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Glomerular Diseases hematuria, flank pain, and, occasionally, obstruction and Aristolochic Acid Nephropathy infection. Affected individuals typically have a history of heavy Aristolochic acid nephropathy (Balkan nephropathy) is a cause analgesic use. of CTIN first described in Southeast Europe and later identified in consumers of certain Chinese herbs. It is caused by inges- Calcineurin Inhibitors tion of a toxin from the Aristolochia clematitis plant. The calcineurin inhibitors cyclosporine and tacrolimus can Aristolochic acid nephropathy is associated with progression cause CTIN. Longer durations of exposure increase risk for to end-stage kidney disease as well as urothelial cancers. CTIN. Associated thrombotic microangiopathy is uncommon Cystoscopy with retrograde pyelography should be performed but may contribute to acute or chronic kidney injury. in patients with aristolochic acid nephropathy and nonglo- merular hematuria. Lithium Lithium exposure can cause distal tubular dysfunction (type Obstruction 1 hypokalemic distal RTA), nephrogenic diabetes insipidus, Obstructive uropathy from prostate disease, malignancy, and CTIN. CTIN occurs in up to 15% to 20% of long-term nephrolithiasis, pelvic radiation, medications such as methy- lithium users. Risk factors for CTIN include advanced age, sergide, and retroperitoneal fibrosis can cause CTIN and pro- cumulative dose, and repeated episodes of lithium toxicity gressive kidney dysfunction. RTA, hyperkalemia, and mild with high serum levels. Kidney dysfunction can progress to proteinuria are common. end-stage kidney disease even after discontinuation of lithium. ¢ Causes of chronic tubulointerstitial nephritis include Antineoplastic Agents various immunologic diseases, infections, malignancy, Multiple chemotherapy agents can cause TIN. Immune medications, drugs of abuse, lead, and obstructive

hematuria, flank pain, and, occasionally, obstruction and Aristolochic Acid Nephropathy infection. Affected individuals typically have a history of heavy Aristolochic acid nephropathy (Balkan nephropathy) is a cause analgesic use. of CTIN first described in Southeast Europe and later identified in consumers of certain Chinese herbs. It is caused by inges- Calcineurin Inhibitors tion of a toxin from the Aristolochia clematitis plant. The calcineurin inhibitors cyclosporine and tacrolimus can Aristolochic acid nephropathy is associated with progression cause CTIN. Longer durations of exposure increase risk for to end-stage kidney disease as well as urothelial cancers. CTIN. Associated thrombotic microangiopathy is uncommon Cystoscopy with retrograde pyelography should be performed but may contribute to acute or chronic kidney injury. in patients with aristolochic acid nephropathy and nonglo- merular hematuria. Lithium Lithium exposure can cause distal tubular dysfunction (type Obstruction 1 hypokalemic distal RTA), nephrogenic diabetes insipidus, Obstructive uropathy from prostate disease, malignancy, and CTIN. CTIN occurs in up to 15% to 20% of long-term nephrolithiasis, pelvic radiation, medications such as methy- lithium users. Risk factors for CTIN include advanced age, sergide, and retroperitoneal fibrosis can cause CTIN and pro- cumulative dose, and repeated episodes of lithium toxicity gressive kidney dysfunction. RTA, hyperkalemia, and mild with high serum levels. Kidney dysfunction can progress to proteinuria are common. end-stage kidney disease even after discontinuation of lithium. ¢ Causes of chronic tubulointerstitial nephritis include Antineoplastic Agents various immunologic diseases, infections, malignancy, Multiple chemotherapy agents can cause TIN. Immune medications, drugs of abuse, lead, and obstructive checkpoint inhibitors and tyrosine kinase inhibitors are the uropathy.

Antineoplastic Agents various immunologic diseases, infections, malignancy, Multiple chemotherapy agents can cause TIN. Immune medications, drugs of abuse, lead, and obstructive checkpoint inhibitors and tyrosine kinase inhibitors are the uropathy. main classes implicated. Other associated agents with TIN e More recently recognized risk factors for chronic tubu- include ifosfamide, pemetrexed, lenalidomide, vemu- lointerstitial nephritis include chronic interstitial rafenib, and nitrosoureas (particularly streptozotocin and nephritis in agricultural communities, affecting young- semustine). to middle-age male agricultural workers, as well as aris- tolochic acid nephropathy from the ingestion of a Drugs of Abuse Chinese herb toxin. Drugs of abuse such as synthetic cannabinoids, anabolic androgenic steroids, toluene, and cocaine are associated with acute interstitial nephritis. The incidence of CTIN associated Management with repeated exposure is unknown. Management of acute and chronic TIN involves treating the underlying cause by discontinuing medications, drugs of

Drugs of abuse such as synthetic cannabinoids, anabolic androgenic steroids, toluene, and cocaine are associated with acute interstitial nephritis. The incidence of CTIN associated Management with repeated exposure is unknown. Management of acute and chronic TIN involves treating the underlying cause by discontinuing medications, drugs of Lead abuse, or toxin exposure; administering immunosuppressive therapy (often glucocorticoids) for immunologic or drug- Lead can result in tubular dysfunction and CTIN. Occupational related allergic causes; treating infection or malignancy; and exposure to lead occurs from welding, smelting, the battery relieving obstruction. Treatment of lead nephropathy consists industry, and mining. Toxicity may also develop after months of ethylenediaminetetraacetic acid chelation therapy or oral to years of exposure to lead in water, soil, paint, or food prod- succimer. In patients with CTIN and progressive kidney dis- ucts. Gout is common. The clinical diagnosis of lead nephropa- ease, management includes control of blood pressure and thy is based on history of exposure, evidence of kidney dys- treatment of proteinuria and metabolic abnormalities (see function, and blood lead levels. Levels may be normal if lead Chronic Kidney Disease). exposure has abated.

Lead abuse, or toxin exposure; administering immunosuppressive therapy (often glucocorticoids) for immunologic or drug- Lead can result in tubular dysfunction and CTIN. Occupational related allergic causes; treating infection or malignancy; and exposure to lead occurs from welding, smelting, the battery relieving obstruction. Treatment of lead nephropathy consists industry, and mining. Toxicity may also develop after months of ethylenediaminetetraacetic acid chelation therapy or oral to years of exposure to lead in water, soil, paint, or food prod- succimer. In patients with CTIN and progressive kidney dis- ucts. Gout is common. The clinical diagnosis of lead nephropa- ease, management includes control of blood pressure and thy is based on history of exposure, evidence of kidney dys- treatment of proteinuria and metabolic abnormalities (see function, and blood lead levels. Levels may be normal if lead Chronic Kidney Disease). exposure has abated. Chronic Interstitial Nephritis in Agricultural Communities Glomerular Diseases Chronic interstitial nephritis in agricultural communities Epidemiology and (CINAC) is an emerging public health problem in many Central American and Asian countries. CINAC is observed most com- Pathophysiology monly in young- to middle-age male agricultural workers and Glomerular diseases are the third leading cause of end-stage often progresses to end-stage kidney disease. The precise etiol- kidney disease (ESKD) in the United States, accounting for ogy is uncertain, but it is postulated that there is an association approximately 10,000 incident cases of ESKD per year and with frequent dehydration, pesticide exposure, and other trailing only diabetes mellitus and hypertension. The term environmental contaminants. glomerular disease encompasses a wide array of conditions

Chronic Interstitial Nephritis in Agricultural Communities Glomerular Diseases Chronic interstitial nephritis in agricultural communities Epidemiology and (CINAC) is an emerging public health problem in many Central American and Asian countries. CINAC is observed most com- Pathophysiology monly in young- to middle-age male agricultural workers and Glomerular diseases are the third leading cause of end-stage often progresses to end-stage kidney disease. The precise etiol- kidney disease (ESKD) in the United States, accounting for ogy is uncertain, but it is postulated that there is an association approximately 10,000 incident cases of ESKD per year and with frequent dehydration, pesticide exposure, and other trailing only diabetes mellitus and hypertension. The term environmental contaminants. glomerular disease encompasses a wide array of conditions 44

Glomerular Diseases Podocyte Endothelial cell Clinical Manifestations Podocyte foot processes of Glomerular Disease The two main categories of glomerular disease are the Mesangial nephrotic and nephritic syndromes, each of which has a dis- cell tinct clinical presentation. The Nephrotic Syndrome Clinical manifestations of the nephrotic syndrome stem from ongoing loss of protein, principally albumin, into the urine. This urinary loss of albumin causes hypoalbuminemia; in response, the liver increases its production of several proteins, including cholesterols, leading to hyperlipidemia. The result- Mesangial Basement ing hallmark features of the nephrotic syndrome include the matrix membrane following: FIGURE 13. The podocyte, a visceral epithelial cell, sits on the outside surface of the glomerular basement membrane. e Urine protein excretion >3500 mg/24 h or a urine protein- creatinine ratio >3500 mg/g (nephrotic-range proteinuria)

