Chester M. Edelmann

Maturational Changes in Renal Blood Flow in Piglets

Extract: Cardiac output, renal blood flow, and intrinsic renal vasuclar resistance were measured in piglets ranging in age from 6 h to 45 days. During this period of time the mean cardiac output increased from 0.9 to 6.5 litres/min/m2, the mean renal blood flow increased from 0.043 to 0.76 litters/min/m2, and intrinsic renal vasuclar resistance dropped from 1,605 to 133 mm Hg/liter/min/m2. These data demonstrate that the large increase in renal blood flow in the pig during the first 6 weeks of life was due to both an increase in cardiac outputs as well as decrease in renal vascular resistance. By 6 weeks of age, cardiac output was at adult levels. Since in the adult pig the kindney receives 20% of the cardiac output, increases in renal blood flow beyond 6 weeks of age must result from further decreases in renal vascular resistance.Speculation: In the human infant, cardiac index is comparable to values observed in the adult. It appears, therefore, that the entire increase in renal blood flow observed during year I of life is due to steadily decreasing renal vascular resistence. Since glomerular filtration rate is modified by the relative resistances in the glomerular afferent and efferent arterioles, the parallel increases in filtration rate during infancy may be related to the same mechanism.

Renal tubular acidosis in infants and children: Clinical course, response to treatment, and prognosis+

Nine children with proximal renal tubular acidosis and four with distal renal tubular acidosis have been followed for periods ranging from six months to eight years. The patients with proximal renal tubular acidosis, predominantly male, presented with growth retardation and acidemia at ages 2 to 19 months. Treated with high-dose alkali therapy, most of these patients have shown improvement in growth rate. Now, one to eight years after diagnosis, seven of the nine patients are completely normal without therapy. The patients with distal renal tubular acidosis, 2 boys and 2 girls, presented at ages 4 to 13 years with growth retardation, polyuria, and recurrent episodes of acidosis and dehydration. Three had nephrocalcinosis and hypokalemia, and all demonstrated a renal concentrating defect. Three to eight years after diagnosis these patients continue to require low-dose alkali therapy; the renal concentrating defect and nephrocalcinosis persist, although the glomerular filtration rate has normalized.

Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis a report of the international study of kidney disease in children

Sixty children, with biopsy diagnosed focal segmental glomerulosclerosis (FSGS) and with unremitting nephrotic syndrome despite intensive therapy with adrenocortical steroids, were randomly allocated into a clinical trial comparing prednisone, 40 mg/m2 on alternate days for a period of 12 months (control group), with the same prednisone regimen plus a 90-day course of daily cyclophosphamide, 2.5 mg/kg in a single morning dose (experimental group). One-quarter of the children in each group had complete resolution of proteinuria. The proportions of children with increased, unchanged, and decreased proteinuria by the end of the study were the same in the two groups. Treatment fialure was defined as an increase in serum creatinine of 30% or more or greater than 0.4 mg/dl, or onset of renal failure. Treatment failure occurred in 36% of the control group and 57% of the experimental group (P>0.1). Five patients died during the trial, 3 in the experimental group and 2 in the control group. A Kaplan-Meier survival analysis revealed no significant differences between the two groups. Cyclophosphamide therapy for children with steroid-resistant FSGS is not recommended.

The maturing kidney: A modern view of well-balanced infants with imbalanced nephrons†

In 1951 Smith wrote: “It is not inappropriate to point to the history of renal physiology as typical of the history of science, and particularly of the history of medicine. It has been a history of rival theories, each based upon inconclusive evidence. Its errors have been compounded by oversimplification in the matter of theory and underexamination in the matter of critical investigation. Renal physiology has now passed into a quantitative phase where unsupported speculation and empirical description are no longer warranted.”

