bubble_chart Overview

Chronic glomerulonephritis refers to a group of primary glomerular diseases characterized by diffuse or focal inflammatory changes in the bilateral glomeruli caused by various disease etiologies. It typically has an insidious onset, a protracted course, and slow disease progression. Strictly speaking, it is not an independent disease. However, due to the limited availability of renal biopsy in clinical practice, the clinical classification of this group of chronic glomerulonephritis syndromes is helpful in formulating treatment plans, preventing disease progression, and delaying renal function deterioration. Therefore, the term "chronic glomerulonephritis" is still retained.

bubble_chart Etiology

Chronic nephritis is a group of glomerular diseases primarily characterized by chronic glomerular lesions caused by multiple etiologies, though the cause remains unknown in most patients and has no clear association with streptococcal infections. Statistics show that only 15–20% of cases develop from acute glomerulonephritis, but since subclinical forms of acute glomerulonephritis are difficult to diagnose, the actual percentage may be higher. Additionally, most chronic nephritis patients have no history of acute nephritis, leading many scholars to conclude that there is no definitive link between chronic glomerulonephritis and acute nephritis. It may instead be triggered by various bacteria, viruses, or parasites through immune mechanisms, inflammatory mediators, or non-immune mechanisms.

bubble_chart Pathological Changes

The pathological changes of chronic glomerulonephritis vary depending on the disease cause, course, and type. It can manifest as diffuse or focal segmental membrane proliferation, membranous proliferation, membranous changes, minimal change disease, focal sclerosis, advanced-stage glomerular fibrosis, or unclassifiable forms. In addition to glomerular lesions, varying degrees of renal interstitial inflammation and fibrosis may also be present, with interstitial damage exacerbating renal dysfunction. In advanced-stage glomerulonephritis, the renal cortex becomes thin, glomerular capillary loops atrophy, progressing to hyalinization or fibrosis. The remaining glomeruli may undergo compensatory hypertrophy, accompanied by tubular atrophy.

bubble_chart Clinical Manifestations

Most cases have an insidious onset, with a prolonged course and slow progression of the disease. Due to different pathological types, clinical manifestations vary. The majority of cases present with edema as the initial symptom, ranging in severity. Mild cases may only show slight swelling of the face and lower limbs, while severe cases may present with nephrotic syndrome. Some cases are discovered as chronic glomerulonephritis due to hypertension as the first symptom. It may also manifest as asymptomatic proteinuria and/or hematuria, or only as polyuria and nocturia. In some cases, there may be no obvious physical decline throughout the course until severe anemia or uremia appears as the initial symptom. Generally, based on different clinical manifestations, it is divided into the following five subtypes:

(1) **Common Type**: Relatively common. The course is prolonged, and the condition is relatively stable, mostly presenting with grade I to grade II edema, hypertension, and renal impairment. Urine protein ranges from (+) to (+++), with centrifuged urine showing >10 red blood cells per high-power field and casts. Pathological changes are mostly mesangial proliferative, focal segmental mesangial proliferative, membranous proliferative, or glomerulonephritis.

(2) **Nephrotic Type**: In addition to the manifestations of the common type, it mainly presents with nephrotic syndrome, with 24-hour urine protein >3.5g, serum albumin below 30g/L, generally severe edema, and with or without hyperlipidemia. Pathological types are mostly minimal change disease, membranous, membranoproliferative, or focal glomerulosclerosis.

(3) **Hypertensive Type**: In addition to the common type manifestations, it primarily presents with persistent moderate hypertension, especially sustained elevation of diastolic pressure, often accompanied by retinal arteriolar narrowing, tortuosity, and arteriovenous crossing phenomena. A few cases may show cotton-wool exudates and/or hemorrhages. Pathologically, focal segmental glomerulosclerosis and diffuse proliferation are common, or advanced-stage cases may show unclassifiable or prominent glomerulosclerosis.

(4) **Mixed Type**: Clinically, it presents with both nephrotic and hypertensive features, often accompanied by varying degrees of renal function decline. Pathological changes may include focal segmental glomerulosclerosis and advanced-stage diffuse proliferative glomerulonephritis.

(5) **Acute Onset Type**: During a relatively stable or progressively worsening course, due to bacterial or viral infections or overexertion, after a short incubation period (mostly 1–5 days), clinical manifestations similar to acute nephritis appear. With treatment and rest, the condition may return to the previous stable level or worsen, gradually leading to uremia. Alternatively, after repeated episodes, renal function may decline sharply, presenting with a series of uremic symptoms. Pathological changes include diffuse proliferation, crescent formation on a background of glomerulosclerosis, or significant interstitial nephritis.