The Nephrotic Syndrome Clinical manifestations of the nephrotic syndrome stem from ongoing loss of protein, principally albumin, into the urine. This urinary loss of albumin causes hypoalbuminemia; in response, the liver increases its production of several proteins, including cholesterols, leading to hyperlipidemia. The result- Mesangial Basement ing hallmark features of the nephrotic syndrome include the matrix membrane following: FIGURE 13. The podocyte, a visceral epithelial cell, sits on the outside surface of the glomerular basement membrane. e Urine protein excretion >3500 mg/24 h or a urine protein- creatinine ratio >3500 mg/g (nephrotic-range proteinuria) with etiologies that span autoimmune disease, malignancy- ¢ Hypoalbuminemia (usually <3.0 g/dL [30 g/L]) associated conditions, sequelae of infection, genetic muta- e Hypercholesterolemia tions, and medication toxicities. These diseases are classified e Edema as either primary (idiopathic), in which the glomerular injury is an intrinsic process generally limited to the kidney, or sec- Edema is typically most severe in the lower extremities. ondary, in which the glomerular lesion is the result of a sys- Many patients report periorbital edema upon awakening. temic disease with kidney involvement as one of many possi- Severe fluid retention can lead to pulmonary edema, pulmo- ble manifestations. nary effusions, and anasarca. Despite avid salt and water The normal, noninflamed glomerulus forms a tight bar- retention, hypertension occurs only in a minority of patients. rier, largely due to the slit diaphragms that connect podocyte Two explanations have been proposed for the edema seen (visceral epithelial cell) foot processes on the outside surface of in the nephrotic syndrome. The “underfill hypothesis” argues the glomerular basement membrane (Figure 13). When healthy, that low serum albumin concentrations lead to a reduction in this filtration barrier prevents passage of blood and protein into intravascular oncotic pressure and a resultant shift of plasma the urinary filtrate. Glomerular diseases involve injury of the from the capillary lumen to the interstitium. The consequent glomerular filter with subsequent passage of protein (proteinu- intravascular depletion activates the renin-angiotensin system ria) and, in the setting of glomerulonephritis, blood (hematu- (RAS), which promotes salt and water retention throughout ria) into the urine. These urinary abnormalities are the earliest the nephron, exacerbating the edema. In contrast, the “overfill manifestations of a glomerular lesion. When left untreated, hypothesis” argues that sodium is primarily retained at the these injuries may result in scarring of the glomerular filters collecting duct, triggered by the abnormally filtered proteins (glomerulosclerosis) with subsequent decline in kidney themselves. Both hypotheses may be correct, and both provide function. a rationale for edema management in patients with the Most etiologies of glomerular disease are diagnosed via nephrotic syndrome. First, resolution of edema is only attain- kidney biopsy. No formal guidelines exist for the indications able long term by remission of proteinuria; lending support to to perform a kidney biopsy in any age group. The decision to the overfill hypothesis, edema will often subside when pro- pursue a kidney biopsy when glomerular disease is sus- teinuria has fallen but before albumin has returned to normal pected should be individualized for each patient, but, in range. Second, diuretics and dietary sodium restriction are general, a kidney biopsy appears justified for patients with crucial to control the symptoms of edema. an otherwise unexplained combination of the following four The nephrotic syndrome is a hypercoagulable state. In findings: hematuria; proteinuria >1000 mg/24 h; reduced addition to albuminuria, patients with the nephrotic syndrome kidney function (glomerular filtration rate <60 mL/min/ excrete a number of low-molecular-weight anticoagulants (for 1.73 m2); and/or positive serologies for systemic diseases example, antithrombin III, protein S) and fibrinolytics (for with known potential for kidney involvement (for example, example, plasminogen). Hepatic overproduction of proteins, as hepatitis B or C virus infection, systemic lupus erythemato- an intrinsic response to hypoalbuminemia, leads not only to sus, and ANCA seropositivity). The risks of kidney biopsy, hyperlipidemia but also to increased levels of procoagulants mainly bleeding, should always be weighed against the (for example, factor V, factor VIII, fibrinogen). As a result, benefits of establishing a more precise diagnosis and treat- patients with the nephrotic syndrome are at increased risk ment plan. for lower extremity, pulmonary, and renal vein thrombosis.

with etiologies that span autoimmune disease, malignancy- ¢ Hypoalbuminemia (usually <3.0 g/dL [30 g/L]) associated conditions, sequelae of infection, genetic muta- e Hypercholesterolemia tions, and medication toxicities. These diseases are classified e Edema as either primary (idiopathic), in which the glomerular injury is an intrinsic process generally limited to the kidney, or sec- Edema is typically most severe in the lower extremities. ondary, in which the glomerular lesion is the result of a sys- Many patients report periorbital edema upon awakening. temic disease with kidney involvement as one of many possi- Severe fluid retention can lead to pulmonary edema, pulmo- ble manifestations. nary effusions, and anasarca. Despite avid salt and water The normal, noninflamed glomerulus forms a tight bar- retention, hypertension occurs only in a minority of patients. rier, largely due to the slit diaphragms that connect podocyte Two explanations have been proposed for the edema seen (visceral epithelial cell) foot processes on the outside surface of in the nephrotic syndrome. The “underfill hypothesis” argues the glomerular basement membrane (Figure 13). When healthy, that low serum albumin concentrations lead to a reduction in this filtration barrier prevents passage of blood and protein into intravascular oncotic pressure and a resultant shift of plasma the urinary filtrate. Glomerular diseases involve injury of the from the capillary lumen to the interstitium. The consequent glomerular filter with subsequent passage of protein (proteinu- intravascular depletion activates the renin-angiotensin system ria) and, in the setting of glomerulonephritis, blood (hematu- (RAS), which promotes salt and water retention throughout ria) into the urine. These urinary abnormalities are the earliest the nephron, exacerbating the edema. In contrast, the “overfill manifestations of a glomerular lesion. When left untreated, hypothesis” argues that sodium is primarily retained at the these injuries may result in scarring of the glomerular filters collecting duct, triggered by the abnormally filtered proteins (glomerulosclerosis) with subsequent decline in kidney themselves. Both hypotheses may be correct, and both provide function. a rationale for edema management in patients with the Most etiologies of glomerular disease are diagnosed via nephrotic syndrome. First, resolution of edema is only attain- kidney biopsy. No formal guidelines exist for the indications able long term by remission of proteinuria; lending support to to perform a kidney biopsy in any age group. The decision to the overfill hypothesis, edema will often subside when pro- pursue a kidney biopsy when glomerular disease is sus- teinuria has fallen but before albumin has returned to normal pected should be individualized for each patient, but, in range. Second, diuretics and dietary sodium restriction are general, a kidney biopsy appears justified for patients with crucial to control the symptoms of edema. an otherwise unexplained combination of the following four The nephrotic syndrome is a hypercoagulable state. In findings: hematuria; proteinuria >1000 mg/24 h; reduced addition to albuminuria, patients with the nephrotic syndrome kidney function (glomerular filtration rate <60 mL/min/ excrete a number of low-molecular-weight anticoagulants (for 1.73 m2); and/or positive serologies for systemic diseases example, antithrombin III, protein S) and fibrinolytics (for with known potential for kidney involvement (for example, example, plasminogen). Hepatic overproduction of proteins, as hepatitis B or C virus infection, systemic lupus erythemato- an intrinsic response to hypoalbuminemia, leads not only to sus, and ANCA seropositivity). The risks of kidney biopsy, hyperlipidemia but also to increased levels of procoagulants mainly bleeding, should always be weighed against the (for example, factor V, factor VIII, fibrinogen). As a result, benefits of establishing a more precise diagnosis and treat- patients with the nephrotic syndrome are at increased risk ment plan. for lower extremity, pulmonary, and renal vein thrombosis. 45

Glomerular Diseases White adults. Epidemiology has remained constant over the past several decades, with a peak incidence between 30 and 50 years of age. Approximately 75% of cases are considered primary; the remaining 25% are considered secondary to sys- temic diseases such as systemic lupus erythematosus, hepatitis B virus infection, medications (for example, penicillamine), and solid tumors. In the past decade, target antigens and their associated autoantibodies responsible for the development of primary membranous nephropathy cases have been identified. The M-type phospholipase A2 receptor (PLA2R) is the specific podocyte antigen responsible for eliciting immune complex formation with circulating autoantibodies in most primary cases. Anti-PLA2R antibodies are detected in approximately

temic diseases such as systemic lupus erythematosus, hepatitis B virus infection, medications (for example, penicillamine), and solid tumors. In the past decade, target antigens and their associated autoantibodies responsible for the development of primary membranous nephropathy cases have been identified. The M-type phospholipase A2 receptor (PLA2R) is the specific podocyte antigen responsible for eliciting immune complex formation with circulating autoantibodies in most primary cases. Anti-PLA2R antibodies are detected in approximately Ms SO eee 75% of primary cases and are rarely found in secondary forms. Additional alternative podocyte autoantigens have been FIGURE 14. Light microscopy in focal segmental glomerulosclerosis shows reported in patients with primary membranous nephropathy, scarring (arrows) in some, but not all, glomeruli in a segmental distribution, as demonstrated by this glomerulus. potentially filling in the missing gaps in PLA2R antibody-

Ms SO eee 75% of primary cases and are rarely found in secondary forms. Additional alternative podocyte autoantigens have been FIGURE 14. Light microscopy in focal segmental glomerulosclerosis shows reported in patients with primary membranous nephropathy, scarring (arrows) in some, but not all, glomeruli in a segmental distribution, as demonstrated by this glomerulus. potentially filling in the missing gaps in PLA2R antibody- Courtesy of Glen Markowitz, MD. negative disease. Membranous nephropathy occurs when cir- culating antibodies permeate the glomerular basement membrane and form immune complexes with epitopes on of individual glomeruli) distribution (Figure 14). Histologic podocyte membranes. variants of FSGS include classic FSGS, perihilar variant, glo- merular tip lesion variant, cellular variant, and collapsing Clinical Manifestations variant. The collapsing variant, associated with HIV infection Patients with membranous nephropathy typically describe but also seen in individuals not infected with HIV, is often slowly progressive edema, and laboratory testing reveals pro- resistant to treatment and therefore carries the worst long- teinuria, hypoalbuminemia, and hyperlipidemia, most often term prognosis, whereas the tip lesion usually responds to with preserved kidney function. Patients are particularly glucocorticoids and is unlikely to progress to ESKD. prone to thrombotic complications. These clots include lower extremity, pulmonary, and renal vein thromboses; they can Treatment and Prognosis occur in up to 25% of patients and are most likely to occur For all patients with FSGS, conservative therapy includes RAS- within the first 2 years of diagnosis. The risk of clotting blocking drugs to control proteinuria, statin therapy, and edema increases when serum albumin is <2.8 g/dL (28 g/L) and is management. Such conservative therapy measures suffice for highest when serum albumin is <2.2 g/dL (22 g/L). patients who have FSGS with subnephrotic proteinuria. When nephrotic-range proteinuria is present and if a Diagnosis primary form of FSGS is suspected, high-dose glucocorticoids The diagnosis of membranous nephropathy is traditionally made remain the mainstay of initial therapy. Other immunosuppres- by kidney biopsy, although testing for anti-PLA2R antibodies has sants, including calcineurin inhibitors, mycophenolate introduced the possibility of diagnosing the disease noninva- mofetil, alkylating agents, and rituximab, have been reported sively. The presence of anti-PLA2R antibodies may eliminate the to provide some benefit as second-line agents for patients who need for kidney biopsy in patients with preserved kidney func- either do not respond to glucocorticoids or whose proteinuria tion and no evidence of secondary causes as well as in patients relapses when glucocorticoids are tapered off. with a clear contraindication to kidney biopsy (for example, Approximately 50% of patients with FSGS progress to patients on anticoagulants that cannot be discontinued). ESKD within 10 years of diagnosis; this poor prognosis is The hallmark biopsy finding is the presence of subepithe- rooted in low rates of treatment response. lial immune deposits that alter the glomerular capillary wall, classically accompanied by intervening “spikes” of glomerular basement membrane extending between the immune deposits e Initial treatment of primary focal segmental glomerulo- in more advanced cases. The biopsy can be stained for the sclerosis is high-dose glucocorticoids. PLA2R antigen, which typically yields a higher sensitivity (>80%) than antibody testing in the serum and helps confirm Membranous Nephropathy primary rather than secondary disease. Such a distinction is Epidemiology and Pathophysiology crucial because secondary forms are expected to remit if the Membranous nephropathy (also known as membranous glo- underlying systemic disease responsible for the lesion is suc- merulopathy) is a leading cause of the nephrotic syndrome in cessfully treated. Notably, in patients with membranous

