The early phase of experimental acute renal failure. III. Tubuloglomerular feedback

Summary Experiments were designed to determine whether tubuloglomerular feedback, which modifies nephron filtration rate in response to alterations in the macula densa sodium chloride concentration, was still apparent in the initiation phase of various types of acute renal failure. The response of the glomerulus to changes in the macula densa stimulus was evaluated in haeme pigment, ischaemic and nephrotoxic induced renal damage by measuring early proximal flow rates. The sodium chloride concentration at the macula densa was varied between low values and isotonicity in two ways: firstly, by interruption of flow through the loop of Henle, followed by orthograde perfusion with Ringer's solution; secondly, by retrograde perfusion of the loop of Henle with isosmotic mannitol or Ringer's solution. In all nephrons examined, filtration rate was inversely correlated to the macula densa sodium chloride concentration, except during orthograde perfusion with 10^–4 M furosemide in Ringer's solution, when, despite the high sodium chloride concentration, filtration rate remained high. It is concluded that the mechanism of tubuloglomerular feedback is viable after the onset of compromised renal function, and may, as postulated, account for the reduction in blood flow and nephron filtration rate occurring in acute renal failure.     

The early phase of experimental acute renal failure

Summary Experiments were designed to determine whether leakage of substances across the tubular epithelium, which are impermeant in the normal kidney, falsifies the measurement of glomerular filtration rate in acute renal failure. Permeability to those substances most commonly used for filtration rate determination, polyfructosan, inulin and ferrocyanide, was estimated by measuring their recoveries following perfusion through various nephron segments in haeme pigment, ischaemic and nephrotoxic models of actue renal failure. Late proximal recovery of¹⁴C ferrocyanide was only marginally decreased compared to controls, by a maximum of 6%. Distal recovery of polyfructosan,¹⁴C and³H inulin were depressed somewhat more, by a maximum of 11%. Urinary recovery of¹⁴C inulin was reduced by only 15% in kidneys showing severely restricted renal function. It is concluded that tubular leakage is not a feature of significance in the early phase of moderate acute renal failure, that ferrocyanide and inulin are reliable markers for the determination of nephron filtration rate and water reabsorption, and that the reduction in whole kidney inulin or polyfructosan clearance reflects primarily a reduction in glomerular filtration rate.     

The early phase of experimental acute renal failure

Experiments were performed to determine whether furosemide, given in doses high enough to induce a strong diuresis and to inhibit the mechanism of tubuloglomerular feedback, offers any protection from acute renal failure induced by a nephrotoxin or ischaemia. Microperfusion of the loop of Henle revealed that a tubular furosemide concentration of 5·10^–5 mol·l^–1 was necessary to fully inhibit the tubuloglomerular feedback response to a raised sodium chloride concentration at the macula densa. The infusion of furosemide systemically to achieve such concentrations in the tubule resulted in an improvement in renal function when given before or after the nephrotoxin but was without effect when given before or after ischaemia. Measurements of furosemide concentrations in the urine, however, confirmed that sufficient amounts were applied to inhibit the feedback mechanism. It is concluded from this and similar studies that furosemide is only beneficial in models of acute renal failure with an obstructive or nephrotoxic pathogenesis, in which it acts by flushing out the noxious material and not by inhibiting the mechanism of tubuloglomerular feedback.     

The early phase of experimental acute renal failure

Experiments were conducted to determine whether suppression of the renin-angiotensin-system and inhibition of the tubuloglomerular feedback response offer protection from acute renal failure, as found in chronically-salt loaded animals. The juxtaglomerular renin activity and tubuloglomerular feedback response were inhibited acutely, by saline expansion, or chronically by DOCA-treatment with saline drinking fluid or salt diet, by high salt diet alone, or by inducing two-kidney Goldblatt hypertension. The chronic pretreatment procedures depressed juxtaglomerular renin to 16, 7, 13 and 4% of control, respectively, inhibited the feedback response to 53, 37, 56, and 38% of control, respectively, but conferred no benefit in the first hours following a nephrotoxin or ischaemia. In contrast, the acute treatment procedure reduced juxtaglomerular renin activity to only 56% and lowered the feedback response to only 71%, but improved renal function after the nephrotoxin, although not after ischaemia. It is concluded that since severe restrictions of renin activity and tubuloglomerular feedback are not protective, neither is primarily involved in generating the functional restrictions early in acute renal failure. The restoration of renal function by saline expansion accompanied only a modest depression of these two systems and suggests that the beneficial effect may result more from volume expansion or diuresis than from suppression of renal renin or inhibition of tubuloglomerular feedback.     

