_Harrison. IgA nephropathy is an immune complex–mediated glomerulonephritis defined by the presence of diffuse mesangial IgA deposits often associated with mesangial hypercellularity. (See Glomerular Schematic 2.) IgM, IgG, C3, or immunoglobulin light chains may be codistributed with IgA. IgA deposited in the mesangium is typically polymeric and of the IgA1 subclass, the pathogenic significance of which is not clear. Abnormalities have been described in IgA production by plasma cells, particularly secretory IgA; in IgA clearance, predominately by the liver; in mesangial IgA clearance and receptors for IgA; and in growth factor and cytokine-mediated events. Currently, however, abnormalities in the O -glycosylation of the hinge region of IgA seem to best account for the pathogenesis of sporadic IgA nephropathy. Despite the presence of elevated serum IgA levels in 20–50% of patients, IgA deposition in skin biopsies in 15–55% of patients, or elevated levels of secretory IgA and IgA-fibronectin


InternalMed_Harrison

InternalMed_Harrison. nephropathy. Despite the presence of elevated serum IgA levels in 20–50% of patients, IgA deposition in skin biopsies in 15–55% of patients, or elevated levels of secretory IgA and IgA-fibronectin complexes, a renal biopsy is necessary to confirm the diagnosis. Although the immunofluorescent pattern of IgA on renal biopsy defines IgA nephropathy in the proper clinical context, a variety of histologic lesions may be seen on light microscopy (see Fig. 62e-8), including DPGN; segmental sclerosis; and, rarely, segmental necrosis with cellular crescent formation, which typically presents as RPGN.


InternalMed_Harrison

InternalMed_Harrison. The two most common presentations of IgA nephropathy are recurrent episodes of macroscopic hematuria during or immediately following an upper respiratory infection often accompanied by proteinuria or persistent asymptomatic microscopic hematuria. Nephrotic syndrome is uncommon. Proteinuria can also first appear late in the course of the disease. Rarely patients present with acute renal failure and a rapidly progressive clinical picture. IgA nephropathy is a benign disease for the majority of patients, and 5–30% of patients may go into a complete remission, with others having hematuria but well preserved renal function. In the minority of patients who have progressive disease, progression is slow, with renal failure seen in only 25–30% of patients with IgA nephropathy over 20–25 years. This risk varies considerably among populations. Cumulatively, risk factors for the loss of renal function identified thus far account for less than 50% of the variation in observed outcome but include


InternalMed_Harrison

InternalMed_Harrison. risk varies considerably among populations. Cumulatively, risk factors for the loss of renal function identified thus far account for less than 50% of the variation in observed outcome but include the presence of hypertension or proteinuria, the absence of episodes of macroscopic hematuria, male sex, older age of onset, and extensive glomerulosclerosis or interstitial fibrosis on renal biopsy. Several analyses in large populations of patients found persistent proteinuria for 6 months or longer to have the greatest predictive power for adverse renal outcomes.


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InternalMed_Harrison. There is no agreement on optimal treatment. Both large studies that include patients with multiple glomerular diseases and small studies of patients with IgA nephropathy support the use of angiotensinconverting enzyme (ACE) inhibitors in patients with proteinuria or declining renal function. Tonsillectomy, steroid therapy, and fish oil have all been suggested in small studies to benefit select patients with IgA nephropathy. When presenting as RPGN, patients typically receive steroids, cytotoxic agents, and plasmapheresis.


