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.     

Increased renal echogenicity in the neonate

We report data on newborn infants with increased renal echogenicity observed at the Division of Neonatal Intensive Care of Pavia during a five-year period. Review of 1600 abdominal ultrasonic evaluations revealed 103 newborn infants (56 females and 47 males, with birth weight from 560 to 3700 g and gestational age from 25 to 42 weeks) whose kidneys showed increased echogenicity. Three patients with infantile polycystic kidney disease, two with renal candidiasis, three with dysplastic kidney and two with renal vein thrombosis showed diffuse hyperechogenicity. Three patients with hemolytic-uremic syndrome showed cortical hyperechogenicity. Increased medullary echogenicity was observed in 90 infants with renal disease secondary to perinatal asphyxia. In 76 of these patients the evaluation of renal echogenicity and the renal function improved, while in the remaining 14 newborns the renal alteration persisted until death.     

Clinical features of unilateral multicystic renal dysplasia in children

A clinical study of 204 patients with unilateral multicystic renal dysplasia referred to 30 nephrology departments was undertaken to assess the frequency of complications in children who underwent nephrectomy (n=40) versus those who were treated conservatively (n=164). Six patients required antihypertensive treatment, 30 (13% of girls, 17% of boys) had at least one episode of urinary tract infection. The number of clinical complications did not differ in patients who underwent nephrectomy in comparison to those who did not. The dysplastic kidney decreased in size in 65% of kidneys with repeated ultrasound values; no change occurred in 16%, while an increase in maximal diameter was observed in 19%. Contralateral kidney length of more than 2 standard deviation scores (SDS) was seen in 30% of patients. There is evidence for a slight impairment of renal function in the whole study group given by a median of serum creatinine level of 0.63 SDS in all patients available for analysis. Among those 35 patients with contralateral anomalies (mainly obstructive changes and vesico-ureteral reflux), all 3 patients with contralateral changes suggestive of hypoplasia and 22% with obstruction, but only 1/7 (14%) with reflux showed elevated serum creatinine level >2 SDS. Conclusion Renal function seems to be slightly impaired in patients with unilateral multicystic renal dysplasia. The apparent tendency to regression of the dysplastic kidney and no difference in the number of complications justify a conservative management rather than operative intervention. Received: 9 May 1997 / Accepted in revised form: 16 February 1998     

Lymph node enlargement as a sign of acute hepatitis A in children

Abdominal ultrasound was performed in 58 children presenting with proven acute hepatitis A and in 63 controls of the same age. There are well-known echographic signs of hepatitis (liver enlargement, gallbladder wall thickening, periportal hyperechogenicity) but they were not constantly found. We describe in all the hepatitis cases an enlargement of lymph nodes located in the hepatic hilum, pancreatic area and small omentum: they appeared hyperechogenic at the centre with hypoechogenic outer layer. Such enlarged lymph nodes were not observed in the controls.Presented at the ESPR meeting in Dublin 1989. Selected for publication by an International Group of the ESPR     

Renal injury in perinatal hypoxia: ultrasonography and changes in renal function

 We studied 12 hypoxaemic neonates (5 mature newborns, birth weight 2850–4200 g, gestational age 37–41 weeks; and 7 premature newborns, birth weight 770–1850 g, gestational age 27–34 weeks;) with repeated urine and blood chemistry on the 1st and 3rd days of life. Nephrosonographical examinations on the 1st, 3rd and 5–7th days of life were also performed. As controls, 12 healthy infants were examined (gestational age 36–42 weeks; birth weight 2450–4200 g). Hypoxic neonates had higher serum creatinine and blood urea nitrogen levels. Tubular markers also demonstrated renal tubular damage. Neonates in both hypoxic groups were hyperuricaemic and hyperuricosuric, and had higher urinary protein concentrations. All these infants exhibited an increased echogenicity of the renal cortex, and 11/12 showed the same finding in the medullary area. These findings disappeared within 1 week in all infants. Among the 12 healthy control infants, no cortical hyperechogenicity was found and only three of these infants displayed transient medullary renal hyperechogenicity. Conclusion Since the hypoxaemic infants demonstrated greatly increased urinary concentrations of uric acid and protein, we suggest that a temporary precipitation of these two agents may be responsible for the ultrasonographic findings. Circulatory redistribution might play a role in the phenomenon of cortical hyperechogenicity. Received: 23 March 2000 / Accepted: 14 March 2001     

