Ekkehart Heidbreder

Norepinephrine-Induced Acute Renal Failure: Beneficial Effects of Atrial Natriuretic Factor

The effect of the atrial natriuretic factor (ANF) on early norepinephrine-induced acute renal failure (ARF) was investigated. In anaesthetized female Sprague-Dawley rats, weighing 247 +/- 36 g, ARF of the left kidneys was induced by 40-min intrarenal arterial infusion of norepinephrine (NE; 0.75 micrograms/kg body weight). In each case the right kidney served as a control organ. Inulin clearance was used as an estimate of glomerular filtration rate (GFR). Urine volume (V), GFR and fractional excretion rates of sodium, potassium and chloride were studies in both kidneys. Immediately after NE-induced ARF one group received ANF (alpha-hANaP) and the other groups 5% glucose or isotonic saline; all infusions were administered intrarenally. In the experimental kidney NE-infusion induced anuria. ANF infusion was able to induce complete reversal of the NE effect, and GFR and diuresis improved markedly in the experimental kidney. In addition, a tremendous rise in fractional excretion rates of sodium and potassium after administration of ANF was observed. In the control kidney an additional increase of GFR and diuresis was seen. Following 5% glucose or isotonic sodium chloride infusion, no profound effects were obtained in both kidneys. The results of the present study demonstrate that ANF provides beneficial effects on the functional damage of NE-induced ARF. We conclude that the NE-antagonistic effect of ANF and the consecutive amelioration of GFR may play an important role in the recovery of impaired renal function.

Role of L-Arginine-Derived NO in Ischemic Acute Renal Failure in the Rat

Nitric oxide (NO) is involved in the regulation of renal perfusion and glomerular hemodynamics under basal conditions. We examined the hypothesis that L-arginine-derived NO modifies ischemic acute renal failure (ARF) in the rat. After a basal period ischemia was induced by clamping of both renal arteries (40 min). Thereafter, in the reperfusion period, we intravenously infused L-arginine (Arg, 300 mg/kg/60 min), or L-monomethylarginine (MeArg, 30 mg/kg/60 min), or Arg + MeArg (300 mg/kg/60 min, 30 mg/kg/60 min, resp.). Besides monitoring of urinary flow rate and arterial blood pressure, and determination of sodium excretion, glomerular filtration rate (GFR, mL/min/100 g) was estimated at the end of the infusion period and again after another 30 and 120 min by inulin clearance (fluorescence-marked inulin). In the basal period GFR showed no differences between the groups (Arg: 0.86 +/- 0.07, MeArg: 0.92 +/- 0.06, Arg + MeArg: 0.89 +/- 0.08, control: 0.84 +/- 0.07). At 180 min after the beginning of the reperfusion period, GFR was 0.13-0.02 in the control group. After administration of Arg, a remarkable and persistent increase in GFR was observed (0.28 +/- 0.03), whereas infusion of MeArg showed no significant effects (0.13 +/- 0.04). Combined administration of Arg + MeArg revealed a moderate increase of GFR (0.19 +/- 0.05), ranging between the Arg and the control group. Also, 60 and 90 min after the beginning of the reperfusion period, the highest values for GFR were obtained in the Arg group. We conclude that in this model of ischemic ARF in the rat, L-arginine-derived NO is capable of improving renal function. These data underline the regulatory role of the L-Arg-NO pathway for renal function, not only under normal conditions, but also in ARF.

Autonomic Neuropathy in Chronic Renal Insufficiency

Disturbances of peripheral and autonomic nervous system function were evaluated in 37 normal subjects, in 52 patients with non diabetic chronic renal insufficiency (25 predialysis patients, 27 dialysis patients), and in 21 patients with diabetic chronic renal failure (10 predialysis patients, 11 dialysis patients). In nondiabetic patients, the predialysis group showed abnormal test results indicating parasympathetic lesions, in dialysis patients these derangements were nearly normalized. In predialysis diabetic patients, the autonomic alterations were much more extensive, corresponding to alterations of electroneurographical findings; in addition to parasympathetic lesions, sympathetic disturbances were seen. In contrast to the nondiabetic groups, in dialysis patients a deterioration of autonomic lesions was observed. In conclusion, these data indicate that deranged autonomic functions are common in uremia; they improve in dialysis patients with nondiabetic renal failure in contrast to diabetic patients; in this group the autonomic functions worsen in dialysis patients as a function of duration of diabetes and hemodialysis.

