Case 1: Nephrotic Syndrome Flashcards
NEPHROTIC SYNDROME
● Nephrotic syndrome classically presents with heavy proteinuria, minimal hematuria, hypoalbuminemia, hypercholesterolemia, edema, and hypertension.
● If left undiagnosed or untreated, some of these syndromes will progressively damage enough glomeruli to cause a fall in GFR, producing renal failure. Therapies for various causes of nephrotic syndrome are noted under individual disease headings below.
● In general, all patients with hypercholesterolemia secondary to nephrotic syndrome should be treated with lipid-lowering agents since they are at increased risk for cardiovascular disease.
● Edema secondary to salt and water retention can be controlled with the judicious use of diuretics, avoiding intravascular volume depletion.
● Venous complications secondary to the hypercoagulable state associated with nephrotic syndrome can be treated with anticoagulants. The losses of various serum binding proteins, such as thyroid-binding globulin, lead to alterations in functional tests.
● Lastly, proteinuria itself is hypothesized to be nephrotoxic, and treatment of proteinuria with inhibitors of the renin-angiotensin system can lower urinary protein excretion.
MINIMAL CHANGE DISEASE
● MCD, sometimes known as nil lesion, causes 70—90% of nephrotic syndrome in childhood but only 10—15% of nephrotic syndrome in adults.
● MCD usually presents as a primary renal disease but can be associated with several other conditions, including Hodgkin’s disease, allergies, or use of nonsteroidal anti-inflammatory agents; significant interstitial nephritis often accompanies cases associated with nonsteroidal use.
● The pathophysiology of this lesion is uncertain. Most agree there is a circulating cytokine, perhaps related to a T cell response that alters capillary charge and podocyte integrity.
● The evidence for cytokine-related immune injury is circumstantial and is suggested by the presence of preceding allergies, altered cell-mediated immunity during viral infections, and the high frequency of remissions with steroids. (Harrisson’s Internal Medicine 18”’ ed.) With the light microscope the glomeruli in minimal change disease appear normal.
● The cells of the proximal convoluted tubules are often heavily laden with protein droplets and lipids, but this is secondary to tubular reabsorption of the lipoproteins passing through the diseased glomeruli.
● This appearance of the proximal convoluted tubules is the basis for the older term for this disorder, lipoid nephrosis. Even with the electron microscope, the GBM appears normal. The only obvious glomerular abnormality is the uniform and diffuse effacement of the foot processes of the podocytes.
● The cytoplasm of the podocytes thus appears flattened over the external aspect of the GBM, obliterating the network of arcades between the podocytes and the GBM.
● There are also epithelial cell vacuolization, microvillus formation, and occasional focal detachments.
● When the changes in the podocytes reverse (e.g., in response to corticosteroids), the proteinuria remits. (Robbin’s Clinical Pathology ‘h ed.) MCD presents clinically with the abrupt onset of edema and nephrotic syndrome accompanied by acellular urinary sediment.
● Less common clinical features include hypertension (30% in children, 50% in adults), microscopic hematuria (20% in children, 33% in adults), atopy or allergic symptoms (40% in children, 30% in adults), and decreased renal function (<5% in children, 30% in adults).
● The appearance of acute renal failure in adults is usually caused by intrarenal edema (nephrosarca) that is responsive to intravenous albumin and diuretics.
● This presentation must be distinguished from acute renal failure secondary to hypovolemia. In children, the abnormal urine principally contains albumin with minimal amounts of higher molecular weight proteins, and is sometimes called selective proteinuria.
● Although up to 30% of children have a spontaneous remission, all children today are treated with steroids; only children who are nonresponders are biopsied in this setting.
● Primary responders are patients who have a complete remission (<0.2 mg/24 h of proteinuria) after a single course of prednisone, steroid-dependent patients relapse as their steroid dose is tapered.