The clinical and pathological classification of chronic glomerulonephritis is not absolute, and different types may transform into one another. For cases where renal biopsy cannot be performed for pathological classification, clinical manifestations can be used to classify them as nephritis, nephrotic syndrome, or hypertension. Combined with renal function tests, this can serve as a rough estimate of disease severity, guide treatment planning, and predict prognosis. A few patients with chronic nephritis may show clinical remission or no obvious symptoms, but pathological changes persist or even worsen, leading to uremia after an acute episode. Therefore, the importance of close dynamic observation and follow-up should be emphasized.

[Chronic Nephritis with Azotemia]

It refers to various disease causes and pathological types of primary glomerular diseases, during the progression of which mild to grade II impairment of glomerular filtration function occurs, manifested by elevated serum creatinine and blood urea nitrogen, as well as reduced endogenous creatinine clearance rate. In fact, varying degrees of tubular function changes have already occurred concurrently with or even before the onset of azotemia. The azotemic stage of chronic nephritis is a prelude to the development of chronic renal failure. However, at this initial stage [first stage], young patients with mild symptoms often feel well and tend to be careless. Additionally, for some cases of nephritis, regardless of the duration, the emergence of azotemia is easily mistaken as a natural progression toward uremia. Clinical observations indicate that many patients with chronic nephritis and azotemia show significant improvement in renal function after a period of treatment and can maintain good renal function for a considerable time, suggesting the presence of reversible factors. Conversely, others may progress to uremia within a short period or several years. Chronic nephritis ranks as the leading cause of uremia in China. Therefore, clinically, it is crucial to investigate the pathological basis, pathophysiology, reversible factors, and other influencing factors of chronic nephritic azotemia, so as to adopt targeted prevention and treatment measures. This approach aims to reverse some cases and more effectively delay the onset and progression of chronic kidney failure. These aspects should be carefully considered during diagnosis and treatment.

1. Clinical assessment of azotemia and its severity should first identify the presence of pre-renal factors and the influence of drugs on creatinine clearance. In patients with normal renal function, grade I reductions in cardiac output or blood volume have minimal impact on glomerular filtration rate (GFR). However, in chronic nephritis patients with azotemia, similar changes in cardiac output or blood volume often lead to a significant, sometimes even doubling, increase in azotemia. Certain commonly used drugs can also cause pseudo-elevation of serum creatinine, such as cimetidine, long-acting sulfonamides, methyldopa, cefoxitin, and ketone bodies. Dynamic evaluation of glomerular filtration function helps assess the severity of kidney disease. Common methods include measuring serum creatinine (Scr), endogenous creatinine clearance rate (Ccr), and blood urea nitrogen (BUN). There is a certain correlation between Scr and Ccr: generally, when Scr is 1 mg/dL, Ccr is approximately 100 mL/min; at 2 mg/dL, Ccr is around 50 mL/min; and at 4 mg/dL, Ccr is about 25 mL/min. Therefore, the severity of azotemia is often graded as follows: grade I for Scr ≤ 2.5 mg/dL and Ccr ≥ 40 mL/min; grade II for Scr > 2.5 mg/dL and Ccr < 40 mL/min; and grade III for Scr ≥ 3.5 mg/dL. BUN is influenced by many factors, but in cases of acute kidney injury, BUN may rise significantly even when Scr changes are minimal. A formula to estimate Ccr based on Scr is also available, which is simple and practical for rough estimation:

C_cr(mL/min) = (140 - age) × weight (kg) / (72 × serum creatinine (mg/dL))