Diminished Parathyroid Gland Responsiveness to Hypocalcemia in Diabetic Patients with Uremia

The parathyroid gland responsiveness to hypocalcemia induced by short-term calcium-free hemodialysis in patients with insulin-dependent diabetes mellitus was investigated in comparison with 10 nondiabetic uremic patients and compared with test results from the autonomic nervous system. Diabetic patients had lower C-terminal parathyroid hormone (cPTH) levels before hemodialysis than uremic control patients and showed a significantly smaller increase in cPTH during hypocalcemia. The neurological tests revealed severe disturbances of the autonomic functions in the diabetic group. In conclusion, the disturbances observed in the parathyroid secretory pattern are probably caused by gland dysfunction; it is hypothesized that the defective autonomic nervous system has an additional effect on the development of this hormonal dysfunction.

Effect of diuresis on urinary erythrocyte morphology in glomerulonephritis.

SummaryThe differentiation between glomerular and non-glomerular haematuria by phase-contrast microscopy has proved to be a useful tool in the diagnosis of glomerulonephritis. In an attempt to evaluate the effect of marked diuresis on the altered red cell morphology in patients with biopsy proven glomerulonephritis, urinary sediments were examined following water or furosemide-induced diuresis. In both diuretic states urine flow increased, urine osmolality decreased and the percentage of glomerular erythrocytes was significantly reduced in the urinary sediment. These data demonstrate that the alteration in urinary red cells in glomerulonephritis is mainly caused by tubular forces. The diagnostic significance is reduced during increased diuresis and the evaluation of urinary red cell morphology should not be performed.

Toxic Acute Renal Failure in the Rat: Effects of Diltiazem and Urodilatin on Renal Function

Beneficial effects of natriuretic peptides have been reported in different models of acute renal failure (ARF). Calcium antagonists can also improve renal function, especially in ischemic models of ARF. The aim of our study was to investigate the effects of urodilatin and diltiazem alone and in combination in uranyl nitrate-induced toxic ARF in the rat. Three hours after induction of ARF glomerular filtration rate (GFR) was clearly diminished to about 50% compared to basal values. Intravenous infusion of diltiazem and urodilatin revealed a significant increase of GFR that even continued after cessation of drug delivery. Combined administration of urodilatin and diltiazem had no additional effect, probably due to a more pronounced fall in blood pressure in this group. Besides their vasorelaxing and blood pressure lowering effects both drugs also revealed diuretic activity. In conclusion both urodilatin and diltiazem are able to elevate GFR in the early phase of toxic ARF in the rat.

Severe Hypertensive Retinopathy

In 205 patients with histologically evaluated glomerulonephritis, 69 patients with essential hypertension and 12 patients with renovascular hypertension, the retina was examined and evaluated by fundu

Reduction of Urea Generation and Muscle Protein Degradation by Adrenalectomy in Acutely Uremic Rats

The effect of adrenalectomy on the enhanced protein degradation in acute uremia was investigated. Therefore, serum urea nitrogen, urea N appearance and Nt-methylhistidine were followed in bilaterally nephrectomized rats. At 48 h after induction of uremia the animals displayed serum urea nitrogen levels of 223 +/- 9.5 mg/dl as compared to 26.0 +/- 1.0 mg/dl in sham-treated rats. This increment was significantly attenuated in acutely uremic, adrenalectomized animals (176 +/- 6.0 mg/dl). When these rats were substituted with corticosterone (5 mg/kg body weight), serum urea nitrogen readily increased to levels of acutely uremic animals with intact adrenal glands (225 +/- 6.0 mg/dl). The net generation of urea, as determined by the urea N appearance, was significantly increased during acute uremia (370 +/- 26 mg/48 h) as compared to SHAM animals (220 +/- 15 mg/48 h). This increment of urea formation could almost be completely reversed by simultaneous adrenalectomy (238 +/- 20 mg/48 h). When these rats were substituted with corticosterone, the urea N appearance rebounded to values quite comparable to acutely uremic rats with intact adrenal glands (363 +/- 30 mg/48 h). To determine whether skeletal muscle proteins might serve as a source for the enhanced protein degradation in acute uremia, plasma levels of Nt-methylhistidine were measured. Bilaterally nephrectomized rats had Nt-methylhistidine values of 9.6 +/- 1.0 micrograms/ml. In acutely uremic rats without adrenal glands, Nt-methylhistidine levels were found to be significantly decreased (6.0 +/- 0.4 micrograms/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of alcohol in clinical nephrology.