Proximal Renal Tubular Acidosis. A Defect in Bicarbonate Reabsorption with Normal Urinary Acidification

Extract: This report concerns two patients with primary renal tubular acidosis (RTA) in whom the abnormality in hydrogen excretion was shown to result from inappropriate urinary loss of bicarbonate due to a low renal hicarbonate threshold. On the basis of the findings, a new definition and reclassification of RTA is proposed.The clinical course and response to medication is illustrated in figs. 1-4. Repeated measurements of clearances of creatinine, inulin, and PAH gave normal values (table I).Excretion of aminoacids (table II) was normal in both patients. After water restriction, the urinary osmolality was 990 mOsm/kg water for K.J. and 1088 mOsm/kg water for S.G. No reducing substance was found in the urine of K.J.; glucose was present in trace amounts on several occasions in the urine of S.G. Tubulare absorptiono f phosphate was always in the normal range, 80 to 90 percent of the filtered amount.Both children had an adequate response to the oral administration of ammonium chloride, providing no alkali therapy was being administered at the time of the test (table III).In fig. 5, rates of reabsorption and excretion of bicarbonate, expressed as mmoles/100 ml glomerular filtrate (GF) are plotted against serum bicarbonate concentration in mmoles/liter. Data from 2 studies are included in the figure. K.J. started to excrete bicarbonate into the urine at a serum bicarbonate level of 18 to 19 mmoles/liter; the Tm of reabsorption was low, being approximately 2.1 mmoles/100 ml GF. In S.G., although the threshold was similarly depressed (19 to 20 mmoles/liter), the Tm of reabsorption was at the lower limit of the normal range (2.5 to 2.6 mmoles/100 ml GF).The ratio of reabsorbed bicarbonate to Tm has been plotted as a function of the ratio of filtered bicarbonateto Tm (fig. 6). The data from the studies in K.J. demonstrate a splay very similar to that of normal infants. S.G., however, has a markedly increased splay.During bicarbonate infusion and when rates of bicarbonate reabsorption were near the Tm, acetazolamide was administered intravenously in a single dose of 100 mg. In both children, marked inhibition of bicarbonate reabsorption was demonstrated. At similar rates of filtered bicarbonate, the urinary excretion increased two-to-three-fold with a concomitant decrease in the rate of reabsorption (table V).Results for glucose reabsorption in K.J. are close to those of normal adults with a threshold of 300 mg/min/1.73 m2 and a Tm of over 400. In contrast, S.G. had small amounts of glucose in the control urines and the glucose threshold was abnormally low, approximately 100 mg/min/1.73 m2. Although blood glucose was not maintained at high values long enough to be certain that the Tm had been reached, values as high as 327 mg/min/1.73 m2 were obtained, suggesting that his glucose Tm was normal.After administration of histamine, the acidity of the gastric fluid increased markedly and the values of free acid and total titratable acid compare closely with that of normal children (table VI).Histologic examination of a percutaneous renal biopsy specimen from K.J. showed minimal hypercellularity of the glomerular stalks. The lumens of the proximal convoluted tubules were frequently open; no significant histologic abnormalities were seen. No glomerular or tubular abnormalities were observed in a biopsy specimen from S.G.Both patients reported here were able to respond normally during metabolic acidosis with excretion of very acid urine containing adequate amounts of titratable acid and ammonium. However, when alkali was administered and serum bicarbonate levels were brought into the range of normal, the urine, normally neutral or slightly acid at this time, contained inappropriately large amounts of bicarbonate and was consistently alkaline.During bicarbonate titration, bicarbonate was found in urine only when the threshold was exceeded. Below this level, the urine was normally acid and therefore bicarbonate free. At a plasma bicarbonate concentration above the threshold, an abrupt increase in urine bicarbonate concentration occurred, as in the normal subject. This observation helps to differentiate this type of abnormality from the bicarbonate loss in gradient type RTA, in which a small constant rate of excretion of bicarbonate in urine persists despite lowering of plasma bicarbonate concentration well below threshold values.A satisfactory classification of RTA must take into account patients with acidification defects as well as those with abnormalities in bicarbonate reabsorption. A distinction should also be made between primary and secondary disease.RTA is a condition in which there is a defect in renal excretion of hydrogen or reabsorption of bicarbonate, or both, out of proportion to impairment of glomerular filtration. It is suggested that RTA be divided into two forms: 1. a proximal form caused by a defect in bicarbonate reabsorption; and 2. a distal form due to inability to establish an adequate pH gradient between blood and distal tubular fluid. Although pH gradients are established throughout the length of the nephron and bicarbonate reabsorption is not confined to the proximal segment, most filtered bicarbonate is reabsorbed in the proximal tubule whereas production of ammonium and titratable acid with low urinary pH is primarily a distal function. The patients described belong to the first category and as such represent a new form of RTA.Patients with proximal RTA require inordinately high doses of citrate or bicarbonate to maintain serum bicarbonate levels within the normal range, due to the great loss of bicarbonate in urine. Failure of a patient with RTA to respond to usual doses of bicarbonate may be a clue that the defect is of the proximal type.Speculation: The studies presented appear to justify distinguishing between two types of renal tubular acidosis; one resulting from a proximal tubular lesion, the other a distal malfunction. Since the ultimate prognosis seems to vary with the site of the acidification deficit, this distinction has more than academic importance.

Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone : a report of the International Study of Kidney Disease in Children

It has been claimed that long-term prednisone treatment ameliorates the course of children with mesangiocapillary glomerulonephritis (MCGN). The International Study of Kidney Disease in Children conducted a randomized, double-blinded, placebo-controlled clinical trial in 80 children with idiopathic MCGN, including 42 patients with type I disease, 14 with type II disease, 17 with type III disease, and 7 with nontypable disease. Criteria for admission included heavy proteinuria and a glomerular filtration rate of greater than or equal to 70 ml/min per 1.73 m2. Prednisone or lactose, 40 mg/m2, was given every other day as a single morning dose. The mean duration of treatment was 41 months, renal failure being the most common reason for termination of therapy. Treatment failure was defined as an increase from baseline of 30% or more in serum creatinine, or more than 35 μmol/l. Overall, treatment failure occurred in 55% of patients treated with lactose, compared with 40% in the prednisone group. Life-table analysis showed a renal survival rate (i.e., stable renal function) at 130 months of 61% among patients receiving prednisone and 12% among patients receiving lactose (P=0.07). Of patients with type I or III MCGN, 33% treated with prednisone were treatment failures, compared with 58% in the lactose group. Long-term treatment with prednisone appears to improve the outcome of children with MCGN.

The Renal Response of Children to Acute Ammonium Chloride Acidosis

Extract: The present observations were undertaken to establish the response of children to the acute administration of ammonium chloride, in order to provide a basis for identifying and interpreting abnormalities in the mechanisms involved in renal acid base regulation. Fifty-eight normal children aged 4 to 13 years were studied before and for 5 hours following administration of ammonium chloride. Group A, consisting of 23 children, received 75 mEq/m2 body surface area or 2.75 mEq/kg body weight. Group B, consisting of 35 children, received 150 mEq/m2, or 5.45 mEq/kg.Values for serum electrolytes, urea, creatinine, osmolality and acid-base parameters in children in Groups A and B are shown in tables I and III. Urinary pH and rates of excretion of titratable acid and ammonium are shown in tables II and IV. The relations between blood tCO2 and urinary concentration of H+, rate of excretion of titratable acid, and rate of excretion of ammonium for all subjects are shown in figures 1-3. Progressively lower values of pH were observed over the entire range of tCO2 studied. During control periods, an inverse correlation was present between tCO2 and rates of excretion of both titratable acid and ammonium. At levels of tCO2 below 22.5 mmoles/l, the rate of excretion of TA and ammonium became constant, with mean rates of excretion of 52 μEq/min/1.73 m2 (range, ± 2 SD, 33 to 71), and 73 μEq/min/1.73 m2 (46 to 100), respectively.These data are interpreted as demonstrating the importance of the blood tCO2 or, more precisely, the concentratibn of bicarbonate in glomerular filtrate in urinary acidification mechanisms as well as in control of excretion of bicarbonate. Assessment of renal acidifying mechanisms requires administration of sufficient ammonium chloride or other acidifying substance to depress blood tCO2 to levels well below the renal threshold.The physiologic validity of the hydrogen ion clearance index must be questioned, since correcting rates of excretion of hydrogen ion for concentration of total CO2 in blood presumes that there is a fixed relation between these two measurements. In figure 4, urinary excretion of total hydrogen ion is plotted as a function of blood tCO2. Hydrogen ion excretion, negligible at tCO2 levels of 26 or more, increases steadily as tCO2 falls to values below the threshold. The rate of excretion then reaches maximal levels, despite further reduction in blood tCO2. Thus, the hydrogen ion clearance index is valid only over the range of blood tCO2 in which there is a linear relationship with rate of excretion of hydrogen ion. Renal acidification mechanisms should be evaluated with blood tCO2 several millimoles below the threshold, assuring a maximal response and permitting direct comparison with normals. In subjects with a normal bicarbonate threshold, blood tCO2 should be depressed at least to 17–18 mmoles/l in infants and 20–21 mmoles/l in older children. If an abnormal bicarbonate threshold is present the dose must be adjusted accordingly.Speculation: These studies suggest that both the concentration of bicarbonate in glomerular filtrate and the level of the bicarbonate threshold play major roles in the regulation of renal excretion of hydrogen ion.

