Single Nephron Filtration Rate Research Articles

Reduced nephron endowment in the neonates of Indigenous Australian peoples.

Rates of chronic kidney disease (CKD) among Indigenous groups in Australia exceed non-Indigenous rates eight-fold. Using kidney volume as a surrogate for nephron number, we carried out a study to determine if Indigenous neonates have a smaller kidney volume (and thus a reduced nephron number) from birth compared with non-Indigenous neonates. We recruited term and preterm neonates (<32 weeks) at a tertiary care neonatal unit over a 12 months period. Preterm neonates were assessed (renal sonography and renal function measurement) at 32 weeks corrected age (CA) and again at 38 weeks CA when blood pressure was also measured. All term neonates were assessed in the first post-natal week, including renal sonography, renal function and blood pressure measurement. The primary outcome measured was total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) was a secondary outcome. Data was available for 44 preterm (11 Indigenous) and 39 term (13 Indigenous) neonates. TKV of Indigenous neonates was significantly lower at 32 weeks [12.0 (2.0) v. 15.4 (5.1) ml; P=0.03] and 38 weeks CA [18.6 (4.0) v. 22.6 (5.9) ml; P=0.04] respectively. Term Indigenous neonates also had smaller kidney volumes compared with non-Indigenous neonates. Despite a smaller kidney volume (and reduced nephron number), Indigenous neonates did not have a significantly lower eGFR. Indigenous neonates achieve similar eGFRs to Non-Indigenous neonates, presumably through a higher single nephron filtration rate. This places Indigenous neonates at a greater risk of long-term kidney damage later in life.

Significant water absorption goes paracellular in kidney proximal tubules

it had been a fundamental dispute for several decades, whether water passes epithelia such as kidney proximal tubule or small intestine along the transcellular, paracellular, or both pathways. By discovery of the transmembranal aquaporin water channels (AQP), the molecular basis of the

Direct micropuncture evidence that matrix extracellular phosphoglycoprotein inhibits proximal tubular phosphate reabsorption

Matrix extracellular phosphoglycoprotein (MEPE) is a putative phosphatonin that we have shown in previous studies to be phosphaturic in rats. Its site of action in the nephron remains to be confirmed. We made micropuncture collections from late proximal convoluted tubules in anaesthetized rats to assess directly the effect of MEPE on phosphate reabsorption in the proximal tubule. MEPE had no effect on glomerular filtration rate or single-nephron filtration rate, but it increased phosphate excretion significantly. In animals infused with vehicle alone (time controls), no significant change was seen in either the proximal tubular fluid:plasma phosphate concentration ratio (TF/P(Pi)) or the fraction of filtered phosphate reaching the late proximal convoluted tubule (FD(Pi)); whereas in rats infused with MEPE, TF/P(Pi) increased from 0.49 ± 0.07 to 0.68 ± 0.04 (n = 22; P = 0.01) and FD(Pi) increased from 0.20 ± 0.03 to 0.33 ± 0.03 (n = 22; P < 0.01). The results confirm the phosphaturic effect of MEPE and indicate that much, if not all, of this effect is a result of reduced reabsorption of phosphate in the proximal convoluted tubule. This is consistent with the recent finding of MEPE-induced reductions in apically located NaPT2a in the proximal tubule.

A computational model for emergent dynamics in the kidney

In this paper, concepts from network automata are adapted and extended to model complex biological systems. Specifically, systems of nephrons, the operational units of the kidney, are modelled and the dynamics of such systems are explored. Nephron behaviour can fluctuate widely and, under certain conditions, become chaotic. However, the behaviour of the whole kidney remains remarkably stable and blood solute levels are maintained under a wide range of conditions even when many nephrons are damaged or lost. A network model is used to investigate the stability of systems of nephrons and interactions between nephrons. More sophisticated dynamics are explored including the observed oscillations in single nephron filtration rates and the development of stable ionic and osmotic gradients in the inner medulla which contribute to the countercurrent exchange mechanism. We have used the model to explore the effects of changes in input parameters including hydrostatic and osmotic pressures and concentrations of ions, such as sodium and chloride. The intrinsic nephron control, tubuloglomerular feedback, is included and the effects of coupling between nephrons are explored in two-, eight- and 72-nephron models.