Mild renal pelvic dilatation is not predictive of vesicoureteral reflux in children

Objective. To determine if mild renal pelvic dilatation at renal ultrasound (RUS) is a reliable sign of vesicoureteral reflux (VUR) at voiding cystourethrogram (VCUG) in children. Materials and methods. All patients less than 10 years of age who had RUS and VCUG on the same day during a 2-year period were identified in a computerized database. The appearance of the collecting system of each kidney was classified into two groups: group 0 – no dilatation (≤ 2-mm anteroposterior diameter of the renal pelvis) and group 1 – 3 to 10-mm AP diameter of the renal pelvis without caliectasis. VUR at VCUG was graded using the International Reflux Study Committee system. Results. Four hundred fifty-five patients (76 boys; 379 girls) with 910 kidneys were included. VUR occurred in 268 kidneys in 174 patients. There were 820 group 0 kidneys and 90 group 1 kidneys. Kidneys classified as group 1 (25.0 % had reflux) were no more likely to have reflux than were kidneys with nondistended (group 0) collecting systems (31.2 % had reflux). There was no statistical difference in the rate of reflux in patients with group 1 renal pelvic distention (39.2 % refluxed) and a normal collecting system (33.3 % refluxed) (P = 0.365). Conclusion. The frequency of vesicoureteral reflux in children with mild renal pelvic distention is not significantly different than in children with no distention. Therefore, mild dilatation of the renal pelvis should not be considered an indication for voiding cystourethrography. Received: 14 April 1997 Accepted: 24 July 1997     

Vesicoureteric reflux and reflux nephropathy

Reflux nephropathy i.e. renal scarring associated with vesico-ureteric reflux (VUR) and urinary tract infection (UTI) was originally considered an acquired disease. The renal scarring seems to get worse with recurrent urine infections especially in the young. Therefore, in the past much effort was undertaken to correct the VUR surgically and minimize the number of recurrent urinary tract infections by antibiotic prophylaxis with the hope of reducing if not arresting the onset of complications that follow i.e. hypertension and renal failure. However, it is now becoming clear that reflux nephropathy encompass at least two major categories of disease; “acquired” renal scarring secondary to UTI and VUR predominantly affecting females and “congenital” scarring with dysplastic features associated with prenatal VUR but with no infection and predominantly affecting boys. The latter is much less common but is disproportionately represented in the group of patients with reflux nephropathy that go on to develop renal failure. Unfortunately, the susceptibility to renal scarring, the onset of hypertension and progression to renal failure seems to be significantly influenced by genetic factors and hence measures undertaken to prevent recurrence of UTI may not change the ultimate outcome although it will certainly improve the comfort of the individual. Therefore, the extensive investigation and management routines adopted today in these children may not be cost-effective in preventing end stage renal disease in VUR. The progression to renal failure, however, can be delayed but not halted with adequate control of high blood pressure and hence the need for life long follow-up.     

Long term outcome of treatment of end stage renal failure.

The most common causes of end stage renal failure in 46 children (mean age 11 years, range 4-14) treated between January 1972 and June 1977 were: reflux nephropathy (n = 12), cystinosis (n = 7), focal and segmental glomerulosclerosis (n = 6), and Schönlein-Henoch disease (n = 5). The quality of life, degree of renal function, and height attainment of the 31 survivors were assessed in June 1985, when their mean age was 22 years (range 14-27), using hospital records and a questionnaire designed to highlight social and psychological problems. Twenty six patients had a functioning transplanted kidney. Average growth during treatment for all survivors was normal, but most were disappointed with their ''final height''. Though five patients had some form of disabling bone disease, all 31 could walk and 27 could run. Sixteen (67%) were in full or part time employment and nine were living independently. A group of 32 patients with juvenile onset diabetes treated at this hospital for at least five years were also asked to complete the questionnaire and of these, 17 responded. On average, their data could usefully be compared with those of cases of end stage renal failure. More of the diabetics had jobs, but most sexually mature patients with renal disease were concerned about their physical appearance and had not achieved any stable long term sexual relationships. We suggest that a poor body image resulting in low self esteem may be responsible for the deficiency and believe that further study in this group is warranted.     