2. Identifying factors contributing to rapidly progressive or newly developed azotemia is crucial. In chronic nephritis patients, Scr typically rises slowly over years as part of disease progression. However, some patients with previously stable or unmonitored renal function may experience a sudden, marked increase in Scr after infections, excessive fatigue, moderate-to-grade III hypertension, pregnancy/childbirth, or certain medications. These cases often involve acute or temporary factors and should not be mistaken for chronic nephritis progressing to uremia. Renal biopsies in such cases may reveal significant glomerular mesangial cell proliferation, fibrinoid necrosis in afferent and efferent arterioles, or even cellular crescent formation in Bowman's capsule and/or moderate-to-grade III inflammatory cell infiltration in the interstitium. Many of these patients remain in relatively good overall condition and can tolerate corticosteroid therapy. After intravenous methylprednisolone (80–240 mg for 5–10 days) or oral prednisone (40–60 mg/day for 2–4 weeks), renal function often improves to varying degrees, sometimes even normalizing Scr. Therefore, in chronic nephritis patients of any subtype presenting with a first-time significant Scr elevation, reversible factors should be thoroughly investigated. For patients with membranous nephropathy, membranoproliferative lesions, or nephrotic syndrome accompanied by a hypercoagulable state, renal vein thrombosis—which can induce or worsen azotemia—should be ruled out. Renal CT scans often detect renal vein thrombosis.

bubble_chart Diagnosis

The diagnosis of typical cases is not difficult. If the patient presents with clinical manifestations of glomerulonephritis such as proteinuria, hematuria (with dysmorphic red blood cells commonly seen under phase-contrast microscopy), hypertension, edema, and renal insufficiency, and the disease course lasts for more than one year while excluding secondary glomerulonephritis, this condition should be considered.

bubble_chart Treatment Measures

(1) General Treatment For patients without significant edema, hypertension, hematuria, or severe proteinuria, and no signs of renal insufficiency, they can manage daily life independently and even engage in light labor. However, they should prevent respiratory infections, avoid overexertion, and refrain from using nephrotoxic drugs. Patients with significant hypertension, edema, or a recent decline in renal function should rest in bed and limit salt intake to 2–3 g. For those with substantial protein loss in urine but preserved renal function, high biological-value animal proteins such as eggs, milk, fish, and lean meat should be supplemented. For patients with impaired renal function (endogenous creatinine clearance around 30 ml/min), protein intake should be moderately restricted to about 30 g, with oral essential amino acids added if necessary.

(2) Hormone and Immunosuppressant Therapy

(3) Management of Azotemia

1. Patients who develop azotemia for the first time, experience a recent progressive increase, or show short-term onset should rest in bed and limit excessive activity.

2. Diet and Nutrition For patients without significant edema or hypertension, water and sodium intake need not be restricted. Adequate hydration to increase urine output is crucial. For patients with mild or grade II azotemia, protein intake should not be restricted to maintain positive nitrogen balance, especially for those with substantial daily protein loss. For patients with heavy proteinuria and grade I azotemia, plant-based proteins such as soybeans can be increased. For grade III azotemia or recent progressive azotemia, protein intake should be moderately restricted.

3. Urine Output and Osmolality In chronic nephritis patients with azotemia, urine osmolality is often 400 mOsm/L or lower. If daily urine output is only 1 L, it is insufficient to excrete nitrogenous solutes. Therefore, a urine output of 1.5 L or more is recommended. Adequate water intake or drinking weak tea can help achieve this goal, and diuretics may be used intermittently if necessary.

4. Controlling Hypertension Chronic nephritis with azotemia and kidney excess hypertension often indicate a poor prognosis. Persistent or grade III renal hypertension can further exacerbate azotemia. While general antihypertensive drugs may reduce peripheral vascular resistance, they do not necessarily decrease intraglomerular vascular resistance. Increased resistance in the afferent and efferent arterioles of the glomerulus reduces glomerular filtration function. There is debate over whether calcium channel blockers like nifedipine can lower intraglomerular pressure and protect renal function. However, it is now widely accepted that angiotensin-converting enzyme inhibitors (ACEIs) not only reduce peripheral vascular resistance but also inhibit the tissue renin-angiotensin system, decrease efferent arteriolar tension, and improve intraglomerular hemodynamics. ACEIs also reduce the degradation of tissue bradykinin, enhancing its vasodilatory effects. Bradykinin can stimulate cell membrane phospholipids to release arachidonic acid, promoting prostaglandin production and further enhancing vasodilation. Additionally, ACEIs inhibit the contractile effect of angiotensin II on glomerular mesangial cells. These mechanisms collectively improve intraglomerular hemodynamics. For patients with moderate or grade III hypertension and cardiac hypertrophy, ACEIs can also reduce or inhibit the effects of angiotensin II on myocardial and vascular smooth muscle hyperplasia, hypertrophy, and medial vascular wall thickening. This is particularly beneficial in preventing vascular wall thickening and myocardial cell hypertrophy in chronic nephritis patients with hypertension. However, ACEIs may reduce efferent arteriolar tension, sometimes leading to a decline in GFR. Therefore, in cases of azotemia, the ACEI dose should not be excessive, and renal function must be closely monitored. Potassium-sparing diuretics should also be avoided to prevent hyperkalemia. Commonly used medications include: - Captopril: 12.5–25 mg per dose, 2–3 times daily. - Benazepril (Lotensin): 10 mg, 1–2 times daily. - Enalapril: 10 mg, once daily. - Cilazapril: 2.5–5 mg, once daily. Benazepril, cilazapril, and enalapril are long-acting ACEIs. If hypertension remains uncontrolled, amlodipine (Norvasc) 5–10 mg, 1–2 times daily, may be added.