InternalMed_Harrison

InternalMed_Harrison. A group of patients with small-vessel vasculitis (arterioles, capillaries, and venules; rarely small arteries) and glomerulonephritis have serum ANCA; the antibodies are of two types, anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) (Chap. 385); Lamp-2 antibodies have also been reported experimentally as potentially pathogenic. ANCA are produced with the help of T cells and activate leukocytes and monocytes, which together damage the walls of small vessels. Endothelial injury also attracts more leukocytes and extends the inflammation. Granulomatosis with polyangiitis, microscopic polyangiitis, and Churg-Strauss syndrome belong to this group because they are ANCA-positive and have a pauci-immune glomerulonephritis with few immune complexes in small vessels and glomerular capillaries. Patients with any of these three diseases can have any combination of the above serum antibodies, but anti-PR3 antibodies are more common in granulomatosis with polyangiitis and anti-MPO antibodies


InternalMed_Harrison

InternalMed_Harrison. Patients with any of these three diseases can have any combination of the above serum antibodies, but anti-PR3 antibodies are more common in granulomatosis with polyangiitis and anti-MPO antibodies are more common in microscopic polyangiitis or Churg-Strauss. Although each of these diseases has some unique clinical features, most features do not predict relapse or progression, and as a group, they are generally treated in the same way. Since mortality is high without treatment, virtually all patients receive urgent treatment. Induction therapy usually includes some combination of plasmapheresis, methylprednisolone, and cyclophosphamide. Monthly “pulse” IV cyclophosphamide to induce remission of ANCA-associated vasculitis is as effective as daily oral cyclophosphamide but may be associated with increased relapses. Steroids are tapered soon after acute inflammation subsides, and patients are maintained on cyclophosphamide or azathioprine for up to a year to minimize the risk of relapse.


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InternalMed_Harrison. with increased relapses. Steroids are tapered soon after acute inflammation subsides, and patients are maintained on cyclophosphamide or azathioprine for up to a year to minimize the risk of relapse. Benefit with using mycophenolate mofetil or rituximab has not been proven.


InternalMed_Harrison

InternalMed_Harrison. Granulomatosis with Polyangiitis Patients with this disease classically present with fever, purulent rhinorrhea, nasal ulcers, sinus pain, polyarthralgias/arthritis, cough, hemoptysis, shortness of breath, microscopic hematuria, and 0.5–1 g/24 h of proteinuria; occasionally there may be cutaneous purpura and mononeuritis multiplex. Presentation without renal involvement is termed limited granulomatosis with polyangiitis, although some of these patients will show signs of renal injury later. Chest x-ray often reveals nodules and persistent infiltrates, sometimes with cavities. Biopsy of involved tissue will show a small-vessel vasculitis and adjacent noncaseating granulomas. Renal biopsies during active disease demonstrate segmental necrotizing glomerulonephritis without immune deposits (see Fig. 62e-13). The disease is more common in patients exposed to silica dust and those with α1-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after achieving remission is common and


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InternalMed_Harrison. Fig. 62e-13). The disease is more common in patients exposed to silica dust and those with α1-antitrypsin deficiency, which is an inhibitor of PR3. Relapse after achieving remission is common and is more common in patients with granulomatosis with polyangiitis than the other ANCA-associated vasculitis, necessitating diligent follow-up care. Although associated with an unacceptable high mortality rate without treatment, the greatest threat to patients, especially elderly patients in the first year of therapy, is from adverse events, which are often secondary to treatment, rather than active vasculitis.


InternalMed_Harrison

InternalMed_Harrison. Microscopic Polyangiitis Clinically, these patients look somewhat similar to those with granulomatosis with polyangiitis, except they rarely have significant lung disease or destructive sinusitis. The distinction is made on biopsy, where the vasculitis in microscopic polyangiitis is without granulomas. Some patients will also have injury limited to the capillaries and venules.


InternalMed_Harrison

InternalMed_Harrison. Churg-Strauss Syndrome When small-vessel vasculitis is associated with peripheral eosinophilia, cutaneous purpura, mononeuritis, asthma, and allergic rhinitis, a diagnosis of Churg-Strauss syndrome is considered. Hypergammaglobulinemia, elevated levels of serum IgE, or the presence of rheumatoid factor sometimes accompanies the allergic state. Lung inflammation, including fleeting cough and pulmonary infiltrates, often precedes the systemic manifestations of disease by years; lung manifestations are rarely absent. A third of patients may have exudative pleural effusions associated with eosinophils. Small-vessel vasculitis and focal segmental necrotizing glomerulonephritis can be seen on renal biopsy, usually absent eosinophils or granulomas. The cause of Churg-Strauss syndrome is autoimmune, but the inciting factors are unknown.