Courtesy of Glen Markowitz, MD. negative disease. Membranous nephropathy occurs when cir- culating antibodies permeate the glomerular basement membrane and form immune complexes with epitopes on of individual glomeruli) distribution (Figure 14). Histologic podocyte membranes. variants of FSGS include classic FSGS, perihilar variant, glo- merular tip lesion variant, cellular variant, and collapsing Clinical Manifestations variant. The collapsing variant, associated with HIV infection Patients with membranous nephropathy typically describe but also seen in individuals not infected with HIV, is often slowly progressive edema, and laboratory testing reveals pro- resistant to treatment and therefore carries the worst long- teinuria, hypoalbuminemia, and hyperlipidemia, most often term prognosis, whereas the tip lesion usually responds to with preserved kidney function. Patients are particularly glucocorticoids and is unlikely to progress to ESKD. prone to thrombotic complications. These clots include lower extremity, pulmonary, and renal vein thromboses; they can Treatment and Prognosis occur in up to 25% of patients and are most likely to occur For all patients with FSGS, conservative therapy includes RAS- within the first 2 years of diagnosis. The risk of clotting blocking drugs to control proteinuria, statin therapy, and edema increases when serum albumin is <2.8 g/dL (28 g/L) and is management. Such conservative therapy measures suffice for highest when serum albumin is <2.2 g/dL (22 g/L). patients who have FSGS with subnephrotic proteinuria. When nephrotic-range proteinuria is present and if a Diagnosis primary form of FSGS is suspected, high-dose glucocorticoids The diagnosis of membranous nephropathy is traditionally made remain the mainstay of initial therapy. Other immunosuppres- by kidney biopsy, although testing for anti-PLA2R antibodies has sants, including calcineurin inhibitors, mycophenolate introduced the possibility of diagnosing the disease noninva- mofetil, alkylating agents, and rituximab, have been reported sively. The presence of anti-PLA2R antibodies may eliminate the to provide some benefit as second-line agents for patients who need for kidney biopsy in patients with preserved kidney func- either do not respond to glucocorticoids or whose proteinuria tion and no evidence of secondary causes as well as in patients relapses when glucocorticoids are tapered off. with a clear contraindication to kidney biopsy (for example, Approximately 50% of patients with FSGS progress to patients on anticoagulants that cannot be discontinued). ESKD within 10 years of diagnosis; this poor prognosis is The hallmark biopsy finding is the presence of subepithe- rooted in low rates of treatment response. lial immune deposits that alter the glomerular capillary wall, classically accompanied by intervening “spikes” of glomerular basement membrane extending between the immune deposits e Initial treatment of primary focal segmental glomerulo- in more advanced cases. The biopsy can be stained for the sclerosis is high-dose glucocorticoids. PLA2R antigen, which typically yields a higher sensitivity (>80%) than antibody testing in the serum and helps confirm Membranous Nephropathy primary rather than secondary disease. Such a distinction is Epidemiology and Pathophysiology crucial because secondary forms are expected to remit if the Membranous nephropathy (also known as membranous glo- underlying systemic disease responsible for the lesion is suc- merulopathy) is a leading cause of the nephrotic syndrome in cessfully treated. Notably, in patients with membranous 48

Glomerular Diseases nephropathy aged 65 years and older, malignancies have been The pathophysiology of MCG is not well understood. detected in up to 25% within 1 year of their biopsy diagnosis. Similar to FSGS, MCG is a podocytopathy; the presumed model Therefore, age-, sex-, and risk factor-appropriate cancer of injury is immunologic, in which a circulating factor (pro- screening is recommended for all patients at the time of their duced by B or T cells) alters podocyte function, resulting in diagnosis, even those with PLA2R positivity. massive proteinuria. Most cases of MCG are primary, but the disease is associated with various conditions, including Treatment and Prognosis malignancies (lymphoma, thymoma), medications (NSAIDs, Patients with newly diagnosed primary forms of membra- lithium), infections (strongyloides, syphilis, mycoplasma, ehr- nous nephropathy are usually observed for 6 to 12 months on lichiosis), and atopy (pollen, dairy products). conservative therapy (RAS blockade, statin therapy, and edema management) before initiating a course of immuno- Clinical Manifestations suppression for patients with persistent nephrotic-range pro- The classic presentation of MCG is sudden-onset nephrotic teinuria. The observation period allows patients a chance to syndrome. Microscopic hematuria is present in 10% to 30% of achieve spontaneous remission, which occurs in approxi- adult cases. Up to 25% of adults with MCG may also have AKI, mately 30% within 1 to 2 years of diagnosis. Three first-line more commonly occurring in older patients with hyperten- immunosuppressive regimens are available for patients who sion, low serum albumin levels, and heavy proteinuria.

nephropathy aged 65 years and older, malignancies have been The pathophysiology of MCG is not well understood. detected in up to 25% within 1 year of their biopsy diagnosis. Similar to FSGS, MCG is a podocytopathy; the presumed model Therefore, age-, sex-, and risk factor-appropriate cancer of injury is immunologic, in which a circulating factor (pro- screening is recommended for all patients at the time of their duced by B or T cells) alters podocyte function, resulting in diagnosis, even those with PLA2R positivity. massive proteinuria. Most cases of MCG are primary, but the disease is associated with various conditions, including Treatment and Prognosis malignancies (lymphoma, thymoma), medications (NSAIDs, Patients with newly diagnosed primary forms of membra- lithium), infections (strongyloides, syphilis, mycoplasma, ehr- nous nephropathy are usually observed for 6 to 12 months on lichiosis), and atopy (pollen, dairy products). conservative therapy (RAS blockade, statin therapy, and edema management) before initiating a course of immuno- Clinical Manifestations suppression for patients with persistent nephrotic-range pro- The classic presentation of MCG is sudden-onset nephrotic teinuria. The observation period allows patients a chance to syndrome. Microscopic hematuria is present in 10% to 30% of achieve spontaneous remission, which occurs in approxi- adult cases. Up to 25% of adults with MCG may also have AKI, mately 30% within 1 to 2 years of diagnosis. Three first-line more commonly occurring in older patients with hyperten- immunosuppressive regimens are available for patients who sion, low serum albumin levels, and heavy proteinuria. remain nephrotic: (1) a combination of glucocorticoids and alkylating agents, which achieves remission in approximately Diagnosis 75% to 80% of patients within 12 months, (2) calcineurin MGG is diagnosed with kidney biopsy demonstrating normal inhibitors (cyclosporine or tacrolimus), which have reported glomerular histology on light microscopy, negative immuno- remission rates of 70% to 75% in the first year of therapy but fluorescence staining for immunoglobulin and complement for which relapse rates are higher in patients treated with proteins, and complete effacement of the podocyte foot pro- calcineurin inhibitors than alkylating agents, or (3) rituxi- cesses on electron microscopy. mab, which was noninferior compared with cyclosporine in inducing remission of proteinuria and proved superior in Treatment and Prognosis maintaining that remission; adverse events were lower in the The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) group treated with rituximab compared with cyclosporine. Clinical Practice Guideline for Glomerulonephritis recom- Treatment of secondary forms of membranous nephropathy mends glucocorticoids as first-line therapy for children and should be aimed at the underlying systemic disease or adults with MCG, with remission achieved in >90% of children etiology. and 80% to 90% of adults. Time-to-response is prolonged in Progression to ESKD depends on remission of proteinu- adults compared with children, and adults are not considered to ria: The 10-year incidence of ESKD in patients who undergo have glucocorticoid-resistant disease until they have not complete or partial remission of proteinuria ranges from 0 to responded to 16 weeks of glucocorticoid therapy. After an initial 10%, compared with a >50% incidence of ESKD in patients course of glucocorticoids, patients are subdivided into catego- who maintain nephrotic-range proteinuria. ries: glucocorticoid-sensitive MCG, glucocorticoid-dependent MCG, infrequently relapsing MCG, frequently relapsing MCG, and glucocorticoid-resistant MCG. Treatment of glucocorticoid- HVC e Primary membranous nephropathy is typically treated dependent, frequently relapsing, and glucocorticoid-resistant with conservative therapy before initiating immuno- MCG has included calcineurin inhibitors, mycophenolate suppression for patients with persistent nephrotic- mofetil, alkylating agents, and rituximab, with variable results. range proteinuria to allow for spontaneous remission, which occurs in approximately 30% of patients. e The classic presentation of minimal change glomeru- Minimal Change Glomerulopathy lopathy is sudden-onset nephrotic syndrome.

remain nephrotic: (1) a combination of glucocorticoids and alkylating agents, which achieves remission in approximately Diagnosis 75% to 80% of patients within 12 months, (2) calcineurin MGG is diagnosed with kidney biopsy demonstrating normal inhibitors (cyclosporine or tacrolimus), which have reported glomerular histology on light microscopy, negative immuno- remission rates of 70% to 75% in the first year of therapy but fluorescence staining for immunoglobulin and complement for which relapse rates are higher in patients treated with proteins, and complete effacement of the podocyte foot pro- calcineurin inhibitors than alkylating agents, or (3) rituxi- cesses on electron microscopy. mab, which was noninferior compared with cyclosporine in inducing remission of proteinuria and proved superior in Treatment and Prognosis maintaining that remission; adverse events were lower in the The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) group treated with rituximab compared with cyclosporine. Clinical Practice Guideline for Glomerulonephritis recom- Treatment of secondary forms of membranous nephropathy mends glucocorticoids as first-line therapy for children and should be aimed at the underlying systemic disease or adults with MCG, with remission achieved in >90% of children etiology. and 80% to 90% of adults. Time-to-response is prolonged in Progression to ESKD depends on remission of proteinu- adults compared with children, and adults are not considered to ria: The 10-year incidence of ESKD in patients who undergo have glucocorticoid-resistant disease until they have not complete or partial remission of proteinuria ranges from 0 to responded to 16 weeks of glucocorticoid therapy. After an initial 10%, compared with a >50% incidence of ESKD in patients course of glucocorticoids, patients are subdivided into catego- who maintain nephrotic-range proteinuria. ries: glucocorticoid-sensitive MCG, glucocorticoid-dependent MCG, infrequently relapsing MCG, frequently relapsing MCG, and glucocorticoid-resistant MCG. Treatment of glucocorticoid- HVC e Primary membranous nephropathy is typically treated dependent, frequently relapsing, and glucocorticoid-resistant with conservative therapy before initiating immuno- MCG has included calcineurin inhibitors, mycophenolate suppression for patients with persistent nephrotic- mofetil, alkylating agents, and rituximab, with variable results. range proteinuria to allow for spontaneous remission, which occurs in approximately 30% of patients. e The classic presentation of minimal change glomeru- Minimal Change Glomerulopathy lopathy is sudden-onset nephrotic syndrome. Epidemiology and Pathophysiology e¢ Minimal change glomerulopathy is initially treated with Minimal change glomerulopathy (MCG; also known as mini- glucocorticoids. mal change disease) is the most common cause of the nephrotic syndrome in children (>90% of cases). For this reason, unless clinical and serologic evidence suggests the presence of a dis- Conditions Associated with the ease other than MCG, a kidney biopsy is not performed in children with the nephrotic syndrome unless they do not Nephritic Syndrome respond to glucocorticoid therapy. In adults, biopsy series have Rapidly Progressive Glomerulonephritis shown that MCG is the cause of up to 10% to 15% of cases of the Epidemiology and Pathophysiology nephrotic syndrome, with a greater representation in older Rapidly progressive glomerulonephritis (RPGN; also known as patients (265 years of age). crescentic glomerulonephritis) is not a specific disease but a

