M. Cohn

Mesangial cells initiate compensatory tubular cell hypertrophy.

Unilateral nephrectomy results in compensatory renal growth, in which both the size and the functional capacity of the remaining kidney are increased. The functional adaptation to the removal of the contralateral kidney consists mostly of an increase in the glomerular filtration rate of the remaining kidney, and hypertrophy of cells comprising the nephron, mainly of the proximal tubular cells. Although the phenomenon of single kidney hypertrophy has been known for the past thousand years and despite intensive research over the past century, the mechanism of this process still remains unclear. The present article reviews the role of mesangial cells in compensatory renal hypertrophy.

Pulse oxymetry evaluation of oxygen saturation in the upper extremity with an arteriovenous fistula before and during hemodialysis

We noticed that some patients with arteriovenous (AV) fistula on chronic hemodialysis experience pain in the limb with the fistula a short time after being connected to the dialysis machine. We postulated that the pain is caused by relative ischemia and therefore performed this study to determine whether oxygen saturation (SaO2) of the extremities with AV fistula decreases during hemodialysis. Seventy-two patients with a side-to-side primary AV fistula were evaluated by pulse oxymetry. SaO2 was measured before hemodialysis and 20 minutes after initiation of dialysis. The contralateral arm served as a control. In 48 patients, SaO2 difference between the arms of each patient before hemodialysis was less than 4%. SaO2 values of this group of patients did not change significantly 20 minutes after initiation of dialysis. In 24 patients, SaO2 differences between the hands of each patient before hemodialysis were 4% or more. In this group of patients, SaO2 values of the hands with the AV fistula decreased significantly 20 minutes after hemodialysis from a mean of 90.85 +/- 2.84% to 81.60 +/- 3.94 (P < 0.001). SaO2 remained unchanged in the contralateral arm. Nine patients in this group complained of pain and change in sensation in the arm with the fistula during hemodialysis. One patient complained of severe pain in the arm with the fistula before hemodialysis, and SaO2 was unmeasurable. We conclude that, in some patients, SaO2 of the arm with the AV fistula decreases only during hemodialysis. This phenomenon may be symptomatic. A predialysis SaO2 difference of 4% or more between the arms predicts decreased SaO2 of the arm with the AV fistula during hemodialysis.

Postnephrectomy Mesangial Cells Secrete a Factor(s) That Stimulate(s) Tubular Cell Growth in vitro

Rat kidney mesangial cells were procured from 5 sham-operated and 10 previously uninephrectomized rats. They were grown in cell culture medium supplemented with 20% fetal calf serum. Cell free conditioned medium was collected on the 10th day. Tubular cell cultures were then prepared from 18 normal unoperated 3-week-old rats. Tubular cells from each separate kidney sample were grown in pooled-mesangium conditioned medium from sham-operated or from nephrectomized rats, supplied with 20% pooled serum from either sham-operated or nephrectomized animals. 3H-thymidine incorporation of normal tubular cell cultures grown in nephrectomy mesangium conditioned medium supplemented with sera from nephrectomized animals proved to be significantly greater than that of any of the other three experimental variations. No statistically significant difference was evident when either preconditioned medium of postnephrectomy mesangial cells or postnephrectomy serum were used alone.

Interleukin-2 receptor is similarly expressed by activated lymphocytes from patients on chronic hemodialysis and healthy subjects.

We studied peripheral blood mononuclear cells (PBMC) from 10 patients on chronic hemodialysis vs 10 healthy controls. T cells were counted by E rosette formation. Interleukin (IL)-2 receptor (IL-2R) carrier cells were identified by Dako-IL-2R, which was chosen as a monoclonal antibody that binds to the alpha chain of IL-2R without interrupting the cell machinery of mitogen-induced IL production. Fluorescein-tagged goat anti-rabbit IgG1* was used for subsequent cell staining, and cells were counted by FACS. Net numbers of PHA-activated IL-2R carrier cells were derived by subtracting appropriate background controls. The average number of these cells relative to numbers of total T cell population in uremic PBMC was statistically not different from healthy controls. Several defects in cellular activation associated with IL-2 mechanisms could be envisaged to account for the impaired proliferative response to PHA, manifested by uremic T cells.

Effect of Exercise Training on Glomerular Filtration Rate of Mice with Various Degrees of Renal Mass Reduction

We studied the effect of repeated heavy physical activity on glomerular filtration rate (GFR) in healthy, uninephrectomized and experimentally uremic mice. Exercise consisted of running uphill in the inner surface of a rotating cylinder in ideal environmental temperature. In the control groups, no extra physical activity was imposed. In sham-operated and nephrectomized mice, GFR rose significantly following training. By contrast, GFR did not change significantly in the exercised mice with experimental renal failure 24 h following the last exercise session. During the same period, no significant change was observed in GFR of any of the control groups. Following training in each experimental group, mean aortic blood pressure as well as fractional kidney weight (kidney weight/body weight) were not different from the respective controls. Our results indicate that the capacity to augment GFR by physical training is dependent upon the amount of remaining functional renal tissue.