Pediatric kidney transplantation is safe and available for patients with urological anomalies as well as those with primary renal diseases

The aim of the current study was to evaluate long-term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1-15 yr), and the median follow-up period was 151 months (range 6-239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo-dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior-urethral valve, urethroplasty, etc. Cumulative post-operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post-transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems.     

膀胱输尿管反流的诊疗争议和研究进展

小儿原发性膀胱输尿管反流(vesicoureteric reflux,VUR)与尿路感染、排尿功能障碍相伴发生,常常导致肾疤痕、肾萎缩、高血压、肾功能减退等一系列反流性肾病的表现,重者甚至进展为终末期肾病.目前,随着对VUR治疗经验的累积,在诊断策略及治疗上都出现了一定的争议.无论手术治疗或非手术治疗结果仍不令人满意,VUR的发病机制目前还不清楚,需要进行进一步的研究和探索.     

Allograft diabetic nephropathy may progress to end-stage renal disease

Mesangial expansion and glomerular basement membrane thickening characteristic of diabetic nephropathy recur in diabetic recipients of renal allografts from non-diabetic donors but progression to renal failure is minimally documented. Three female renal allograft recipients (aged 40, 62 and 73 yr), who developed end-stage renal disease (ESRD) due to recurrent diabetic nephropathy (two patients) and de novo diabetes (one patient) are reported. Onset of proteinuria, uncontrolled hypertension, azotemia, renal allograft pathologic findings and the need for hemodialysis were analyzed. None of the kidney donors (one cadaver, two living related) had known diabetes or perturbed glucose metabolism pre-transplantation. The three patients presented had different varieties of diabetes; type 1, type 2 and new onset diabetes after transplantation (NODAT). In each subject, proteinuria was detected by dipstick at a mean of 8.3 yr (range 8-9) post-transplantation and increased to the nephrotic range (3.7-4.8 g/day) inducing hypoalbuminemia and azotemia. A histopathologic diagnosis of allograft diabetic nephropathy was made in a mean of 11.7 yr (range 10-14), based on glomerular basement membrane thickening, nodular and diffuse intercapillary glomerulosclerosis, arteriolosclerosis, and tubular atrophy with marked tubular basement membrane thickening characteristic of advanced diabetic nephropathy. All three patients manifested uremia and resumed hemodialysis. Two patients died from sepsis within 2 months and one patient died 2.5 yr later after resumption of maintenance hemodialysis. We infer that recurrent or de novo diabetic nephropathy in renal allografts follows a clinical decade-long course irrespective of diabetes. Reports of ESRD due to allograft diabetic nephropathy (ADN) have been limited because of shorter survival of diabetic transplant recipients and few kidney biopsies performed in patients with chronic allograft dysfunction. The occurrence of allograft diabetic nephropathy in some, but not all patients, however, suggests that individual genetic variability modulates disease expression.     

Urinary 3-hydroxyproline excretion in Alport's syndrome: a non-invasive screening test?

Alport''s syndrome is characterised by morphological and structural changes of the renal basement membranes. As the hydroxyproline content of isolated glomerular basement membranes is reduced in patients with Alport''s syndrome, it is possible that the renal excretion of 3-hydroxproline (3-OHP), a key substrate of basement membrane collagen, may be altered in such patients. The urinary excretion of 3-OHP was determined by thin layer chromatography in 20 patients with Alport''s syndrome, in healthy control subjects, and in patients with other renal diseases. These included patients with poststreptococcal glomerulonephritis, lower urinary tract infection, severe reflux nephropathy, lithium induced nephropathy, polycystic kidney disease, familiar benign haematuria, and renal graft rejection. Urinary excretion of 3-OHP was significantly higher in patients with Alport''s syndrome compared with the patients with other renal diseases and the healthy control subjects. All other renal diseases investigated had 3-OHP values within the normal range. Urinary 3-OHP determination detected patients with Alport''s syndrome with a high sensitivity (95.2%) and specificity (97.2%). We therefore suggest using urinary 3-OHP determinations as a simple non-invasive screening test for Alport''s syndrome.     