The early phase of experimental acute renal failure

Summary Tubular obstruction in acute renal failure, postulated to cause the restricted excretory function, is suggested by raising intratubular pressure, to lower effective filtration pressure and diminish urine output. To examine the applicability of the obstruction hypothesis to the pathogenesis of experimental acute renal failure, proximal intratubular pressure and renal function were measured after renal insults of different origins and severity. Obstruction in acute renal failure kidneys should manifest itself as an increase in intratubular pressure for a least 12 h, for within this time period following ureteral occlusion, elevated pressures were found to reflect obstruction. The consistent existence of raised proximal intratubular pressure in acute renal failure kidneys could not be detected; ischaemic and nephrotoxic models were found in which no rise in intratubular pressure could be demonstrated. The oliguric nature of acute renal failure kidneys could not be verified; ischaemic and nephrotoxic models were found in which urine output was either normal or enhanced. Only for methaemoglobin induced renal failure were raised intratubular pressure, oliguria and casts concurrent. It is concluded that obstruction is not a consistent feature of experimental acute renal failure and that the obstruction hypothesis may be specifically applicable to only a few models, which include haeme pigment and folic acid induced renal failure.     

Acute renal failure — An integrative discussion of morphologic and functional findings

Summary The ultrastructural alterations at the nephron established in animal experiments, were also confirmed, by means of an electron-microscopic examination, in eight cases of human acute renal failure (ARF). Special consideration was given in this study to single cell alterations, particularly in proximal tubular cells, with emphasis being placed on alterations due to single cell damage in the region of the renal fluid compartments. The ultrastructural alterations of the tubular cells in ARF, suggest serious impairment of the cellular capacity for electrolyte transport and metabolic processes. The shunt paths between the tubular fluid compartment and the functional interstitium, arising from necrosis of the tubular cells or dissolution of the gap or tight junctions, were discussed in terms of their significance for the directional, active transport processes of the tubular cells for sodium chloride and the passive water flow. The morphologic findings were reviewed in light of recent findings on cellular membrane processes and electrolyte transport. A reinterpretation of the morphologic and functional findings in ARF is suggested. This takes into consideration single cell function and the integrity of the renal fluid compartments.This study was supported by the Deutsche Forschungsgemeinschaft (Gi 117/2-2 and Bo 216/22-2)     

Plasma renin activity in folic acid induced acute renal failure

Summary Peripheral plasma renin activity in acute renal failure induced in rats by a single i.v. injection of folic acid (250 mg/kg b. w., dissolved in 0.3 M NaHCO₃) remained normal during the first 6 hours and fell to low levels 24 hours and 4 days following the injection. Bleeding, however, induced a considerable increase of plasma renin activity on the 4th day after folate injection. There was no evidence of a participation of renin in the development of the functional and morphological renal disturbances produced by folic acid.Supported by Deutsche Forschungsgemeinschaft.     

黑木耳粗提物在大鼠急性肾功能衰竭过程中的作用

 目的： 探讨黑木耳粗提物对大鼠腹腔注射顺铂诱发急性肾功能衰竭的作用及其可能机制。方法：将健康雄性Wistar大鼠32只随机分为对照组、模型组、黑木耳组及尿毒清组,每组8只。采用RT-PCR方法检测各组大鼠肾脏组织内皮素1（ET-1） mRNA的表达水平。同时测定血尿素氮（BUN）、肌酐（Cr）的含量及血气指标。结果：模型组与尿毒清组中ET-1 mRNA的表达,BUN和Cr的含量均高于对照组和黑木耳组（P<0.05）,而黑木耳组中ET-1 mRNA的表达与对照组比较差异无统计学意义（P>0.05）。血气分析也表明,黑木耳组发生了代偿性的酸碱平衡紊乱,且血K+浓度与对照组比较差异无统计学意义（P>0.05）。结论：黑木耳粗提物在急性肾功能衰竭过程中可能通过影响血管活性物质的合成与释放,调节体内电解质和酸碱的平衡而发挥保护作用。     

