Clinical And Pathologic Conditions Associated With Edema Formation In Nephrotic Patients

Background and Objective:Interstitial edema is a common clinical expression ofnephrotic syndrome.It is often massive and constitutes a functional constraint,owing to locomotive restriction and eyelid shutting.While some nephrotic patients without edema are also common in clinical.Although the syndrome has been long recognized,the mechanism of edema formation remains controversial.Expansion of the interstitial component is secondary to the accumulation of sodium in the extracellular compartment due to an imbalance between oral or parenteral sodium intake and urinary sodium output.To identify the factors that can predict this increased risk of edema in some patients,we performed a retrospective and prospective review to characterize the clinico-pathophysiological characteristics between the two groups of nephrotic patients divided by with or without edema.Methods:(1),Retrospective review:Among the patients with adult-onset idiopathic nephrotic syndrome who were admitted to the Department of Nephrology in the fifth people' s hospital of Fudan University between 2000 and 2007,the data of 79 patients with an entire records of the weight and urine volume were reviewed.We divided the patients into two groups,namely, the edema group(n = 58) and the non-edema group(n= 21),and compared the clinico-pathophysiological characteristics, including blood pressure,hart rates,and serum levels of albumin,between the two groups.(2),Prospective study:Twenty-five consecutive patients,16 males and 10 females,ranging in age from 20 to 83 years(mean 32.8 +- 14.5 years) were included in the study.These included 9 NS patients with edema,5 NS patients without edema,and 10 patients without NS as control.The following laboratory tests,conducted according to standard hospital procedures,were performed:urinalysis,measurement of the serum and urinary protein,serum albumin,serum cholesterol,Hct and serum concentrations of sodium,potassium and chloride.Diuretics were discontinued at least one week prior to the study.Patients were put on a low protein diet containing 100mmol/day of sodium for three to four days prior to the study.Water intake was restricted to 1.5 liter/day.During this period patients were asked to strictly observe bed rest.Daily collection of urine was made for three consecutive days.Urine was analyzed for sodium,potassium,chloride and concentrations.Each urinary data represents the mean value of total consecutive determinations.Plasma renin,angiotensin and aldosterone levels were measured by specific radioimmunoassay when the urinary sodium excretion is stable.(3),Water Channel Expression of human kidney in patients with and without NS:Archival human renal biopsy samples of NS,non-NS and normal human kidney tissue(nephrectomy specimens) were processed for immunohistochemistry by means of standard techniques.A semiquantitative analysis has been made for the four AQPs.Results:(1),The non-edema group included21 patients withamean age of 38.53±15.91 years at the time of diagnosis,and the edema group included 58 patients with a mean age of 30.28±13.84 years(P =0.0045).Patients with edema had a serum albumin/total protein concentration,urine volume,and urine protein excretion significantly lower than those without edema.In contrast,the serum level of creatinine was significantly elevated(98.10±47.84 VS73.29±22.13.P=0.0469) in all the patients with edema as compared to the patients without edema.The renal biopsy pathology in the two groups were also investigated and compared between the edema and the non-edema groups.Data of 49 patients with renal biopsy were available for analysis.The pathology of NS with edema in descending order of incidence,were MCD(72.7%),lupus nephritis(15.2%),mesangial prolif- -erative glomerulonephritis(MsPGN,6.0%)and IgA nephropathy(6.0%).The pathology of NS without edema in descending order of incidence, were MsPGN(37.5%),MCD(31.3%),lupus nephritis(18.8%) and others(12.5%).(2),In 14 patients(9 with edema,5 without edema) with nephrotic syndrome and 10 controls,we observed that the sodium balance was positive in nine patients with edema and controls, however,negative in the remaining five patients during a 3-day controlled sodium intake.In sodium/water retentive patients, serum albumin and total protein was lower than in the excretors, and proteinuria was higher than in the excretors.Results of plasma renin activity(PRn)and plasma aldosterone(PA)are similar in three groups of patients.Blood pressure and heart rates were not different in all the patients.(3),AQP-1 is located on the basolateral and apical membranes of the proximal tubules.The experiment demonstrated that NS with edema were associated with marked decreases in expression of aquaporin].In contrast,the expression of aquaporin 1 in controls and NS without edema was not significant altered.The most striking observation was the increase in AQP-1 immunostaining in the glomerular endothelium of NS patients, especially of the edema patients,compared to the controls.AQP-2 is localized to the apical membranes of the collecting duct principal cells.AQP-2 expression was marked increased in the NS patients,especially in the edema patients.AQP-4 staining was absent,presumably the result of the lack of inner medullary tissue on the biopsy specimens that contain tissue predominantly from the cortex andjuxtamedullary regions of the kidney.Conclusions:(1),Patients with edema had a serum albumin/total protein concentration,urine volume,and urine protein excretion significantly lower than those without edema:(2),Interstitial edema observed in nephrotic syndrome results from primary renal sodium retention.Aldosterone and activation of mineralo-corticoid receptors are maybe not involved in sodium retention in nephrotic syndrome;(3),The changes in the expression ofaquaporins has been investigated in this study.The experiment demonstrated that NS with edema were associated with marked decreases in expression of aquaporin 1.AQP-2 expression was marked increased in the NS patients,especially in the edema patients. AQP2 expression is significantly increased suggesting a role in the development of free water retention.It is very likely that the increased AQP2 expression in the NS patients with edema is a direct result of increased vasopressin levels.However, contribution of other regulatory factors cannot be totally excluded.The downregulation of AQP-1 observed in NS with edema patients may represent a compensatory mechanism to prevent development of water retention.