Primary Glomerulopathies
Ying Chen
General Principles
Primary glomerular diseases are a group of disorders in which the main manifestations of disease are directly related to kidney involvement rather than as part of a systemic disease process. Systemic diseases associated with glomerular disease are discussed in a separate chapter.
Primary glomerular diseases can present with nephrotic syndrome, asymptomatic proteinuria, isolated hematuria, or a nephritic picture. In many cases, they are described as being idiopathic without known association or cause. For each of the primary glomerulopathies, secondary causes are also discussed. For instance, medications, infections, and malignancies are all associated with glomerular pathology that is otherwise indistinguishable from the idiopathic forms.
Proper diagnosis and management of the primary glomerulopathies requires an understanding of patient characteristics, risk of progressive kidney disease, and safe use of immunosuppressive agents.
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) has become the most important form of primary glomerular disease, both because of increasing incidence and because of its contribution to the growth of end-stage renal disease (ESRD).
In the United States, FSGS is the most common cause of idiopathic nephrotic syndrome in adult African Americans. Idiopathic FSGS is also the most common primary glomerular disease detected on renal biopsy that leads to ESRD in all races.
FSGS is a group of disorders that shares several histologic features. Renal biopsy shows some glomeruli (focal) with sclerosis in part of the glomerular tuft (segmental). Patients with these abnormalities often present with nephrotic syndrome, but may also have asymptomatic proteinuria.
Several means of categorizing FSGS are in use.
FSGS can be described as a primary or secondary disorder associated with a range of causes and potential differences in treatment. For instance, primary FSGS is usually treated with corticosteroids or immunosuppressive regimens, whereas secondary disease typically does not respond to this regimen.
Histologic variants have been described that take into account subglomerular localization of the sclerotic lesion, presence of proliferation, and presence of glomerular capillary collapse. The value of this system is thought to arise from better prediction of causation and outcomes.
The collapsing FSGS variant is associated with human immunodeficiency virus (HIV) and some drug-associated diseases. Of all the histologic variants, collapsing FSGS is notable for a poor renal prognosis.
Patients with the tip lesion pattern of FSGS have the most favorable outcome.
Table 9-1 summarizes the histologic variants and some of their associations.
In addition, a variant of FSGS has been termed C1q nephropathy.
TABLE 9-1 HISTOLOGIC VARIANTS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS | |||||||||||||||||||||
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Primary Idiopathic FSGS
General Principles
FSGS is responsible for 7% to 20% of idiopathic NS in children and 40% in adults.
The disease is markedly more common in African Americans and the mean age of onset in adults is 40 years.
Proteinuria is typically nonselective.
Secondary forms of FSGS typically have lower levels of proteinuria than classic idiopathic FSGS.
Other common features on presentation are hypertension (30% to 50%), microscopic hematuria (25% to 75%), and renal insufficiency (20% to 30%).
Serologic testing and complement levels should be normal.
Treatment
There is still considerable debate over the appropriate treatment for patients with FSGS.
Corticosteroid and immunosuppressive therapy should be considered only in idiopathic FSGS associated with clinical features of the nephrotic syndrome.
Standard therapy is initiated with high-dose daily corticosteroids (prednisone, 1 mg/kg of ideal body weight per day to maximum dose of 80 mg/d or 2 mg/kg alternate-day treatment).
The initial high dose of corticosteroids should be given for a minimum of 4 weeks up to a maximum of 16 weeks, as tolerated, or until complete remission has been achieved, whichever is earlier.
The median duration of steroid treatment to achieve complete remission is 3 to 4 months. However, potential morbidities associated with steroid-related side effects need to be considered if this approach is planned.
If remission occurs, the steroids may be tapered slowly. Longer courses may be used in patients who achieve only partial remission or who relapse with steroid tapering.
Calcineurin inhibitors (CNIs) are considered first-line therapy for patients with relative contraindications or intolerance to high-dose corticosteroids (e.g., uncontrolled diabetes, psychiatric conditions, or severe osteoporosis). Cyclosporine (3 to 5 mg/kg ideal body weight per day in two divided doses) for steroid-resistant FSGS. If there is a partial or complete remission, continue CSA treatment for at least 12 months, followed by a slow taper.
Mycophenolate mofetil (MMF) has been investigated in a large multicenter National Institutes of Health trial (FSGS-CT) in the United States comparing cyclosporine and a regimen of oral MMF plus dexamethasone for steroid-resistant FSGS patients. There was no statistical difference in the primary or main secondary outcomes between the two therapies. However, there are limitations in this study.
Recurrence of FSGS after renal transplantation is common (up to 30%) and is associated with decreased graft survival. Plasmapheresis has been used with limited success in the management of posttransplant FSGS recurrence.1
Outcome/Prognosis
Spontaneous remission of proteinuria is unusual.
Poor prognostic indicators are nephrotic range proteinuria or massive proteinuria, elevated serum creatinine, greater degree of tubulointerstitial fibrosis, and presence of collapsing lesions at the time of biopsy, African American, and failure to achieve partial or complete remission.
FSGS has a significant risk of progression to ESRD, with 5- and 10-year renal survival rates of 76% and 57% in those initially presenting with nephrotic syndrome.2
Nonnephrotic proteinuria is associated with >90% 10-year kidney survival.