Erythropoietin in thrombotic thrombocytopenic purpura and acute renal failure

Summary In this study, erythropoietin serum levels were serially determined in eight patients with acute renal failure to get a lead on the etiology of anemia in acute renal failure and to address the relationship between erythropoietin synthesis and renal excretory performance. Erythropoietin serum levels rapidly decreased after onset of acute renal failure to values of 12.8 ± 10.3 mU/ml compared to 16.8 ± 9.4 mU/ml in healthy controls. After restoration of renal function, erythropoietin levels climbed slowly in six patients (15.2 ±5.3 mU/ml), and in relation to prolonged anemia in these patients, a relative deficiency of erythropoietin could be observed. In one patient with thrombotic thrombocytopenic purpura causing acute renal failure, the decline of erythropoietin secretion was not observed, and in a phase of the disease when plasma exchange therapy was interrupted, markedly increased erythropoietin levels, up to 182 mU/ml, were detected despite the renal failure. Focusing on erythropoietin secretion in thrombotic thrombocytopenic purpura, we followed hormone synthesis in two other patients with the same disease, one of whom had mild renal insufficiency and one had normal renal function. High erythropoietin levels of up to 205 mU/ml were found in these patients, similar to the peak levels found in the patient with complete renal failure. Plasmapheresis treatment reduced erythropoietin production in all three patients with thrombotic thrombocytopenic purpura. In summary, our study indicates that in most cases of acute renal failure, erythropoietin synthesis is compromised and may contribute to the development of anemia in renal failure and aggravate the persistence of anemia after restoration of renal function. Comparing erythropoietin production in patients with acute renal failure and in those with thrombotic thrombocytopenic purpura with varying renal involvement we conclude that erythropoietin secretion is not closely linked to renal excetory performance, and that hemolysis or other stimuli in thrombotic thrombocytopenic purpura can override the decline of erythropoietin production implied by renal failure.Abbreviations ARF acute renal failure - EPO erythropoietin - TTP thrombotic thrombocytopenic purpura     

Tubular ultrastructure in acute renal failure in man: Epithelial necrosis and regeneration

Summary It is not clear whether tubular cell necrosis is present or not in acute renal failure (ARF) of ischaemic type (acute tubular necrosis). In order to get quantitative data, using precisely defined criteria for tubular cell necrosis, 25 renal biopsies from 24 patients with ARF (11 obtained in the active phase, 14 in the early recovery period) were compared with 12 control biopsies. In all 1959 proximal cells and 1603 distal cells were analysed by electron microscopy. Cellular disintegration was very rare in all groups. Shrinkage necrosis (apoptosis) was not present in the proximal tubules of the controls and was rare in ARF (1.6–2.1%). In the distal tubules of controls 2.7% of all cells showed shrinkage necrosis. The incidence in ARF was not significantly increased. Non-replacement sites in distal tubules (probablyloci where cells have recently been desquamated) were significantly increased in number (5.2%) in the active phase in ARF compared to controls and recovery. The relative number of regenerating cells was not increased.These data show that there is no widespread necrosis of tubular cells in ARF. The increased incidence in distal tubules of focal, denuded areas of the basement membrane in the active phase of ARF indicates a slightly increased desquamation of cells and/or a failure to cover such sites by adjacent cells. This process is not restricted to the brief induction phase of ARF but continues during the whole active phase.     

