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Solitary functioning kidneys form an important subgroup of congenital anomalies of the kidney and urinary tract (CAKUT). A solitary kidney can be congenital or acquired after unilateral nephrectomy and is often associated with ipsilateral urogenital anomalies. Both types of solitary functioning kidney are associated with an increased risk of chronic kidney disease (CKD). A low functional nephron number results in compensatory glomerular hypertension and enlargement of remnant nephrons, indicating glomerular hyperfiltration. Glomerular hyperfiltration may lead to glomerulosclerosis, which further results in hypertension, proteinuria, and decline of the glomerular filtration rate (GFR) in the long run. About 20–30% of patients with solitary functioning kidney have hypertension, proteinuria, or reduced GFR during childhood, especially those with associated CAKUT. Regular and lifetime monitoring (including growth, blood pressure, serum creatinine, proteinuria or microalbuminuria, and renal ultrasound) is required. The frequency and modality of follow-up should be adapted to individual risk for CKD. Early detection of renal injury and timely nephroprotective measures are critical.     

Renal functional reserve in children with a history of hemolytic uremic syndrome through technetium-99m diethylene-triamine-penta-acetic acid clearance

Protein loads in normal subjects increase glomerular filtration rate (GFR), which implies a renal functional reserve (RFR). Patients who have suffered a loss in the number of nephrons may show normal values of GFR due to hyperfiltration of remnant nephrons, with subsequent loss of RFR. This could be an early sign of renal damage, and probably a contributory factor to renal damage progress. The objective of this study is to determine the RFR through technetium-99m diethylene-triamine-penta-acetic acid (99m Tc-DTPA) clearance in patients who have recovered from hemolytic uremic syndrome. Renal functional reserve was determined in 33 children from 2 to 16 years old, with normal values of proteinuria, serum creatinine and creatinine clearance after over a year of having suffered hemolitic uremic syndrome. For that purpose 99m Tc-DTPA clearance was determined in basal condition and following protein load. In 17 patients DTPA clearance increased 20% or more after protein load compared to basal condition, and they were considered to have normal RFR, a probably index of totally recovered renal function; in the remaining 16 patients the increases were lower than 20%, and were considered to have no RFR, condition that was postulated as a contributing factor to renal damage progress. There was not significant differences either in age or basal GFR between both groups. Being the test easier than inuline clearance and more accurate than creatinine clearance, it proves particularly useful for early diagnosis of patients that need special follow-up and treatment.     

Paleonephrology and reflux nephropathy. From the 'big bang' to end-stage renal disease

Urinary tract infections, in association with ureteral reflux or dysperistalsis, may lead to invasive renal parenchymal infection and residual scarring (reflux nephropathy). Such infections in infants are often not diagnosed during the acute phase. Late sequelae of reflux nephropathy include hypertension, proteinuria, or chronic renal failure. The latter may eventuate in the subset of patients with urinary tract infection and unilateral reflux extending to a solitary kidney or bilateral reflux. Proteinuria may herald the inexorable progression of glomerular sclerosis in patients destined to progress to end-stage renal disease, despite the absence of further recurrences of urinary tract infections. The mechanism of progression is probably similar to that occurring in other forms of chronic, diffuse parenchymal renal disease, which all have similar alterations in glomerular hemodynamics (an increase in glomerular capillary flow, pressure, and filtration). The consequent hyperfiltration per nephron may be related to the level of dietary protein intake or to some derivative of the protein load. Hyperfiltration appears to recapitulate the presumed renal hemodynamic response to the relatively high level of episodic meat consumption by paleolithic hunter-gatherers. A prudent therapeutic intervention in children with progressive reflux nephropathy may be a proportional reduction in protein intake.     

Renal histological changes in relation to renal function and urinary protein excretion in IgA nephropathy.

Renal function and urinary protein excretion (UPE) were investigated at the time of kidney biopsy in 24 children with IgA nephropathy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by clearances of inulin and para-aminohippuric acid. For UPE albumin, IgG, beta 2 microglobulin, and creatinine were analysed. Glomerular global/segmental sclerosis and crescents in the biopsy specimens were assessed, and glomerular and tubulointerstitial changes classified on a five degree scale. The patients with tubulointerstitial or mesangial biopsy changes or glomerular sclerosis had significantly lower GFR than those without corresponding lesions. Patients with segmental sclerosis also had higher excretion rates of IgG, which increased with increasing segmental sclerosis. Six patients had GFRs below 2SD of the controls. Within the group of patients with reduced GFR overt albuminuria, a raised excretion rate of IgG, interstitial fibrosis, and advanced mesangial lesions were more frequent. A rising excretion rate of IgG seems to indicate both reduced GFR and increasing segmental glomerulosclerosis and may be a marker of progressive disease.     

