John E. Lewy

Somatomedin and Growth after Renal Transplantation

Extract: Hormonal and metabolic factors which influence growth were studied in nine growth-retarded uremic children who received renal homografts. Post-transplant growth velocity based on bone age (GVBA) became normal in four (88–103%), accelerated in two (127–139%), and remained subnormal in three (18–50%). Serum somatomedin (SM), was very low in all children before transplant (0.39 ± 0.10 U/ml), but rose in each child after transplantation. Post-transplant somatomedin (0.84 ± 0.14 U/ml) was not significantly different from the somatomedin of eight healthy male control subjects matched for bone age (1.03 ± 0.16). Post-transplant GVBA was directly correlated (P < 0.05) with serum somatomedin and creatinine clearance (Ccr), but was not related to stimulated growth hormone response or to other variables of endocrine function. The data suggested that the growth failure in our patients with severe chronic uremia was due, at least in part, to lack of serum somatomedin. However, in four of five patients with persisting moderate azotemia (Ccr 11.8–42.5 ml/min/1.73 m2), subnormal growth continued despite relatively normalized serum somatomedin activity. Three of the four poorly growing azotemic patients had the highest average steroid dosages in the group (prednisolone > 9.1 mg/m2/24 hr).Speculation: If low serum somatomedin activity develops in the course of end stage renal disease in children, growth retardation may be the consequence. After renal transplantation normalization of serum somatomedin activity may be a necessary although not sufficient condition for the resumption of growth.

Ultrafast Contrast Enhanced Magnetic Resonance Imaging of Congenital Hydronephrosis in a Rat Model

Since new ultrafast magnetic resonance imaging (MRI) might offer unique advantages for evaluating renal blood flow, anatomy and urinary excretion, we used this technique to characterize a rat model with congenital partial ureteropelvic junction obstruction. MRI of 9 rats from an inbred colony with unilateral congenital (nonsurgical) hydronephrosis was compared with the contralateral nonhydronephrotic kidney serving as control. Our new imaging technique consisted of a 1-minute ultrafast gradient recalled imaging sequence during the first minute (64 images per imaging time 960 milliseconds) after contrast bolus injection with gadolinium-diethylenetriaminepentaacetic acid for assessment of renal blood flow followed by a 30-minute period with image acquisition every 30 seconds to study contrast distribution and excretion. Signal intensities were analyzed continuously over selected, different regions of interest. Anatomic analysis of MRI noncontrast studies showed precise delineation of the hydronephrotic pelvis and corticomedullary junction. After contrast gadolinium-diethylenetriaminepentaacetic acid injection signal intensity from the region of interest from hydronephrotic kidneys differed from nonhydronephrotic kidneys by showing less cortical decrease, suggesting decreased blood flow, less medullary decrease and delayed contrast excretion. Clear contrast distribution among the cortex, medulla and collecting system allowed selective estimation of different regions of interest and excellent anatomic evaluation. Renal anatomy and renal pelvic pressures were confirmed after scans were completed. Ultrafast contrast enhanced MRI allows simultaneous assessment of renal morphology, blood flow and function. In hydronephrotic partially obstructed kidneys distinct flow and excretion patterns measured with contrast enhanced MRI allow differentiation between the obstructed and nonobstructed kidney on physiological rather than purely anatomic means. This imaging technique may provide a useful method of evaluating congenital hydronephrosis obviating the need for multiple different diagnostic procedures.

Congenital Unilateral Hydronephrosis in a Rat Model: Continuous Renal Pelvic and Bladder Pressures

We investigated a rat model with inbred unilateral congenital hydronephrosis. Simultaneous bladder and renal pelvic pressures were measured during different urinary flows, and during bladder filling and voiding in these congenitally hydronephrotic rats (approximately 45 days old) and normal nonhydronephrotic rats from the same colony. Differential pressures between pelvis and proximal ureter were determined. Upon termination of the experiment the urinary tract was removed and processed for histological examination. Hydronephrotic rats had significantly higher renal pelvic pressures throughout bladder filling at all urinary flow rates than normal rats. These elevated renal pelvic pressures exceeded bladder pressures at high flows (for example bladder pressure at 50% capacity was 8.9 +/- 3.1 cm. water and corresponding pelvic pressure was 20.8 +/- 2.1 [hydronephrosis] versus pelvic pressure 7.4 +/- 1.1 [control]). While pressures in the proximal ureter were higher than in the pelvis in normal rats the hydronephrotic rats showed significantly higher pressures in the pelvis, suggesting that the site of obstruction is the ureteropelvic junction. Histological evaluation of the excised kidneys revealed only minimal tubular changes. This study represents a unique animal model with unilateral hydronephrosis from a partially obstructing ureteropelvic junction. Moreover, the data indicate that partial urinary obstruction and the associated renal pelvic pressures should be defined with reference to bladder fullness and urinary flow rates.

Renal Function in Rats with Unilateral Proteinuria Produced by Renal Perfusion with Aminonucleoside

Summary: Left (L) renal perfusion with an aminonucleoside of puromycin (PA), was used to produce unilateral proteinuria in 15 rats to examine the mechanisms responsible for renal salt retention in the nephrotic syndrome. Thirteen control rats underwent L renal perfusion with isotonic saline. Animals were studied 8 (group I) or 13 (group II) days after perfusion. Renal perfusion with saline per se did not change the glomerular filtration rate, renal plasma flow, or absolute and fractional excretion of sodium (Na) from the perfused kidney. PA animals showed a significant decrease in glomerular filtration rate from the perfused kidney and a proportional decrease in the absolute excretion of Na from the PA perfused kidney as compared to the right kidney. The fractional excretion of Na was equivalent in the L and R kidneys of the PA animals. The mean absolute Na excretion from the nonproteinuric R kidney of PA rats was almost twice that of the R kidney of the controls. The increased Na excretion by the nonproteinuric kidney of the PA animals compensated for the sodium retention by the proteinuric kidney.Speculation: In rats with unilateral proteinuria, unilateral sodium retention occurs due to mechanisms intrinsic to the proteinuric kidney. Systemic natriuretic factors may compensate for the unilateral sodium retention when contralateral kidney is nonproteinuric. When both kidneys are proteinuric, systemic counterbalancing events may not be operative and net sodium retention may result.