Epidemiology and Pathophysiology e¢ Minimal change glomerulopathy is initially treated with Minimal change glomerulopathy (MCG; also known as mini- glucocorticoids. mal change disease) is the most common cause of the nephrotic syndrome in children (>90% of cases). For this reason, unless clinical and serologic evidence suggests the presence of a dis- Conditions Associated with the ease other than MCG, a kidney biopsy is not performed in children with the nephrotic syndrome unless they do not Nephritic Syndrome respond to glucocorticoid therapy. In adults, biopsy series have Rapidly Progressive Glomerulonephritis shown that MCG is the cause of up to 10% to 15% of cases of the Epidemiology and Pathophysiology nephrotic syndrome, with a greater representation in older Rapidly progressive glomerulonephritis (RPGN; also known as patients (265 years of age). crescentic glomerulonephritis) is not a specific disease but a 49

TABLE 23. Categorization of Glomerulonephritis Based on Serum Complement Levels | Low Serum C3 and/or Normal Serum C3 and C4 Levels || C4 Levels Lupus nephritis IgA nephropathy Infection-related GN ANCA-associated GN | MPGN Anti-GBM antibody disease | Cryoglobulinemic GN | GBM =glomerular basement membrane; GN = glomerulonephritis;, MPGN = | membranoproliferative glomerulonephritis. | anti-glomerular basement membrane antibodies, antinuclear antibodies) aids in the diagnosis. An alternative classification scheme for glomerulonephritis is based on low versus normal FIGURE 15. Aglomerular crescent (arrows) signals focal rupture of the complement levels (Table 23). Although any form of glomerulone- glomerular capillary walls. phritis can display an aggressive disease course that would fit the Courtesy of Glen Markowitz, MD. definition of an RPGN, the most common etiologies seen in RPGN cases are ANCA-associated glomerulonephritis, lupus nephritis, clinical entity that can be caused by multiple diseases and and anti-glomerular basement membrane glomerulonephritis. manifests as (1) at least a 50% decline in glomerular filtration rate over a short period (usually days to weeks) with (2) pathol- Treatment and Prognosis ogy findings of extensive glomerular crescents (Figure 15). Treatment is based on the specific etiology of RPGN. If

clinical entity that can be caused by multiple diseases and and anti-glomerular basement membrane glomerulonephritis. manifests as (1) at least a 50% decline in glomerular filtration rate over a short period (usually days to weeks) with (2) pathol- Treatment and Prognosis ogy findings of extensive glomerular crescents (Figure 15). Treatment is based on the specific etiology of RPGN. If Crescents signal focal rupture of the glomerular capillary untreated, RPGN is expected to progress to dialysis depend- walls. This rupture allows accumulation of fibrin and fibronec- ence in a matter of days to weeks. If treated early, lesions can tin in the urinary space, where they activate de-differentiated be reversed, although CKD is often a lingering consequence. glomerular parietal epithelial cells to proliferate, surround, and compress the glomerular tuft. Anti-Glomerular Basement Membrane Antibody Disease Clinical Manifestations Epidemiology and Pathophysiology RPGN typically presents with oliguria and rising serum creati- Anti-glomerular basement membrane (anti-GBM) antibody nine along with macroscopic or microscopic hematuria, disease is a rare form of RPGN with an incidence of less than erythrocyte casts, and varying ranges of proteinuria. AKI can one case per million per year. Anti-GBM antibody disease rapidly progress to dialysis dependence. accounts for about 20% of RPGN cases in adults. The lesion is more frequently seen in White patients and has a bimodal age Diagnosis and gender distribution, with peak incidences in young men The diagnosis of all forms of glomerulonephritis is traditionally in the second and third decades of life and in older women in

glomerular parietal epithelial cells to proliferate, surround, and compress the glomerular tuft. Anti-Glomerular Basement Membrane Antibody Disease Clinical Manifestations Epidemiology and Pathophysiology RPGN typically presents with oliguria and rising serum creati- Anti-glomerular basement membrane (anti-GBM) antibody nine along with macroscopic or microscopic hematuria, disease is a rare form of RPGN with an incidence of less than erythrocyte casts, and varying ranges of proteinuria. AKI can one case per million per year. Anti-GBM antibody disease rapidly progress to dialysis dependence. accounts for about 20% of RPGN cases in adults. The lesion is more frequently seen in White patients and has a bimodal age Diagnosis and gender distribution, with peak incidences in young men The diagnosis of all forms of glomerulonephritis is traditionally in the second and third decades of life and in older women in made by kidney biopsy, which can distinguish among the three the sixth and seventh decades of life. More than half of patients major categories of glomerulonephritis (Table 22) and their with anti-GBM antibody disease present with RPGN and pul- associated etiologies. Serologic testing (for example, ANCA, monary hemorrhage. About one third of patients present with isolated glomerulonephritis. Notably, up to one third of patients also have concurrent circulating ANCA (usually anti- TABLE 22. Categorization of Glomerulonephritis Based myeloperoxidase [MPO]) antibodies. on Immunofluorescence Microscopy Findings Circulating anti-GBM antibodies target the alpha-3 chain | Immunofluorescence Staining Pattern of type IV collagen. When anti-GBM antibodies bind to the i] | Granular Pauci-immune Linear GBM, they incite an intense inflammatory response that trans- _ Lupus nephritis ANCA- Anti-GBM lates to the typically fulminant nature of this disease, in the

made by kidney biopsy, which can distinguish among the three the sixth and seventh decades of life. More than half of patients major categories of glomerulonephritis (Table 22) and their with anti-GBM antibody disease present with RPGN and pul- associated etiologies. Serologic testing (for example, ANCA, monary hemorrhage. About one third of patients present with isolated glomerulonephritis. Notably, up to one third of patients also have concurrent circulating ANCA (usually anti- TABLE 22. Categorization of Glomerulonephritis Based myeloperoxidase [MPO]) antibodies. on Immunofluorescence Microscopy Findings Circulating anti-GBM antibodies target the alpha-3 chain | Immunofluorescence Staining Pattern of type IV collagen. When anti-GBM antibodies bind to the i] | Granular Pauci-immune Linear GBM, they incite an intense inflammatory response that trans- _ Lupus nephritis ANCA- Anti-GBM lates to the typically fulminant nature of this disease, in the | Infection-related GN associated GN antibody disease | absence of treatment.

made by kidney biopsy, which can distinguish among the three the sixth and seventh decades of life. More than half of patients major categories of glomerulonephritis (Table 22) and their with anti-GBM antibody disease present with RPGN and pul- associated etiologies. Serologic testing (for example, ANCA, monary hemorrhage. About one third of patients present with isolated glomerulonephritis. Notably, up to one third of patients also have concurrent circulating ANCA (usually anti- TABLE 22. Categorization of Glomerulonephritis Based myeloperoxidase [MPO]) antibodies. on Immunofluorescence Microscopy Findings Circulating anti-GBM antibodies target the alpha-3 chain | Immunofluorescence Staining Pattern of type IV collagen. When anti-GBM antibodies bind to the i] | Granular Pauci-immune Linear GBM, they incite an intense inflammatory response that trans- _ Lupus nephritis ANCA- Anti-GBM lates to the typically fulminant nature of this disease, in the | Infection-related GN associated GN antibody disease | absence of treatment. IgA nephropathy Clinical Manifestations | MPGN | The presentation of anti-GBM antibody disease is similar to | Cryoglobulinemic GN | that of other forms of RPGN, with macroscopic or micro- GBM = glomerular basement membrane; GN = glomerulonephritis; MPGN = scopic hematuria, erythrocyte casts, varying ranges of membranoproliferative glomerulonephritis. proteinuria, and usually moderate to severe AKI. Lung

IgA nephropathy Clinical Manifestations | MPGN | The presentation of anti-GBM antibody disease is similar to | Cryoglobulinemic GN | that of other forms of RPGN, with macroscopic or micro- GBM = glomerular basement membrane; GN = glomerulonephritis; MPGN = scopic hematuria, erythrocyte casts, varying ranges of membranoproliferative glomerulonephritis. proteinuria, and usually moderate to severe AKI. Lung 50

Glomerular Diseases involvement (Goodpasture syndrome) occurs in >50% of and flu-like symptoms that can include fever. Kidney involve- patients; hemoptysis can be a presenting symptom, although ment can produce dark brown (tea-colored) urine, and labora- shortness of breath or cough should also raise suspicion for tory studies will confirm the presence of hematuria, proteinu- a pulmonary-renal syndrome even in the absence of ria, and AKI. Lung and sinus involvement often occurs in hemoptysis. ANCA-associated glomerulonephritis, with patients reporting hemoptysis and/or epistaxis. Diagnosis Kidney biopsy in anti-GBM disease shows a crescentic glo- Diagnosis merulonephritis on light microscopy and pathognomonic Serologic testing for ANCA using enzyme-linked immuno- linear staining on immunofluorescence for IgG along the sorbent assay is usually performed at the time of presentation glomerular capillaries, indicative of antibodies directed if RPGN is suspected. Light microscopy of the kidney biopsy against the GBM. Serologic testing for anti-GBM antibodies is shows a crescentic glomerulonephritis, but immunofluores- performed at the time of diagnosis. The serologic test is done cence shows a paucity or absence of immune-type deposits. by indirect immunofluorescence or direct enzyme-linked Foci of necrosis or cellular crescents are highlighted by immu- immunosorbent, with sensitivity ranging from 60% to 100%; nofluorescence staining for fibrinogen. therefore, a kidney biopsy to confirm diagnosis is recom- mended unless contraindicated. Even with a kidney biopsy Treatment and Prognosis diagnosis, antibody levels should be measured, as titers can be The initial treatment of organ-threatening disease is an area followed to assess efficacy of therapy. of ongoing controversy. Typical induction therapy consists of high-dose glucocorticoids combined with either cyclo- Treatment and Prognosis phosphamide or rituximab. The PEXIVAS study showed no Outcomes in anti-GBM disease are based largely on the evidence of benefit when plasmapheresis was used for degree of AKI at the time of diagnosis and treatment. In an severe kidney failure; in addition, this study reported non- oft-cited series, patients with anti-GBM disease who pre- inferior results comparing a reduced dose of glucocorticoids sented with serum creatinine <5.6 mg/dL (495 pmol/L) had, versus a standard high-dose regimen. Plasmapheresis at 10 years, a <5% overall mortality and a <20% risk for ESKD. should still be used for patients with evidence of alveolar In contrast, patients who presented with dialysis-dependent hemorrhage. kidney failure had a 35% mortality rate within the first year After remission is induced, maintenance therapy is usu- of diagnosis, and only 8% were able to be taken off dialysis ally continued for at least 12 to 24 months using rituximab, during this time. azathioprine, or mycophenolate mofetil. Patients with Treatment for anti-GBM antibody disease consists of plas- c-ANCA/anti-PR3 have a significantly higher rate of relapse mapheresis, pulse glucocorticoids (high doses of intravenous than patients with p-ANCA/anti-MPO, particularly if there is a glucocorticoids over a short period of time) followed by oral history of lung or sinus involvement. ANCA-associated glo- prednisone, and cyclophosphamide. merulonephritis is associated with an approximately 20% mortality rate within the first year of diagnosis and results in ANCA-Associated Glomerulonephritis ESKD in up to 25% of surviving patients within the first 4 years See MKSAP 19 Rheumatology for more information on ANCA- after diagnosis. associated vasculitis.

