Ulla Berg

Strict blood-pressure control and progression of renal failure in children.

BACKGROUNDnAlthough inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor.nnnMETHODSnAfter a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion.nnnRESULTSnA total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease.nnnCONCLUSIONSnIntensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Renal scarring after acute pyelonephritis.

Seventy six children, 18 boys and 58 girls, aged 0-15.9 (median 1.0) years, with acute pyelonephritis were prospectively studied with a technetium-99m dimercaptosuccinic acid (DMSA) scan during infection and two months later. Fifty nine of these children were also studied two years after the infection. Seventeen children with a normal DMSA scan during infection or at two months after infection, or both, were not investigated by a DMSA scan at two years after acute pyelonephritis. A micturition cystourethrogram was performed in all the children after two months. Changes on the DMSA scan were found in 65 (86%) children during acute pyelonephritis, in 45 (59%) children at two months, and in 28 (37%) children at two years after infection. Vesicoureteric reflux (VUR) was found in 19 (25%) children at two months. Renal scarring was significantly correlated with the presence of gross VUR and recurrent pyelonephritis, but 62% of the scarred kidneys were drained by non-refluxing ureters. Children with scars were older at the time of acute pyelonephritis than those without scars but no difference was found between the groups with regard to duration of illness, levels of C reactive protein and maximum white cell count, glomerular filtration rate, nor renal concentration capacity at the time of infection. It is concluded that renal scarring after acute pyelonephritis in children is more common than has been previously thought. Although children with gross VUR and recurrent pyelonephritis are at the greatest risk, renal scarring is more often seen without these risk factors.

ABO-Incompatible Kidney Transplantation Using Antigen-Specific Immunoadsorption and Rituximab: A 3-Year Follow-up

Background. In 2001 a protocol for ABO-incompatible (ABOi) kidney transplantation based on antigen-specific immunoadsorption and rituximab was introduced at our center, short-term results being comparable with those of ABO-compatible (ABOc) living donor kidney transplantation. Of greater importance, however, is long-term graft function, thus far not evaluated. The aim of this study was therefore to assess long-term results of this protocol. Methods. Twenty ABOi kidney recipients with more than 12-month follow-up were included in the study: all adult crossmatch negative ABOi kidney recipients (n=15) were compared with an adult ABOc living donor recipient control group (n=30), and all pediatric ABOi kidney recipients (<16 years of age) (n=5) were compared with a group of pediatric ABOc kidney recipients (n=18). Results. Mean follow-up was three years. There was no significant difference in patient survival, nor in graft survival or in the incidence of acute rejection in any of the groups. In the adult kidney recipients mean glomerular filtration rate was equivalent at all time points (79–83 mL/min), as was &Dgr;s-creatinine. In the pediatric groups, &Dgr;s-creatinine was similar but glomerular filtration rate lower among the ABOi kidney recipients. There was a significant reduction (P<0.0001) without rebound in A/B antibody titers after transplantation (median IgG 1:2 and median IgM 1:1>1 year posttransplant) compared with pretransplant levels (median IgG 1:32 and IgM 1:16). Conclusion. We conclude that ABOi kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to ABOc living donor kidney transplantation. ABOi transplantation after this protocol does not have a negative impact on long-term graft function.

99mTechnetium-dimercaptosuccinic acid scan in the diagnosis of acute pyelonephritis in children: relation to clinical and radiological findings

Seventy-two children, 59 girls and 13 boys, 0.1–15.9 (median 1.1) years of age, with acute pyelonephritis (APN) were investigated with the aid of a dimercaptosuccinic acid (DMSA) scan, renal ultrasonography (US) and a desmopressin test within 5 days of admission. Sixty-two children were reinvestigated approximately 2 months later when intravenous urography (IVU) and micturition cysto-urethrography were also performed. During infection, 92% of the children showed changes in the DMSA scan with 69% by US, and the two investigations agreed in 58% of the kidneys. At follow-up, 68% showed changes in the DMSA scan, 47% by US and 48% by IVU. The DMSA scan and IVU agreed in 60% of the kidneys. Twenty-nine percent of the children had vesico-ureteric reflux (VUR). The presence of grade>-3 VUR was associated with greater defects on the DMSA scan during infection, and at follow-up with a higher frequency of persistent changes compared with no VUR (P<0.02 and 0.01, respectively). During infection the size of the defect on the DMSA scan correlated with renal vooume and C-reactive protein and inversely with the glomerular filtration rate, and at follow-up it correlated inversely with the renal concentration capacity. The DMSA scan is a sensitive method for diagnosing and localizing APN in children, and findings on DMSA scan show a weak but significant correlation with routine clinical and radiological parameters. It is suggested that persistent renal damage after APN in children without VUR may be more common than previously assumed.