Anomalous Renal Effects of Tin Protoporphyrin in a Murine Model of Sickle Cell Disease

In human and murine models of sickle cell disease (SCD), heme oxygenase-1 (HO-1) is induced in the kidney, an organ commonly involved in SCD. The present study assessed the role of HO-1 by using a competitive inhibitor of HO activity, tin protoporphyrin (SnPP), in protocols affording a composite, clinically relevant analysis of the kidney in SCD under unstressed and stressed conditions. Whereas short-term administration of SnPP exerted comparable renal hemodynamic effects in wild-type and sickle mice, chronic administration of SnPP exerted divergent effects: SnPP provoked tubulointerstitial inflammation and up-regulation of injury-related genes in wild-type mice, whereas in sickle mice SnPP reduced expression of injury-related genes and vascular congestion without provoking tubulointerstitial inflammation. SnPP also protected against the heightened sensitivity to renal ischemia observed in sickle mice, preventing ischemia-induced worsening of renal injury in sickle mice above that observed in wild-type mice. Effective and comparable inhibition of HO activity by SnPP in wild-type and sickle mice was confirmed. These findings suggest that induction of HO-1, at least as assessed by this approach, may contribute to renal injury in this murine model of SCD and uncover an experimental maneuver that protects the kidney in murine SCD.

Aprotinin uptake in the proximal tubules in the rat kidney. II. Uptake site relative to glomerulus

Glomerular filtration rates in whole kidney and in outer, middle and inner cortical zones have previously been estimated by measuring the amount of iodinated Aprotinin, filtered and taken up in the first two thirds of the proximal convoluted tubules, in part positioned more superficial than the parent glomerulus. Thus, an appreciable amount of the absorbed Aprotinin may be located superficial to its filtration site and lead to an underestimate of glomerular filtration in deep cortical layers. Therefore, in this study we have measured the distance from the glomerulus to the center of proximal convoluted tubular ball and the site of Aprotinin uptake. Measurements were made on photos of Microfil-injected tubules and on camera lucida drawings of tubular transections from autoradiographs of nephrons containing both Microfil and iodinated Aprotinin. Both techniques showed that the center of the tubular ball was localized more superficial in all cortical layers. The average distance, in percent of cortical thickness, from all proximal convoluted tubular transections to the parent glomerulus was 9% in deep and 13% in middle and superficial cortex. Corresponding distances for tubular transections containing Aprotinin were 7 and 12%. Grain density in five reconstructed proximal convoluted tubules showed a continuous and exponential fall of Aprotinin along the uptake segment. The results may be used to estimate single nephron filtration rate from Aprotinin uptake and glomerular density in outer, middle, and inner cortex.

Failure of loop diuretics to improve the long term outcome of ischaemic damage in rat kidneys.

The effects of furosemide administered at the onset of postischaemic renal failure were investigated in Sprague-Dawley rats one month after exposing the left kidney to 45 min of renal ischemia. In the experimental group, 13 mg furosemide was given intravenously both before and a few minutes after induction of the ischaemia and then, by an osmotic pump, in a daily dose of 2-3 mg for the following 7 days. The animals of the control group were treated similarly but with saline alone. After one month, the glomerular filtration rate (GFR) in the damaged left kidneys of the furosemide-treated rats was 0.5 ± 0.08 ml/min, which was not significantly different from that in the untreated control rats, of 0.8 ± 0.14 ml/min. As expected, the right intact kidneys responded with an increase in GFR to about 2 ml/min. Further effects that were similar in the damaged kidneys of the furosemide-treated and untreated animals were a decrease in potassium secretion and in the urine concentration ability; the urine osmolality in the diseased left kidneys was thus 1000-1500 mOsm/kg, as against over 2000 mOsm/kg in the right, intact kidneys. The function of the individual nephrons in terms of such variables as single nephron filtration rate, fractional fluid reabsorption and tubular and vascular hydrostatic pressures remained unaltered, however. Hence, the severe reduction in whole kidney GFR appeared to be due to a loss of nephrons rather than to an equal decrease in each individual nephron. It is also clear that furosemide did not improve the long-term outcome of acute postischaemic renal failure.