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InternalMed_Harrison. MPGN is sometimes called mesangiocapillary glomerulonephritis or lobar glomerulonephritis. It is an immune-mediated glomerulonephritis characterized by thickening of the GBM with mesangioproliferative changes; 70% of patients have hypocomplementemia. MPGN is rare in African Americans, and idiopathic disease usually presents in childhood or young adulthood. MPGN is subdivided pathologically into type I, type II, and type III disease. Type I MPGN is commonly associated with persistent hepatitis C infections, autoimmune diseases like lupus or cryoglobulinemia, or neoplastic diseases (Table 338-4). Types II and III MPGN are usually idiopathic, except in patients with complement factor H deficiency, in the presence of C3 nephritic factor and/or in partial lipodystrophy producing type II disease, or complement receptor deficiency in type III disease. MPGN has been proposed to be reclassified into immunoglobulin-mediated disease (driven by the classical complement pathway) and


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InternalMed_Harrison. type II disease, or complement receptor deficiency in type III disease. MPGN has been proposed to be reclassified into immunoglobulin-mediated disease (driven by the classical complement pathway) and non–immunoglobulin-mediated disease (driven by the alternative complement pathway).


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InternalMed_Harrison. Idiopathic Subacute bacterial endocarditis Systemic lupus erythematosus Hepatitis C ± cryoglobulinemia Mixed cryoglobulinemia Hepatitis B Cancer: Lung, breast, and ovary (germinal)


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InternalMed_Harrison. Type I MPGN, the most proliferative of the three types, shows mesangial proliferation with lobular segmentation on renal biopsy and mesangial interposition between the capillary basement membrane and endothelial cells, producing a double contour sometimes called tram-tracking (see Fig. 62e-9). (See Glomerular Schematic 3.) Subendothelial deposits with low serum levels of C3 are typical, although 50% of patients have normal levels of C3 and occasional intramesangial deposits. Low serum C3 and a dense thickening of the GBM containing ribbons of dense deposits and C3 characterize type II MPGN, sometimes called dense deposit disease (see Fig. 62e-10). Classically, the glomerular tuft has a lobular appearance; intramesangial deposits are rarely present and subendothelial deposits are generally absent. Proliferation in type III MPGN is less common than the other two types and is often focal; mesangial interposition is rare, and subepithelial deposits can occur along widened segments of the


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InternalMed_Harrison. absent. Proliferation in type III MPGN is less common than the other two types and is often focal; mesangial interposition is rare, and subepithelial deposits can occur along widened segments of the GBM that appear laminated and disrupted.


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InternalMed_Harrison. Type I MPGN is secondary to glomerular deposition of circulating immune complexes or their in situ formation. Types II and III MPGN may be related to “nephritic factors,” which are autoantibodies that stabilize C3 convertase and allow it to activate serum C3. MPGN can also result from acquired or genetic abnormalities in the alternative complement pathway. Patients with MPGN present with proteinuria, hematuria, and pyuria (30%); systemic symptoms of fatigue and malaise that are most common in children with type I disease; or an acute nephritic picture with RPGN and a speedy deterioration in renal function in up to 25% of patients. Low serum C3 levels are common. Fifty percent of patients with MPGN develop end-stage disease 10 years after diagnosis, and 90% have renal insufficiency after 20 years. Nephrotic 1841 syndrome, hypertension, and renal insufficiency all predict poor outcome. In the presence of proteinuria, treatment with inhibitors of the renin-angiotensin system is prudent.