Role of sodium and urea in the renal concentrating mechanism inPsammomys obesus

Summary Micropunctures were performed at the tip of Henle's loops and vasa recta accessible at the extrarenal surface of the papilla in a desert rodent (Psammomys obesus) studied under mild NaCl (NaCl 4%, 0.0375 ml/min) and mild urea (urea 4%, 0.0375 ml/min) loading conditions.In NaCl loaded animals, it was confirmed that solute addition (mainly sodium) contributes in a large proportion to the concentrating process along the thin descending limb. Comparison of sodium and urea concentrations in the loops with those in vasa recta at the same level of the papilla demonstrated that 1. the transepithelial sodium gradient was compatible with a diffusion transport of this ion from the interstitium to the thin descending limb; 2. the sodium concentration higher in interstitium than in the loop fluid was not compatible with the existence of a purely passive concentrating process in inner medulla as was recently proposed [8], 3. the transepithelial urea gradient was very limited which indicates that this solute does not play an important part in the concentrating process.In urea loaded psammomys, solute addition (mainly urea) to the thin descending limb fluid was still present but water abstraction was enhanced as compared to salt loaded animals, probably on account to the higher interstitial urea concentration. It is, thus, brought to evidence that the relative contribution of water abstraction and solute addition to the concentrating process along the thin descending limb can vary in a given species as a function of the physiological state.     

Distal tubule [Na+] and juxtaglomerular apparatus renin activity in uranyl nitrate induced acute renal failure in the rat

Summary It has been previously demonstrated that single nephron filtration rate, whole kidney glomerular filtration rate and total renal blood flow decreased by 30–35% 6 h after uranyl nitrate induced acute renal failure in the rat. In order to evaluate a role of the renin-angiotensin system in the initiating phase (0–6 h) of this model of acute renal failure, determinations of plasma renin activity, superficial (S) and deep (D) juxtaglomerular apparatus (JGA) renin activity and distal nephron [Na⁺] were obtained. Plasma renin activity increased from the control value of 1.5±0.3 (S.E.M.) to 2.9±0.4 ng/ml/h (P<0.005) at 6 h. Mean renin activity in S- and D-JGA's of control rats was 6.99±0.41 and 2.67±0.21 ng/JGA/h, respectively. After uranyl nitrate, renin activity in S-JGA's increased to 13.62±0.80 ng/JGA/h (P<0.001) at 2 h and remained elevated, 12.56±0.90 and 12.75±0.87 ng/JGA/h at 4 and 6 h. D-JGA renin activity increased (P<0.05) to 7.04±0.53, 6.23±0.31 and 3.44±0.33 ng/JGA/h at 2, 4 and 6 h after uranyl nitrate. Distal tubule [Na⁺], 27 samples in 6 rats, increased from a mean control value of 53.7±1.2 mEq/l to 116.9±2.5 mEq/1, 24 samples in 6 rats (P<0.001).Prompt increases in JGA renin activity were observed in the initiating phase of acute renal failure, suggesting a role for the renin-angiotensin system in the pathophysiology of this nephrotoxic model. The association of increased JGA renin activity and increased distal [Na⁺] is consistent with a role for the tubuloglomerular feedback mechanism in the initiating phase of uranyl nitrate induced acute renal failure in the rat.     

Autosomal dominant Fanconi syndrome with early renal failure

The “idiopathic” Fanconi syndrome occurs mostly sporadically, occasionally as an autosomal recessive trait. However, few instances of autosomal dominant inheritance have been reported. We described a father and son with the Fanconi syndrome, ie, with renal glycosuria, generalized aminoaciduria, phosphaturia, metabolic acidosis, and bone disease. No other causes of the Fanconi syndrome were found. Both father and son developed end stage renal disease. Aminoaciduria in excess of that seen in renal insufficiency is shown by comparison with published data for amino acid excretion in uremia. Renal transplantation in the father has improved kidney function with no evidence of Fanconi syndrome. This family is unique in that there are no other reports of autosomal dominant Fanconi syndrome with progression to early renal failure.     