Outcome of primary vesicoureteric reflux detected following fetal renal pelvic dilatation

OBJECTIVE: Postnatal investigation of mild degrees of fetal hydronephrosis has allowed subsequent detection of infants with vesicoureteric reflux (VUR). This study was designed to provide short to medium term information on such infants who had primary VUR, the rates of renal damage and progression over time, the risk factors for such damage and to compare the characteristics of those who had mild dilatation of the fetal renal pelvis (4-9 mm) with those who had moderate-severe dilatation (> or = 10 mm). METHODOLOGY: Since June 1989, infants whose antenatal sonography had identified a fetal renal pelvis with an anteroposterior diameter of > 4 mm were investigated postnatally with renal ultrasonography and micturating cystourethrogram (MCU), and placed on antimicrobial prophylaxis. Those with VUR received 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy. Infants were followed until discharge based on resolution of VUR, surgery, or low grade VUR. A 5.5 year cohort between June 1989 and December 1994 formed the study population. A review of notes and clinical review (if still under follow up) was undertaken. Vesicoureteric reflux on MCU was regraded according to the International Classification, and reflux nephropathy on DMSA scans was regraded according to criteria proposed by Goldraich. Regression analysis was used to assess risk factors for renal damage. RESULTS: There were 69 infants (37 girls, 32 boys) who were identified with primary VUR, with 37/69 having bilateral reflux. Eight had a urinary tract infection during the follow-up period. There was a broad distribution of grades of reflux detected (Grades I-3, Grades II-23, Grades III-19, Grades IV - 17, Grades V-7). 99m-Tc-dimercaptosuccinic acid scans on 57/69 (83%) demonstrated renal damage in eight infants (14%). This was predominantly global contraction of function. No progression of renal damage was seen over 2-7 years. Regression analysis showed a strong association between Grades IV, V reflux and the presence of renal damage (P < 0.001). Review of the degrees of fetal renal pelvic dilatation showed that 60/69 infants were detected because of mild (4-9 mm) dilatation. The majority (43/60) had lower grades of reflux (Grades I, II, 3), but there was no obvious cut-off between 4 and 9 mm that could predict high grade VUR (Grades IV, V). CONCLUSIONS: The use of 4 mm to define an abnormal fetal renal pelvis allows a much larger group of infants with high grade primary VUR to be detected than if a higher cut-off measurement is used. Although it also detects many more infants with low grade primary VUR, there is no obvious cut-off point at which this effect predominates. Progressive renal damage was not seen in follow up of up to 7 years of age. Renal damage on DMSA scanning in this group is almost exclusively a pattern of global contraction of function. The presence of high-grade VUR appears to be the only important factor in predicting the presence of renal damage.     

Selective renal embolisation for renovascular hypertension?

An 11 year old girl developed hypertensive encephalopathy and renal failure from reflux nephropathy. Resection of her shrunken left kidney did not control her hypertension. Two selective arterial embolisations of the scarred right lower pole produced only transient benefit, but a heminephrectomy gave good control. Embolisation may delay definitive treatment.     

Antenatal diagnosis of renal pelvic dilatation — The natural history of conservative management

Seventy children with an antenatal diagnosis of unilateral renal pelvic dilatation underwent Tc 99 m DTPA diuretic renograms. There were 16 kidneys with moderate function, and 54 with good function, 31 underwent pyeloplasty, all had a renal pelvis >12 mm diameter on ultrasound. Thirty nine children with good function were treated conservatively. Long term follow up has demonstrated that conservative management for PUJ dilatation with a good functioning kidney may be justified but a randomised control study is required.This paper represents a long abstract of the oral presentation at the ESPR Munich 1990.     

