INULIN, 57Co-LABELLED VITAMIN B12 AND ENDOGENOUS CREATININE CLEARANCES IN THE MEASUREMENT OF GLOMERULAR FILTRATION RATE IN MAN

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The long-term effect of propranolol therapy on renal function.

It has been reported that the intravenous administration of beta blocking agents reduces renal plasma flow and glomerular filtration rate from 10 to 20 per cent. In contrast, little is known about the chronic effects of these agents on renal function when given orally. To assess this question, eight normal subjects underwent timed true and regular creatinine clearances (C_cr), inulin clearances (C_in) and para-amino hippurate clearances (C_PAH) after sequential weeks of therapy with 0, 80, 160, 240 and 320 mg of propranolol/day. Weight, blood pressure and heart rate were measured on each visit. Compliance was tested and confirmed by monitoring plasma propranolol concentrations.The results indicate that the use of propranolol in normal man significantly reduces C_in (27 per cent) and C_PAH (26 per cent). Such decreases are probably, in part, due to reductions in cardiac output, as suggested by reductions in systolic blood pressure and heart rate. Furthermore, there was a sustained reduction in C_in following the withdrawal of propranolol therapy. C_cr technics did not reflect the magnitude of the reduction in glomerular filtration rate. The fractional excretion of creatinine demonstrated a significant inverse relationship to C_in, suggesting that creatinine secretion is increased with propranolol.We conclude that propranolol therapy results in prolonged changes in glomerular filtration rate, which may not revert to normal following its withdrawal.     

Renal failure in minimal change nephrotic syndrome

Renal insufficiency, with serum creatinines ranging from 2.3 to 13.4 mg/dl, was observed in 15 patients with the minimal change nephrotic syndrome. Recovery of renal function occurred in association with diuretic therapy in 13, eight of whom subsequently underwent steroid-induced remission of the nephrotic syndrome. Two patients failed to undergo diuresis or to have a remission of the nephrotic syndrome and died with persistent renal failure.Glomerular filtration rate (C_inulin) was reduced out of proportion to renal plasma flow (C_PAH) as evidenced by remarkably low filtration fractions ranging from 0.03 to 0.095.The invariable association between diuresis and recovery of renal function, the recurrence of renal failure when fluid reaccumulated and the finding of markedly depressed filtration fractions lead us to postulate that renal failure in minimal change nephrotic syndrome may be due to a reversible alteration in glomerular hemodynamics which is related to fluid retention and associated intrarenal edema.     

Glomerular and tubular function in non-oliguric acute renal failure

Glomerular and tubular function were evaluated in 30 non-oliguric patients with increasing azotemia following open heart surgery. Fractional clearances (theta) of test solutes relative to that of inulin were determined. In 16 patients, theta dextran (radius 22 to 30 A) exceeded unity, a finding attributed to inulin backleak through necrotic tubules. These patients were classified as having acute renal failure; 14 subsequently required dialysis. In the remaining patients (N = 14), theta dextran was normal. These patients were considered to have prerenal failure; all recovered spontaneously. clearance of inulin (Cin) was lower in acute renal failure than in prerenal failure (12 +/- 2 versus 18 +/- 2 ml/min/1.73 m2; p less than 0.025). The apparent difference in glomerular filtration rate when Cin is used as an index was abolished, however, when Cin in acute renal failure was corrected for tubule backleak of inulin. In acute renal failure, fractional clearance of p-aminohippurate (theta PAH) was 7.1 +/- 1.0, and fractional excretion of potassium (FEk) was 160 +/- 18 percent. These findings strongly suggest that secretory ability in both proximal and terminal tubule augments, respectively, is preserved in acute renal failure. Compared with prerenal failure, the urine-to-plasma inulin ratio was lower (U/Pin = 10 +/- 1 versus 25 +/- 4; p less than 0.005) and FENa was higher (FENa = 5.1 +/- 1.5 versus 0.5 +/- 1.0 percent; p less than 0.01) in acute renal failure.     

Comparison of three methods of glomerular filtration rate measurement with and without captopril pretreatment in groups of patients with left ventricular dysfunction.