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InternalMed_Harrison. years. Nephrotic 1841 syndrome, hypertension, and renal insufficiency all predict poor outcome. In the presence of proteinuria, treatment with inhibitors of the renin-angiotensin system is prudent. Evidence for treatment with dipyridamole, Coumadin (warfarin), or cyclophosphamide is not strongly established. There is some evidence supporting the efficacy of treatment of primary MPGN with steroids, particularly in children, as well as reports of efficacy with plasma exchange and other immunosuppressive drugs. If defects in the complement pathway are found, treatment with eculizumab is of hypothetical but unproven benefit. In secondary MPGN, treating the associated infection, autoimmune disease, or neoplasms is of demonstrated benefit. In particular, pegylated interferon and ribavirin are useful in reducing viral load. Although all primary renal diseases can recur over time in transplanted renal allografts, patients with MPGN are well known to be at risk for not only a histologic


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InternalMed_Harrison. are useful in reducing viral load. Although all primary renal diseases can recur over time in transplanted renal allografts, patients with MPGN are well known to be at risk for not only a histologic recurrence but also a clinically significant recurrence with loss of graft function.


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InternalMed_Harrison. Mesangioproliferative glomerulonephritis is characterized by expansion of the mesangium, sometimes associated with mesangial hypercellularity; thin, single contoured capillary walls; and mesangial immune deposits. Clinically, it can present with varying degrees of proteinuria and, commonly, hematuria. Mesangioproliferative disease may be seen in IgA nephropathy, Plasmodium falciparum malaria, resolving postinfectious glomerulonephritis, and class II nephritis from lupus, all of which can have a similar histologic appearance. With these secondary entities excluded, the diagnosis of primary mesangioproliferative glomerulonephritis is made in less than 15% of renal biopsies. As an immune-mediated renal lesion with deposits of IgM, C1q, and C3, the clinical course is variable. Patients with isolated hematuria may have a very benign course, and those with heavy proteinuria occasionally progress to renal failure. There is little agreement on treatment, but some clinical reports suggest


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InternalMed_Harrison. isolated hematuria may have a very benign course, and those with heavy proteinuria occasionally progress to renal failure. There is little agreement on treatment, but some clinical reports suggest benefit from use of inhibitors of the renin-angiotensin system, steroid therapy, and even cytotoxic agents.


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InternalMed_Harrison. Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension. If left undiagnosed or untreated, some of these syndromes will progressively damage enough glomeruli to cause a fall in GFR, producing renal failure. Multiple studies have noted that the higher the 24-h urine protein excretion, the more rapid is the decline in GFR.


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InternalMed_Harrison. Therapies for various causes of nephrotic syndrome are noted under individual disease headings below. In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents because they are at increased risk for cardiovascular disease. Edema secondary to salt and water retention can be controlled with the judicious use of diuretics, avoiding intravascular volume depletion. Venous complications secondary to the hypercoagulable state associated with nephrotic syndrome can be treated with anticoagulants. The losses of various serum binding proteins, such as thyroid-binding globulin, lead to alterations in functional tests. Lastly, proteinuria itself is hypothesized to be nephrotoxic, and treatment of proteinuria with inhibitors of the renin-angiotensin system can lower urinary protein excretion.


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InternalMed_Harrison. Minimal change disease (MCD), sometimes known as nil lesion, causes 70–90% of nephrotic syndrome in childhood but only 10–15% of nephrotic syndrome in adults. Minimal change disease usually presents as a primary renal disease but can be associated with several other conditions, including Hodgkin’s disease, allergies, or use of nonsteroidal anti-inflammatory agents; significant interstitial nephritis often accompanies cases associated with nonsteroidal drug use. Minimal change disease on renal biopsy shows no obvious glomerular lesion by light microscopy and is negative for deposits by immunofluorescent microscopy, or occasionally shows small amounts of IgM in the mesangium (see Fig. 62e-1). (See Glomerular Schematic 4.) Electron microscopy, however, consistently demonstrates an effacement of the foot process supporting the epithelial podocytes with weakening of slit-pore membranes. The pathophysiology of this lesion is uncertain. Most agree there is a circulating cytokine, perhaps


InternalMed_Harrison

InternalMed_Harrison. of the foot process supporting the epithelial podocytes with weakening of slit-pore membranes. The pathophysiology of this lesion is uncertain. Most agree there is a circulating cytokine, perhaps related to a T cell response that alters capillary charge and podocyte integrity. The evidence for cytokine-related immune injury is circumstantial and is suggested by the presence of preceding allergies, altered cell-mediated immunity during viral infections, and the high frequency of remissions with steroids.