SummaryDifferent nephrological derangements are observed in severe alcoholics. Until now the direct toxicity of ethanol is only shown in the fetal alcohol syndrome with various malformations of the genitourinary tract. In the adult the kidney is often involved in the development, maintenance and counterregulation of complex electrolyte disturbances like phosphate and potassium hypoglycemia etc. The alcohol associated retention of urate, induced by hyperlactatemia and/or increasedβ-hydroxybutyrate concentration is only rarely complicated by urate nephropathy. Alcohol intoxication (acute and chronic) predisposes to rhabdomyolysis with the risk of acute renal failure. There are some hints that chronic alcoholism with myopathy increases the vulnerability of the kidney for further toxic agents. In rats glycerol induced renal failure is enhanced by alcohol pretreatment. Finally, regular alcohol consumption raises the blood pressure, which per se is a risk factor for renal damage.ZusammenfassungNephrologisch wichtige Störungen des schwereren Alkoholismus manifestieren sich auf verschiedenen Ebenen. Eine direkte Schädigung der Nieren und abführenden Harnwege ist bislang ausschließlich bei alkoholischer Embryopathie nachgewiesen. Beim Erwachsenen dominieren unspezifische und komplexe Elektrolytstörungen mit Akzentuierung im Alkohol-Entzugssyndrom. Die Niere ist nicht selten primäre Ursache verschiedener Störungen, sie trägt ferner zur — oft inadäquaten — Kompensation extrarenal entstandener Stoffwechselstörungen (z.B. Phosphatmangel, Hypoglykämie) bei. Der alkoholassoziierten Uratretention, hervorgerufen durch Hyperlaktatämie oder Erhöhung derβ-Hydroxybuttersäure, kommt — wegen meist mäßiger Ausprägung — für die Entwicklung einer hyperurikämischen Nephropathie nur geringe Bedeutung zu. Alkoholexzeß (akut oder chronisch) prädisponiert zur Rhabdomyolyse mit konsekutivem Nierenversagen. Möglicherweise ist bei schwerem Alkoholismus und Myopathie die Vulnerabilität der Nieren für andere Noxen gesteigert. Bei der Ratte wird das Glyzerin-induzierte akute Nierenversagen durch Alkoholvorbehandlung verstärkt. Alkohol begünstigt ferner bei Normotonikern und Hypertonikern einen Blutdruckanstieg, der seinerseits das Risiko einer Nierenschädigung erhöht.

Granulocyte lysosomal factors and plasma elastase in uremia: A potential factor of catabolism

SummaryIn uremic intoxication proteolytic activity in plasma and striated muscle is enhanced. To get further insights into the underlying mechanisms the lysosomal factors of polymorphonuclear (PMN) leukocytes and the plasma elastase-α1-proteinase inhibitor complex were investigated in patients with acute and chronic renal failure. Lysosomal activity was evaluated in peripheral blood smears by the lysis of erythrocytes and plasma (halo formation) around each neutrophil induced by 0.25 M NaCl borate buffer.In about half of the patients with chronic renal insufficiency on dietary treatment lysosomal activity of PMN leukocytes was reduced. The plasma concentration of elastase-α1-proteinase inhibitor complex was normal in most subjects, but increased in three patients with the highest serum creatinine levels (>13 mg/dl).In the patients with acute renal failure (ARF) of various origin (postoperatively, septicemia, pancreatitis, or dye-induced) halo formation was either reduced or absent. The plasma elastase-α1-proteinase inhibitor complex was increased in 5/6 of the patients by a factor of two to four. Also in the patients on regular hemodialysis treatment halo formation of PMN leukocytes was substantially reduced, whereas the plasma levels of elastase-α1-proteinase inhibitor complex was slightly increased.The finding of reduced lysosomal activity of PMN neutrophils in uremia may be partly due to an enhanced release of neutral proteinases into the circulation as indicated by the elevated plasma levels of elastase-α1-proteinase inhibitor complex in some patients. This release might be in part due to the effect of “uremic toxins”. In the patients on hemodialysis treatment the contact of the blood with the dialyzer (cuprophane) membrane might be an additional factor. Moreover, in the patients with acute renal failure the underlying disease (infection, shock, trauma) contributes to the release of proteinases.These disturbances may be harmful to the patient if the blood concentration or function of the most important proteinase inhibitors (α1-proteinase inhibitor,α2-macroglobulin) is reduced.