Methods of glomerular filtration rate measurement by 51Cr EDTA elimination, inulin clearance and creatinine clearance were compared with and without captopril pretreatment in 10 chronic heart failure patients and in 20 patients after transmural myocardial infarction. Strong intermethod correlations were found in chronic heart failure patients (EDTA: inulin r = 0.87; EDTA: creatinine r = 0.84; inulin: creatinine r = 0.9; all P less than 0.00001). Despite this, substantial absolute differences were observed in results obtained by different techniques. In particular, creatinine clearance significantly overestimated both 51Cr EDTA (18.0 +/- 18.4 ml.min-1, mean difference +/- SD, P less than 0.001) and inulin clearance (26.8 +/- 17.0 ml.min-1, P less than 0.001). The slight reduction in 51Cr EDTA elimination on captopril versus placebo (-8.3 +/- 9.2 ml.min-1, P less than 0.05) was related to a similar treatment difference in inulin clearance (r = 0.67, p = 0.03), but changes observed by either method were unrelated to captopril-induced changes in creatinine clearance. Thus, creatinine clearance is an unsatisfactory means of assessing the effect of angiotensin converting enzyme inhibition on glomerular filtration rate in chronic heart failure. In the post-myocardial infarction group, correlations between methods were poorer (EDTA: inulin r = 0.79; EDTA: creatinine r = 0.76; inulin: creatinine r = 0.67). In this group no significant effect of captopril on glomerular filtration rate was detected by any technique. As compared to the chronic heart failure patients, the weaker relationship between techniques post-myocardial infarction may be related to interference by thrombolytic or aspirin treatment.     

Minimal change nephropathy: an electrochemical disorder of the glomerular membrane

To investigate the mechanism of proteinuria in minimal change nephropathy, the renal handling of dextrans was studied in seven nephrotic patients with this disorder. Although the urinary excretion of albumin was greatly increased, the urinary excretion and fractional clearance of dextrans (Einstein-Stokes radius (ESR), range 20 to 48 A) were depressed relative to those in nonproteinuric healthy volunteers. This suggests that mean glomerular pore size or pore density was reduced. Uptake of colloidal iron by glomeruli obtained from these patients by needle biopsy was diminished, suggesting loss of glomerular polyanion. Since the fractional clearance of dextrans similar in size to albumin was depressed, not increased, it is proposed that the lack of electrostatic interaction between the glomerular capillaries and polyanionic plasma albumin (ESR = 36 A) accounts for the selective albuminuria which characterizes minimal change nephropathy.     

Glomerular hyperfiltration in microalbuminuric NIDDM patients

Summary Glomerular hyperfiltration and microalbuminuria are both regarded as risk factors for the development of diabetic nephropathy in insulin-dependent diabetic patients. Information on glomerular hyperfiltration is scarse in microalbuminuric non-insulin-dependent diabetic (NIDDM) patients. Therefore, we performed a cross-sectional study of glomerular filtration rate (single i. v. bolus injection of ⁵¹Cr-EDTA, plasma clearance for 4 h) in 158 microalbuminuric NIDDM patients compared to 39 normoalbuminuric NIDDM patients and 20 non-diabetic control subjects. The groups were well-matched with regard to sex, age and body mass index. The uncorrected (ml/min) and the adjusted (ml · min^–1· 1.73 m^–2) glomerular filtration rate were both clearly elevated in the microalbuminuric patients: 139 ± 29 and 117 ± 24 as compared to 115 ± 19 and 99 ± 15; 111 ± 23 and 98 ± 21 in normoalbuminuric NIDDM patients and control subjects, respectively (p < 0.001). The glomerular filtration rate (ml · min^–1· 1.73 m^–2) in NIDDM patients who had never received antihypertensive treatment was also clearly elevated in the microalbuminuric patients (n = 96): 119 ± 22 as compared to 100 ± 14 and 98 ± 21 in normoalbuminuric NIDDM patients (n = 27) and control subjects (n = 20), respectively (p < 0.001). Glomerular hyperfiltration (elevation above mean glomerular filtration rate plus 2 SD in normoalbuminuric NIDDM patients) was demonstrated in 37 (95 % confidence interval 30–45)% of the microalbuminuric patients. Multiple regression analysis revealed that HbA_{1 c}, 24-h urinary sodium excretion, age and known duration of diabetes were correlated with glomerular filtration rate in microalbuminuric NIDDM patients (r ² = 0.21, p < 0.01). Our cross-sectional study indicates that NIDDM patients at high risk of developing diabetic nephropathy are also characterized by an additional putative risk factor for progression, glomerular hyperfiltration. [Diabetologia (1996) 39: 1584–1589]     