Systemic and intratubular effects of cyclosporin-A and tacrolimus on the rat kidney

Cyclosporin-A and tacrolimus can cause hypertension and renal failure through endothelin receptors. The importance of tubular function was never investigated. The aim of this study was to compare the effects of intratubular injection of cyclosporin-A and tacrolimus with effects observed during systemic infusion. In 20 rats, either cyclosporin-A or tacrolimus was infused, 30 and 1 mg/kg i.v., respectively, in 30 min. Before and after administration, glomerular filtration rate, single nephron filtration rate, proximal and distal absolute reabsorption and percent reabsorption were measured by clearance and micropuncture techniques. In 22 other rats, single nephron filtration rate, absolute reabsorption, percent reabsorption, were measured at the last proximal and early distal tubules before and during intraluminal microinjection of either cyclosporin-A or tacrolimus. During cyclosporin-A and tacrolimus i.v. infusion, glomerular filtration rate fell from 536±43 to 448±37 μl/min ( P<0.026) and from 408±33 to 284±81 μl/min ( P<0.02), single nephron filtration rate from 26.4±2.0 to 20.6±1.9 ( P<0.002) and from 21.6±2.2 to 17.4±2.0 nl/min, respectively ( P<0.02). The last proximal absolute reabsorption remained unchanged with cyclosporin-A (16.8±2.2 vs. 15.1±1.7 nl/min, P>0.444), but was slightly reduced by tacrolimus (14.4±1.7 vs. 11.3±1.7 nl/min, P<0.05). During microinjection, single nephron filtration rate was increased by cyclosporin-A (20±1 vs. 63±8 nl/min, P<0.0001), and tacrolimus (from 17±2 to 49±9 nl/min, P<0.0001), and so was reabsorption, independent of the sampling site. Cyclosporin-A and tacrolimus, indeed, raise single nephron filtration rate directly when injected intraluminally. Since this effect occurs in the direction opposite to that recorded during systemic infusion, it must be mediated through different pathways. The i.v. infusion of cyclosporin-A, but not tacrolimus, impairs glomerulo-tubular balance.

Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit.

It has been suggested that a reduced number of nephrons may predispose to systemic hypertension and glomerular injury. Compensatory hemodynamic changes, due to a low number of glomeruli, might be responsible for glomerular functional and structural changes. It is difficult to evaluate this hypothesis in humans because of limitations in estimating the number of nephrons in the living kidney. The aim of the present study was to estimate nephron number, single glomerular hemodynamics, and glomerular volume in male and female MWF rats, a strain that spontaneously develops systemic hypertension, proteinuria, and glomerulosclerosis. Male and female Wistar rats were used as controls. At 12 to 14 wk of age, male MWF rats developed proteinuria, whereas female MWF and Wistar rats showed normal urinary protein excretion rate. Glomerular number was significantly reduced in male and female MWF rats (13,690+/-1,489 and 12,855+/-1,781 gl/ kidney, respectively) compared with Wistar rats (26,955+/-2,171 and 27,166+/-1,754 gl/kidney, respectively). The mean number of nephrons per unit of body weight was also lower in MWF males (88+/-10) compared with MWF females (139+/-20) and compared with male and female Wistar animals (142+/-14 and 221+/-22 gl/g body wt). Whole-kidney hemodynamic parameters and the number of nephrons were used to calculate single-nephron filtration rate and plasma flow. Both measures were markedly elevated in male MWF rats relative to values obtained in the other three groups. Similarly, glomerular volume was significantly greater in MWF males than in other animals. These results suggest that an inborn deficit of nephrons may be responsible for spontaneous development of later-in-life hypertension and renal dysfunction. The data also indicate the need to investigate the role of this potential pathogenetic factor for human hypertension and kidney disease in humans.

Microinjection studies on the effect of furosemide on the rat nephron.

The tubular site of furosemide (F) action was studied by the technique of diuretic microinjection (MIJ) into proximal tubules of the rat nephron. F was injected into the last proximal superficial loop of 51 proximal tubules, at the concentration of 3 x 10(-4) mol/l in an infusate that contained 14C-inulin. Collections were performed at the early distal tubule before and after MIJ. Single nephron filtration rate (SNGFR) remained unchanged, while the percent of filtered volume reabsorbed up to the site of collection was 85+/-2 before, 79+/-2% after MIJ, p < 0.005. The calculated concentration of F in the collected distal tubular fluid during the post-MIJ measurements averaged 3 x 10(-5) mol/l. This experiment was repeated by injecting F into the early proximal convolutions of 43 nephrons, while the collections were performed at the last proximal segments. In these studies of proximal volume absorption, SNGFR was 34+/-3 before, 35+/-4 nl/min after F (p > 0.6). The respective percent reabsorptions were 70+/-3 and 73+/-3% (p +/- 0.3). In order to determine whether the technique per se was suitable to detect changes in reabsorption, the proximal MIJ study was repeated by using the carbonic anhydrase inhibitor dichlorphenamide 3 x 10(-5) mol/l in the microinjectate: while SNGFR remained unchanged, percent reabsorption fell from 63+/-5 to 45+/-7% during injection of the diuretic, p < 0.03. We conclude that the technique is adequate to examine the effects of drugs, and that F does not reduce proximal volume absorption at concentrations of 3 x 10(-5) mol/l. The loop diuretic decreases distal volume absorption by abolishing the osmotic gradient between blood and tubular fluid along the early distal convoluted tubule.