Short-term effect of low and high protein intake on renal function in children with renal disease

The short-term effect of different levels of protein intake on renal function was investigated in 18 children with moderately (51-85 ml/min/1.73 m2 BSA) or severely (9-50 ml/min/1.73 m2 BSA) reduced glomerular filtration rates (GFR). The GFR and effective renal plasma flow (ERPF), estimated as the clearances of respectively inulin and para-aminohippuric acid during uncontrolled (2-2.5 g/kg bw), low (1.2 g/kg bw for 12 days) and high (3-5 g/kg bw for 24 h) protein intake were determined by a standard clearance method employing continuous infusion and spontaneous voiding. There were no significant differences in GFR or ERPF during uncontrolled and low protein intake. During high protein intake the GFR and ERPF increased significantly in patients with GFRs above 50 ml/min/1.73 m2 BSA and ERPFs above 150 ml/min/1.73 m2 BSA. It is concluded that these findings might indicate a functional reserve capacity in children with only moderately reduced renal function.     

Persisting Glomerular Hyperfiltration in Short-term Diabetic Children without Microalbuminuria

ABSTRACT. The renal function in a group of diabetic children ( n =29; age: 4–17 yr; IDDM duration: 1.5–13 yr) was studied with a 3 year interval. At the first evaluation glomerular filtration rate (GFR) as assessed by inulin clearance was significantly increased compared to control values (167±32 vs. 124±18 ml/min/1.73 m²; p ≤0.01). Eighteen out of 29 children exhibited a glomerular hyperfiltration (GFR ≥ 160). Three years later mean GFR was identical (169±25 ml/min/1.73 m²) and 16 children were hyperfiltrating. Among them, 11 have had a persisting glomerular hyperfiltration over the 3-year period. Renal plasma flow (RPF) was positively correlated to GFR ( r =0.7; p ≤0.01) and remained elevated at both evaluations (794±163 and 812±157 ml/min/1.73 m², p ≤0.01 vs. control values). When the children were separated into 3 groups according to IDDM duration no significant differences were observed in the results for GFR and RPF. Mean urinary albumin excretion was comparable at the 3-year interval, and not significantly different from the control values (5.2±3.7 and 8.2±6.6 respectively vs. 8.65±4 |ig/min). None of the children demonstrated a persistent microalbuminuria. This study reveals a high proportion of diabetic children with a persisting glomerular hyperfiltration, without any other symmptom of incipiens nephropathy. If elevated GFR plays an important role in the development of diabetic nephropathy, this study emphasizes the value of regular evaluation of renal function in diabetic children.     

Persisting glomerular hyperfiltration in short-term diabetic children without microalbuminuria

The renal function in a group of diabetic children (n=29;age;4-17 yr; IDDM duration: 1,5-13 yr) was studied with a 3 year interval. At the first evaluation glomerular filtration rate (GFR) as assessed by inulin clearance was significantly increased compared to control values (167 +/- 32 vs. 124 +/- 18 ml/min/1.73 m2; pl less than 0.01). Eighteen out of 29 children exhibited a glomerular hyperfiltration (GFR greater than 160). Three years later mean GFR was identical (169 +/- 25 ml/min/1.73 m2) and 16 children were hyperfiltrating. Among them, 11 have had a persisting glomerular hyperfiltration over the 3-year period. Renal plasma flow (RPF) was positively correlated to GFR (r=0.7; p less than 0.01) and remained elevated at both evaluations (794 +/- 163 and 812 +/- 157 ml/min/1.73 m2, p greater than 0.01 vs, control values). When the children were separated into 3 groups according to IDDM duration no significant differences were observed in the results for GFR and RPF, Mean urinary albumin excretion was comparable at the 3-year interval, and not significantly different from the control values (5.2 +/- 3.7 and 8.2 +/- 6.6 respectively vs. 8.65 +/- 4 microgram/min). None of the children demonstrated a persistent microalbuminuria. This study reveals a high proportion of diabetic children with a persisting glomerular hyperfiltration, without any other symptom of incipiens nephropathy, If elevated GFR plays an important role in the development of diabetic nephropathy, this study emphasizes the value of regular evaluation of renal function in diabetic children.     