Effects of insulin and lipid emulsion on renal haemodynamics and renal sodium handling in IDDM patients

Summary To evaluate the role of insulin and hypertriglyceridaemia in the regulation of renal haemodynamics and sodium handling in insulin-dependent diabetes mellitus (IDDM), 11 IDDM patients without microalbuminuria and 13 weight-, age-, protein intake- and sex-matched healthy control subjects were studied. Clearances of inulin (C_in), para-amino-hippuric acid (C_PAH), sodium (C_Na), and lithium (C_Li) were measured in four 60-min clearance periods (periods I, II, III and IV) during isoinsulinaemia with lipid emulsion infusion (study 1), a hyperinsulinaemic isoglycaemic clamp with Intralipid infusion (study 2), and during time-controlled isoinsulinaemia (study 3). We found that C_in, C_PAH and filtration fraction were comparable in IDDM and control subjects, whereas C_Na was decreased in diabetic subjects (2.01±1.11 vs 3.03±1.32 ml/min; p<0.05) due to elevations of proximal tubular fractional and absolute reabsorptions of sodium (p<0.05). Insulin infusion did not affect C_in, increased C_PAH (p<0.05) and, consequently, lowered the filtration fraction (p<0.01) in both groups. While acute hyperinsulinaemia resulted in increases in distal tubular fractional and absolute reabsorptions of sodium (p<0.01) contributing to a fall in C_Na (p<0.01) in control subjects, in diabetic subjects the sodium-retaining effect of insulin was not significant. The lipid emulsion did not alter any of the estimated parameters. We conclude that IDDM without microalbuminuria is associated with a tendency to sodium retention which is not aggravated by insulin when compared to control subjects. Acutely induced hypertriglyceridaemia does not alter renal haemodynamics or renal sodium handling.Abbreviations IDDM Insulin-dependent diabetes mellitus - GFR glomerular filtration rate - RPF renal plasma flow - C_in clearance of inulin - C_PAH clearance of para-amino-hippuric acid - C_Na clearance of sodium - C_Li clearance of lithium - APR_Na absolute proximal tubular reabsorption of sodium - FPR_Na fractional proximal tubular reabsorption of sodium - ADR_Na absolute distal tubular reabsorption of sodium - FDR_Na fractional distal tubular reabsorption of sodium - FIRI free plasma immunoreactive insulin - TG serum triglycerides - NEFA serum non-esterified fatty acids - MCR metabolic clearance rate of glucose - FF filtration fraction - ANOVA analysis of variance     

Abnormal Renal Sodium Excretion in the Nephrotic Syndrome after Furosemide: Relation to Glomerular Filtration Rate

ABSTRACT. Danielsen H, Pedersen EB, Madsen M, Jensen T. (Department of Internal Medicine C, Aarhus Kommunehospital, and University of Aarhus, Aarhus, Denmark.) Abnormal renal sodium excretion in the nephrotic syndrome after furosemide: relation to glomerular filtratoni rate. The effect of 40 mg furosemide intravenously on sodium excretion, the renin-aldosterone system and arginine vasopressin (AVP) was studied in 14 patients with the nephrotic syndrome and in 13 control subjects. Creatinine clearance (C_cr) was reduced in all patients but four. Before furosemide, AVP, but not angiotensin II (AII) or aldosterone (Aldo), was increased in the nephrotic patients. After fursoemide, sodium excretion (Na_E) increased less and changes in AVP, AII and Aldo were blunted in the patients. C_cr and Na_E were positively correlated in the nephrotic syndrome. The reduced sodium response after furosemide in the nephrotic syndrome seems to be closely correlated to a reduced glomerular filtration rate but not to an increased activity of the renin-angiotensin-aldosterone system. The reduced response of AVP, AII and Aldo after furosemide is consistent with a lower degree of volume depletion in nephrotic patients.     

