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Glomerular Diseases Clots are most often seen in patients with membranous nephropathy, but any patient with nephrotic-range proteinuria e The hallmark features of the nephrotic syndrome and significant hypoalbuminemia (usually <2.5 g/dL [25 g/L]) include a urine protein excretion >3500 mg/24 h or a should be considered at risk, especially early in the course of the urine protein-creatinine ratio >3500 mg/g, hypoalbu- disease. Patients with the nephrotic syndrome are also at higher minemia, hypercholesterolemia, and edema. risk for arterial thrombosis than the general population. ¢ Common features of the nephritic syndrome are hema- Albuminuria should be treated with RAS-blocking turia (with dysmorphic erythrocytes or erythrocyte casts) drugs to control blood pressure and reduce proteinuria. and proteinuria; hypertension, edema, and kidney dys- Hyperlipidemia should be treated with statin therapy. This function may also occur. combination of RAS-blocking drugs, statins, and diuretics is generally considered conservative therapy for most forms of glomerular disease. A general strategy for edema man- agement in a patient with newly diagnosed nephrotic syn- Conditions Associated with the drome is to start with a loop diuretic and a goal weight loss Nephrotic Syndrome of 1 to 2 kg (2.2-4.4 lb) per week. In severe cases of edema Diabetic Kidney Disease when loop diuretics have been maximally up-titrated and Epidemiology and Pathophysiology weight loss/edema control are insufficient, it is often neces- Diabetes mellitus is the leading cause of chronic kidney disease sary to add a second diuretic (a thiazide diuretic and/or (CKD) and ESKD worldwide. In the United States, diabetes potassium-sparing diuretic) that works distal to the loop of accounts for >50,000 new cases of ESKD requiring dialysis each Henle. In patients taking high doses of loop diuretics, year. Diabetic kidney disease (DKD), defined as clinical evidence increased delivery of salt and water to the distal portions of of kidney injury in response to chronic, long-standing hypergly- the nephron can lead to hypertrophy of these segments and cemia, is detected in approximately 10% of patients with type 1 overabsorption of sodium, undermining the effects of the diabetes and 35% to 50% of patients with type 2 diabetes. loop diuretic. Advanced glycation end products are believed to be the primary mediator of injury in DKD, activating signaling cas- cades that promote endothelial injury and mesangial cell syn- The Nephritic Syndrome thesis of profibrogenic cytokines. The nephritic syndrome, also termed glomerulonephritis, can present as a number of clinical variants. Common features are Clinical Manifestations hematuria (microscopic or macroscopic) and proteinuria with DKD manifests initially as mildly increased albuminuria. Over the more severe variants typically including hypertension, time, in some patients, progressive proteinuria is followed by edema, and kidney dysfunction (elevated serum creatinine). a decline in glomerular filtration rate, with progression to later The glomerular hematuria seen in the nephritic syndrome can stages of CKD and ESKD. be distinguished from other causes of urinary tract bleeding DKD is often accompanied by extrarenal microvascular by the presence of either dysmorphic erythrocytes (resulting complications of diabetes, including retinopathy and peripheral from passage through a damaged glomerular basement mem- neuropathy as well as macrovascular complications, such as brane) or erythrocyte casts on urine microscopy (see Clinical peripheral vascular disease, coronary artery disease, and stroke. Evaluation of Kidney Function). The mildest forms of the nephritic syndrome are asymp- Diagnosis tomatic, with microscopic hematuria with or without pro- The American Diabetes Association recommends yearly teinuria often discovered on routine laboratory assessment. assessment of albuminuria in patients with type 2 diabetes, Recurrent gross hematuria, in which the hematuria occurs and assessment after 5 years of disease in patients with type 1 several days after an upper respiratory infection or physical diabetes. The diagnosis of DKD is usually made clinically in the exertion, is a classic presentation of IgA nephropathy, particu- presence of hallmark features: proteinuric CKD in a patient larly in younger patients. This nephritic presentation also usu- with long-standing diabetes and evidence of other (microvas- ally