Hypertension but Not Sodium Intake Determines Progression of Renal Failure in Experimentally Uremic Rats

Background/Aims: High sodium intake is implicated in contributing to progression of chronic renal failure. We studied the effect of high sodium consumption on progression of rat experimental renal failure while sodium-induced hypertension was pharmacologically controlled. Methods: 64 Sprague-Dawley rats underwent 5/6 nephrectomy. Subsequently, they were divided in three groups which were fed either low, normal, or high sodium diet. Only the high sodium-consuming group developed hypertension. This group was further divided in two subgroups in which hypertension was either untreated or titrated to normotension by hydralazine alone or with propranolol. Results: Sequential GFR values did not differ between the respective normotensive groups. Survival downslopes of all three normotensive groups (including the pharmacologically treated, high sodium-consuming subgroup) were also similar, extending over 10 weeks. By contrast, pharmacologically untreated animals exhibited severe hypertension and 100% mortality within 3 weeks. In all experimental groups, 24-hour urinary sodium excretion paralleled sodium intake. Proteinuria rose similarly and significantly in all animals on high sodium. A significant correlation between 24-hour sodium and proteinuria was evident throughout the experimental period. Conclusions: (1) In 5/6 nephrectomized rats, renal function deterioration was not affected by dietary sodium, provided hypertension was pharmacologically controlled. (2) Enhanced proteinuria secondary to high sodium consumption had no adverse effect on progression of renal failure in this model.

The Proliferative Responsiveness of Mesangial Cells to Postnephrectomy Serum Declines Progressively with Time Elapsing after Contralateral Nephrectomy

Postnephrectomy serum has been proved to enhance proliferation of mesangial cells in culture. Studies in offspring to uninephrectomized (UNx) mothers indicate that it remains active for a long period following UNx. On the other hand, postnephrectomy renal compensatory growth in vivo is known to be completed within a short period. In this study we assessed the proliferative responses of mesangial cells from single kidneys of rats which were cultured 48 h or 4 months following contralateral nephrectomy. The proliferative stimulus was provided by different postnephrectomy sera. Proliferation of both experimental cell populations was significantly greater than that of controls. Moreover, the proliferation rate of early postcontralateral nephrectomy mesangial cells was greater than those harvested 4 months after nephrectomy. We, therefore, propose that the early in vivo completion of single kidney compensatory hypertrophy, at least in part, is due to progressive blunting of renal cell responsiveness to the mitotic stimulus of the animal’s serum.

High-protein diet or unilateral nephrectomy induces a humoral factor(s) that enhances mesangial cell proliferation in culture

Background: A high-protein diet is one of the maneuvers which produce hypertrophy of kidney mass. The underlying mechanism(s) has not been elucidated. In the present study, we investigated the possibility that a humoral factor may be involved. Methods: Twenty-eight 3-week-old Charles River rats were studied. Fourteen underwent right nephrectomy and 14 sham operation. Each of these groups was divided into two equal subgroups (n = 7 in each): one maintained on a regular diet (20% protein) and the other on a high-protein diet (60% protein) for 7 days. Following this period the animals were sacrificed. Sera from the animals were added to mesangial cell cultures from kidneys of intact 3-week-old rats, and the thymidine incorporation was assessed. Results: The parameters of kidney mass indicated that the high-protein diet indeed produced kidney hypertrophy. Sera from the sham-nephrectomized animals fed a high-protein diet produced a significantly greater proliferative effect on mesangial cells in culture than sera from the respective animals on a normal-protein diet. Sera from either nephrectomized group or from the high-protein sham-operated group all had similar magnitudes of enhancement of mesangial cell proliferation. Conclusion: We conclude that the renal hypertrophy produced by a high-protein diet is mediated, at least in part, by a humoral factor(s).

Effect of Dietary Manipulations on Glomerular Filtration Rate of Mice Offspring of Nephrectomized Mothers

We have previously reported that mice, offspring to uninephrectomized mothers, have greater than normal kidneys with supernumerary glomeruli. In this study we assessed glomerular filtration rate (GFR) in 40 mice offspring of nephrectomized mothers and 40 mice offspring of sham-nephrectomized animals aged 7 weeks. Each group was divided into 4 equal subgroups according to the following dietary manipulations: regular, high protein, high salt and high protein/high salt. At the end of 1 week, GFR was determined by 51Cr EDTA. In the first group, GFR was significantly greater in each experimental subgroup compared to control. In the offspring of sham-nephrectomized mothers, only the subgroup on the combined diet had a significantly greater GFR. We conclude that the capacity to raise GFR in response to dietary manipulations is greater in offspring of nephrectomized mothers. It remains to be elucidated whether the difference results from the increased number of nephrons or from an augmented single nephron GFR reserve.

Proliferative responses of mesangial cells to growth factors during compensatory versus dietary hypertrophy.

While the bulk of renal hypertrophy induced by contralateral nephrectomy or a high-protein diet consists of tubular cell growth, there is some evidence suggesting that mesangial cells play a role in this phenomenon. Previous data suggest that this role of mesangial cells is associated with their proliferation. We, therefore, undertook this investigation to assess the proliferative responses of mesangial cells, originating from single remaining kidneys or from kidneys of rats fed a high-protein diet, to epinephrine, endothelin, arginine vasopressin, neo-synephrine, or epidermal growth factor (EGF). All agents significantly enhanced the proliferation of normal mesangial cells, though the responses to neo-synephrine and EGF were significantly lower as compared with the other growth promoters. The mitogenic effects of the first three agents on single kidney mesangial cells were significant, but blunted as compared with control cells. This blunting was not evident in the case of the latter two mitogens. A significant enhancement of proliferation of mesangial cells originating from protein-fed rats was produced by epinephrine, neo-synephrine, and EGF. These effects were statistically not different from those observed in normal mesangial cells. The proliferative response to each of the mitogens used in the study proved highly specific for each mitogen, since it was abolished by respective specific inhibitors. Mesangial cells may play a role in the activation and later in progressive inhibition of renal hypertrophy in vivo.