A comparison between estimates of GFR using [99m– Tc]DTPA clearance and the approximation of Cockcroft and Gault

Background: The formula of Cockcroft and Gault, relating age, weight, sex and plasma creatinine is widely used to estimate glomerular function. Its ability to predict [^99mTc]DTPA clearance, an accepted measure of GFR, is therefore of interest. Aim: To test prospectively the reliability of the formula in predicting the [^99mTc]DTPA clearance in subjects with normal and sub-normal renal function. Methods: The 24 hour creatinine clearance (Ccr), the derived clearance using the formula (C_der), and the [^99mTc]DTPA clearance have been compared in 47 male and 47 female subjects, aged between 15 and 71 years. Obese and non-obese subjects (males >90 kg, females >80 kg body weight) were considered separately. Results: Across the range of [^99mTc]DTPA clearance studied (14 to 125 mL/minute), in non-obese subjects, both Ccr and C_der were correlated similarly with [^99mTc]DTPA clearance in males and females. In obese subjects as a group, C_der was also closely correlated with [^99mTc]DTPA clearance but the scatter of data was wider. Among non-obese subjects, correlations were high between either Ccr or C_der and [^99mTc]DTPA clearance values < 101 mL/minute but were not significant at [^99mTc]DTPA clearance values > 100 mL/minute. For [^99mTc]DTPA clearance values between 14 and 100 mL/minute, C_der was a more direct and more precise predictor of [^99mTc]DTPA clearance [DTPA clearance = 1.01(C_der) + 2.34, with 95% confidence limits of ± 18 mL/minute] than of Ccr [Ccr= 1.34(C_derC)- 10.86, confidence limits ±28 mL/minute]. Conclusion: For very mild through to moderate renal failure, the formula of Cockcroft and Gault can evidently be used as a reasonable estimate of GFR. (Aust NZ J Med 1993; 23: 494–497.)     

Changing glomerular filtration with progression from impaired glucose tolerance to Type II diabetes mellitus (Short Communications)

Summary Glomerular filtration rate (iothalamate clearance) was measured serially for 48 months in 26 Pima Indians with impaired glucose tolerance and 27 with normal glucose tolerance. At baseline, the mean glomerular filtration rate (SEM) was 133 ± 8 ml/min in subjects with impaired glucose tolerance and 123 ± 5 ml/min in those with normal glucose tolerance (p = 0.12). In the 12 subjects with impaired glucose tolerance who progressed to Type II (non-insulin-dependent) diabetes during follow-up, mean glomerular filtration rate increased by 30 % (p = 0.011). Among the remaining 14 subjects with impaired glucose tolerance, 12 reverted to normoglycaemia. The glomerular filtration rate both at baseline and after 48 months in this subgroup exceeded the values of subjects with normal glucose tolerance by 20 % (p = 0.008) and 14 % (p = 0.013), respectively. A pronounced rise in the glomerular filtration rate occurs at the onset of Type II diabetes but a trend to hyperfiltration is also present in those with impaired glucose tolerance. [Diabetologia (1999) 42: 90–93] Received: 18 May 1998 and in revised form: 21 August 1998     

Pulmonary capillary filtration and reflection coefficients in the newborn rabbit

In an isolated, Ringer-perfused lung preparation, we measured values of the filtration coefficient and reflection coefficients of NaCl, mannitol, sucrose, raffinose, inulin, and albumin for the pulmonary capillaries of newborn rabbits. We found the capillary filtration coefficient value to be 8.3 × 10^?5 cm³ sec^?1 cm H₂O^?1, which, when normalized for the estimated exchange area, is at least a factor of 2 larger than the value found for adult rabbit lungs. Using the osmotic transient technique we measured the osmotic flow induced by adding test molecules to the perfusate. NaCl, mannitol, sucrose, and raffinose were found to have equivalent effects. Assuming these molecules only draw fluid from cells, and not across the capillary endothelium (capillary σ = 0) we estimate that σ_inulin = 0.04 and σ_albumin = 0.07. These results indicate that the pulmonary capillaries of newborn rabbits are less selective (“leakier”) than those of adult rabbits. We estimate an equivalent pore radius of 150–300 Å for the newborn pulmonary capillary endothelium, although the data are not consistent with a uniformly sized population of pores.     