follows a benign clinical course without associated chronic cular and/or macrovascular) complications of disease. If the kidney disease. clinical presentation is not entirely consistent with DKD, a On the other hand, the term acute glomerulonephritis is kidney biopsy is performed. The biopsy finding of nodular used to denote the more classical nephritic syndrome presen- mesangial sclerosis with glomerular and tubular basement tation, with variable degrees of kidney dysfunction, hyperten- thickening, in the absence of immune deposits, is the classic sion, edema, proteinuria, and hematuria. The most severe description of DKD. form of the nephritic syndrome is termed rapidly progressive glomerulonephritis, in which patients experience a rapid Treatment and Prognosis decline of kidney function over days or weeks that will pro- The cornerstone of treatment of DKD involves glycemic con- gress to ESKD if untreated. trol and blood pressure control. Blockade of the RAS with an

Clots are most often seen in patients with membranous nephropathy, but any patient with nephrotic-range proteinuria e The hallmark features of the nephrotic syndrome and significant hypoalbuminemia (usually <2.5 g/dL [25 g/L]) include a urine protein excretion >3500 mg/24 h or a should be considered at risk, especially early in the course of the urine protein-creatinine ratio >3500 mg/g, hypoalbu- disease. Patients with the nephrotic syndrome are also at higher minemia, hypercholesterolemia, and edema. risk for arterial thrombosis than the general population. ¢ Common features of the nephritic syndrome are hema- Albuminuria should be treated with RAS-blocking turia (with dysmorphic erythrocytes or erythrocyte casts) drugs to control blood pressure and reduce proteinuria. and proteinuria; hypertension, edema, and kidney dys- Hyperlipidemia should be treated with statin therapy. This function may also occur. combination of RAS-blocking drugs, statins, and diuretics is generally considered conservative therapy for most forms of glomerular disease. A general strategy for edema man- agement in a patient with newly diagnosed nephrotic syn- Conditions Associated with the drome is to start with a loop diuretic and a goal weight loss Nephrotic Syndrome of 1 to 2 kg (2.2-4.4 lb) per week. In severe cases of edema Diabetic Kidney Disease when loop diuretics have been maximally up-titrated and Epidemiology and Pathophysiology weight loss/edema control are insufficient, it is often neces- Diabetes mellitus is the leading cause of chronic kidney disease sary to add a second diuretic (a thiazide diuretic and/or (CKD) and ESKD worldwide. In the United States, diabetes potassium-sparing diuretic) that works distal to the loop of accounts for >50,000 new cases of ESKD requiring dialysis each Henle. In patients taking high doses of loop diuretics, year. Diabetic kidney disease (DKD), defined as clinical evidence increased delivery of salt and water to the distal portions of of kidney injury in response to chronic, long-standing hypergly- the nephron can lead to hypertrophy of these segments and cemia, is detected in approximately 10% of patients with type 1 overabsorption of sodium, undermining the effects of the diabetes and 35% to 50% of patients with type 2 diabetes. loop diuretic. Advanced glycation end products are believed to be the primary mediator of injury in DKD, activating signaling cas- cades that promote endothelial injury and mesangial cell syn- The Nephritic Syndrome thesis of profibrogenic cytokines. The nephritic syndrome, also termed glomerulonephritis, can present as a number of clinical variants. Common features are Clinical Manifestations hematuria (microscopic or macroscopic) and proteinuria with DKD manifests initially as mildly increased albuminuria. Over the more severe variants typically including hypertension, time, in some patients, progressive proteinuria is followed by edema, and kidney dysfunction (elevated serum creatinine). a decline in glomerular filtration rate, with progression to later The glomerular hematuria seen in the nephritic syndrome can stages of CKD and ESKD. be distinguished from other causes of urinary tract bleeding DKD is often accompanied by extrarenal microvascular by the presence of either dysmorphic erythrocytes (resulting complications of diabetes, including retinopathy and peripheral from passage through a damaged glomerular basement mem- neuropathy as well as macrovascular complications, such as brane) or erythrocyte casts on urine microscopy (see Clinical peripheral vascular disease, coronary artery disease, and stroke. Evaluation of Kidney Function). The mildest forms of the nephritic syndrome are asymp- Diagnosis tomatic, with microscopic hematuria with or without pro- The American Diabetes Association recommends yearly teinuria often discovered on routine laboratory assessment. assessment of albuminuria in patients with type 2 diabetes, Recurrent gross hematuria, in which the hematuria occurs and assessment after 5 years of disease in patients with type 1 several days after an upper respiratory infection or physical diabetes. The diagnosis of DKD is usually made clinically in the exertion, is a classic presentation of IgA nephropathy, particu- presence of hallmark features: proteinuric CKD in a patient larly in younger patients. This nephritic presentation also usu- with long-standing diabetes and evidence of other (microvas- ally follows a benign clinical course without associated chronic cular and/or macrovascular) complications of disease. If the kidney disease. clinical presentation is not entirely consistent with DKD, a On the other hand, the term acute glomerulonephritis is kidney biopsy is performed. The biopsy finding of nodular used to denote the more classical nephritic syndrome presen- mesangial sclerosis with glomerular and tubular basement tation, with variable degrees of kidney dysfunction, hyperten- thickening, in the absence of immune deposits, is the classic sion, edema, proteinuria, and hematuria. The most severe description of DKD. form of the nephritic syndrome is termed rapidly progressive glomerulonephritis, in which patients experience a rapid Treatment and Prognosis decline of kidney function over days or weeks that will pro- The cornerstone of treatment of DKD involves glycemic con- gress to ESKD if untreated. trol and blood pressure control. Blockade of the RAS with an 46

Glomerular Diseases ACE inhibitor or angiotensin receptor blocker (ARB) is recom- mended, typically to the maximal tolerated dose, because e For patients with type 2 diabetes mellitus and chronic these agents both reduce blood pressure and levels of pro- kidney disease, the American Diabetes Association rec- teinuria, which, along with glycemic control, are the most ommends that physicians consider therapy with a important modifiable risk factors for progression of DKD to sodium-—glucose cotransporter 2 inhibitor or a glucagon- ESKD. Combined use of any two of the three RAS drug classes like peptide 1 receptor agonist to delay progression of (ACE inhibitors, ARBs, and direct renin inhibitors) is not rec- kidney disease and decrease cardiac mortality. ommended given the results of several clinical trials that revealed more adverse events with these combinations (hyper- kalemia, hypotension, acute kidney injury [AKI]) without Focal Segmental Glomerulosclerosis additional cardiovascular or renal benefits. Combining ACE Epidemiology and Pathophysiology inhibitors or ARBs with mineralocorticoid receptor blockers Following DKD, focal segmental glomerulosclerosis (FSGS) is (spironolactone or eplerenone) has been shown in small stud- the most common form of primary nephrotic syndrome in ies to be a safe and effective antiproteinuric strategy in DKD, Black patients and, in certain parts of the world, has replaced but the risk for hyperkalemia should be considered and moni- membranous nephropathy as the leading cause of the tored appropriately. For patients with type 2 diabetes and CKD, nephrotic syndrome in White patients. the American Diabetes Association recommends that physi- FSGS stems from abnormalities in the podocyte. Podocyte

but the risk for hyperkalemia should be considered and moni- membranous nephropathy as the leading cause of the tored appropriately. For patients with type 2 diabetes and CKD, nephrotic syndrome in White patients. the American Diabetes Association recommends that physi- FSGS stems from abnormalities in the podocyte. Podocyte cians consider use of a sodium-glucose cotransporter 2 inhibi- detachment and death lead to the segmental sclerosis that is tor when the estimated glomerular filtration rate is >30 mL/ the hallmark histopathology of FSGS. The podocyte injury in min/1.73 m? with a urine albumin-creatinine ratio >30 mg/g. FSGS, in turn, can stem from immunologic, genetic, and/or The recommendation is more strongly advised in patients with glomerular hyperfiltration causes and may be primary or sec- a higher-grade albuminuria (urine albumin-creatinine ratio