Metolazone and spironolactone in cirrhosis and the nephrotic syndrome.

Eighteen patients with hepatic cirrhosis or nephrotic syndrome and having edema and/or ascites were treated during successive periods with metolazone 5 to 40 mg/day, spironolactone 100 mg/day, and with both diuretics concurrently. Metolazone alone produced a marked diuresis, natriuresis, and weight loss in 8 patients. Spironolactone alone had little effect, but the addition of metolazone renewed diuresis and natriuresis and resulted in additional substantial weight losses in all patients responsive to metolazone alone. Concurrent spironolactone and metolazone also induced moderate diuretic effects in some patients who failed to respond to either drug alone. The drugs were well tolerated; the administration of spironolactone with metolazone prevented decreases in serum potassium, which had occurred during treatment with metolazone alone.     

Studies on vitamin D binding protein in the nephrotic syndrome

We studied the properties of vitamin D binding protein in plasma and urine from nine patients with nephrotic syndrome. Samples were incubated with 25-[3H]hydroxyvitamin D3, after which we determined binding capacity and apparent dissociation constants. Binding capacity was markedly less in plasma from patients with nephrotic syndrome than that from normal subjects, but binding affinity was unchanged. Specific binding of 25-hydroxy[3H]vitamin D3 could be demonstrated in urine from all the nephrotic patients, and sucrose density-gradient analysis of these urines revealed a single binding peak with sedimentation characteristics similar to those of vitamin D binding protein in plasma.     

甘露糖结合凝集素的基因多态性与复发性肾病综合征的关系

目的：探讨甘露糖结合凝集素（MBL ）的基因多态性与复发性肾病综合征的关系。方法对66例复发的肾病综合征患者和40例健康成人用序列特异性引物聚合酶链反应（SSP-PCR）和实时定量荧光聚合酶链反应分别检测MBL启动子和外显子1第54号密码子的基因多态性位点,同时采用酶联免疫吸附试验检测血清中MBL浓度。结果复发性肾病综合征患者和健康对照者中高表达MBL的基因型血清MBL浓度均高于低表达MBL的基因型,差异有统计学意义（P＜0．05）;复发的肾病综合征患者血清MBL浓度低于对照组,差异有统计学意义（P＜0．05）。复发性肾病综合征患者有前驱感染病史者,MBL的基因型低表达者多于高表达者,差异有统计学意义（P＜0．05）。结论推测MBL的基因变异导致血清MBL浓度降低,诱发感染发生,引起肾病综合征患者经常复发。     

Electrochemical determination of all-trans-retinol, and correlation with retinol binding protein in liver cirrhosis

All-trans-retinol (vitamin A1) levels were determined in the sera of patients with cirrhosis of the liver and in normal healthy individuals, using a recently developed method involving high-performance liquid chromatography with electrochemical detection. The vitamin levels were significantly lower in the cirrhotic group. (P less than 0.01), and the correlation between retinol and retinol-binding protein levels was good (r = 0.9678, 0.0000 less than P less than 0.0001). It is suggested that retinol levels may be used to monitor the disease, the assay described being less time-consuming and more convenient than the commonly used retinol-binding protein or 'dark adaption' methods.     

History of nephrotic syndrome

The history of nephrotic syndrome can go back to beginning of the era. In old Alexandria, urine was conceived to be produced in kidneys. In 1827, Bright classified diseases with proteinuria into three categories, and lipoid nephrosis seemed to be included in group 1. Mechanisms of urinary protein leakage have been in great controvesies, and nowadays defects of slit-membrane protein are supposed to play important roles. In the middle of the 20th centuries, electron microscopy and renal biopsy technique were adopted in practical use. Since then, the treatment and research of nephrotic syndrome have been remarkably progressed. Clinical strategies including diet therapy, immuno-suppressive and antihypertensive drugs and other modalities have improved the prognosis of nephrotic syndrome.     