involvement (Goodpasture syndrome) occurs in >50% of and flu-like symptoms that can include fever. Kidney involve- patients; hemoptysis can be a presenting symptom, although ment can produce dark brown (tea-colored) urine, and labora- shortness of breath or cough should also raise suspicion for tory studies will confirm the presence of hematuria, proteinu- a pulmonary-renal syndrome even in the absence of ria, and AKI. Lung and sinus involvement often occurs in hemoptysis. ANCA-associated glomerulonephritis, with patients reporting hemoptysis and/or epistaxis. Diagnosis Kidney biopsy in anti-GBM disease shows a crescentic glo- Diagnosis merulonephritis on light microscopy and pathognomonic Serologic testing for ANCA using enzyme-linked immuno- linear staining on immunofluorescence for IgG along the sorbent assay is usually performed at the time of presentation glomerular capillaries, indicative of antibodies directed if RPGN is suspected. Light microscopy of the kidney biopsy against the GBM. Serologic testing for anti-GBM antibodies is shows a crescentic glomerulonephritis, but immunofluores- performed at the time of diagnosis. The serologic test is done cence shows a paucity or absence of immune-type deposits. by indirect immunofluorescence or direct enzyme-linked Foci of necrosis or cellular crescents are highlighted by immu- immunosorbent, with sensitivity ranging from 60% to 100%; nofluorescence staining for fibrinogen. therefore, a kidney biopsy to confirm diagnosis is recom- mended unless contraindicated. Even with a kidney biopsy Treatment and Prognosis diagnosis, antibody levels should be measured, as titers can be The initial treatment of organ-threatening disease is an area followed to assess efficacy of therapy. of ongoing controversy. Typical induction therapy consists of high-dose glucocorticoids combined with either cyclo- Treatment and Prognosis phosphamide or rituximab. The PEXIVAS study showed no Outcomes in anti-GBM disease are based largely on the evidence of benefit when plasmapheresis was used for degree of AKI at the time of diagnosis and treatment. In an severe kidney failure; in addition, this study reported non- oft-cited series, patients with anti-GBM disease who pre- inferior results comparing a reduced dose of glucocorticoids sented with serum creatinine <5.6 mg/dL (495 pmol/L) had, versus a standard high-dose regimen. Plasmapheresis at 10 years, a <5% overall mortality and a <20% risk for ESKD. should still be used for patients with evidence of alveolar In contrast, patients who presented with dialysis-dependent hemorrhage. kidney failure had a 35% mortality rate within the first year After remission is induced, maintenance therapy is usu- of diagnosis, and only 8% were able to be taken off dialysis ally continued for at least 12 to 24 months using rituximab, during this time. azathioprine, or mycophenolate mofetil. Patients with Treatment for anti-GBM antibody disease consists of plas- c-ANCA/anti-PR3 have a significantly higher rate of relapse mapheresis, pulse glucocorticoids (high doses of intravenous than patients with p-ANCA/anti-MPO, particularly if there is a glucocorticoids over a short period of time) followed by oral history of lung or sinus involvement. ANCA-associated glo- prednisone, and cyclophosphamide. merulonephritis is associated with an approximately 20% mortality rate within the first year of diagnosis and results in ANCA-Associated Glomerulonephritis ESKD in up to 25% of surviving patients within the first 4 years See MKSAP 19 Rheumatology for more information on ANCA- after diagnosis. associated vasculitis. e Rapidly progressive glomerulonephritis is a syndrome Epidemiology and Pathophysiology characterized by at least a 50% decline in glomerular ANCA-associated glomerulonephritis (also known as pauci- filtration rate over a short period with histologic find- immune crescentic glomerulonephritis) accounts for more ings of extensive glomerular crescents. than half of all RPGN cases and has a particularly high preva- lence in patients >65 years of age presenting with AKI and ¢ More than half of patients with anti-glomerular base- active urinary sediment. ANCA are autoantibodies that target ment membrane antibody disease have lung involve- proteins within neutrophil granules and monocyte lysosomes. ment manifesting as hemoptysis, shortness of breath, There are two types of vasculitis-associated ANCA: p-ANCA or cough.

e Rapidly progressive glomerulonephritis is a syndrome Epidemiology and Pathophysiology characterized by at least a 50% decline in glomerular ANCA-associated glomerulonephritis (also known as pauci- filtration rate over a short period with histologic find- immune crescentic glomerulonephritis) accounts for more ings of extensive glomerular crescents. than half of all RPGN cases and has a particularly high preva- lence in patients >65 years of age presenting with AKI and ¢ More than half of patients with anti-glomerular base- active urinary sediment. ANCA are autoantibodies that target ment membrane antibody disease have lung involve- proteins within neutrophil granules and monocyte lysosomes. ment manifesting as hemoptysis, shortness of breath, There are two types of vasculitis-associated ANCA: p-ANCA or cough. (perinuclear) is directed against the neutrophil enzyme mye- ¢ Treatment of anti-glomerular basement membrane loperoxidase (MPO), and c-ANCA (cytoplasmic) is directed antibody disease consists of pulse glucocorticoids fol- against the neutrophil proteinase 3 (PR3). lowed by oral prednisone, and cyclophosphamide. e Plasmapheresis should be used to treat ANCA-associated Clinical Manifestations glomerulonephritis in patients with concomitant pul- Most patients with ANCA-associated glomerulonephritis monary alveolar hemorrhage. report a vasculitic prodrome of malaise, arthralgia, myalgia, 51

Glomerular Diseases Immune Complex-Mediated Glomerulonephritis empiric diagnosis of IgAN without a biopsy because the dis- The glomerulonephritides with granular immunofluorescence ease course is expected to be mild in these cases. In other cent- microscopy staining patterns all fall under the umbrella category ers, patients with microscopic hematuria that is deemed to be of immune complex-mediated glomerulonephritis, with antigen- glomerular in origin (that is, presence of dysmorphic erythro- antibody complexes depositing in the kidney at various locations cytes or erythrocyte casts in the urine sediment) elicits a and in various patterns (see Table 22). Immune complex deposi- biopsy regardless of kidney function or proteinuria. tion activates the classical complement pathway as a co-mediator of glomerular inflammation, injury, and, potentially, scarring. For Treatment and Prognosis this reason, most immune complex-mediated glomerulonephrit- There are no current standard care therapies for IgAN ides are associated with low levels of C3 and/or C4 (see Table 23). other than conservative, nonimmunomodulatory therapies. IgA nephropathy, which usually presents with normal C3 and C4 Antiproteinuric therapy using an ACE inhibitor or ARB is a levels, is an exception because of the chronic, gradual nature of the first-line therapy for treating IgAN; it is usually coupled with disease; complement consumption is at a rate slow enough for lipid-lowering therapy and fish oil, although the efficacy of the hepatic production to replace complement proteins. latter two as specific IgAN therapies is unproven. The use of immunosuppression in IgAN remains controversial. In the IgA Nephropathy United States, it is common for most patients with IgAN who Epidemiology and Pathophysiology progress to ESKD to have done so despite long-term RAS block- IgA nephropathy (IgAN) is the most common primary glomeru- ade and at least one course of immunosuppressive therapy. lar disease worldwide, diagnosed in up to 10% of all kidney biop- Approximately one third of patients with IgAN will have a

Epidemiology and Pathophysiology progress to ESKD to have done so despite long-term RAS block- IgA nephropathy (IgAN) is the most common primary glomeru- ade and at least one course of immunosuppressive therapy. lar disease worldwide, diagnosed in up to 10% of all kidney biop- Approximately one third of patients with IgAN will have a sies done in the United States and approximately one third of all benign long-term course, with continued microscopic hema- kidney biopsies in Asian countries, where the disease is the lead- turia but little to no proteinuria and no evidence of kidney ing cause of ESKD. In contrast, IgAN is very rare among patients dysfunction. The disease progresses to CKD or ESKD in the of African ancestry. IgAN can be diagnosed at any age, particu- remainder of patients, with up to 40% reaching ESKD within larly because a significant subgroup of patients is asymptomatic, 15 years of diagnosis. The Oxford histopathology classification but is most commonly diagnosed in youth or early adulthood, of IgAN provides evidence that advanced disease chronicity, with a 2:1 male-to-female ratio. In the United States, the overall manifesting as >50% tubular atrophy and interstitial fibrosis on incidence of IgAN is estimated at 2.5 cases per 100,000 person- kidney biopsy, is the most reliable predictor of progression to years, with a prevalence of approximately 80,000 individuals. ESKD. Among clinical parameters, proteinuria >1000 mg/24 h In IgAN, there is a defect in IgA1-producing cells leading has been shown to be a risk factor for progression. to hypogalactosylation of the hinge region of IgA1. Blood levels of galactose-deficient IgA1 (Gd-IgA1) are elevated in patients IgA Vasculitis with IgAN. Patients then develop antibodies directed against IgA vasculitis (also known as Henoch-Schénlein purpura) can Gd-IgA1 to form immune complexes that accumulate in the present with the classic tetrad of rash, arthralgia, abdominal