Contralateral renal abnormalities in multicystic-dysplastic kidney disease.

Multicystic-dysplastic kidney (MCDK) disease has been associated with contralateral genitourinary tract abnormalities; however, neither the nature nor the prevalence of the contralateral renal lesion has been delineated. We retrospectively studied patients with MCDK disease to determine the prevalence of contralateral renal abnormalities and of other urologic anomalies. Forty-nine patients, ranging in age from neonates to 6 years, were examined by renal ultrasonography, excretory urography or nuclear medicine scanning, and voiding cystourethrography; 51% of the patients had an associated urologic abnormality. The abnormality was contralateral to the MCDK in 19 patients (39%), ipsilateral in 3 patients (6%), and involved the bladder wall in 3 patients (6%). The most common contralateral genitourinary tract abnormality was vesicoureteral reflux (18%) followed by ureteropelvic junction obstruction (12%). We conclude that urologic anomalies are common in patients with MCDK disease; contralateral vesicoureteral reflux is the most common abnormality identified.     

Covert bacteriuria: long term follow up.

In a longitudinal prospective study 58 schoolgirls with covert bacteriuria were followed up for an average of 11.2 years (range 8.8 to 13.5 years). Intravenous urography was carried out at the start of the study (aged 4 to 11 years) and after completion of the follow up period (aged 14.8 to 22.3 years). After random allocation 27 of these girls received intermittent treatment for covert bacteriuria for the first four years and the control group received no treatment. The effect of covert bacteriuria, treatment, vesicoureteric reflux, and reflux nephropathy at presentation on the final renal length, progression of scarring, and development of new scars was analysed. No new scars were found in girls with bilaterally normal kidneys. In girls with reflux nephropathy, three kidneys showed progression of existing scars and two kidneys developed new scars. It was shown that final renal length was not influenced by vesicoureteric reflux or treatment, but reduced renal length at final assessment was associated with the presence of kidney scarring at initial assessment.     

INTRARENAL REFLUX

Abstract. Seventy-six children with a total of 123 ureters showing vesico-ureteric reflux were reviewed in order to detect intrarenal reflux (pyelotubular backflow) occuring during micturating cystourethrography. This was found in 7 patients (9.2%). Five patients had unilateral and two bilateral intrarenal reflux. In only 7 out of the 9 kidneys with intrarenal reflux was it possible to outline the kidney contour precisely on excretion urography. In 3 cases renal damage corresponded exactly to the areas with intrarenal reflux. One kidney showed damage which did not correspond to the location of intrarenal reflux and 3 were without signs of damage. Renal damage of varying localization was found in 54 of the 123 kidneys with vesico-ureteric reflux and intrarenal reflux was present in 6 of these (11%). The significance of intrarenal reflux as a cause of renal damage and whether intrarenal reflux might be primary or secondary to the renal damage are discussed, and it is concluded that presence of intrarenal reflux is a definite indication for operation.     

INTERNAL REFLUX

ABSTRACT. Seventysix children with a total of 123 ureters showing vesico-ureteric reflux were reviewed in order to detect intrarenal reflux (pyelotubular backflow) occuring during micturating cystourethrography. This was found in 7 patients (9.2%). Five patients had unilateral and two bilateral intrarenal reflux. In only 7 out of the 9 kidneys with intrarenal reflux was it possible to outline the kidney contour precisely on excretion urography. In 3 cases renal damage corresponded exactly to the areas with intrarenal reflux. One kidney showed damage which did not correspond to the location of intrarenal reflux and 3 were without signs of damage. Renal damage of varying localization was found in 54 of the 123 kidneys with vesico-ureteric reflux and intrarenal reflux was present in 6 of these (11%). The significance of intrarenal reflux as a cause of renal damage and whether intrarenal reflux might be primary or secondary to the renal damage are discussed, and it is concluded that presence of intrarenal reflux is a definite indication for operation.