Effect of intratubular application of angiotensin 1-7 on nephron function.

Cleavage of the C-terminal tripeptide of angiotensin I (Ang I) by neutral endopeptidase 24.11 releases angiotensin 1-7 (Ang 1-7). Because Ang I and neutral endopeptidase 24.11 are present in proximal tubular fluid and brush border, respectively, Ang 1-7 could be released into proximal tubular fluid to affect nephron function. Therefore, we studied the effect of intratubular Ang 1-7 (10(-12) to 10(-8) M) on nephron function employing in vivo renal micropuncture in inactin-anesthetized Munich-Wistar-Frömter rats. We observed that: (i) Intratubular application of Ang 1-7 for 3, 15, or 30 min did not affect reabsorption in the microperfused proximal convoluted tubule determined as net fluid reabsorption. (ii) During perfusion of Henle's loop for 15 min with artificial tubular fluid (time control), we observed a decline in fluid, potassium and sodium reabsorption by 20, 18 and 5%, respectively. A similar decline in reabsorption was seen with intratubular application of Ang 1-7 in a concentration of 10(-12) or 10(-10) M. In contrast, intratubular application of Ang 1-7 in a concentration of 10(-8) M increased fluid, potassium and sodium reabsorption in that nephron segment by 11, 9 and 3%, respectively. The latter response was completely abolished by AT1 angiotensin II receptor antagonist losartan (10[-6] M). (iii) Intratubular application of Ang 1-7 did not affect net sodium, potassium, or fluid reabsorption in the distal tubule. (iv) TGF response assessed by measuring proximal tubular stop-flow pressure or single nephron filtration rate during orthograde open-loop perfusion of Henle's loop was not significantly altered by intratubular application of Ang 1-7. These findings show that intratubular application of Ang 1-7 in concentrations which possibly cover the physiological range does not significantly alter (i) tubular reabsorption in proximal convoluted or distal tubule, or (ii) TGF response. Intratubular Ang 1-7 at a concentration of 10(-8) M appears to increase reabsorption in Henle's loop by an AT1 angiotensin II receptor-mediated mechanism, the physiological relevance of which remains to be established.

Antidiuretic action of vasoactive endothelins in the in situ perfused rainbow trout kidney

The present studies examined, for the first time, the renal actions of endothelin-1 (ET-1) and Sarafotoxin S6b (SRTX-6b) (an endothelin-like peptide from snake venom) at 10-11 M and 10-9 M, using the in situ perfused kidney of the rainbow trout, Oncorhynchus mykiss. In further studies ET-1 (10-9 M) was accompanied by Captopril (5 × 10-4 M) to inhibit angiotensin II formation and determine whether the newly-identified intrarenal renin-angiotensin system (RAS) in the trout kidney was involved in ET-1's actions. These studies demonstrated that ET-1 and SRTX-S6b constrict the trout trunk vasculature, increasing vascular resistance and decreasing perfusate flow rates. Captopril did not affect this response and therefore angiotensin II is not implicated in the vascular responses. Direct action of endothelins on vascular receptors is indicated which, in vivo, is likely to be involved in regulation of renal vascular tone. Both ET-1 and SRTX-6b induced immediate decreases in glomerular filtration rates (GFR) reaching 30% and 34% decrease with 10-11 M ET-1 and SRTX-6b respectively and 50% and 57% decrease with 10-9 M ET-1 and SRTX-6b respectively. Urine flow rates decreased to a slightly lesser extent because of decreased tubular reabsorption of water; relative free water clearances increased from approximately 17% to 21% while urine/plasma inulin concentration ratios decreased slightly. This significant depressed urine osmolarity. Captopril completely blocked the effects of endothelins on tubular water reabsorption suggesting intrarenal RAS involvement in this action, although a kinin-mediated effect cannot, at this stage, be excluded. The glomerular antidiuretic action of ET-1 and SRTX-6b partially reflected a decreased population of filtering nephrons (41% filtering in control kidneys, 32–36% filtering in the presence of 10-11 M M ET-1/SRTX-6b, 31–32% filtering in the presence of 10-9 M ET-1/SRTX-6b). In addition, 25–40% reductions of single nephron filtration rates were estimated. Glomerular actions of endothelins were partially inhibited by Captopril, suggesting either that renal endothelins have both direct renal actions and secondary effects through activation of the renal RAS, or that kinins can modulate the renal actions of endothelins.