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InternalMed_Harrison. Minimal change disease presents clinically with the abrupt onset of edema and nephrotic syndrome accompanied by acellular urinary sediment. Average urine protein excretion reported in 24 h is 10 g with severe hypoalbuminemia. Less common clinical features include hypertension (30% in children, 50% in adults), microscopic hematuria (20% in children, 33% in adults), atopy or allergic symptoms (40% in children, 30% in adults), and decreased renal function (<5% in children, 30% in adults). The appearance of acute renal failure in adults is often seen more commonly in patients with low serum albumin and intrarenal edema (nephrosarca) that is responsive to intravenous albumin and diuretics. This presentation must be distinguished from acute renal failure secondary to hypovolemia. Acute tubular necrosis and interstitial inflammation are also reported. In children, the abnormal urine principally contains albumin with minimal amounts of highermolecular-weight proteins, and is sometimes called


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InternalMed_Harrison. necrosis and interstitial inflammation are also reported. In children, the abnormal urine principally contains albumin with minimal amounts of highermolecular-weight proteins, and is sometimes called selective proteinuria. Although up to 30% of children have a spontaneous remission, all children today are treated with steroids; only children who are nonresponders are biopsied in this setting. Primary responders are patients who have a complete remission (<0.2 mg/24 h of proteinuria) after a single course of prednisone; steroid-dependent patients relapse as their steroid dose is tapered. Frequent relapsers have two or more relapses in the 6 months following taper, and steroid-resistant patients fail to respond to steroid therapy. Adults are not considered steroid-resistant until after 4 months of therapy. Ninety to 95% of children will develop a complete remission after 8 weeks of steroid therapy, and 80–85% of adults will achieve complete remission, but only after a longer course of


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InternalMed_Harrison. of therapy. Ninety to 95% of children will develop a complete remission after 8 weeks of steroid therapy, and 80–85% of adults will achieve complete remission, but only after a longer course of 20–24 weeks. Patients with steroid resistance may have FSGS on repeat biopsy. Some hypothesize that if the first renal biopsy does not have a sample of deeper corticomedullary glomeruli, then the correct diagnosis of FSGS may be missed.


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InternalMed_Harrison. Relapses occur in 70–75% of children after the first remission, and early relapse predicts multiple subsequent relapses, as do high levels of basal proteinuria. The frequency of relapses decreases after puberty. There is an increased risk of relapse following the rapid tapering of steroids in all groups. Relapses are less common in adults but are more resistant to subsequent therapy. Prednisone is first-line therapy, either given daily or on alternate days. Other immunosuppressive drugs, such as cyclophosphamide, chlorambucil, and mycophenolate mofetil, are saved for frequent relapsers, steroid-dependent patients, or steroid-resistant patients. Cyclosporine can induce remission, but relapse is also common when cyclosporine is withdrawn. The longterm prognosis in adults is less favorable when acute renal failure or steroid resistance occurs.


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InternalMed_Harrison. Focal segmental glomerulosclerosis (FSGS) refers to a pattern of renal injury characterized by segmental glomerular scars that involve some but not all glomeruli; the clinical findings of FSGS largely manifest as proteinuria. When the secondary causes of FSGS are eliminated (Table 338-5), the remaining patients are considered to have primary FSGS. The incidence of this disease is increasing, and it now represents up to one-third of cases of nephrotic syndrome in adults and one-half of cases of nephrotic syndrome in African Americans, in whom it is seen more commonly. The pathogenesis of FSGS is probably multifactorial. Possible mechanisms include a T cell–mediated circulating permeability factor, increased soluble urokinase receptor levels, TGF-β–mediated cellular proliferation and matrix synthesis, and podocyte abnormalities associated with genetic mutations. Risk polymorphisms at the APOL1 locus encoding apolipoprotein L1 expressed in podocytes substantially explain the increased


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InternalMed_Harrison. synthesis, and podocyte abnormalities associated with genetic mutations. Risk polymorphisms at the APOL1 locus encoding apolipoprotein L1 expressed in podocytes substantially explain the increased burden of FSGS among African Americans with or without HIV-associated disease.