Secondary FSGS
General Principles
FSGS represents a common phenotypic expression of diverse clinicopathologic syndromes with distinct etiologies.
Genetic causes of FSGS:
Mutations in more than 30 podocyte genes can cause FSGS. Most have been related to defects in structural proteins of podocytes and slit diaphragms.
Mutations in the NPHS1 gene, which codes for nephrin, are responsible for the autosomal recessive congenital nephrotic syndrome of the Finnish type. Compound heterozygous mutations in small numbers of tested adults have been linked to steroid-resistant FSGS.3
Mutations in the NPHS2 gene, which codes for podocin, are responsible for autosomal recessive steroid-resistant FSGS in children and rarely in adults.
Autosomal dominant FSGS in children or adults is caused by mutations in INF2 encoding inverted formin 2, ACTN4 encoding podocyte cytoplasmic protein α-actinin-4, as well as TRPC6 encoding transient receptor potential cation 6 channel.4
Viral infection:
HIV-associated nephropathy may occur at any time during the course of HIV infection, although it is usually diagnosed when CD4 count falls below 200.
The glomerular disease appears to result from direct infection of podocytes, leading to podocyte proliferation and dedifferentiation.
Up to 95% of HIV-associated nephropathy cases occur in young African-American men with HIV infection contracted by any route (mean age, 33 years; male-to-female ratio, 10:1).
The clinical presentation includes nephrotic or nonnephrotic proteinuria, progressive azotemia, and the relative rarity of hypertension.
Laboratory evaluation reveals HIV seropositivity, normal C3, normal C4, and CD4 count usually <200.
Renal ultrasound typically shows enlarged kidneys with increased echogenicity.
The pathology of HIV-associated nephropathy includes collapsing FSGS, mesangial proliferation, hypertrophied podocytes with protein resorption droplets, microcystic dilated tubules, and endothelial cell tubuloreticular inclusions.
Parvovirus B19 infection has also been associated with collapsing FSGS.
Drugs:
Drugs associated with FSGS include pamidronate, heroin, lithium, and interferon-α.
Pamidronate has been associated with the collapsing form.
Secondary FSGS was attributed to heroin use in older studies. These cases presented with nephrotic syndrome and with rapid progression to ESRD. More recent studies have shown that the incidence of heroin-associated disease has declined markedly.
Sickle cell nephropathy:
Kidney disease can occur in persons with sickle cell disease.
The prevalence of proteinuria was 26% in one series.
Chronic kidney disease has been seen in 7% to 30% of patients with long-term follow-up.
Hyperfiltration and increased glomerular pressure are thought to be the mechanism for injury.
The most common lesion on kidney biopsy is FSGS, although other histology can sometimes be found (e.g., membranoproliferative glomerulonephritis [MPGN]).
Other:
Reduced renal mass (unilateral renal agenesis, surgical renal ablation, chronic allograft nephropathy, and chronic vesicoureteral reflux).
Secondary FSGS may also be seen in the setting of chronic hypoperfusion and ischemia to the kidney. Some examples are hypertension, morbid obesity, congenital cyanotic heart disease, obstructive sleep apnea (OSA), and atheroemboli.
Treatment
Therapy for the underlying disorder is first-line management. Lesions of FSGS may regress with management of the underlying condition (e.g., treatment of obesity with bariatric surgery or continuous positive airway pressure for OSA).
Nonspecific therapy to reduce edema and proteinuria with diuretics, dietary sodium restriction, and angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) therapy should be aggressively pursued.
Steroid treatment as for idiopathic FSGS can be considered in refractory cases, but limited data do not support the use of aggressive immunosuppressive or cytotoxic agents.
Other FSGS Variants: C1q Nephropathy
Distinctive features of C1q nephropathy are a predominance of C1q staining in the glomerulus and mesangial electron-dense deposits.
It is predominant in males and African Americans are commonly affected.
Proteinuria is usually in the nephrotic range and hematuria is present in ∼20% of the patients.
The best treatment for this lesion is unclear but should include antiproteinuric strategies, such as ACE inhibitors.
Minimal Change Disease
General Principles
Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children (∼65%) and in up to 10% to 15% of cases of adult nephrotic syndrome. The peak incidence of MCD is in children aged 2 to 7 years, but the disease may occur at any age.
The typical presentation of MCD is nephrotic syndrome. Clinical presentation is usually characterized by rapid onset of edema, often with periorbital edema, marked weight gain, pleural effusions, and ascites.
Children presenting with typical features of nephrotic syndrome usually undergo empiric steroid therapy without a definitive diagnosis by renal biopsy. Steroid responsiveness in this group is equated with a diagnosis of MCD.
Acute kidney injury can occur in up to 20% to 25% of adults. Major risk factors for this presentation are male, older and hypertensive with lower serum albumin and more proteinuria.
Other complications of MCD include sepsis, peritonitis in ascitic fluid, and thromboembolism.
The pathogenesis remains unknown but may be related to a disorder of T or B lymphocytes. There is a postulated circulating factor acting on podocytes. The majority of cases are idiopathic.Related posts:
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