to hypogalactosylation of the hinge region of IgA1. Blood levels of galactose-deficient IgA1 (Gd-IgA1) are elevated in patients IgA Vasculitis with IgAN. Patients then develop antibodies directed against IgA vasculitis (also known as Henoch-Schénlein purpura) can Gd-IgA1 to form immune complexes that accumulate in the present with the classic tetrad of rash, arthralgia, abdominal glomerulus. pain, and kidney disease. Considered a systemic version of IgAN, this vasculitis is often diagnosed empirically in the pedi- Clinical Manifestations atric setting, because the differential diagnosis of vasculitis in IgAN can present with any of the manifestations of the nephritic children is extremely limited. In adults, the diagnosis should be syndrome. The mildest presentation, seen in up to one third of confirmed with tissue biopsy (kidney or skin), because the patients, is asymptomatic microscopic hematuria with or with- presentation of IgA vasculitis can be mimicked by other forms out proteinuria, usually discovered incidentally as part of a of vasculitis. Skin biopsy is usually adequate to make the diag- routine examination. Recurrent gross hematuria, in which the nosis when lesions less than 24 hours old in appearance are hematuria occurs in the setting of an upper respiratory infec- sampled. Kidney involvement in IgA vasculitis typically is more tion (synpharyngitic hematuria) is a common presentation in severe in adults than in children, with higher rates of AKI and younger patients; it usually portends a benign clinical course the nephrotic syndrome. Treatment includes glucocorticoids with recurrent episodes of gross hematuria without progres- and, in cases of associated RPGN, cyclophosphamide. sion to CKD. IgAN can also present as an acute glomerulone- See MKSAP 19 Rheumatology for more information. phritis or an even more aggressive RPGN, with variable degrees of AKI, hypertension, edema, proteinuria, and hematuria. Lupus Nephritis See MKSAP 19 Rheumatology for more information on sys- Diagnosis temic lupus erythematosus. The diagnosis of IgAN may be suspected clinically but can only be made by kidney biopsy showing dominant mesangial Epidemiology and Pathophysiology immune-deposits of IgA with C3, and occasionally IgG or IgM. Kidney involvement in systemic lupus erythematosus (SLE), In some centers, patients with microscopic hematuria, normal generally termed lupus nephritis (LN), is a major contributor kidney function, and proteinuria <500 mg/24 h are given an to SLE-associated morbidity and mortality. Up to 50% of

glomerulus. pain, and kidney disease. Considered a systemic version of IgAN, this vasculitis is often diagnosed empirically in the pedi- Clinical Manifestations atric setting, because the differential diagnosis of vasculitis in IgAN can present with any of the manifestations of the nephritic children is extremely limited. In adults, the diagnosis should be syndrome. The mildest presentation, seen in up to one third of confirmed with tissue biopsy (kidney or skin), because the patients, is asymptomatic microscopic hematuria with or with- presentation of IgA vasculitis can be mimicked by other forms out proteinuria, usually discovered incidentally as part of a of vasculitis. Skin biopsy is usually adequate to make the diag- routine examination. Recurrent gross hematuria, in which the nosis when lesions less than 24 hours old in appearance are hematuria occurs in the setting of an upper respiratory infec- sampled. Kidney involvement in IgA vasculitis typically is more tion (synpharyngitic hematuria) is a common presentation in severe in adults than in children, with higher rates of AKI and younger patients; it usually portends a benign clinical course the nephrotic syndrome. Treatment includes glucocorticoids with recurrent episodes of gross hematuria without progres- and, in cases of associated RPGN, cyclophosphamide. sion to CKD. IgAN can also present as an acute glomerulone- See MKSAP 19 Rheumatology for more information. phritis or an even more aggressive RPGN, with variable degrees of AKI, hypertension, edema, proteinuria, and hematuria. Lupus Nephritis See MKSAP 19 Rheumatology for more information on sys- Diagnosis temic lupus erythematosus. The diagnosis of IgAN may be suspected clinically but can only be made by kidney biopsy showing dominant mesangial Epidemiology and Pathophysiology immune-deposits of IgA with C3, and occasionally IgG or IgM. Kidney involvement in systemic lupus erythematosus (SLE), In some centers, patients with microscopic hematuria, normal generally termed lupus nephritis (LN), is a major contributor kidney function, and proteinuria <500 mg/24 h are given an to SLE-associated morbidity and mortality. Up to 50% of 52

Glomerular Diseases patients with SLE will have clinically evident kidney disease at These immune complexes, when deposited in the mesangium presentation; during follow-up, kidney involvement occurs in and subendothelial space, are in direct communication with the up to 75% of patients. LN has been shown to affect clinical systemic circulation. Subsequent activation of the classical outcomes in SLE both directly via target organ damage and complement pathway, triggered by the DNA/anti-DNA antibody indirectly through complications of therapy. complex formation, generates the potent chemoattractants, C3a The immune deposits that incite LN are primarily com- and CS5a, which elicit an influx of neutrophils and mononuclear plexes of anti-double-stranded DNA antibodies directed against cells. The pattern on light microscopy is a proliferative glomeru- nucleosomal antigens. A smaller fraction of autoantibodies can lonephritis that can be mesangial (class II), focal endocapillary also bind directly to chromatin in the GBM and mesangium. (class III), or diffuse endocapillary (class IV) (Table 24). TABLE 24. Classification of Lupus Nephritis with Associated Presentation and Treatment Options | ISN/RPS Class Biopsy Findings Clinical Features Treatment Induction Phase Maintenance Phase | f | Class |: minimal No LM abnormalities; Normal urine or Conservative therapy (e.g., Not applicable mesangial LN isolated mesangial IC microscopic RAS blockade) deposits on IF and EM hematuria

Induction Phase Maintenance Phase | f | Class |: minimal No LM abnormalities; Normal urine or Conservative therapy (e.g., Not applicable mesangial LN isolated mesangial IC microscopic RAS blockade) deposits on IF and EM hematuria | Class II: mesangial Mesangial Microscopic Conservative therapy (e.g., Not applicable proliferative LN hypercellularity or hematuria and/or RAS blockade) | matrix expansion with low-grade | mesangial |lC deposits —_ proteinuria | on IF and EM

| Class II: mesangial Mesangial Microscopic Conservative therapy (e.g., Not applicable proliferative LN hypercellularity or hematuria and/or RAS blockade) | matrix expansion with low-grade | mesangial |lC deposits —_ proteinuria | on IF and EM | Class Ill: focal LN <50% of glomeruli Nephritic urine Pulse IV glucocorticoids Lowest tolerable amount of oral | on LM display sediment and followed by tapering doses glucocorticoids endocapillary and/or subnephrotic of oral glucocorticoids and extracapillary proteinuria and proliferation; Mycophenolate mofetil (tapered mesangial and focal IV cyclophosphamide down assuming stable disease) subendothelial IC or or deposits on IF and EM Mycophenolate mofetil Azathioprine (tapered down assuming stable disease)

| Class Ill: focal LN <50% of glomeruli Nephritic urine Pulse IV glucocorticoids Lowest tolerable amount of oral | on LM display sediment and followed by tapering doses glucocorticoids endocapillary and/or subnephrotic of oral glucocorticoids and extracapillary proteinuria and proliferation; Mycophenolate mofetil (tapered mesangial and focal IV cyclophosphamide down assuming stable disease) subendothelial IC or or deposits on IF and EM Mycophenolate mofetil Azathioprine (tapered down assuming stable disease) Class IV: diffuse 250% of glomeruli Nephritic and Pulse IV glucocorticoids Lowest tolerable amount of oral LN on LM display nephrotic followed by tapering doses glucocorticoids endocapillary and/or syndromes; of oral glucocorticoids and extracapillary hypertension; and proliferation; reduced kidney Mycophenolate mofetil (tapered mesangial and diffuse function IV cyclophosphamide down assuming stable disease) subendothelial IC or or deposits on IF and EM Mycophenolate mofetil Azathioprine (tapered down assuming stable disease)

Class IV: diffuse 250% of glomeruli Nephritic and Pulse IV glucocorticoids Lowest tolerable amount of oral LN on LM display nephrotic followed by tapering doses glucocorticoids endocapillary and/or syndromes; of oral glucocorticoids and extracapillary hypertension; and proliferation; reduced kidney Mycophenolate mofetil (tapered mesangial and diffuse function IV cyclophosphamide down assuming stable disease) subendothelial IC or or deposits on IF and EM Mycophenolate mofetil Azathioprine (tapered down assuming stable disease) Class V: Diffuse thickening of Nephrotic Pulse IV glucocorticoids Lowest tolerable amount of oral membranous LN? the glomerular syndrome followed by tapering doses glucocorticoids capillary walls on LM of oral glucocorticoids and with subepithelial IC | deposits on IF and EM, arid Mycophenolate mofetil (tapered | with or without IV cyclophosphamide down assuming stable disease) | mesangial IC deposits | or or

Class V: Diffuse thickening of Nephrotic Pulse IV glucocorticoids Lowest tolerable amount of oral membranous LN? the glomerular syndrome followed by tapering doses glucocorticoids capillary walls on LM of oral glucocorticoids and with subepithelial IC | deposits on IF and EM, arid Mycophenolate mofetil (tapered | with or without IV cyclophosphamide down assuming stable disease) | mesangial IC deposits | or or | Calcineurin inhibitor Azathioprine (tapered down | (cyclosporine or tacrolimus) assuming stable disease) | | or | Mycophenolate mofetil | | Class VI: >90% of glomeruli Advanced CKD or Preparation for renal Not applicable | advanced on LM are globally ESKD with varying replacement therapy | sclerosing LN sclerosed with no degrees of residual activity hematuria and/or proteinuria

| Calcineurin inhibitor Azathioprine (tapered down | (cyclosporine or tacrolimus) assuming stable disease) | | or | Mycophenolate mofetil | | Class VI: >90% of glomeruli Advanced CKD or Preparation for renal Not applicable | advanced on LM are globally ESKD with varying replacement therapy | sclerosing LN sclerosed with no degrees of residual activity hematuria and/or proteinuria | CKD = chronic kidney disease; EM = electron microscopy; ESKD = end-stage kidney disease; |C = immune complex; IF = immunofluorescence; ISN/RPS = International Society of | Nephrology/Renal Pathology Society; IV = intravenous; LM = light microscopy; LN = lupus nephritis; RAS = renin-angiotensin system. | ; °ClassV may coexist with class III or class IV, in which case both classes are diagnosed. |