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InternalMed_Harrison. The pathologic changes of FSGS are most prominent in glomeruli located at the corticomedullary junction (see Fig. 62e-2), so if the renal biopsy specimen is from superficial tissue, the lesions can be missed, which sometimes leads to a misdiagnosis of MCD. In addition to focal and segmental scarring, other variants have been described, including cellular lesions with endocapillary hypercellularity and heavy proteinuria; collapsing glomerulopath y (see Fig. 62e-3) with segmental or global glomerular collapse and a rapid decline in renal function; a hilar stalk lesion (see Fig. 62e-4); or the glomerular tip lesion (see Fig. 62e-5), which may have a better prognosis. (See Glomerular Schematic 5.)


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InternalMed_Harrison. FSGS can present with hematuria, hypertension, any level of proteinuria, or renal insufficiency. Nephrotic-range proteinuria, African-American race, and renal insufficiency are associated with a poor outcome, with 50% of patients reaching renal failure in 6–8 years. FSGS rarely remits spontaneously, but treatment-induced remission of proteinuria significantly improves prognosis. Treatment of patients with primary FSGS should include inhibitors of the renin-angiotensin system. Based on retrospective studies, patients with nephrotic-range proteinuria can be treated with steroids but respond far less often and Viruses: HIV/hepatitis B/parvovirus


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InternalMed_Harrison. Viruses: HIV/hepatitis B/parvovirus Drugs: Heroin/analgesics/pamidronate after a longer course of therapy than patients with MCD. Proteinuria remits in only 20–45% of patients receiving a course of steroids over 6–9 months. Limited evidence suggests the use of cyclosporine in steroid-responsive patients helps ensure remissions. Relapse frequently occurs after cessation of cyclosporine therapy, and cyclosporine itself can lead to a deterioration of renal function due to its nephrotoxic effects. A role for other agents that suppress the immune system has not been established. Primary FSGS recurs in 25–40% of patients given allografts at end-stage disease, leading to graft loss in half of those cases. The treatment of secondary FSGS typically involves treating the underlying cause and controlling proteinuria. There is no role for steroids or other immunosuppressive agents in secondary FSGS.


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InternalMed_Harrison. Membranous glomerulonephritis (MGN), or membranous nephropathy as it is sometimes called, accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30 and 50 years and a male to female ratio of 2:1. It is rare in childhood and the most common cause of nephrotic syndrome in the elderly. In 25–30% of cases, MGN is associated with a malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, schistosomiasis), or rheumatologic disorders like lupus or rarely rheumatoid arthritis (Table 338-6).


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InternalMed_Harrison. Uniform thickening of the basement membrane along the peripheral capillary loops is seen by light microscopy on renal biopsy (see Fig. 62e-7); this thickening needs to be distinguished from that seen in diabetes and amyloidosis. (See Glomerular Schematic 6.) Immunofluorescence demonstrates diffuse granular deposits of IgG and C3, and electron microscopy typically reveals electron-dense subepithelial deposits. While different stages (I–V) of progressive membranous lesions have been described, some published analyses indicate the degree of tubular atrophy or interstitial fibrosis is more predictive of progression than is the stage of glomerular disease. The presence of subendothelial deposits or the presence of tubuloreticular inclusions strongly points to a diagnosis of membranous lupus nephritis, which may precede the extrarenal manifestations of lupus. Work in Heyman nephritis, an animal model of MGN, suggests that glomerular lesions result from in situ formation of immune complexes