Hyperacute rejections of two consecutive renal allografts and early loss of the third transplant caused by non-HLA antibodies specific for endothelial cells

The immunological rejection of HLA-identical kidney transplants indicates that non-HLA antigens may also be targets for transplant rejection. Interest in the possible role of endothelial specific antigens has grown steadily over the years. Most of the studies published, regarding the association of such antibodies with rejection, have demonstrated the reactivity of endothelial antibodies also with monocytes and keratinocytes, but not with lymphocytes. Such antibodies escape detection in conventional crossmatch tests. In this paper, we present a case report of a 10-year-old girl, whose two consecutive kidney allografts, (one living and one cadaveric donor) were hyperacutely rejected in spite of the fact that she had neither been alloimmunized, nor had any HLA-specific antibodies. Endothelial cell specific antibodies were detected in vivo and in vitro after transplantation only 11 days apart, which were considered to be responsible for rejection. The third cadaveric kidney was lost within 1 week post-transplant. Immunopathological investigation of the three rejected grafts revealed deposition of IgM in the endothelium of arteries and in some glomeruli. No deposition of IgG antibodies was found. Antibodies from this patient did not react with lymphocytes, monocytes or keratinocytes. Patient serum had IgM antibodies that were specifically reactive with cultured endothelial cells, demonstrated by binding in vitro and by complement-dependent cytotoxicity of IL-beta stimulated endothelial cells. No HLA antibodies were found following the first two transplantations, but were demonstrated 1 week after the third transplantation, at the time of an acute irreversible rejection. Western blots of proteins solubilized from endothelial cell membranes, indicated that the antibodies reacted with a 97-110 kD protein. Endothelial cell antigen preparations were made from several different umbilical cord veins. Some primary cell cultures, but not all, reacted with the patients serum. Therefore, we suggest that the target determinant might be polymorphic. These findings imply that the non-HLA endothelial cell specific molecules may function as target(s) for hyperacute antibody-mediated destruction of kidney allografts.

Kidney morphological changes in relation to long-term renal function and metabolic control in adolescents with IDDM

Summary For the past 10–15 years all the children at our unit with insulin-dependent diabetes mellitus have been repeatedly followed-up with renal function tests. Renal biopsy, examined by light and electron microscopy, was included in the follow-up of 36 adolescents and young adults, aged 13–25 years, with a disease duration of 7–19 years. All subjects had undergone at least three renal function tests before biopsy and none had persistent microalbuminuria. Renal function was evaluated as glomerular filtration rate and effective renal plasma flow determined by clearances of inulin and para-amino hippuric acid. Glomerular filtration rate and filtration fraction were increased before and at the time of the biopsy. Glomerular basement membrane thickness (331–858 nm) and mesangial matrix volume fraction (7.4–17.1 %) were increased. Long-term hyperfiltration and hyperperfusion before biopsy correlated inversely with mean glomerular volume. Increased filtration fraction before the biopsy correlated directly with mean of all HbA1c (r = 0.485, p < 0.01) and both variables correlated directly with mesangial matrix volume fraction, basement membrane thickness and structural index (r = 0.433, p < 0.01 and r = 0.626, p < 0.001, respectively). Urinary albumin excretion rate correlated directly with foot process width (r = 0.645, p < 0.001). By multiple regression analysis the most important variable for the increase in basal membrane thickness was the metabolic control while the mean of previous filtration fraction was most important for the increase in mesangial matrix volume. In conclusion, although none of the patients showed constant microalbuminuria, early diabetic structural changes were evident with basal membrane thickening and increased mesangial matrix volume. The structural changes related to long-standing hyperfiltration and poor metabolic control. [Diabetologia (1998) 41: 1047–1056]

Diagnostic significance of 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy in urinary tract infection.

A total of 106 children with symptomatic urinary tract infection (73 girls and 33 boys, 0-15.9 years of age) were studied by means of a dimercaptosuccinic acid (DMSA) scan, renal ultrasound, and a desmopressin test during infection and at follow up approximately two months later. At follow up they were also investigated by means of intravenous urography (IVU) and micturition cystourethrography (MCU). During infection 23 children had a normal DMSA scan while 83 children had an abnormal one. The median C reactive protein and SD score for renal concentration capacity in the former group were 15 (range < 10-178) mg/l and -1.0 SD score (range -2.4 to 1.8), respectively, and in the latter group 98 (range < 10-320) mg/l and -3.1 SD score (range -5.7 to 1.1), respectively. In the former group there was no significant finding in any child on ultrasound or IVU and only one had significant vesicoureteric reflux (VUR) (grade 3). At follow up 51 children had a normal DMSA scan while 55 children showed persistent changes. The median SD score for renal concentration capacity in the former group was -0.9 SD score (range -3.2 to 1.4) and in the latter group -1.6 SD score (range -4.6 to 2.5). No significant changes were found in the former group on ultrasound or IVU and only two children had significant VUR (grade 3). In the latter group 20 children showed changes on ultrasound, 15 showed changes on IVU, and 23 had VUR. These results suggest that a normal DMSA scan during or approximately two months after urinary tract infection in children indicates a low risk of finding significant pathology of the urinary tract.