The effect of intraluminal flow rate on glomerulotubular balance in the proximal tubule of the rat kidney.

To differentiate intraluminal from peritubular factors in mediating the glomerulotubular balance, single nephron filtration rate (SNGFR) and reabsorption were measured by total collection from the last proximal segment before, and during, externally applied mechanical compression of an early proximal convolution of ninety-three rat nephrons. SNGFR fell from 55.6 +/- 2.3 nl min-1 during control conditions to 34.5 +/- 2.0 nl min-1 during compression (P < 0.0001) in sixty tubules ('responders'). Absolute reabsorption fell from 41.8 +/- 2.0 to 28.4 +/- 1.8 nl min-1 (P < 0.0001), while percentage reabsorption rose from 75 +/- 2 to 82 +/- 2% (P < 0.0001). These effects were reversible and independent of whether the compression was applied before or after the control collection. In thirty-three proximal tubules the compression procedure was not successful ('non-responders'), SNGFR remaining unchanged (36.1 +/- 2.9 vs. 36.9 +/- 2.9 nl min-1, P > 0.3). Absolute and percentage reabsorptions rose slightly, albeit significantly, from 26.1 +/- 2.1 to 30.7 +/- 2.4 nl min-1 (P < 0.0001) and from 75 +/- 3 to 85 +/- 2% (P < 0.0001). Thus, the response of reabsorption to changes in intraluminal flow is composed of two different adaptive mechanisms. The slowing of flow is present in both sets of tubules and causes a slight increase in resorption; the change in filtration per se is present only in the first set of responders, and causes an SNGFR-dependent consensual change in resorption.

Progression of renal disease and renal hypertrophy.

Growth of residual renal tissue in response to loss of other renal tissue is usually termed compensatory hypertrophy. This process occurs not only when unilateral nephrectomy is performed with the contralateral organ increasing its mass but also when undamaged nephrons within a kidney undergo enlargement as other nephron units in that same kidney are destroyed either by natural disease or experimentally (34, 41, 49, 51). Allhough compensatory hypertro­ phy is a standard term for this phenomenon, it deserves some further clarifi­ cation. Hyperplasia (often experimentally defined as an increase in DNA content) as well as hypertrophy (often defined as an increase of proteinIDNA ratio) underlie compensatory hypertrophy. Although the compensatory nature of the response seems obvious, the exact physiologic functions of the kidney targeted for compensation are undefined. Furthermore, it is possible that com­ pensatory growth and associated functional alterations, despite mitigating the fall in renal function for the organism, have long-term deleterious conse­ quences for these residual nephrons. Along with structural enlargement, the residual nephrons take on a large number of functional adaptations, most notably, an increase in single-nephron filtration rate and net reabsorption of solutes and water (32). Other metabolic processes presumably associated with heightened transport, such as oxygen consumption, increase in remaining nephrons as do synthetic pathways such as ammoniagenesis (32, 40, 56). Undoubtedly, structural growth and functional

Proximal tubular function in transgenic mice overexpressing atrial natriuretic factor

A transgenic mouse model in which atrial natriuretic factor (ANF) expression is targeted to the liver was used to study intrarenal adjustments to the chronically elevated hormone level. Such animals, designated TTR-ANF, are characterized by reduced arterial blood pressure but similar sodium excretion compared with nontransgenic siblings. Proximal tubular micropuncture gave the following results: single-nephron filtration rate = 12.7 +/- 1.1 vs. 15.6 +/- 1.9 nL/min (TTR-ANF versus nontransgenic, ns); end-proximal tubular fluid/plasma concentration ratio of inulin = 1.93 +/- 0.09 vs. 1.97 +/- 0.15 (ns); fractional reabsorption of sodium = 45.5 +/- 2.8 vs. 46.0 +/- 3.8% (ns); fractional reabsorption of chloride = 33.6 +/- 3.3 vs. 32.4 +/- 4.1% (ns). These data indicate that life-long elevation of plasma ANF concentration was not associated with significant alteration in single-nephron filtration rate and proximal tubular function. We conclude that compensatory antinatriuretic mechanisms, localized downstream from the proximal tubule, can prevent ANF natriuresis.