Capillary permeability in the isolated rabbit heart as measured by local tissue clearance

The relatively simple method of local tissue clearance was used to measure capillary permeability-surface area products (PS) in the isolated, Ringer-perfused rabbit heart. Ten microliters of a mixture of [³H]inulin and [¹⁴C]sucrose was injected at a depth of 2 mm into the left ventricular myocardium and clearance rate constants (k in min^?1) were determined by analyzing the draining perfusion fluid. PS (ml/min per 100 ml) for each solute was calculated by the following equation: $\text{PS = ?F}\text{ln}\text{(1 ?}\text{λk}\text{F}\text{)}$, where F is perfusate flow (ml/min per 100 ml) and λ is the equilibrium tissue/Ringer partition coefficient. At a perfusion pressure of 40 mm Hg, F = 133 ± 9.7 (mean ± SEM), PS_sucrose = 77 ± 8.0, and PS_inulin = 13.9 ± 0.7. These PS products are within the range of values previously reported by others using several different techniques. The mean inulin/sucrose permeability ratio was 0.189 ± 0.018 which is significantly less than the separately measured free diffusion coefficient ratio (= 0.41 ± 0.005), thus indicating that sucrose and inulin crossed myocardial capillary walls by restricted diffusion. The reasons why some investigators did not find similar evidence of restricted diffusion are discussed.     

Divalent cation metabolism: Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism

Twenty-three members of three families with a syndrome of hypercalcemia without hypercalciuria (familial hypocalciuric hypercalcemia) were compared to a group of 64 subjects with hypercalcemia due to typical primary hyperparathyroidism. Patients with familial hypocalciuric hypercalcemia had higher creatinine clearance values than those with primary hyperparathyrodism (115 ± 27 versus 87 ± 27 ml/min/1.73 m² (mean ± 1 standard deviation [SD] p < 0.0001). Although renal function was well preserved, the group with familial hypocalciuric hypercalcemia showed a mean serum magnesium concentration of 2.05 ± 0.17 meq/liter, significantly higher than that in normal subjects (1.74 ± 0.12 meq/liter, p < 0.0001) or than in the group with primary hyperparathyroidism (1.71 ± 0.21 meq/liter, p < 0.0001). In familial hypocalciuric hypercalcemia the degree of hypermagnesemia was directly proportional to the degree of hypercalcemia (R = +0.54, p < 0.01), contrasting with an inverse relation of serum calcium and magnesium concentrations in primary hyperparathyroidism (R = ?0.32, p < 0.02). Urinary excretion of both calcium (calcium:creatinine clearance ratio 0.006 ± 0.004 versus 0.024 ± 0.01, p < 0.0001) and magnesium (magnesium:creatinine clearance ratio 0.031 ± 0.0008 versus 0.047 ± 0.03, p < 0.003) was significantly lower in familial hypocalciuric hypercalcemia than in primary hyperparathyroidism. There was no evidence that abnormal protein binding of cations in serum from those with familial hypocalciuric hypercalcemia accounted for the hypercalcemia and hypermagnesemia or for the disproportionately low urinary excretion of divalent cations by rendering them resistant to glomerular filtration. After fractionation by electrophoresis on cellulose acetate, the major plasma protein components were quantitatively similar in both groups. Furthermore, ionized and ultrafiltrable calcium and ultrafiltrable magnesium showed consistent relations to total calcium and total magnesium concentrations in plasma from both groups. Therefore, in familial hypocalciuric hypercalcemia there are increased serum concentrations of the physiologically active forms of both calcium and magnesium, and the renal handling of the filtered load of these divalent cations differs in familial hypocalciuric hypercalcemia and primary hyperparathyroidism.     