To be or not to be a living donor: questionnaire to parents of children who have undergone renal transplantation.

BACKGROUNDnBetween 1981 and 1994, 67 transplantations were performed in 59 children below 16 years of age at Huddinge University Hospital. In most of the cases, one of the parents was the donor. The aim of this study was to evaluate how the transplantation influenced the parents.nnnMETHODSnOne hundred sixteen individual questionnaires were sent out to the donor parents and to the parents who for different reasons had not been donors. Of special interest was to investigate the emotional reactions, the social consequences, the relationship to the child, and the parents attitudes toward donation.nnnRESULTSnThirty-five donors and 41 nondonors replied. The majority of both donors and nondonors were satisfied with the medical information. The nondonors expressed more stress and anxiety before the transplantation. More than half of the donors experienced the operation as more painful than they had expected. Despite this fact, the nondonors showed significantly more psychosomatic/psychiatric symptoms than the donors after the operation. The donors reported an improved relation to the recipient child after the transplantation to a greater extent than the nondonors. Half of the donors reported an improved self-esteem after the donation. None of the donors regretted their donation and all of them would do the same again.nnnCONCLUSIONSnThis study indicates that ethical and psychological risks in parental kidney donation should not be regarded as a major obstacle. However, irrespective of the parents being a donor or not, they wanted more psychosocial support both before, during, and after the transplantation.

Renal function before and long after liver transplantation in children

Background. Renal dysfunction occurs in children with liver diseases and renal function is often further impaired after orthotopic liver transplantation (OLT). Inaccurate methods of determining renal function are used in many cases. We studied renal function with accurate methods before and repeatedly after OLT to analyze the effect of the underlying diseases, hypertension, and the immunosuppressive agents. Methods. A total of 46 children were studied both before and annually after OLT with clearances of inulin and paraaminohippuric acid to determine the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). The clearance of inulin was also compared with the formula creatinine clearance. Results. GFR and ERPF decreased from before to after OLT and decreased further during the first years after OLT. Patients with extrahepatic biliary atresia and with tumours showed higher GFR 1 year after OLT than those with metabolic and miscellaneous disorders. No significant change in GFR of individual patients occurred from the first to the last values determined at around 1 and 6 years after OLT. No difference in renal function was seen during the first years between patients treated with cyclosporine as compared to those treated with tacrolimus, but 4 years after OLT, the GFR was higher in the tacrolimus-treated patients. Patients on antihypertensive agents had lower GFR than the normotensive ones. There was no agreement between GFR, determined by clearance of inulin, and that calculated on the basis of serum creatinine and the height of the patients. Conclusions. Renal function is reduced by OLT and decreases further during the first years after OLT. Patients with metabolic disorders and those on antihypertensive treatment have the lowest GFR. Determination of GFR by the formula creatinine clearance is inaccurate in children after liver transplantation.

DEVELOPMENT OF RENAL CELL CARCINOMA IN LIVING DONOR KIDNEY GRAFTS

Background. Although development of malignancies after transplantation is well recognized, de novo development of cancer in renal transplants is a rare phenomenon.We describe two cases of de novo development of renal cell carcinoma in two living donor grafts. Materials and results. The recipients were 45 and 4 years, respectively, at transplantation and their fathers were donors. Because of failure to grow, they were both treated with human growth hormone. Over the years a number of cysts developed in the grafts and after 8 and 7 years the echogenecity of some of the cysts changed. Biopsy confirmed the diagnosis renal cell carcinoma 9 and 11 years after transplantation. The grafts were removed and the immunosuppressive therapy discontinued. The two fathers are well with normal function of the native kidney and no signs of cyst formation or cancer. Conclusion. Two cases of de novo development of cancer in living donor kidney transplants are described. Because a stimulatory effect of growth hormone on tumor genesis has been described, this treatment may have been of importance in the tumor development. The findings emphasize the importance of annual ultrasonographic surveillance of renal grafts, especially in the pediatric population.