ondary, which is associated with a more systemic process. >300 mg/g), in which the sodium-glucose cotransporter 2 Immunologic injury is considered the main pathogenic mech- inhibitor will reduce progression of kidney disease and/or anism behind primary forms of FSGS, with leukocytes pro- cardiovascular events. In patients with CKD who have addi- ducing a soluble circulating factor that directly targets tional cardiovascular risk factors, a glucagon-like peptide 1 podocytes. This mechanism is supported by cases of FSGS receptor agonist will also reduce the risk for CKD progression, recurring almost immediately after kidney transplantation cardiovascular events, or both. and responding briskly to plasmapheresis, although definitive The 2017 American College of Cardiology (ACC)/American identification of such a circulating factor has yet to occur. Heart Association (AHA) blood pressure guideline recom- Identified genetic causes of FSGS are chiefly mutations in mends a blood pressure target of <130/80 mm Hg for patients podocyte-specific proteins (for example, nephrin, podocin,

The 2017 American College of Cardiology (ACC)/American identification of such a circulating factor has yet to occur. Heart Association (AHA) blood pressure guideline recom- Identified genetic causes of FSGS are chiefly mutations in mends a blood pressure target of <130/80 mm Hg for patients podocyte-specific proteins (for example, nephrin, podocin, with hypertension and diabetes and/or CKD. The American formin). These mutations are more commonly found in Diabetes Association recommends that most patients with infants, young (<25 years of age) patients who do not respond diabetes and hypertension should be treated to a systolic blood to glucocorticoid therapy, and patients with a family history of pressure goal of <140 mm Hg and a diastolic blood pressure ESKD. Individuals of African ancestry carry approximately a goal of <90 mm Hg; lower systolic and diastolic blood pressure five times higher risk for FSGS than those of European descent targets, such as 130/80 mm Hg, may be appropriate for indi- (see Genetic Disorders and Kidney Disease). Hyperfiltration, viduals at high risk for cardiovascular disease if they can be the third mechanism and major form of secondary FSGS, is achieved safely. seen classically in patients with obesity but also can manifest in patients with a history of premature birth or solitary kidney. Finally, drug-induced FSGS can occur as a rare complication of e The American Diabetes Association recommends yearly some commonly used treatments, including lithium, inter- assessment of albuminuria in patients with type 2 dia- feron, and pamidronate. betes mellitus, and assessment after 5 years of disease in patients with type 1 diabetes mellitus. Clinical Manifestations ¢ The cornerstone of treatment of involves glycemic control All patients with FSGS have proteinuria, ranging from severe and blood pressure control with an ACE inhibitor or angio- with other features of classic nephrotic syndrome, to more

achieved safely. seen classically in patients with obesity but also can manifest in patients with a history of premature birth or solitary kidney. Finally, drug-induced FSGS can occur as a rare complication of e The American Diabetes Association recommends yearly some commonly used treatments, including lithium, inter- assessment of albuminuria in patients with type 2 dia- feron, and pamidronate. betes mellitus, and assessment after 5 years of disease in patients with type 1 diabetes mellitus. Clinical Manifestations ¢ The cornerstone of treatment of involves glycemic control All patients with FSGS have proteinuria, ranging from severe and blood pressure control with an ACE inhibitor or angio- with other features of classic nephrotic syndrome, to more tensin receptor blocker, titrated to maximal tolerated dose. modest with otherwise asymptomatic proteinuria. Any form of FSGS can present with reduced glomerular filtration rate, HVC e In the treatment of diabetic kidney disease, combining particularly when diagnosed late in the disease course. any two renin-angiotensin system drug classes (ACE inhibitors, angiotensin receptor blockers, or direct Diagnosis renin inhibitors) is not recommended, as side effects are increased and there is no additional clinical benefit. FSGS is diagnosed by kidney biopsy. On light microscopy, glo- merulosclerosis (scarring of glomeruli) is seen in a focal (Continued) (<50%) and segmental (affecting a portion but not the entirety 47