Renal and single-nephron function is comparable in thiobutabarbitone- and thiopentone-anaesthetised rats.

The thiobutabarbitone(TB, Inactin)-anaesthetised rat is an extremely widely used preparation for the study of renal function at the whole-organ and nephron levels. The recent withdrawal of TB from the market has made it essential to find an anaesthetic producing experimental conditions as similar as possible to TB to allow comparison of past and future data. Blood gas analysis, clearance and micropuncture studies were therefore performed in rats anaesthetised with TB or the related thiobarbiturate thiopentone (TP) (both 100 mg/kg body weight) to establish whether the latter meets this requirement. Both barbiturates caused similar transient respiratory depression and acidosis. Mean values (TP versus TB) over the total 8-h observation period for glomerular filtration rate (0.94 versus 1.05 ml/min), urine flow (3.8 versus 4.4 microliters/min) and K+ excretion (0.98 versus 1.18 mumol/min) were slightly lower (P < 0.05) in TP rats, whereas renal blood flow (6.26 versus 6.24 ml/min), filtration fraction (0.31 versus 0.34) and Na+ excretion (0.11 versus 0.098 mumol/min) did not differ. The single-nephron filtration rate (SNGFR) (42.1 versus 41.1 nl/min) and fractional reabsorption (42% versus 47%), both measured in the proximal tubule, did not differ, although in the TP group SNGFR rose with time (4.4%/h) whereas the fractional reabsorption did not change significantly; in the TB group SNGFR was constant but fractional reabsorption declined with time (1.5%/h). Fractional reabsorption up to the distal convoluted tubule declined with time, this was more pronounced in the TP group. SNGFR measured at this site did not differ between TP and TB (30.3 versus 30.1 nl/min) but increased with time with TP (2.7%/h).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma vasopressin and cortical nephron function in aging rats

The role of vasopressin and Henle's loop transport in age-related polyuria and decrease in urine osmolality was investigated in female WAG/Rij rats free of kidney disease. In these animals, urine osmolality dropped from 2000 mosmol/kg H 2O to 1000–1200 mosmol/kg H 2O between 10 and 30 months, and urinary volume increased in proportion. Vasopressin concentration measured in plasma withdrawn from conscious, unrestrained, chronically catheterized rats was not significantly different in 10, 20 and 30-month-old animals (mean values 2.5 ± 0.7, 2.2 ± 0.2 and 2.0 ± 0.3 pg/ml ( n = 8), respectively). This suggest an impaired responsiveness of old kidney to antidiuretic hormone. The possible involvement of Henle's loop in this defect was studied by micropuncture. Paired collections of tubular fluid were done in the early distal and late proximal convolutions of the same cortical nephrons. Single nephron filtration rates did not significantly differ with age. Tubular fluid osmolalities in the early distal convolution were 165 ± 13, 178 ± 9 and 160 ± 11 ( n = 14) mosmol/kg H 2O in 10-, 20- and 30-month-old rats, indicating similar diluting capacity of the cortical thick ascending limb. The amount of sodium transported from lumen to peritubular space by Henle's loop was also unchanged with age as were water, calcium, magnesium and potassium reabsorptions. These data indicate that the age-related decrease in urine osmolality is not related to either a significant reduced vasopressen plasma concentration or an increa single glomerular sed filtration rate or a reduced transport capacity of Henle's loop of the cortical nephron. Rather they suggest an impaired response to vasopressin of other segments of the nephron that is, the medullary thick ascending limb of Henle's loop and/or the collecting duct.