● Frequent relapsers have two or more relapses in the 6 months following taper, and steroid- resistant patients fail to respond to steroid therapy.
● 90 to 95% of children will develop a complete remission after 8 weeks of steroid therapy, and 80—85% of adults will achieve complete remission, but only after a longer course of 20—24 weeks.
● Patients with steroid resistance can develop FSGS on repeat biopsy. Some hypothesize that if the first renal biopsy does not have a sample of deeper glomeruli, then the correct early diagnosis of FSGS may be missed. Relapses occur in 70—75% of children after the first remission, and early relapse predicts multiple subsequent relapses.
● The frequency of relapses decreases after puberty, although there is an increased risk of relapse following the rapid tapering of steroids in all groups.
● Relapses are less common in adults but are more resistant to subsequent therapy. Prednisone is first-line therapy, and other immunosuppressive drugs, such as cyclophosphamide, chlorambucil, and mycophenolate mofetil, are saved for frequent relapsers, steroid-dependent, or steroid-resistant patients.
● Cyclosporine can induce remission, but relapse is also common when cyclosporine is withdrawn. The long-term prognosis in adults is less favorable when acute renal failure or steroid resistance occurs. (Harrisson’s Internal Medicine 180’ ed.)
FOCAL SEGMENTAL GLOMERULONEPHRITIS
● FSGS refers to a pattern of renal injury characterized by segmental glomerular scars that involve some but not all glomeruli; the clinical findings of FSGS largely manifest as proteinuria. VA.men the secondary causes of FSGS are eliminated, the remaining patients are considered to have FSGS.
● The incidence of this disease is increasing, and it now represents up to one-third of cases of nephrotic syndrome in adults and one-half of cases of nephrotic syndrome in African Americans, in whom it is seen more commonly.
● The pathogenesis of FSGS is probably multifactorial. Possible mechanisms include a T cell-mediated circulating permeability factor, TGF—mediated cellular proliferation and matrix and podocyte abnormalities associated with genetic synthesis, mutations. (Harrisson’s Internal Medicine 18th ed.)
● In FSGS, the disease first affects only some of the glomeruli (hence the term “focal”) and initially only the juxtamedullary glomeruli. With progression, eventually all levels of the cortex are affected. Histologically, FSGS is characterized by lesions occurring in some tufts within a glomerulus and sparing of the others (hence the term “segmental”).
● Thus, the involvement is both focal and segmental. The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumens, and deposition of hyaline masses (hyalinosis) and lipid droplets. Occasionally, glomeruli are completely sclerosed (global sclerosis).
● In affected glomeruli, immunofluorescence microscopy often reveals nonspecific trapping of immunoglobulins, usually lgM, and complement in the areas of hyalinosis. On electron microscopy, the podocytes exhibit effacement of foot processes, as in MCD.
● In time, progression of the disease leads to global sclerosis of the glomeruli with pronounced tubular atrophy and interstitial fibrosis. This advanced picture is difficult to differentiate from other forms of chronic glomerular disease, described below.
● A morphologic variant called collapsing glomerulopathy is being increasingly reported. It is characterized by collapse of the entire glomerular tuft and podocyte hyperplasia.
● This is a more severe manifestation of FSGS that may be idiopathic or associated with human immunodeficiency virus infection or drug-induced toxicities. It carries a particularly poor prognosis. (Robbin’s Clinical Pathology 8th ed)
● FSGS can present with any level of proteinuria, hematuria, hypertension, or renal insufficiency. Nephrotic range proteinuria, African-American race, and renal insufficiency are associated with a poor outcome, with 50% of patients reaching renal failure in 6-8 years FSGS rarely remits spontaneously, but treatment-induced remission of proteinuria significantly improves prognosis.
● Treatment of patients with primary FSGS should include inhibitors of the renin- angiotensin system. Based on retrospective studies, patients with nephrotic range proteinuria can be treated with steroids but respond far less often than patients with MCD.