Microdissection study of the length of different tubular segments of rat superficial nephrons

Summary Anatomical investigations have been carried out on rats of two different strains. The kidney weight was shown to be linearly dependent upon body weight. Microdissections of superficial nephrons revealed that there is a significant correlation between kidney weight and the length of the proximal convolution, loop of Henle and distal convolution. The mean length of the proximal convolution in a 1 g kidney was 5.91 mm, and of the loop of Henle (pars recta of the proximal tubule included) 6.50 mm. The bend of loops of Henle belonging to superficial nephrons was always situated in the outer medulla.

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Zusammenfassung An den Nieren von Ratten zweier unterschiedlicher Stämme wurde die Länge oberflächlich gelegener Nephrone mit der Mikrodissektionsmethode bestimmt. Dabei war eine direkte Korrelation zwischen dem Nierengewicht und den einzelnen Abschnitten des Nephrons (proximales Konvolut, Henlesche Schleife, distales Konvolut) nachweisbar. Die mittlere Länge des proximalen Konvoluts betrug für ein Nierengewicht von 1 g 5,91 mm und für die Henlesche Schleife einschließlich der pars recta des proximalen Tubulus 6,5 mm. Die Umbiegungsstelle von Schleifen oberflächlich gelegener Nephrone lag immer im äußeren Nierenmark. Diese Längenvariationen in Abhängigkeit vom Nierengewicht sind auch auf das Körpergewicht beziehbar, da sich eine annähernd lineare Beziehung zwischen Nierengewicht und Bruttokörpergewicht ergab.

     

The influence of long-term infusion of the calcium antagonist diltiazem on postischemic acute renal failure in conscious dogs

Summary The influence of long-term infusion of the calcium-entry blocker diltiazem on postischemic acute renal failure was investigated in conscious dogs monitored by implanted instruments. In 18 uninephrectomized beagle dogs on a salt-rich diet, an electromagnetic flow probe and an inflatable plastic cuff were placed around the renal artery. Acute renal failure was induced by inflating the cuff for 180 min in the conscious animal. Group A (n=5, control) received an intraaortic injection of 0.9% NaCl (5 ml/day) from the 3rd day before until the 7th day after ischemia and group B (n=6, posttreatment) an intra-aortic injection of diltizem (5 µg·min^–1·kg^–1) beginning at the end of ischemia until the 7th day. Group C (n=7, pre- and posttreatment) received diltiazem from the 3rd day before until the 7th day after ischemia. In group A, renal blood flow dropped from 149±16 (preischemic) to 129±29 ml·min^–1 on the 1st day after ischemia. In contrast, renal blood flow increased on the 1st postischemic day in both treatment groups by 29±15% (group B,P 0.05) and 14±13% (group C). In the following days, there was no significant difference in renal blood flow between groups A, B and C. In group B, the reduction of the glomerular filtration rate was similar to that in the control group. In group C, the glomerular filtration rate was significantly less reduced than in group A (34±1.8 preischemically to 17±5.4 on day 1,P 0.05 and 20±4.1 ml·min^–1 on day 7,P 0.05). Plasma renin activity increased in both diltiazem groups, more pronounced so in group B (from 3.7±1.0 on day 1 to 16.2±7.9 ng ATI·ml^–1·h^–1 on day 7,P 0.05). In contrast to groups A and B, the increase in fractional sodium excretion was less pronounced in group C. Likewise, the decrease in free water-reabsorption was less marked than in groups A or B. It was apparent that diltiazem, when administered pre- and post-ischemically, preserved glomerular filtration rate and renal blood flow. When diltizem was given solely postischemically there was an improvement in renal blood flow, but no significant influence on glomerular filtration rate. We therefore conclude that mainly tubular factors, in addition to the attenuation of postischemic vasoconstriction, are involved in the protective effect of diltiazem on postischemic acute renal failure in conscious dogs.Abbreviations ARF acute renal failure - C_osmol clearance of osmolarity - E_Na urinary excretion rate of sodium - FE_Na fractional excretion rate of sodium - GFR glomerular filtration rate - HR heart rate - NE norepinephrine - PAM mean arterial blood pressure - PRA plasma renin activity - RBF renal blood flow - RVR renal vascular resistance - T_H2_O free water reabsorption - V_U urine volume     