Glomerular Diseases Endocapillary proliferation refers to an increased number of the time of development of glomerulonephritis. IRGN is pre- inflammatory cells within glomerular capillary lumina, causing ferred to the formerly used term “postinfectious glomerulone- luminal narrowing or obliteration. Immune complex deposits phritis,” which adequately described classic poststreptococcal in the subepithelial space are separated from contact with the glomerulonephritis but did not address the increasingly rec- systemic circulation by the GBM, and hence no influx of inflam- ognized forms of glomerulonephritis that are manifestations matory cells occurs into this space. The injury in this class V LN of ongoing infection and nonstreptococcal infectious agents. (membranous) is limited to the glomerular epithelial cells, the Diabetes is the most common comorbidity; malignancy, primary clinical manifestation is proteinuria, and the histologic immunosuppression, AIDS, alcoholism, and injection drug pattern on light microscopy is similar to primary membranous use are other recognized comorbidities. Older age is a key risk nephropathy. factor. Patients >65 years of age account for about one third of IRGN cases in the developed world. Clinical Manifestations The incidence of poststreptococcal glomerulonephritis Kidney involvement is uncommon at the time of the initial has declined throughout most of the world because of improve- diagnosis of SLE but will usually manifest with proteinuria ments in infection control and sanitation. The entity, however, and/or microscopic hematuria during the first 3 years of the remains a health concern in developing countries. In industri- disease. This eventually progresses to reduction in kidney alized countries, much of the burden of IRGN has shifted from function. Early in the course of disease, it is unusual for children to adults, with a decrease in IRGN attributed to strep- patients to present with decreased kidney function, except for tococcal infections and an increase in IRGN cases associated very aggressive cases of LN that present as RPGN. When kid- with Staphylococcus aureus and gram-negative bacteria. ney function is impaired, elevated blood pressure is common. In the classic view of the pathogenesis of IRGN, antibodies directed at bacterial antigens form immune complexes in the Diagnosis circulation that subsequently deposit in the glomerulus. The diagnosis of LN is suspected by changes in laboratory Additionally, however, antibodies directed at bacterial antigens parameters (elevated serum creatinine, hematuria and/or pro- planted within glomeruli can result in in situ formation of teinuria, low serum complements) but can only be made glomerular immune complexes. definitively by kidney biopsy. The classic pattern of LN is an immune complex-mediated glomerulonephritis with a varied Clinical Manifestations pathology that includes six distinct classes of disease (see The variable presentation of IRGN ranges from asymptomatic Table 24). On immunofluorescence microscopy, the glomeru- microscopic hematuria to RPGN. Proteinuria is usually lar deposits in LN stain dominantly for IgG with co-deposits of subnephrotic. IgA, IgM, C3, and Clq in a “full house” pattern. On electron In classic poststreptococcal glomerulonephritis, sympto- microscopy, tubuloreticular inclusions, which represent matic patients (typically children) present with an acute nephritic “interferon footprints” in the glomerular endothelial cell cyto- syndrome of hematuria, proteinuria, hypertension, edema, and, plasm, are pathognomonic for LN. in some cases, kidney dysfunction. The urine sediment is active

Endocapillary proliferation refers to an increased number of the time of development of glomerulonephritis. IRGN is pre- inflammatory cells within glomerular capillary lumina, causing ferred to the formerly used term “postinfectious glomerulone- luminal narrowing or obliteration. Immune complex deposits phritis,” which adequately described classic poststreptococcal in the subepithelial space are separated from contact with the glomerulonephritis but did not address the increasingly rec- systemic circulation by the GBM, and hence no influx of inflam- ognized forms of glomerulonephritis that are manifestations matory cells occurs into this space. The injury in this class V LN of ongoing infection and nonstreptococcal infectious agents. (membranous) is limited to the glomerular epithelial cells, the Diabetes is the most common comorbidity; malignancy, primary clinical manifestation is proteinuria, and the histologic immunosuppression, AIDS, alcoholism, and injection drug pattern on light microscopy is similar to primary membranous use are other recognized comorbidities. Older age is a key risk nephropathy. factor. Patients >65 years of age account for about one third of IRGN cases in the developed world. Clinical Manifestations The incidence of poststreptococcal glomerulonephritis Kidney involvement is uncommon at the time of the initial has declined throughout most of the world because of improve- diagnosis of SLE but will usually manifest with proteinuria ments in infection control and sanitation. The entity, however, and/or microscopic hematuria during the first 3 years of the remains a health concern in developing countries. In industri- disease. This eventually progresses to reduction in kidney alized countries, much of the burden of IRGN has shifted from function. Early in the course of disease, it is unusual for children to adults, with a decrease in IRGN attributed to strep- patients to present with decreased kidney function, except for tococcal infections and an increase in IRGN cases associated very aggressive cases of LN that present as RPGN. When kid- with Staphylococcus aureus and gram-negative bacteria. ney function is impaired, elevated blood pressure is common. In the classic view of the pathogenesis of IRGN, antibodies directed at bacterial antigens form immune complexes in the Diagnosis circulation that subsequently deposit in the glomerulus. The diagnosis of LN is suspected by changes in laboratory Additionally, however, antibodies directed at bacterial antigens parameters (elevated serum creatinine, hematuria and/or pro- planted within glomeruli can result in in situ formation of teinuria, low serum complements) but can only be made glomerular immune complexes. definitively by kidney biopsy. The classic pattern of LN is an immune complex-mediated glomerulonephritis with a varied Clinical Manifestations pathology that includes six distinct classes of disease (see The variable presentation of IRGN ranges from asymptomatic Table 24). On immunofluorescence microscopy, the glomeru- microscopic hematuria to RPGN. Proteinuria is usually lar deposits in LN stain dominantly for IgG with co-deposits of subnephrotic. IgA, IgM, C3, and Clq in a “full house” pattern. On electron In classic poststreptococcal glomerulonephritis, sympto- microscopy, tubuloreticular inclusions, which represent matic patients (typically children) present with an acute nephritic “interferon footprints” in the glomerular endothelial cell cyto- syndrome of hematuria, proteinuria, hypertension, edema, and, plasm, are pathognomonic for LN. in some cases, kidney dysfunction. The urine sediment is active with dysmorphic erythrocytes, erythrocyte casts, and leukocytu- Treatment and Prognosis ria. Hypocomplementemia is common, with decreased C3 in up The current approach to treating LN is guided by histologic to 90% of cases. There is usually a latent period (1 to 2 weeks after findings with appropriate consideration of presenting clinical upper respiratory infections; 2 to 4 weeks after skin infections) parameters and the degree of kidney function impairment (see between the resolution of the streptococcal infection and the Table 24). Mycophenolate mofetil is equally effective as cyclo- onset of the nephritic syndrome. Serologic markers of a recent phosphamide (56% response versus 53% response, respec- streptococcal infection, including elevated antistreptolysin O, tively) and is less toxic as induction therapy for LN classes III, antistreptokinase, antihyaluronidase, and antideoxyribonuclease IV, and V. Fertility is more likely to be preserved with B antibody levels, are often detected. In adults, most cases of mycophenolate. IRGN are no longer poststreptococcal, and the glomerulonephri- Up to 30% of patients with LN will progress to ESKD tis often coexists with the triggering infection. Low complement within 10 years of diagnosis, depending in large part on the levels may be absent in these peri-infectious cases. response to the initial course of immunosuppression. Severity of disease at the time of diagnosis as well as Black race, Diagnosis Hispanic ethnicity, and socioeconomic status have also been The diagnosis of IRGN can be made clinically in the appropri- reported to influence outcomes in LN. ate setting (for example, classic nephritic presentation with low complements and clear evidence of a recent infection), Infection-Related Glomerulonephritis although the only definitive way to make the diagnosis is by Epidemiology and Pathophysiology kidney biopsy. The most common finding on light microscopy Infection-related glomerulonephritis (IRGN) results from a is a proliferative glomerulonephritis with significant presence recently resolved infection or an infection that is ongoing at of infiltrating neutrophils. On electron microscopy, the classic

with dysmorphic erythrocytes, erythrocyte casts, and leukocytu- Treatment and Prognosis ria. Hypocomplementemia is common, with decreased C3 in up The current approach to treating LN is guided by histologic to 90% of cases. There is usually a latent period (1 to 2 weeks after findings with appropriate consideration of presenting clinical upper respiratory infections; 2 to 4 weeks after skin infections) parameters and the degree of kidney function impairment (see between the resolution of the streptococcal infection and the Table 24). Mycophenolate mofetil is equally effective as cyclo- onset of the nephritic syndrome. Serologic markers of a recent phosphamide (56% response versus 53% response, respec- streptococcal infection, including elevated antistreptolysin O, tively) and is less toxic as induction therapy for LN classes III, antistreptokinase, antihyaluronidase, and antideoxyribonuclease IV, and V. Fertility is more likely to be preserved with B antibody levels, are often detected. In adults, most cases of mycophenolate. IRGN are no longer poststreptococcal, and the glomerulonephri- Up to 30% of patients with LN will progress to ESKD tis often coexists with the triggering infection. Low complement within 10 years of diagnosis, depending in large part on the levels may be absent in these peri-infectious cases. response to the initial course of immunosuppression. Severity of disease at the time of diagnosis as well as Black race, Diagnosis Hispanic ethnicity, and socioeconomic status have also been The diagnosis of IRGN can be made clinically in the appropri- reported to influence outcomes in LN. ate setting (for example, classic nephritic presentation with low complements and clear evidence of a recent infection), Infection-Related Glomerulonephritis although the only definitive way to make the diagnosis is by Epidemiology and Pathophysiology kidney biopsy. The most common finding on light microscopy Infection-related glomerulonephritis (IRGN) results from a is a proliferative glomerulonephritis with significant presence recently resolved infection or an infection that is ongoing at of infiltrating neutrophils. On electron microscopy, the classic 54

finding in poststreptococcal glomerulonephritis is hump- antibody, eculizumab, may bring disease-specific therapy for shaped subepithelial electron dense deposits, although these the complement-mediated forms of MPGN. are not required for the diagnosis of IRGN. The overall prognosis of MPGN as a chronic form of glo- merulonephritis is poor, with >50% of patients progressing to Treatment and Prognosis ESKD within 15 years of diagnosis. Treatment is typically supportive and aimed at the infectious etiology, although in some cases with severe proliferative glo- Cryoglobulinemia merulonephritis on biopsy, a trial of glucocorticoids is used. Cryoglobulinemia can be associated with the nephritic syn- In children, prognosis for complete recovery is excellent, drome. Of the three types of cryoglobulins, kidney involve- and treatment usually is supportive and aimed at the infecting ment is typically due to type II cryoglobulins. organism. The prognosis of the newly recognized forms of IRGN See MKSAP 19 Hematology for details on cryoglobulinemia; (for example, due to S. aureus and gram-negative organisms) in MKSAP 19 Rheumatology for information on cryoglobulinemic adults is different, with more patients developing severe kidney vasculitis; and Kidney Manifestations of Deposition Diseases for dysfunction and progressing to CKD and sometimes ESKD. information on kidney involvement in cryoglobulinemia.