● Proteinuria remits in only 20—45% of patients receiving a course of steroids over 6—9 months. Limited evidence suggests that the use of cyclosporine in steroid-responsive patients helps ensure remissions, while other cytotoxic agents confer little added benefit over steroid therapy.
● Primary FSGS recurs in 25—40% of patients given allografts at end-stage disease, leading to graft loss in half of those cases. The treatment of secondary FSGS typically involves treating the underlying æuse and controlling proteinuria. There is no role for steroids or other immunosuppressive agents in secondary FSGS.
Focal Segmental Glomerulosclerosis
Primary focal segmental glomerulosclerosis
Secondary focal segmental glomerulosclerosis
Adaptive response to hyperfiltration/reduced renal mass, obesity
Viruses: HIV/hepatitis B/parvovirus
Hypertensive nephropathy
Reflux nephropathy
Cholesterol emboli
Drugs: Heroin/analgesics/bisphosphonates/ecstasy Oligomeganephronia
Sickle cell disease
Radiation nephritis
Familial podocytopathies
NPHS1 mutation/nephrin
NPHS2 mutation/podocin
PLCE1 mutation/phospholipase Cε1
INF2 mutation/inverted formin 2
WT1 mutation/Wilms tumor
TRPC6 mutation/cation channel
ACTN4 mutation/actinin
α-Galactosidase A deficiency/Fabry’s disease
N-Acetylneuraminic acid hydrolase deficiency/nephrosialidosis
MEMBRANOUS GLOMERULONEPHRITIS
● MGN, or membranous nephropathy as it is sometimes called, accounts for approximately 30% of cases of nephrotic syndrome in adults, with a peak incidence between the ages of 30—50 years and a male to female ratio of 2:1.
● It is rare in childhood and by far the most common cause of nephrotic syndrome in the elderly In 25—30% of cases, MGN is secondary to malignancy (solid tumors of the breast, lung, colon), infection (hepatitis B, malaria, schistosomiasis), or like or rarely rheumatoid arthritis (Harrison’s Internal Medicine 18th ed)
● Seen by light microscopy with H&E stain, the basic change in membranous nephropathy appears to be diffuse thickening of the GBM (Fig. 14-8A).
● By electron microscopy, this apparent thickening is determined to be caused in part by subepithelial deposits that nestle against the GBM and are separated from each other by small, spikelike protrusions of GBM matrix that form in reaction to the deposits (“spike and dome” pattern) (Fig. 14-8B).
● As the disease progresses, these spikes close over the deposits, incorporating them into the GBM. In addition, the podocytes show effacement of foot processes.
● Later in the disease, the incorporated deposits may be catabolized and eventually disappear, leaving cavities within the GBM.
● Continued deposition of basement membrane matrix leads to progressively thicker basement membranes. With further progression, the glomeruli can become sclerosis.
● Immunofluorescence microscopy shows typical granular deposits of immunoglobulins and complement along the GBM (Robbin’s Clinical Pathology 8th ed.) Eighty percent of patients with MGN present with nephrotic syndrome and nonselective proteinuria.
● Microscopic hematuria is seen in up to 50% of patients. Spontaneous remissions occur in 20—33% of patients and often occur late in the course after years of nephrotic syndrome.
● One-third of patients continue to have relapsing nephrotic syndrome but maintain normal renal function, and approximately another third of patients develop renal failure or die from the complications of nephrotic syndrome.
● Male gender, older age, hypertension, and the persistence of proteinuria are associated with worse prognosis. Although thrombotic complications are a feature of all nephrotic syndromes, MGN has the highest reported incidences of renal vein thrombosis, pulmonary embolism, and deep vein thrombosis.
● Prophylactic anticoagulation is controversial but has been recommended for patients with severe or prolonged proteinuria in the absence of risk factors for bleeding In addition to the treatment of edema, dyslipidemia, and hypertension, inhibition of the renin-angiotensin system is recommended.