Short-Term Effect of Low and High Protein Intake on Renal Function in Children with Renal Disease

ABSTRACT. The short-term effect of different levels of protein intake on renal function was investigated in 18 children with moderately (51–85 ml/min/1.73 m² BSA) or severely (9–50 ml/min/1.73 m² BSA) reduced glomerular filtration rates (GFR). The GFR and effective renal plasma flow (ERPF), estimated as the clearances of respectively inulin and para-aminohippuric acid during uncontrolled (2-2.5 g/kg bw), low (1.2 g/kg bw for 12 days) and high (3–5 g/kg bw for 24 h) protein intake were determined by a standard clearance method employing continuous infusion and spontaneous voiding. There were no significant differences in GFR or ERPF during uncontrolled and low protein intake. During high protein intake the GFR and ERPF increased significantly in patients with GFRs above 50 ml/min/1.73 m² BSA and ERPFs above 150 ml/min/1.73 m² BSA. It is concluded that these findings might indicate a functional reserve capacity in children with only moderately reduced renal function.     

实验性糖尿病大鼠肾组织一氧化氮与肾小球高滤过的关系

目的　探讨一氧化氮 (NO)在糖尿病大鼠肾组织中的动态变化及其与肾小球高滤过的关系。方法　用链脲佐菌素(STZ)制造大鼠糖尿病模型 ,在模型成功后 4、8、1 2周分别采用硝酸还原酶间接法和吸光度比较法测定肾组织NO含量、一氧化氮合酶 (NOS)活性。同时取肾组织在光镜下镜检 ,并利用计算机图像分析仪测定肾小球截面积。以内生肌酐清除率 (Ccr) ,代表肾小球滤过率 (GFR)。结果　糖尿病大鼠肾组织NO含量、NOS活性 4周时升高 ,8、1 2周时渐下降 ,与对照组比较有显著差异 (P <0 .0 5)。与同期正常对照组比较 ,糖尿病组肾重 /体质量、2 4h尿蛋白排泄量、GFR和肾小球平均截面积均明显升高 (P<0 .0 5) ,且随病程延长 2 4h尿蛋白排泄量渐升高 ,GFR渐下降 ,但仍高于正常。经相关分析表明 ,肾组织中NO与GFR呈正相关 ,与尿蛋白排泄量呈负相关。结论　糖尿病大鼠存在血管内皮分泌功能紊乱 ,早期内皮舒张因子分泌增多 ,后期减少 ,内皮源性舒张因子NO水平变化与NOS活性变化一致 ,并与糖尿病早期肾小球高滤过相关。     

Clinical practice

Proteinuria detection in children is a challenge. Five percent to 15% and 0.4–1% of school children present either transient (benign) or persistent increased amount of protein in urine, respectively. Persistent proteinuria constitutes not only a sign of overt kidney disease but may also be the first indicator of silent renal damage. Proteinuria is a marker for hyperfiltration in individuals with reduced nephron mass and one of the most important independent risk factor for renal disease progression as well. It constitutes the single most important risk factor for future loss of kidney function, preceding glomerular filtration rate reduction. Further, proteinuria itself is diagnostic of cardiovascular disease with prognostic value and target organ involvement in high-risk populations such as diabetic, obese, hypertensive children, or those with known reduced renal mass or previous renal injury. Current strategies to prevent CKD progression, a concept known as renoprotection, are focused on reducing urinary protein excretion among other factors. Reversibility of organ damage in early stages is possible; therefore, pediatricians should screen children for proteinuria or microalbuminuria, mainly in high-risk groups.     

Reduced Glomerular Filtration and Elevated Urinary Protein Excretion in Diabetic Ketoacidosis

ABSTRACT. Glomerular filtration rate (GFR) was measured by two methods in 9 children with diabetic ketoacidosis (DKA), directly by true creatinine clearance and indirectly by means of serum beta-2-microglobulin levels. We found significantly reduced GFR in the first hours of DKA. The rapid improvement in GFR after fluid and electrolyte replacement indicates that volume depletion is the major cause of low filtration rate. In spite of the reduced GFR we observed pronounced albuminuria and low molecular weight (LMW) proteinuria. We conclude that the pathological albuminuria and microalbuminuria in DKA are caused not by glomerular hyperfiltration but by tubular dysfunction     

Long-term follow up of renal function in IgA nephropathy.