5. Management of Azotemia During the Treatment of Nephrotic Syndrome In chronic nephritis with nephrotic syndrome, the glomerular filtration rate (GFR) is often reduced to varying degrees during both the edema phase and the edema resolution phase. This reduction is associated with the following factors: ① The degree of pathological activity and sexually transmitted disease progression; ② Renal interstitial edema; ③ Decreased glomerular ultrafiltration coefficient; ④ Reduced blood volume (occurring in 7–38% of cases); ⑤ Increased catabolism in the body due to high-dose hormone therapy; ⑥ Use of nephrotoxic drugs; ⑦ Interstitial nephritis; ⑧ Renal vein thrombosis. Clinically, it is often difficult to promptly determine the cause. Except for factors ①, ⑥, and ⑦, which require immediate intervention, other factors may require patience and observation in the absence of infection, without overly aggressive treatment. For cases complicated by acute interstitial nephritis, whether due to autoimmune reactions or drug allergies, short-term high-dose hormone therapy can often reduce azotemia and should be addressed promptly. Bingben

6. Anticoagulation Therapy Our hospital has treated over 400 cases of various pathological types of glomerulonephritis accompanied by hypercoagulability and intraglomerular fibrinoid necrosis using a combination of heparin (50–80 mg/day) and urokinase (20,000–80,000 units/day) via intravenous drip (for 2–8 weeks). Renal function often improved to varying degrees, with no cases of severe bleeding. For refractory or difficult-to-treat renal vein thrombosis, catheter-directed injection of urokinase (200,000 units) into the renal artery and vein has achieved excellent therapeutic outcomes.

7. Management of Hyperuricemia A minority of chronic nephritis patients with azotemia also exhibit hyperuricemia. The increase in hematuria acid is not proportional to the decrease in endogenous creatinine clearance, indicating that hyperuricemia is not solely a result of azotemia. The use of allopurinol to reduce hematuria acid can improve renal function, but the dose should be small, the duration of treatment short, and tapering rapid. Drugs that increase uric acid excretion should be avoided.

8. Other Considerations In glomerulonephritis, infiltrating inflammatory cells in renal tissue can produce large amounts of oxygen free radicals. Glomerular mesangial cells, stimulated by immune complexes, membrane attack complexes, and platelet-activating factors, can also generate reactive oxygen species. Oxygen free radicals can directly injure or damage the glomerular basement membrane and epithelial cells through membrane lipid peroxidation. Additionally, many patients with glomerular diseases exhibit reduced antioxidant capacity, manifested by decreased blood antioxidant enzymes (e.g., serum superoxide dismutase) and lower levels of antioxidants such as vitamins B2 and E, zinc, and selenium. Therefore, clinical strategies to inhibit oxygen free radical production in renal tissue, whether to use antioxidants, and which antioxidants are most effective, warrant further observation and experience accumulation. Chronic nephritis with nephrotic syndrome is often accompanied by varying degrees of hyperlipidemia. It is known that hypercholesterolemia, particularly low-density lipoprotein abnormalities, can induce lipid peroxidation in renal tissue, accelerating glomerulosclerosis and tubular injury. Increasing serum albumin levels can reduce blood lipid concentrations.

In summary, patients with chronic nephritis and azotemia stand at a crossroads between progression to chronic kidney failure and disease stabilization. For cases of rapidly progressive azotemia or newly developed azotemia, careful investigation of the underlying cause is essential, and it should not be simplistically attributed to a stage of chronic nephritis progression. In many cases, after removing precipitating factors, renal function can remain stable for an extended period.

bubble_chart Differentiation

In differential diagnosis, it should be distinguished from chronic pyelonephritis, chronic interstitial nephritis, lupus nephritis, purpuric nephritis, and hereditary nephritis.