● Therapy with immunosuppressive drugs is also recommended for patients with primary MGN and persistent proteinuria (>3.0 g/24 h). The choice of immunosuppressive drugs for therapy is controversial, but current recommendations based on small clinical studies are to treat with steroids and cyclophosphamide, chlorambucil, or cyclosporine.
● Experience with mycophenolate mofetil or anti-CD20 antibody is even more limited.
DIABETIC NEPHROPATHY
● Diabetic nephropathy is the single most common cause of chronic renal failure in the United States, accounting for 45% of patients receiving renal replacement therapy, and is a rapidly growing problem worldwide.
● The dramatic increase in the number of patients with diabetic nephropathy reflects the epidemic increase in obesity, metabolic syndrome, and Type 2 diabetes mellitus.
● Approximately 40% of patients with Types I or 2 diabetes develop nephropathy, but due to the higher prevalence of Type 2 diabetes (90%) compared to Type I (10%), the majority of patients with diabetic nephropathy have Type 2 disease.
● Renal lesions are more common in African-American, Native American, Polynesian, and Maori populations.
● Risk factors for the development of diabetic nephropathy include hyperglycemia, hypertension, dyslipidemia, smoking, a family history of diabetic nephropathy, and gene polymorphisms affecting Within 1—2 years after the onset of clinical diabetes, morphologic changes appear in the kidney.
● Thickening of the GBM is a sensitive indicator for the presence of diabetes but correlates poorly with the presence or absence of clinically significant nephropathy.
● The composition of the GBM is altered notably with a loss of heparan sulfate moieties that form the negatively charged filtration barrier. This change results in increased filtration of serum proteins into the urine, predominantly negatively charged albumin.
● The expansion of the mesangium due to the accumulation of extracellular matrix correlates with the clinical manifestations of diabetic nephropathy. This expansion in the mesangial matrix can be associated with the development of mesangial sclerosis. Some patients also develop eosinophilic, PAS+ nodules called nodular glomerulosclerosis or Kimmelstiel-Wilson nodules.
● Immunofluorescence microscopy often reveals the nonspecific deposition of lgG (at times in a linear pattern) or complement staining without immune deposits on electron microscopy. Prominent vascular changes are frequently seen with hyaline and hypertensive arteriosclerosis.
● This is associated with varying degrees of chronic glomerulosclerosis and tubulointerstitial changes. Renal biopsies from patients with Types 1 and 2 diabetes are largely indistinguishable.
● These pathologic changes are the result of a number of postulated factors. Multiple lines of evidence support an important role for increases in glomerular capillary pressure (intraglomerular hypertension) in alterations in renal structure and function.
● Direct effects of hyperglycemia on the actin cytoskeleton of renal mesangial and vascular smooth-muscle cells as well as diabetes-associated changes in circulating factors such as atrial natriuretic factor, angiotensin Il, and insulin-like growth factor (IGF) may account for this.
● Sustained glomerular hypertension increases matrix production, alterations in the GBM with disruption in the filtration barrier (and hence proteinuria) and glomerulosclerosis.
● A number of factors have also been identified which alter matrix production, including the accumulation of advanced glycosylation end products, circulating factors including growth hormone, IGF-I, angiotensin Il, connective tissues growth factor, TGF-, and dyslipidemia.
● The natural history of diabetic nephropathy in patients with Types I and 2 diabetes is similar. However, since the onset of Type I diabetes is readily identifiable and the onset of Type 2 diabetes is not, a patient newly diagnosed with Type 2 diabetes may have renal disease for many years before nephropathy is discovered and presents as advanced diabetic nephropathy.
● At the onset of diabetes, renal hypertrophy and glomerular hyperfiltration are present. The degree of glomerular hyperfiltration correlates with the subsequent risk of clinically significant nephropathy.