Fifty one children with IgA nephropathy verified at biopsy have been followed up clinically and functionally for 0.4-16.8 years from the onset of symptoms. Renal function was evaluated by determining the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) from the clearances of inulin and para-aminohippuric acid. Fifteen (29%) of the children had raised serum creatinine concentrations at the onset. Mean GFR was significantly lower than that of controls at the first investigation. During the follow up GFR and ERPF decreased and were significantly lower than in the controls after eight years of disease. The significant fall in renal function was found in children with proteinuria and especially in boys, in whom GFR and ERPF decreased from a mean (SEM) of 117 (5) and 616 (31) at 2.8 years to 97 (6) and 509 (36) ml/min/1.73 m2 at 7.5 years. Patients with raised serum creatinine concentrations at the onset had significantly lower GFRs, and patients with macroscopic haematuria at this time did not show decreased renal function at follow up. In conclusion, children with IgA nephropathy do not seem to have a benign clinical course. Boys with proteinuria show a significant decrease in renal function during follow up.     

Evaluation of renal function after successful treatment for unilateral,non‐syndromic wilms tumor

Impaired renal function may occur in experimental animals following surgical removal of most functioning renal tissue (“hyperfiltration injury”). Although end‐stage renal disease is uncommon among long‐term survivors of unilateral, non‐syndromic Wilms tumor, concern has been expressed that there may be an increased risk of less serious, but progressive, renal function impairment among these individuals. The recent development of equations for estimating glomerular filtration rate (eGFR) has facilitated the study of renal function in Wilms tumor survivors. However, the estimating equations were developed to categorize individuals with chronic kidney disease and have significant limitations with regard to the accuracy of individual GFR estimates. These limitations must be considered when utilizing the estimating equations in cross‐sectional or longitudinal evaluations of renal function in cohorts of patients who have been treated successfully for Wilms tumor or other childhood cancers. Pediatr Blood Cancer 2013;60:1929–1935. © 2013 Wiley Periodicals, Inc.     

Studies in Renal Response to Various Protein Intakes in Preterm Infants

ABSTRACT. The renal effects of two diets—breast-milk and breast-milk with extra human protein (7 g/l breast-milk)—were compared in very low birth weight infants with a gestational age of 26 to 30 weeks. When the infants were given the high protein diet for one week the glomerular filtration rate (GFR) increased significantly more than when breast-milk alone was given. Sodium clearance showed a similar increase in proportion to the GFR during the two diets. The high protein diet raised the urine osmolality moderately in all individuals, while the diuresis remained unchanged. The data in the present study indicate that the function of the immature kidney is influenced by the amount of protein in the diet. However, the long-term renal effects in preterm infants maintained on a high protein intake remain unknown.     

Studies in renal response to various protein intakes in preterm infants

The renal effects of two diets--breast-milk and breast-milk with extra human protein (7 g/l breast-milk)--were compared in very low birth weight infants with a gestational age of 26 to 30 weeks. When the infants were given the high protein diet for one week the glomerular filtration rate (GFR) increased significantly more than when breast-milk alone was given. Sodium clearance showed a similar increase in proportion to the GFR during the two diets. The high protein diet raised the urine osmolality moderately in all individuals, while the diuresis remained unchanged. The data in the present study indicate that the function of the immature kidney is influenced by the amount of protein in the diet. However, the long-term renal effects in preterm infants maintained on a high protein intake remain unknown.     

Hypertension and microalbuminuria in children with congenital solitary kidneys

Aim:   According to the hyperfiltration hypothesis, a low nephron endowment will lead to hyperfiltration in the remaining glomeruli and is associated with systemic hypertension, proteinuria and glomerulosclerosis. Being born with one functioning kidney instead of two, for instance because of unilateral renal agenesis or multicystic dysplastic kidney, is a cause of congenital renal mass reduction.
Methods:   In order to study the effect of congenital renal mass reduction on renal function and blood pressure, a retrospective chart review of 66 patients at the Pediatric Renal Center of the VU University Medical Center was performed. As intrauterine growth restriction is associated with a low nephron endowment, the additional effect of birthweight was also studied.
Results:   A total of 50% of patients with congenital renal mass reduction is found to be hypertensive, using anti-hypertensive drugs, and/or having microalbuminuria (>20 μg/min). Patients born small for gestational age have significantly smaller kidneys and lower estimated glomerular filtration rate than patients with a normal birthweight.
Conclusions:   We conclude that microalbuminuria and/or hypertension is present in 50% of patients with congenital solitary kidneys, which warrants a systematic follow-up of blood pressure, proteinuria and renal function in all patients with congenital solitary functioning kidneys, especially in patients with a low birthweight.     

