| disease | Focal Segmental Glomerulosclerosis |
| alias | Focal Glomeruloscerosis |
Focal glomerulosclerosis refers to a type of glomerular capillary characterized by focal and segmental sclerosis or hyalinosis of the glomerular capillary loops, without significant cellular proliferation. It can manifest as mesangial proliferation, mesangial IgM deposition, and focal glomerulosclerosis, and may result from steroid-resistant minimal change nephropathy with recurrent episodes and chronic progression. Some cases of primary nephrotic syndrome that are unresponsive to hormones may also show focal glomerulosclerosis in early renal biopsies. Therefore, whether this condition should be classified as an independent glomerular disease remains debated. However, as it represents a distinct clinicopathological type different from other kidney diseases, it can also be considered an independent condition. It is relatively common and shows a gradually increasing trend.
bubble_chart Etiology
(1) The cause of primary focal segmental glomerulosclerosis is unknown.
(2) Secondary focal segmental glomerulosclerosis
1. Glomerular diseases: heroin-associated nephropathy, tumor-associated nephropathy, diabetes, Acquired Immune Deficiency Syndrome, hereditary nephritis, IgA nephropathy, preeclampsia, and Hodgkin's disease, etc.
2. Tubulointerstitial and vascular diseases: reflux nephropathy, radiation nephritis, analgesic nephropathy, and sickle cell disease, etc.
3. Others: renal hypoplasia, obesity, and senility, etc.
The exact cause remains unclear. Most theories suggest that changes in glomerular hemodynamics or basement membrane injury lead to overloaded uptake of macromolecular substances by the mesangial tissue, resulting in glomerulosclerosis. In humans, juxtamedullary nephrons develop early in embryogenesis, are larger in size, and have higher filtration rates. The resulting intraglomerular hypertension and hyperfiltration ultimately cause structural damage. In this disease, juxtamedullary nephron damage occurs early and is severe. Additionally, segmental injury to glomerular epithelial cells may impair the anionic charge barrier on the basement membrane. Chronic proteinuria overload, sustained hyperfiltration, and hyperperfusion eventually lead to glomerulosclerosis. Glomerular hypertrophy and foam cell formation play significant roles in the development and progression of this disease. In the 5/6 nephrectomy animal model, glomerular capillary plasma flow and pressure both increase, glomerular epithelial cells are significantly damaged, and residual nephrons exhibit hyperfunction, leading to hyalinosis. Fogo et al. correlated the pathophysiology of primary focal segmental glomerulosclerosis (FSGS) with clinical findings and observed that the mean glomerular area in both adult and pediatric patients with this disease was significantly larger than in age-matched individuals with minimal change disease. Repeat renal biopsies also confirmed that some cases initially presenting as minimal change disease already exhibited marked glomerular hyperplasia. Moreover, foam cells—which exhibit histochemical characteristics of macrophages and may derive from circulating monocytes or mesangial cell transformation—are frequently observed in the glomeruli of many primary FSGS patients. Certain cytokines and growth factors, such as IL-1, α-TNF, and IL-6, contribute to glomerulosclerosis. Animal studies have also shown a correlation between serum cholesterol levels and the degree of sclerosis.
Immune-mediated injury is also involved in the pathogenesis and progression of this disease. In pathological studies, IgM and C3 granular deposits are observed in sclerotic glomerular areas. Electron microscopy reveals abundant electron-dense deposits in sclerotic lesions. Furthermore, this disease frequently recurs after kidney transplantation.bubble_chart Pathological Changes
The diagnosis of this disease mainly relies on renal biopsy. Under light microscopy, some segments of certain glomeruli appear as glassy homogeneous proteinaceous material, while the non-sclerotic areas remain relatively normal. Typical lesions in the sclerotic regions show abundant acellular matrix and hyaline material, with a positive PAS staining reaction. Capillary collapse, foam cell formation, and local epithelial cell proliferation are observed, along with adhesion between the glomerulus and Bowman's capsule. The glomeruli at the corticomedullary junction are the first to be affected. In non-sclerotic areas, glomerular capillary epithelial cells exhibit swelling and proliferation, with vacuolar degeneration and large PAS-positive droplets visible in the cytoplasm. Corresponding tubular atrophy and interstitial fibrosis are distributed focally. Immunofluorescence examination often reveals IgM and C3 deposition in sclerotic areas. Under electron microscopy, sclerotic lesions show massive electron-dense deposits. In non-sclerotic areas, glomerular capillary loops exhibit extensive fusion and effacement of epithelial cell foot processes. In severe cases, epithelial cells may detach and slough off from the basement membrane.