Hemodiafiltration for vancomycin overdose in a neonate with end-stage renal failure

Abstract We describe continuous venovenous hemodiafiltration (CVVHD) with a high-flux membrane as a novel treatment modality for vancomycin overdose associated with renal insufficiency. CVVHD was used in a 6-day-old male with a solitary hypodysplastic kidney, suspected sepsis, and anuric renal failure who subsequently received an accidental tenfold overdose of vancomycin. We furthermore present evidence for the importance of countercurrent dialysis in addition to continuous hemofiltration for optimal vancomycin removal.

Reversible vasoconstriction in rats with congenital unilateral hydronephrosis

We studied the effects of inhibition of either prostaglandins or the role of prostanoids and the renin-angiotensin system on renal function in rats with congenital unilateral hydronephrosis. Wistar rats with congenital unilateral hydronephrosis were infused with normal saline (control), captopril dissolved in normal saline or indomethacin dissolved in a solution of sodium chloride and sodium carbonate. In the control group both glomerular filtration rate (GFR) and effective renal plasma flow were reduced in the right hydronephrotic kidney (RHK) compared with the normal left kidney. Indomethacin did not improve renal function in the RHK. Captopril significantly improved GFR in the RHK. These results support the conclusion that the renin-angiotensin system is an important mediator of reduced GFR in congenital unilateral hydronephrosis in rats.

Familial nephrotic syndrome and focal segmental glomerulosclerosis

Three of five siblings developed a steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis within a four-month period. Two of the siblings with nephrotic syndrome (Patients 1 and 2) also have sickle cell anemia; the third (Patient 3) carries the thalassemia trait. The dizygotic twin brother of Patient 2 has sickle cell anemia, but does not have the nephrotic syndrome. The nephrotic syndrome of patient 1 was resistant to corticosteroid and cyclophosphamide therapy and she developed severe renal failure 14 months after onset. The nephrotic syndrome of Patients 2 and 3 was steroid resistant but was partially responsive to cyclophosphamide therapy. They have persistent proteinuria with mild elevation of serum creatinine concentration and hypertension 5 1/2 years after diagnosis. In this family, the nephrotic syndrome appeared unrelated to the specific hemoglobinopathy, HLA type or mixed lymphocyte culture responsiveness despite the similarity of the renal disease.

Safety of Intravenous Diazoxide in Children with Severe Hypertension

The safety and efficacy of diazoxide administered intravenously in the treat ment of children with acute severe hypertension have been evaluated by a col laborative study. Observations of the response of blood pressure in 36 patients, ranging in age from two months to 18 years, during the initial episode of hos pitalization reveal diazoxide treatment to be effective in lowering blood pres sure in 94 per cent of the cases. No serious adverse circulatory, fluid and electrolyte, metabolic or hematologic effects were observed. Symptomatic and subjective reactions observed with diazoxide administered intravenously to children were identical with those described in adults. Reinstitution of other means of antihypertensive therapy is safe and effective when delayed until the transiently induced period of hypotension has passed. Repeated use of diaz oxide for subsequent recurrence of severe hypertension was equally effective and safe in 93 per cent of the instances. The results lead us to recommend the use of intravenous diazoxide for treatment of children with severe symptomatic hypertension especially when it is refractory to control by other hyper tensive agents.

Stimulation of p-Aminohippurate Extraction in the Maturing Rabbit Kidney

Summary: In vivo studies were performed to evaluate maturational changes in PAH extraction (EPAH) in the rabbit and to determine whether accelerated maturation of this process could be achieved. Fifty-four animals were injected with penicillin before study at 10, 14, 21, or 28 days of life. Forty-eight rabbits served as saline-injected controls. PAH extraction in controls increased from 29.3 ± 2.4% at 10 days of age to 35.9 ± 3.3% at 14 days, 59.7 ± 3.5% at 21 days, 71.6 ± 1.9% at 28 days, and 72.7 ± 2.3% at 35 days of life. Penicillin injection on the 3 days before study resulted in enhancement of EPAH on days 10 and 14 to 42.7 ± 2.4% and 65.0 ± 3.2% (P < 0.005). On days 21 and 28 less stimulation was noted (68.7 ± 2.3%; 76.0 ± 4.1%). Preinjection on days 6–9 with study delayed to day 14 also led to augmentation (46.7 ± 3.7% P < 0.05) but less than that achieved after injection on days 10–13. These data suggest that EPAH stimulation may be transient, descreases as maturation is approached and is likely related to substrate availability.Speculation: The mechanism(s) responsible for the transport of organic anions in young rabbits responds to factors related to subtrate availability by increasing the rate of transfer of these substances. Enzyme systems, tubular mass, transport proteins, and blood flow distribution may be involved; singly, or in combination.

Estimation of parenteral fluid requirements.

This article reviews the normal physiologic losses of water and electrolytes from the body, the source of the loss, and the increased body loss of water associated with fever. The three different methods for estimating replacement of water and electrolyte losses are described in this review.