finding in poststreptococcal glomerulonephritis is hump- antibody, eculizumab, may bring disease-specific therapy for shaped subepithelial electron dense deposits, although these the complement-mediated forms of MPGN. are not required for the diagnosis of IRGN. The overall prognosis of MPGN as a chronic form of glo- merulonephritis is poor, with >50% of patients progressing to Treatment and Prognosis ESKD within 15 years of diagnosis. Treatment is typically supportive and aimed at the infectious etiology, although in some cases with severe proliferative glo- Cryoglobulinemia merulonephritis on biopsy, a trial of glucocorticoids is used. Cryoglobulinemia can be associated with the nephritic syn- In children, prognosis for complete recovery is excellent, drome. Of the three types of cryoglobulins, kidney involve- and treatment usually is supportive and aimed at the infecting ment is typically due to type II cryoglobulins. organism. The prognosis of the newly recognized forms of IRGN See MKSAP 19 Hematology for details on cryoglobulinemia; (for example, due to S. aureus and gram-negative organisms) in MKSAP 19 Rheumatology for information on cryoglobulinemic adults is different, with more patients developing severe kidney vasculitis; and Kidney Manifestations of Deposition Diseases for dysfunction and progressing to CKD and sometimes ESKD. information on kidney involvement in cryoglobulinemia. Membranoproliferative Glomerulonephritis Collagen Type IV-Related Nephropathies Epidemiology and Pathophysiology Type IV collagen is an integral component of the GBM. Membranoproliferative glomerulonephritis (MPGN) is a rare Structural defects in this protein due to genetic variations form of chronic glomerulonephritis diagnosed primarily in can result in a hereditary form of glomerulonephritis (Alport children and young adults. The name stems from its pattern of syndrome; also termed hereditary nephritis) discussed in glomerular injury. The entity is divided into immune-complex more detail in Genetic Disorders and Kidney Disease. In forms of MPGN (mediated by antigen-antibody interactions addition, whole exome and whole genome sequencing stud- triggering the classical complement pathway) versus ies have shown that type IV collagen variants are identified complement-mediated forms of MPGN (also termed C3 glo- in up to 10% to 15% of adult patients with FSGS. merulopathies, because of a hyperactive alternative comple- ment pathway). An immune-complex MPGN, with or without ¢ Treatment of IgA nephropathy consists of conservative ther- cryoglobulinemia, is the classic form of kidney involvement apy using an ACE inhibitor or angiotensin receptor blocker. seen in patients with hepatitis C virus infection. The alterna- tive complement pathway abnormalities that drive the C3 ¢ Kidney biopsy is required to diagnose and classify lupus glomerulopathies are either mutations in regulators (for nephritis, which guides therapy. example, complement factor H) or activators (for example, e Treatment of classes I and II lupus nephritis (LN) complement factor B) of the alternative pathway, or antibodies includes conservative therapy with an ACE inhibitor or directed at regulator or activator complement proteins. angiotensin receptor blocker; classes III, IV, and V LN require immunosuppressive therapy; and class VI LN Clinical Manifestations should be treated with conservative therapy. Although MPGN can rarely present as an acute and severe ¢ Infection-related glomerulonephritis results from a form of glomerulonephritis, the more common presentation is recently resolved infection or an infection that is ongo- a chronic glomerulonephritis that initially manifests with ing at the time of development of glomerulonephritis; microscopic hematuria and subnephrotic proteinuria. As dis- in industrialized countries, clinical disease is seen more ease progresses, proteinuria can reach nephrotic range, and often in adults and is associated with Staphylococcus kidney dysfunction ensues. aureus and gram-negative bacteria.

Membranoproliferative Glomerulonephritis Collagen Type IV-Related Nephropathies Epidemiology and Pathophysiology Type IV collagen is an integral component of the GBM. Membranoproliferative glomerulonephritis (MPGN) is a rare Structural defects in this protein due to genetic variations form of chronic glomerulonephritis diagnosed primarily in can result in a hereditary form of glomerulonephritis (Alport children and young adults. The name stems from its pattern of syndrome; also termed hereditary nephritis) discussed in glomerular injury. The entity is divided into immune-complex more detail in Genetic Disorders and Kidney Disease. In forms of MPGN (mediated by antigen-antibody interactions addition, whole exome and whole genome sequencing stud- triggering the classical complement pathway) versus ies have shown that type IV collagen variants are identified complement-mediated forms of MPGN (also termed C3 glo- in up to 10% to 15% of adult patients with FSGS. merulopathies, because of a hyperactive alternative comple- ment pathway). An immune-complex MPGN, with or without ¢ Treatment of IgA nephropathy consists of conservative ther- cryoglobulinemia, is the classic form of kidney involvement apy using an ACE inhibitor or angiotensin receptor blocker. seen in patients with hepatitis C virus infection. The alterna- tive complement pathway abnormalities that drive the C3 ¢ Kidney biopsy is required to diagnose and classify lupus glomerulopathies are either mutations in regulators (for nephritis, which guides therapy. example, complement factor H) or activators (for example, e Treatment of classes I and II lupus nephritis (LN) complement factor B) of the alternative pathway, or antibodies includes conservative therapy with an ACE inhibitor or directed at regulator or activator complement proteins. angiotensin receptor blocker; classes III, IV, and V LN require immunosuppressive therapy; and class VI LN Clinical Manifestations should be treated with conservative therapy. Although MPGN can rarely present as an acute and severe ¢ Infection-related glomerulonephritis results from a form of glomerulonephritis, the more common presentation is recently resolved infection or an infection that is ongo- a chronic glomerulonephritis that initially manifests with ing at the time of development of glomerulonephritis; microscopic hematuria and subnephrotic proteinuria. As dis- in industrialized countries, clinical disease is seen more ease progresses, proteinuria can reach nephrotic range, and often in adults and is associated with Staphylococcus kidney dysfunction ensues. aureus and gram-negative bacteria. Diagnosis e Treatment of membranoproliferative glomerulonephri-

Membranoproliferative Glomerulonephritis Collagen Type IV-Related Nephropathies Epidemiology and Pathophysiology Type IV collagen is an integral component of the GBM. Membranoproliferative glomerulonephritis (MPGN) is a rare Structural defects in this protein due to genetic variations form of chronic glomerulonephritis diagnosed primarily in can result in a hereditary form of glomerulonephritis (Alport children and young adults. The name stems from its pattern of syndrome; also termed hereditary nephritis) discussed in glomerular injury. The entity is divided into immune-complex more detail in Genetic Disorders and Kidney Disease. In forms of MPGN (mediated by antigen-antibody interactions addition, whole exome and whole genome sequencing stud- triggering the classical complement pathway) versus ies have shown that type IV collagen variants are identified complement-mediated forms of MPGN (also termed C3 glo- in up to 10% to 15% of adult patients with FSGS. merulopathies, because of a hyperactive alternative comple- ment pathway). An immune-complex MPGN, with or without ¢ Treatment of IgA nephropathy consists of conservative ther- cryoglobulinemia, is the classic form of kidney involvement apy using an ACE inhibitor or angiotensin receptor blocker. seen in patients with hepatitis C virus infection. The alterna- tive complement pathway abnormalities that drive the C3 ¢ Kidney biopsy is required to diagnose and classify lupus glomerulopathies are either mutations in regulators (for nephritis, which guides therapy. example, complement factor H) or activators (for example, e Treatment of classes I and II lupus nephritis (LN) complement factor B) of the alternative pathway, or antibodies includes conservative therapy with an ACE inhibitor or directed at regulator or activator complement proteins. angiotensin receptor blocker; classes III, IV, and V LN require immunosuppressive therapy; and class VI LN Clinical Manifestations should be treated with conservative therapy. Although MPGN can rarely present as an acute and severe ¢ Infection-related glomerulonephritis results from a form of glomerulonephritis, the more common presentation is recently resolved infection or an infection that is ongo- a chronic glomerulonephritis that initially manifests with ing at the time of development of glomerulonephritis; microscopic hematuria and subnephrotic proteinuria. As dis- in industrialized countries, clinical disease is seen more ease progresses, proteinuria can reach nephrotic range, and often in adults and is associated with Staphylococcus kidney dysfunction ensues. aureus and gram-negative bacteria. Diagnosis e Treatment of membranoproliferative glomerulonephri- The diagnosis of MPGN is made by kidney biopsy. The distinc- tis includes immunosuppression when nephrotic-range

Membranoproliferative Glomerulonephritis Collagen Type IV-Related Nephropathies Epidemiology and Pathophysiology Type IV collagen is an integral component of the GBM. Membranoproliferative glomerulonephritis (MPGN) is a rare Structural defects in this protein due to genetic variations form of chronic glomerulonephritis diagnosed primarily in can result in a hereditary form of glomerulonephritis (Alport children and young adults. The name stems from its pattern of syndrome; also termed hereditary nephritis) discussed in glomerular injury. The entity is divided into immune-complex more detail in Genetic Disorders and Kidney Disease. In forms of MPGN (mediated by antigen-antibody interactions addition, whole exome and whole genome sequencing stud- triggering the classical complement pathway) versus ies have shown that type IV collagen variants are identified complement-mediated forms of MPGN (also termed C3 glo- in up to 10% to 15% of adult patients with FSGS. merulopathies, because of a hyperactive alternative comple- ment pathway). An immune-complex MPGN, with or without ¢ Treatment of IgA nephropathy consists of conservative ther- cryoglobulinemia, is the classic form of kidney involvement apy using an ACE inhibitor or angiotensin receptor blocker. seen in patients with hepatitis C virus infection. The alterna- tive complement pathway abnormalities that drive the C3 ¢ Kidney biopsy is required to diagnose and classify lupus glomerulopathies are either mutations in regulators (for nephritis, which guides therapy. example, complement factor H) or activators (for example, e Treatment of classes I and II lupus nephritis (LN) complement factor B) of the alternative pathway, or antibodies includes conservative therapy with an ACE inhibitor or directed at regulator or activator complement proteins. angiotensin receptor blocker; classes III, IV, and V LN require immunosuppressive therapy; and class VI LN Clinical Manifestations should be treated with conservative therapy. Although MPGN can rarely present as an acute and severe ¢ Infection-related glomerulonephritis results from a form of glomerulonephritis, the more common presentation is recently resolved infection or an infection that is ongo- a chronic glomerulonephritis that initially manifests with ing at the time of development of glomerulonephritis; microscopic hematuria and subnephrotic proteinuria. As dis- in industrialized countries, clinical disease is seen more ease progresses, proteinuria can reach nephrotic range, and often in adults and is associated with Staphylococcus kidney dysfunction ensues. aureus and gram-negative bacteria. Diagnosis e Treatment of membranoproliferative glomerulonephri- The diagnosis of MPGN is made by kidney biopsy. The distinc- tis includes immunosuppression when nephrotic-range tion between immune-complex and complement-mediated proteinuria and/or kidney dysfunction is present.

Diagnosis e Treatment of membranoproliferative glomerulonephri- The diagnosis of MPGN is made by kidney biopsy. The distinc- tis includes immunosuppression when nephrotic-range tion between immune-complex and complement-mediated proteinuria and/or kidney dysfunction is present. MPGN is based on immunofluorescence microscopy, in which the absence of immunoglobulin staining signals an antibody- independent manner of triggering complement and hence Kidney Manifestations alternative pathway hyperactivity. of Deposition Diseases Treatment and Prognosis Currently, treatment of MPGN includes immunosuppression Overview (for example, glucocorticoids) when nephrotic-range protein- Various kidney diseases are associated with deposition of immu- uria and/or kidney dysfunction is present. The advent of com- noglobulin (Ig) and non-Ig proteins. On electron microscopy, plement-targeting therapies such as the C5 monoclonal these deposits can be unstructured or organized into fibrils or 55