Phosphorus intake in preterm babies and variation of tubular reabsorption for phosphate per liter glomerular filtrate.

Inadequate low intake of phosphorus can induce a hypophosphatemic depletion syndrome resulting in hypercalcemia, hypercalciuria, hypophosphatemia, and rickets. Tubular reabsorption for phosphate per liter glomerular filtration rate (TP/GFR) has been proposed as a reliable index of renal phosphate handling for all age groups. In the present study, carried out in 12 healthy premature babies fed unmodified pooled human milk and then a preterm formula for two periods of 10 days, we demonstrated clearly that TP/GFR as well as calciuria can reflect the poor phosphorus intake and that the kidney of preterm babies is able to rapidly adapt itself to an increase in phosphorus diet content.     

Early detection and treatment of diabetic nephropathy

Renal involvement in diabetes, known as diabetic nephropathy (DN), is a progressive disease and occurs as a result of direct and indirect effects of hyperglycemia. DN is a serious public health concern because it is the leading cause of end stage renal disease (ESRD) in most developed countries and is associated with increased cardiovascular mortality and morbidity. DN is characterized by an initial period of glomerular hyperfiltration, associated with progressively increasing proteinuria, followed by a gradual decline in glomerular filtration rate, resulting in ESRD. Prevention of DN depends on awareness of risk factors for DN, screening for microalbuminuria and hypertension, monitoring glycemic control, and initiating or modifying treatment as needed. Risk factors for development of DN include hyperglycemia, hypertension, positive family history of nephropathy and hypertension, and smoking. Significant advances have been made in recent years in understanding the pathogenesis of DN, raising the possibility that newer therapies may prevent or slow the progression of DN.     

Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease

OBJECTIVES: Glomerular disease and renal failure cause substantial morbidity for patients with sickle cell disease (SCD). Proteinuria is an early manifestation of sickle nephropathy, but the prevalence of proteinuria and its clinical correlations in children with SCD are unknown. STUDY DESIGN: Data were collected prospectively on children with SCD for 10 years including physical measurements, laboratory test results, and clinical complications. Persistent proteinuria was defined as > or =1+ protein on urinalysis for at least 6 months. The glomerular filtration rate was estimated with serum creatinine concentration and height. Proteinuria was correlated with other variables by chi(2) analysis. RESULTS: Proteinuria occurred in 20 of 442 pediatric patients including 15 (6.2%) with sickle cell anemia. Proteinuria increased with age, affecting 12% of older teenagers with sickle cell anemia. Proteinuria was significantly associated with lower hemoglobin concentration, higher mean corpuscular volume, and higher leukocyte count. For children of some ages, proteinuria was associated with complications including stroke, acute chest syndrome, cholelithiasis, and hospitalizations. Glomerular filtration rate hyperfiltration occurred early in life, followed by normalization. CONCLUSIONS: Sickle nephropathy, manifested as persistent proteinuria, begins early in life, occurs in all forms of SCD, and is associated with severity of disease. Early detection of proteinuria may allow therapy to prevent progressive renal insufficiency.     

Influence of different protein intake on renal growth in young rats

We have examined the effect of high protein intake on kidney growth and function in growing rats. The rats were kept on an isocaloric diet containing 12%, 21% and 50% protein, from weaning (16 days) until the time of investigation (18, 20, 24, 40 or 80 days). There was no significant difference between the 12% and 21% protein groups in any of the parameters studied. 50% protein increased body weight (BW) and kidney weight (KW). The increase in kidney weight was already evident after 2 days and exceeded the increase in body weight in all age groups. At 24 days renal cortical DNA and the protein/DNA ratio were significantly increased in the 50% protein group. At 40 days the cortical DNA content, but not the protein/DNA ratio, was significantly increased in the 50% group. The glomerular filtration rate GFR) was studied at 40 days. Total GFR as well as GFR/BW was significantly higher in the 50% group than in the 21% group. In one protocol the diet was discontinued at age 40 days and the rats were studied at age 80 days. In these rats all parameters of renal size and function were the same as in the rats that had had a normal (21%) protein intake from weaning. We conclude that in young rats high protein intake reversibly increases GFR out of proportion to BW and selectively and reversibly stimulates kidney growth by stimulating cell proliferation.