Tryptophan glycoconjugate as a novel marker of renal function

PURPOSE: Neither serum creatinine concentration nor creatinine clearance assess renal function accurately. Serum creatinine concentration is affected by muscle mass, and the creatinine clearance overestimates the glomerular filtration rate because of tubular secretion of creatinine. The present study was designed to determine whether serum concentrations of 2-(alpha-mannopyranosyl)-L-tryptophan (MPT), a tryptophan glycoconjugate, can be used as a marker of renal function. METHODS: Clearances of MPT and of inulin were compared in normal rats and in rats with cisplatin-induced acute renal failure. We also compared the clearances of MPT and of creatinine with inulin clearance in 25 patients with chronic renal disease. Serum concentrations of MPT and creatinine as a function of MPT clearance were determined in 108 patients with chronic renal disease. RESULTS: There was strong linear correlation between clearances of MPT and inulin in rats (r = 0.97) and humans (r = 0.87), indicating that renal handling of MPT is similar to that of inulin. In humans, linear regression analyses indicated that MPT was a better indicator of inulin clearance than was creatinine clearance. At the same level of renal function, serum creatinine concentrations tended to be lower in patients with less muscle mass (as indicated by a urinary creatinine excretion <1,000 mg in 24 hours) than in those who excreted >1,000 mg in 24 hours, whereas serum MPT concentrations were not affected by creatinine excretion. CONCLUSION: MPT clearance can replace inulin clearance in the clinical setting. The serum MPT concentration is an accurate measure of renal function even in patients with diminished muscle mass, and thus is a better indicator of renal function than is the serum creatinine concentration.     

Inverse association of estimated cystatin C- and creatinine-based glomerular filtration rate with left ventricular mass: Results from the Study of Health in Pomerania

Background

Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular disease in the general population and in patients with chronic kidney disease. The objective of this study was to investigate the association of estimated glomerular filtration rate (eGFR) with left ventricular mass index (LVMI), LVH and left ventricular geometry. A question of clinical relevance is whether estimated glomerular filtration rate based on cystatin C (eGFR_cystatinC) is a better marker for cardiovascular risk than estimated glomerular filtration rate based on creatinine (eGFR_creatinine).

Methods

The study sample included 2830 individuals from the population-based Study of Health in Pomerania (SHIP). LVH was defined as echocardiographic LVMI > 48 g/m^2.7 in men and > 44 g/m^2.7 in women. Kidney function, as assessed by eGFR, was determined from established equations: the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and a cystatin-based multivariable equation.

Results

We found an inverse association between eGFR and LVMI. This association was stronger in models with eGFR_cystatinC than in models with eGFR_creatinine. Subjects with moderately-to-severely decreased kidney function (defined as eGFR 15–< 60 mL/min per 1.73 m²) had higher odds for abnormal geometric patterns of the left ventricle than subjects with normal eGFR when eGFR_cystatinC was used.

Conclusions

The findings suggest that eGFR_cystatinC is superior to eGFR_creatinine for assessing the risk of cardiovascular disease.     