bubble_chart Clinical Manifestations
This disease can occur at any age, primarily in young adults. It is more common in males. All cases present with persistent non-selective proteinuria. Typical cases often manifest as nephrotic syndrome at onset, accounting for about 50% of cases and representing 5–20% of primary nephrotic syndrome cases. Hematuria is present in 50–60% of patients. Reports on hypertension and renal impairment vary, ranging from 10% to 50%. The clinical manifestations, particularly the level of proteinuria, are related to prognosis.
(I) General Treatment For patients presenting with massive proteinuria and edema, a low-salt diet should be administered, and diuretics may be appropriately used. For those with significant hypoalbuminemia, albumin may be supplemented in moderate amounts. For patients with marked hypertension, if sodium restriction and diuretics are ineffective, antihypertensive drugs such as angiotensin-converting enzyme inhibitors or calcium channel blockers may be added.
(II) Hormones and Other Immunosuppressants
1. Hormones For patients primarily presenting with nephrotic syndrome, especially those whose previous renal biopsy showed minimal change disease progressing to focal segmental glomerulosclerosis, hormones remain the first-line treatment, with most patients responding well. The adult dose is prednisone 0.5–1 mg/(kg·d) for 6–8 weeks, followed by gradual tapering to alternate-day therapy, with a total treatment course exceeding one year. Pei et al. reported that prednisone treatment for primary focal glomerulosclerosis achieved a complete remission rate of 47%, and the 5-year renal survival rate in these patients was significantly higher than in non-responders (96% vs. 55%). Although some data suggest that combining hormones with cytotoxic drugs does not yield better outcomes than hormones alone, most experts recommend combination therapy for hormone-resistant, dependent, or frequently relapsing cases. Cytotoxic drugs can significantly reduce relapse rates, prolong the stage of remission, decrease hormone dosage, and minimize side effects. Cyclophosphamide is often chosen, administered intermittently intravenously, with a total dose <150 mg/kg. Oral chlorambucil may also be used. In recent years, cyclosporine A has been employed to treat this condition, showing short-term efficacy but a high relapse rate during dose reduction or discontinuation. Due to its high cost and potential nephrotoxicity, it is not recommended as a first-line drug.
(III) Other Treatments Angiotensin-converting enzyme inhibitors not only lower blood pressure but also reduce proteinuria, potentially delaying renal failure. Additionally, patients with nephrotic syndrome in this condition often exhibit hypercoagulability and intraglomerular coagulation with capsular adhesions, warranting anticoagulant therapy such as dipyridamole 25–75 mg/d or warfarin 2.5 mg/d, which may reduce proteinuria and improve renal function.
It is related to multiple factors: ① Urinary protein levels: If urinary protein exceeds 10g/24h, the disease progresses rapidly, often leading to loss of kidney function within 6 years; for those with 3–3.5g/24h, 50% develop end-stage uremia in 6–8 years. If <3g/24h, kidney function remains normal after 10 years. ② Remission status and treatment response: Those sensitive to hormones rarely progress to renal failure. The incidence of end-stage renal failure is 15% in those with complete remission, compared to 85% in those without. ③ Age: Adults generally fare better. Reports indicate the incidence and recurrence rates of nephrotic syndrome in adults are 55% and 15%, respectively, versus 76% and 80% in children. ④ Race: Ingulli et al. found that among children with nephrotic syndrome, Black individuals had a higher incidence and faster progression than White individuals. 78% of Black individuals developed end-stage uremia within 8.5 years, compared to only 33% of White individuals in the same period. ⑤ Disease duration and severity of hypertension: Prognosis is poor for those diagnosed at a late stage (third stage) or with severe hypertension. ⑥ Renal histopathology: Severe damage or concurrent membranous, mesangial proliferative, and vascular injuries increase the likelihood of progressing to renal failure.