● In the approximately 40% of patients with diabetes who develop diabetic nephropathy, the earliest manifestation is an increase in albuminuria detected by sensitive radioimmunoassay.
● Albuminuria in the range of 30—300 mg/24 h is called microalbuminuria. In patients with Types 1 or 2 diabetes, microalbuminuria appears 5—10 years after the onset of diabetes.
● It is currently recommended to test patients with Type I disease for microalbuminuria 5 years after diagnosis of diabetes and yearly thereafter, and, because the time of onset of Type 2 diabetes is often unknown, to test Type 2 patients at the time of diagnosis of diabetes and yearly thereafter.
● Patients with small rises in albuminuria increase their levels of urinary albumin excretion, typically readling dipstick positive levels of proteinuria (>300 mg albuminuria) 5—10 years after the onset of early albuminuria.
● Microalbuminuria is a potent risk factor for cardiovascular events and death in patients with Type 2 diabetes.
● Many patients with Type 2 diabetes and microalbuminuria succumb to cardiovascular events before they progress to proteinuria or renal failure . Proteinuria in frank diabetic nephropathy can be variable, ranging from 500 mg to 25 g/24h, and is often associated with nephrotic syndrome More than 90% of patients with Type 1 diabetes and nephropathy have diabetic retinopathy, so the absence of retinopathy in Type 1 patients with proteinuria should prompt consideration of a diagnosis other than diabetic nephropathy; only 60% of patients with Type 2 diabetes with nephropathy have diabetic retinopathy.
● There is a highly significant correlation between the presence of retinopathy and the presence of Kimmelstiel-Wilson nodules. Also, characteristically, patients with advanced diabetic nephropathy have normal to enlarged kidneys, in contrast to other glomerular diseases where kidney size is usually decreased.
● Using the above epidemiologic and clinical data, and in the absence of other clinical or serologic data suggesting another disease, diabetic nephropathy is usually diagnosed without a renal biopsy.
● After the onset of proteinuria >500 mg/24h, renal function inexorably declines, with 50% of patients reaching renal failure in 5—10 years; thus, from the earliest stages of microalbuminuria, it usually takes 10—20 years to reach end-stage renal disease.
● Hypertension may predict which patients develop diabetic nephropathy, as the presence of hypertension accelerates the rate of decline in renal function.
● Once renal failure appears, however, survival on dialysis is far shorter for patients with diabetes compared to other dialysis patients; some diabetics do better clinically if they are started on dialysis before they reach advanced renal failure.
● Survival is best for patients with Type 1 diabetes who receive a transplant from a living related donor.
● Good evidence supports the benefits of blood sugar and blood pressure control as well as inhibition of the renin-angiotensin system in retarding the progression of diabetic nephropathy. In patients with Type I diabetes, intensive control of blood sugar clearly prevents the development or progression of diabetic nephropathy.
● Evidence in patients with Type 2 disease, although less compelling, also supports intensive control of blood sugar.
● Controlling systemic blood pressure to levels of 130/80 mmHg or less decreases renal and cardiovascular adverse events in this high-risk population. ??????
● The vast majority of patients with diabetic nephropathy require three or more antihypertensive drugs to achieve this goal. Drugs that inhibit the renin-angiotensin system, independent of their effects on systemic blood pressure, have been repeatedly shown to slow the progression of diabetic nephropathy at early (microalbuminuria) and late (proteinuria with reduced glomerular filtration) stages. independent of any effect they may have on systemic blood pressure.
● Since angiotensin II increases different arteriolar resistance and, hence, glomerular capillary pressure, one key mechanism for the efficacy of ACE inhibitors or angiotensin receptor blockers (ARBs) is reducing glomerular hypertension.
● Patients with Type I diabetes for 5 years who develop albuminuria or declining renal function should be treated with ACE inhibitors. Patients with Type 2 diabetes and microalbuminuria or proteinuria may be treated with ACE inhibitors or ARBs.