Serial Glomerular and Tubular Dynamics in Thyroidectomized Rats With Remnant Kidneys

Serial measurements were performed in Munich-Wistar rats with five-sixths nephrectomy that had undergone prior selective thyroidectomy (Tx group) or thyroidectomy with thyroxine replacement (TxT4 group) to determine the effects of Tx on glomerular and tubular dynamics in relation to Tx attenuation of renal failure progression. At 1 week, inulin clearance rates (CIn) in TxT4 and Tx rats were 0.367 ± 0.171 and 0.120 ± 0.036 mL/min, respectively, different at P < 0.01. Corresponding single-nephron filtration rate (SNGFR), glomerular plasma flow (QA), glomerular transcapillary hydraulic pressure (ΔP), and proximal tubular reabsorption (Jv) were all reduced in Tx compared with TxT4 rats (P < 0.01). Protein excretion (UPROT) was 151 ± 40 in TxT4 rats, and 9 ± 5 mg/d in Tx animals. Glomerular mesangial matrix expansion and focal tubulointerstitial changes were more frequent in TxT4 than Tx rats. By 4 weeks, CIn, SNGFR, QA, glomerular ultrafiltration coefficient (K1) and Jv were similar in Tx and TxT4. Only glomerular capillary pressure (PGC) remained lower in Tx rats (35 ± 3 v 50 ± 3 mm Hg in TxT4, P < 0.001). UPROT was 161 ± 24 in TxT4 and 17 ± 12 mg/d in Tx rats. While 7% ± 4% of glomeruli showed focal sclerosis in TxT4 rats, there was none in the Tx group. Maximal glomerular planar area increased between 1 and 4 weeks in the TxT4 group, but not in the Tx group. However, this measurement was not significantly different between TxT4 and Tx glomeruli at 1 or 4 weeks. Minimal focal tubulointerstitial changes were found in TxT4, but these were not progressive from those observed at 1 week. The reduced PGC at 1 week was the result of a disproportionately greater increase in afferent (RA) than efferent arteriolar resistance (RE) in Tx rats (P < 0.025); however, at 4 weeks, both RA and RE had decreased to values identical to those in TxT4 animals and the lower PGC in Tx rats was the result of a reduced mean arterial pressure. In conclusion, a reduced PGC was the sole functional correlate of decreased proteinuria and glomerulosclerosis afforded by Tx in this partial nephrectomy model. Suppression of either nephrectomy-related hypertrophy or tubulointerstitial injury by Tx could not be excluded as at least partially protective factors.

Single-nephron filtration rate and proximal reabsorption in aging rats

Age-related changes in the function of individual nephrons were investigated by micropuncture experiments measuring single-nephron filtration rates (SNGFR) and proximal reabsorptions in 10-, 20-, and 30-mo-old rats. The animals were female WAG/Rij rats with low incidence of chronic progressive nephropathy, no loss of nephrons, and renal hypertrophy of both kidneys in the oldest animals. Mean SNGFR values per gram kidney weight were 41.4 +/- 1.1, 37.1 +/- 1.5, and 32.2 +/- 1.1 nl.min-1.g kidney wt-1 (n = 41) in the 10-, 20-, and 30-mo-old animals, respectively. This age-related decrease in filtration was no longer apparent when SNGFR values were expressed per nephron (means 24.3 +/- 0.7, 23.7 +/- 0.9, and 24.4 +/- 0.9 nl/min. Individual filtered loads of sodium, potassium, calcium, and magnesium and their absolute reabsorption by the proximal tubule were not different in the three age groups; however, absolute and fractional reabsorptions of phosphate decreased significantly in the 30-mo-old rats. These results indicate that, with the exception of phosphate, individual filtrations and proximal reabsorptions are well maintained in aging rats free of disease. This may be related to the observed renal hypertrophy.

Adverse effects of growth in the glomerular microcirculation

Compensatory renal and glomerular hypertrophy accompanies the many functional and structural changes associated with a reduction in functional renal mass. Increased levels of dietary sodium supplementation ranging from deficient to 2.3% Na+ (38-fold above the minimal daily requirement for the rat) in rats with subtotal nephrectomy were associated with a progressive rise in proteinuria and renal size without any significant change in arterial pressure. To further define these relationships, groups of rats on two intermediate levels of sodium intake were studied in detail. Single-nephron filtration rate and glomerular capillary pressure were similar in subtotally nephrectomized rats fed the 0.06 and 0.46% Na+ diets. Both the volume fraction and absolute volume of periodic acid-Schiff staining mesangial lesions in the glomerulus were greater in the 0.46% Na+ group. Glomerular volume and the mean glomerular capillary radius was larger in the 0.46% Na+ group. Increased glomerular tension, as predicted by the Laplace law, may represent a final common pathway by which compensatory growth and/or glomerular hypertension result in glomerular injury.