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InternalMed_Harrison. which may precede the extrarenal manifestations of lupus. Work in Heyman nephritis, an animal model of MGN, suggests that glomerular lesions result from in situ formation of immune complexes with megalin receptor–associated protein as the putative antigen. This antigen is not found in human podocytes. Human antibodies have been described against neutral endopeptidase expressed by podocytes in infants whose mothers lack this protein. In most adults, autoantibodies against the M-type phospholipase A2 receptor (PLA2R) circulate and bind to a conformational epitope present in the receptor on human podocytes, producing in situ deposits characteristic of idiopathic membranous nephropathy. Other renal diseases and secondary membranous nephropathy do not appear to involve such


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InternalMed_Harrison. Infection: Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy, Cancer: Breast, colon, lung, stomach, kidney, esophagus, neuroblastoma Drugs: Gold, mercury, penicillamine, nonsteroidal anti-inflammatory agents, probenecid Autoimmune diseases: Systemic lupus erythematosus, rheumatoid arthritis, primary biliary cirrhosis, dermatitis herpetiformis, bullous pemphigoid, myasthenia gravis, Sjögren’s syndrome, Hashimoto’s thyroiditis


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InternalMed_Harrison. Other systemic diseases: Fanconi’s syndrome, sickle cell anemia, diabetes, Crohn’s disease, sarcoidosis, Guillain-Barré syndrome, Weber-Christian disease, angiofollicular lymph node hyperplasia autoantibodies and levels of these autoantibodies have correlated with the severity of MGN. Eighty percent of patients with MGN present with nephrotic syndrome and nonselective proteinuria. Microscopic hematuria is seen but less commonly than in IgA nephropathy or FSGS. Spontaneous remissions occur in 20–33% of patients and often occur late in the course after years of nephrotic syndrome, which make treatment decisions difficult. One-third of patients continue to have relapsing nephrotic syndrome but maintain normal renal function, and approximately another third of patients develop renal failure or die from the complications of nephrotic syndrome. Male gender, older age, hypertension, and the persistence of proteinuria are associated with worse prognosis. Although thrombotic complications are


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InternalMed_Harrison. die from the complications of nephrotic syndrome. Male gender, older age, hypertension, and the persistence of proteinuria are associated with worse prognosis. Although thrombotic complications are a feature of all nephrotic syndromes, MGN has the highest reported incidences of renal vein thrombosis, pulmonary embolism, and deep vein thrombosis. Prophylactic anticoagulation is controversial but has been recommended for patients with severe or prolonged proteinuria in the absence of risk factors for bleeding.


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InternalMed_Harrison. In addition to the treatment of edema, dyslipidemia, and hypertension, inhibition of the renin-angiotensin system is recommended. Therapy with immunosuppressive drugs is also recommended for patients with primary MGN and persistent proteinuria (>3.0 g/24 h). The choice of immunosuppressive drugs for therapy is controversial, but current recommendations are to treat with steroids and cyclophosphamide, chlorambucil, mycophenolate mofetil, or cyclosporine. In patients who relapse or fail to respond to this therapy, the use of rituximab, an anti-CD20 antibody directed at B cells, or synthetic adrenocorticotropic hormone may be considered.


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InternalMed_Harrison. Diabetic nephropathy is the single most common cause of chronic renal failure in the United States, accounting for 45% of patients receiving renal replacement therapy, and is a rapidly growing problem worldwide. The dramatic increase in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity, metabolic syndrome, and type 2 diabetes mellitus. Approximately 40% of patients with types 1 or 2 diabetes develop nephropathy, but due to the higher prevalence of type 2 diabetes (90%) compared to type 1 (10%), the majority of patients with diabetic nephropathy have type 2 disease. Renal lesions are more common in African-American, Native American, Polynesian, and Maori populations. Risk factors for the development of diabetic nephropathy include hyperglycemia, hypertension, dyslipidemia, smoking, a family history of diabetic nephropathy, and gene polymorphisms affecting the activity of the renin-angiotensin-aldosterone axis.