How to assess glomerular function and damage in humans

In human subjects, the assessment of renal function and of its changes by interventions is limited to the measurement of glomerular filtration rate (GFR), renal blood flow and the estimation of proteinuria. In humans, GFR can be determined exactly by measuring the clearance of an ideal filtration marker, such as inulin. The classic method of measuring inulin clearance in humans includes constant intravenous infusion of the compound and timed collections of urine. In order to avoid the need for timed urine collections, a number of alternative procedures have been devised. All these methods only use determinations of inulin in plasma or serum. From these, the total body inulin clearance is obtained using pharmacokinetic calculations. In order to measure total body clearance, usually called plasma clearance, inulin is either given as a constant intravenous infusion or as a bolus infusion. Both procedures overestimate GFR because of incomplete distribution of inulin during the study periods. The error may be minimized by using model-independent pharmacokinetic calculations. Unlike inulin, creatinine is not a perfect filtration marker. This is because the substance is not only eliminated by glomerular filtration but also by tubular secretion. The extent of tubular creatinine secretion is not constant in various individuals. Serum creatinine concentration is a commonly used measure of renal function in clinical practice. This parameter is determined both by the renal elimination and by the production of the compound. Differences in creatinine production among subjects and over time in a single individual may occur because of changes in muscle mass. Radioisotopic filtration markers can easily and accurately be measured in plasma and serum. Using this method, the plasma concentration-time curve of these compounds can easily be studied after intravenous bolus injection. From the plasma concentration-time curves obtained, the total body clearance (plasma clearance) of the substances can be calculated using pharmacokinetic models. Most frequently, 125l-iothalamate, 99mTc-diethylenethiaminepenta-acetic acid and 51Cr-ethylenediaminetetra-acetic acid are used for the estimation of GFR in humans. The total body clearance of all these filtration markers overestimates GFR. The error induced by this phenomenon is particularly relevant at low levels of GFR. In recent years, iohexol has been used as a filtration marker. The substance can be measured in plasma, serum and urine using high-performance liquid chromatography. So far, good agreement has been shown for GFR determined by the classic inulin clearance and by the iohexol plasma clearance. Screening for proteinuria is commonly performed using reagent test strips. Quantitative measurements of marker proteins can be used to estimate the extent and the site of damage in the nephron. These measurements may be used to estimate the progression of renal disease and the response to therapeutic interventions. Of particular interest is the degree of albuminuria which indicates nephropathy in diabetic patients and end-organ damage in patients with hypertension.     

Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate

This study was designed to investigate the effect of protein intake on glomerular filtration rate, and to demonstrate and evaluate the functional reserve of the kidney. Normal subjects ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet. A progressive increment in protein intake in normal volunteers resulted in a significant increase in creatinine clearance. Diurnal variations in creatinine clearance were found. These daily variations correlated well with the periods of food intake. The capacity of the kidney to increase its level of function with protein intake suggests a renal function reserve. In short-term studies, the effect of a protein load on glomerular filtration rate was evaluated. Normal subjects showed an increase in glomerular filtration rate two and a half hours after protein load to a maximal glomerular filtration rate of 171.0 +/- 7.7 ml per minute. In patients with a reduced number of nephrons, renal functional reserve may be diminished or absent.     

Impaired renal mevalonate metabolism in nephrotic syndrome: A stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia

Increased hepatic lipogenesis in the nephrotic syndrome is not adequately explained by hypoalbuminemia. In this disorder an enhanced delivery of the cholesterol precursor mevalonic acid (MVA) to the liver may be an unidentified stimulus to cholesterogenesis. Since the kidneys are the major site of mevalonate excretion and metabolism by either the sterol or nonsterol shunt pathways, an impairment of any of these metabolic alternatives could result in redistribution of mevalonate to the liver. Male Sprague-Dawley rats rendered nephrotic by puromycin aminonucleoside had their kidneys perfused with Krebs-Henseleit-bicarbonate buffer containing albumin, glucose and 5-¹⁴C-MVA. The number five carbon label was utilized so that any ¹⁴CO₂ produced would represent mevalonate shunt pathway activity. The isolated perfused kidney was used to eliminate confounding variables. In eight control kidneys perfused for 2 hr 62 ± 2% of the MVA was removed from the perfusate compared to 50 ± 2% in five nephrotic kidneys (p < .006). Urinary MVA recovery was 22 ± 2% in controls, 15 ± 1% in nephrotics (p < .05). The incorportion of ¹⁴C into renal tissue lipids was not different in the two groups. Recovery of ¹⁴CO₂ was two times greater in controls than in nephrotics (p < .006). Inulin clearance per gram of kidney and sodium reabsorption were similar for the two groups. Isolated perfused kidneys from nephrotic rats metabolize MVA abnormally such that less is excreted, less is oxidized, and more is available for recirculation to the liver. This occurs independently of hypoalbuminemia, a change in glomerular filtration rate, or an overt histo-pathologic lesion. These events create an environment for increased hepatic cholesterol synthesis.     

Effects of hyperglycemia and mannitol infusions on renal hemodynamics in normal subjects

Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.