The prevalence of bacteriuria in full-term and premature newborn infants.

Examinations of urine were performed in 836 full-term and 206 prematurely born infants, using specimens obtained by a clean-voided technique and by suprapubic puncture. Persistent proteinuria, leukocyturia, or hematuria was found in none, and none of these findings correlate well with bacteriologic studies. Bacteriuria was found in 0.7 per cent of the full-term and 2.9 per cent of the premature infants, mostly in asymptomatic subjects. Bacteriuria occurs with sufficient frequency in prematurely born infants to warrent repeated examinations of the urine during their nursery stay. In view of the difficulty in obtaining adequate specimens of urine, as well as the paucity of positive findings, routine screening of full-term infants does not appear to be indicated.

The congruence of creatinine and inulin clearances in children: Use of the Technicon Auto Analyzer

TI-IE U S ~ F U L N ~ . S S and validity of the clearance of endogenous creatinine as an estimate of the rate of glomerular filtration has generated continuous debate since its introduction by Rehberg 1 in 1926. Any other procedure provoking such controversy would have been discarded long ago; however, the lack of an acceptable substitute, offering to the clinician a practical, reasonably reliable estimate of glomerular filtration rate (GFR) , explains the continued popularity, of the creatinine clearance. One of the serious objections to the creatinine clearance is that the commonly employed Jaff6 reaction measures not only creatinine, but also a variety of other socalled noncreatinin6 chromogens. 2 Thus the apparent value of blood creatinine determined with this method is erroneously and unpredictably high, serving to depress clearance values. On the other hand, the moiety of urinary creatinine contributed by tubular secretion increases the clearance, particularly

Bicarbonate reabsorption and hydrogen ionexcretion in children with renal tubular acidosis

Nine children with renal tubular acidosis have been evaluated on the basis ofbicarbonate reabsorption during intravenous infusion, and of excretion of hydrogen ion following administration of ammonium chloride. In 3, who were shown to have distal renal tubular acidosis, bicarbonate threshold and rate of reabsorption were normal; they had small amounts of bicarbonate in urine, however, even at low levels of serum bicarbonate, owing to their inability to depress urinary pH below 6.5. Six children had proximal renal tubular acidosis, primary in 4 and due to the Fanconi syndrome in 2. Although all had a low bicarbonate threshold and 4 had a low Tm, urinary pH and excretion of hydrogen ion during metabolic acidosis were within normal limits in each subject when the serum bicarbonate was below the threshold. Classification of patients with renal tubular acidosis as either proximal or distal is of importance because of major differences in clinical features, complications, and therapy.