Factors affecting the binding of disopyramide to serum proteins

We investigated the influence of the following factors on the binding of disopyramide to serum proteins: method of drug quantification [enzyme immunoassay (EMIT) compared with liquid chromatography (HPLC)], separation technique (ultrafiltration vs equilibrium dialysis), temperature, pH, and total concentration of disopyramide. EMIT and HPLC measurements of disopyramide in ultrafiltrates prepared from 50 sera agreed well: EMIT = 1.046 HPLC + 0.042, (r = 0.928, SEE = 0.04 mg/L). Free disopyramide concentrations in ultrafiltrates of dialyzed sera were similar to those measured in the corresponding dialysates by the EMIT method for 30 patients' sera: ultrafiltrate of serum retentate = 1.053 dialysate + 0.042. Concentrations of free [14C]disopyramide were little affected by temperature. The concentration of free disopyramide decreased as the pH was increased from 7.0 to 7.8. The concentration of free disopyramide, as determined by ultrafiltration, is strongly and directly related to total drug concentration. In the sera of 50 cardiac patients receiving chronic therapy with disopyramide and with total disopyramide concentrations of 0.5 to 5.8 mg/L, the proportion of free disopyramide ranged from 16 to 54%.     

Epidemiology of nephrotic syndrome

Causes of nephrotic syndrome are varied with age, the times, geographical location and race. In children, minimal change nephrotic syndrome (MCNS) is common; however, membranous nephropathy (MN) is most frequent in adult. Incidence of membranoproliferative glomerulonephritis (MPGN) is decreased in advanced nations, although it remains a common in developing countries. In advanced nations, incidence of focal and segmental glomerular sclerosis (FGS) is increased, particularly in black populations. In Japan, MCNS was most frequent (37.7%), and then, MN was 23.3%, FGS was 7.2% and MPGN was 8.3% by a former research (in 1985). The recent research (in 1994) showed that MCNS was 41.5%, and next MN was 24.7%. FGS was increased to 11.8% and MPGN was decreased to 4.9%.     

Improved outcomes in nephrotic syndrome

Nephrotic syndrome can now be treated effectively in most cases. All patients should be treated with a low-salt diet, diuretics to reduce edema, and statins to normalize serum lipid concentrations. Patients with nephrotic syndrome are prone to deep vein thrombophlebitis, renal vein thrombosis, and pulmonary emboli. Depending on the condition, additional treatment may include corticosteroids, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), cyclosporine, cytotoxic agents, or mycophenolate.     

Edema and the nephrotic syndrome

If proteinuria is of sufficient amount, and persists for long enough, then a series of consequences arises which is called the nephrotic syndrome. The most notable consequence of massive proteinuria is salt and water retention leading to edema formation. This edema is found in association with proteinuria usually greater than 3.5 g/day, accompanied by hypoalbuminemia, usually less than 25 g/l. The underlying disease is usually a glomerulonephritis, albeit in rare situations severe renal artery stenosis can lead to proteinuria by hyperfiltration. Two theories have been proposed. In the classical "underfill" theory edema is considered to be secondary to salt retention resulting from renal hypoperfusion. According to this theory the primary event is the decrease in plasma volume due to the diminution of plasma oncotic pressure resulting from hypoalbuminemia, causing transfer of fluid from the plasma to the interstitial space "underfilling" the blood compartment and resulting to secondary renal sodium retention. This mechanism applies mainly to the nephrotic syndrome associated with minimal change disease observed in children. By contrast, in most adults with the nephrotic syndrome due to minimal change disease or other glomerular lesions such as membranous or proliferative glomerulonephritis, an initial plasma volume expansion is observed. Therefore, the primary event responsible for the sodium retention is a renal intrinsic excretory defect, which leads to extracellular fluid expansion and edema formation. Therapy is specific for the specific glomerular disease and symptomatic for the edema (diuretics), anticoagulation therapy for prevention of venous thrombosis and embolism, antibiotics for infections, and most of all, omission of triggering factors such as specific xenobiotics.