维拉帕米对缺血性急性肾功能衰竭的保护作用

目的：观察维拉帕米对缺血性急性肾功能衰竭是否具有保护作用。方法：以维拉帕米灌注切除右肾的成年雄性ＳＤ大鼠之左肾，５ｍｉｎ后夹闭左肾动脉４５ｍｉｎ，对照组则灌注生理盐水。再灌注２４ｈ后，观察左肾血流量（ＬＲＢＦ），尿量（ＵＶ），血尿素氮（ＢＵＮ），血肌酐，肌酐清除率（ＣＣｒ），左／右肾重量之比，肾脏组织学评分ＨＳＫ，尿中Ｎ＿乙酰氨基葡萄糖苷酶（ＮＡＧ）和丙氨酸氨基肽酶（ＡＡＰ）活性的变化。结果：与对     

Dietary protein restriction in chronic renal failure: An update

Summary In recent years dietary protein restriction (DPR) to slow down the progression rate of chronic renal disease has been a major field in nephrological science. In this update a brief historical overview is given, as well as a critical review regarding the now available data from clinical trials. Furthermore, the theoretical backgrounds of DPR are discussed. It is concluded that DPR has profound effects on the kidney. In certain diseases, especially primary glomerular disease, the beneficial effect seems proven. However, many questions remain to be answered, e.g. how to apply reliable statistics in chronic renal failure, how to obtain and monitor patient compliance, and the definition of the exact target group since the diet has a selective effect.Most of these questions will be answered in the coming years when data becomes available from large scale multicenter trials.Awaiting these results, proposals for the treatment with diet are made, based on the facts that are now to our knowledge.     

Expression of epidermal growth factor and its receptor in rabbits with ischaemic acute renal failure

Urinary immunoreactive epidermal growth factor (EGF) levels decrease, and renal immunoreactive EGF levels increase in rats with ischaemic acute renal failure (ARF). We investigated the immunohistochemical localization of EGF and EGF receptor in rabbits with ischaemic ARF to clarify the significance of renal EGF. Male New Zealand White rabbits underwent right nephrectomy prior to a 60 min renal artery clamp. At 3, 6, 24, 48, 72 and 96 h after ischaemia, serum urea nitrogen and serum creatinine were determined. Guinea pig anti-rabbit EGF antibody and monoclonal anti-EGF receptor antibody were used for the primary incubation. EGF was immunolocalized to the ascending limb of Henle and the distal convoluted tubule in the normal right kidneys. However, in the post ischaemic left kidneys at 6, 24, 48 and 72 h, immunoreactivity of EGF was associated with proximal tubules. In the normal kidneys, antibody to EGF receptor reacted with distal tubules and collecting ducts. In the ischaemic kidneys, EGF receptor was localized in the basolateral membrane in the proximal tubules. The expression of EGF and EGF receptor in renal tubules may play an important role in repair following ischaemic renal damage.     

Tubular ultrastructure in acute renal failure: Alterations of cellular surfaces (Brush-border and basolateral infoldings)

Summary Using a blind, semiquantitative technique, the degree of reduction of proximal tubular brush border (BB) and proximal and distal basolateral infoldings (BI) were measured in 25 renal biopsies from patients with acute renal failure (ARF) of ischaemic type. For comparison 12 biopsies from patients without ARF were studied, 6 were normal controls, six were from patients with minor change disease and slight glomerulonephritis. The mean scores for reduction of BB as well as proximal and distal BI were strongly increased in ARF compared to controls and the differences were highly significant. Some of the biopsies were taken during recovery and there was a significant negative correlation between the individual scores for reduction of BB and BI and simultaneous renal function. The disappearance of BB microvilli was correlated to tubular dilatation, but it could not be explained exclusively by stretching of the luminal surface due to dilatation. There was no correlation between reduction of BI and tubular dilatation.The data indicate a disturbance of cell membrane turnover in the active phase of ARF, possibly due to decreased synthesis, and they are consistent with a pathogenetic hypothesis implicating a decreased proximal Na⁺ resorption and consequently a pre-glomerular vasoconstriction.