Potential influence of tubular dysfunction on the difference between estimated and measured glomerular filtration rate after kidney transplantation.

PURPOSE: Because no consensus exists regarding the most accurate calculation to estimate glomerular filtration rate (GFR) based on serum creatinine concentrations (sCr) after kidney transplantation, this study sought to assess the potential role of tubular dysfunction on GFR estimates using various equations as well as the effect of pharmacologic blockades on tubular secretion of creatinine on creatinine clearance (ClCr). METHODS: Iohexol GFR (mGFR) was performed in 17 stable kidney transplant recipients(R) at >24 months post-transplantation. Their mean age was 48.3 ± 11.3 years. All R were treated with a calcineurin inhibitor (CNI). At the time of study we measured sCr, 24 hour-ClCr, cystatin C, 24-hour proteinuria, microalbuminuria, FE Na, alfa1-microglobulinuria (alfa1-MG), and CNI concentrations. To block tubular secretion of Cr, recipients were prescribed cimetidine (2400 mg) 2 days before the sCr measurement. Additionally, to exclude dietary influences on sCr, R did not eat meat for 2 days before testing. GFR was estimated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Cockroft-Gault (C&G), and Cystatin C (Cyst C) GFR equations. Mean kidney graft function over the previous 6 months was used as the control. Pearson correlation was determined between the differences between mGFR and estimatedGFR: Iohexol minus MDRD, EPI, Cyst C or C&G GFR for paired estimates. The diagnostic accuracy of the eGFRs to detect an mGFR of 60 mL/min/1.73 m(2) was examined by receiver operating characteristic curves. RESULTS: Mean mGFR was 75.2 ± 35.8 mL/min/1.73 m(2). The sCr increased but the 24-hour ClCr, MDRD, EPI, and C&G decreased after vs before cimetidine. The difference was significant for sCr (F = 12.933; P = .002) and MDRD GFR (F = 15.750; P = .001). mGFR was not significantly higher than all pair values of eGFRs, and not significantly lower than 24-hour ClCr before and after cimetidine. However, in comparison to all eGFRs, ClCr after cimetidine most approached mGFR. A significant positive correlation was observed between alfa1-MG and the difference between mGFR and MDRD (before, r = .543 [P = .045]; after cimetidine, 0.568 [P = .034]), EPI (before, r = 0.516 [P = .050]; after cimetidine, r = 0.562 [P = .036]), and ClCr (r = 0.633; P = .016), C&G (P = .581; P = .029) before cimetidine. Accuracy of eGFRs to detect mGFR of 60 mL/min/1.73 m(2) showed EPI GFR before cimetidine to show diagnostic accuracy for patients with GFR >60 mL/min/1.73 m(2) with a sensitivity of 81.8% and a specificity of 71.4%. CONCLUSIONS: Because mGFR is unavailable in many transplant centers, determination of ClCr after cimetidine may help to achieve a more accurate diagnosis of CKD among transplant patients.

Molecular analysis of ring y chromosome in a 10-year-old boy with mixed gonadal dysgenesis and growth hormone deficiency.

Ring Y chromosome is a very rare chromosomal aberration. The published mixed gonadal dysgenesis (MGD) patients with a ring Y chromosome are short in stature, but are not growth hormone (GH) deficient. We present the molecular cytogenetic and molecular characterization of ring Y chromosome mosaicism in a 10-year-old boy with MGD whose short stature could be explained by the high percentage of cells monosomic for the X-chromosome, but also by the presence of severe GH deficiency. The ring Y chromosome in our patient is a de novo structural aberration. The father's karyotype was normal.

Conversion of azathioprine to mycophenolate mofetil and chronic graft failure progression.

The purpose of the study was to evaluate the impact of conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) on graft function in 35 renal transplant recipients with chronic allograft nephropathy (CAN). The immunosuppressive regimen originally consisted of AZA, cyclosporine (CsA), and prednisone (Pr). At the onset of the study (mean period = 39 posttransplant months), a graft biopsy was performed on all patients who were randomly divided into group 1 (n = 17) in whom MMF was introduced instead of AZA. The remaining 18 subjects (group 2) were maintained on the previous regimen. Two periods were analyzed: period I: 12 months before, and period II: 12 months after biopsy and therapy conversion. Graft function was assessed monthly by measurements of the 24-hour creatinine clearance (CCr). Analysis of variance (ANOVA) was used to compare the differences in CCr and proteinuria between the two groups. No difference was observed in the baseline characteristics, in the incidence of delayed graft function and acute rejection, or in the mean CsA dose. Pathohistological analysis revealed advanced CAN in the majority of patients in both groups. The morphological changes negatively correlated with graft function. The graft function showed parallel deterioration in the two groups; no significant difference was observed in the mean CCr values in the periods studied. Proteinuria was similar for both groups throughout the study. Conversion of AZA to MMF in recipients with CAN, albeit safe, was without significant benefit on the progression of chronic graft failure over the period of a year.

[Deletions in the dystrophin gene and its phenotype expression]. / Delecije u genu za distrofin i njihova fenotipska ekspresija.

About 60% of both Duchenne's muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) is due to deletions of dystrophin gene. For cases with deletion mutations the "reading frame" hypothesis predicts that deletions which result in disruption of the translation reading frame prevent production of stable protein and are associated with DMD. In contrast, intragenic deletions that involve exons encoding an integral number of triplet codons maintain proper reading frame. The resulting abnormal proteins are stable and partially functional, resulting in a milder and more variable BMD phenotype. To test the validity of this theory,we analyzed 40 patients-19 independent deletions at the DMD/BMD locus. Clinical/molecular correlations based on the altera-tions of the reading frame were valid in 69.2% of cases. After exclusion of: --2 patients with del 3-6 (with no consistent clinical expression); --1 DMD patient with large in-frame deletion; --2 patients that were too young to be classified; --4 patients in whom it was impossible to identify the extent of deletion (del 47 and del 44-45), the correlation between deletion and clinical severity was as predicted in 92.4% of cases. The present data should be useful in establishing the prognosis in individual patients even in sporadic cases with no affected relatives.

[Relation between gene mutations and pancreatic exocrine function in patients with cystic fibrosis]. / Povezanost izmedju genskih mutacija i egzokrine funkcije pankreasa kod osoba obolelih od cisticne fibroze.

Cystic fibrosis (CF), is the most common autosomal-recessive disease in Caucasians, with an incidence of approximately 1:2500 live births and a carrier frequency of approximately 4-5%. Causes of the disease are mutations in the CF gene which is located on chromosome 7 (region 7q31). Although a single mutation, a deletion of phenylalanine at position 508 (DF508) in exon 10, accounts for almost 70% of all CF chromosomes, over 900 other mutations have been identified in this large gene. CF gene encodes a membrane protein, which functions as aion channel- CFTR (cystic fibrosis transmembrane regulator protein). The exocrine pancreas is a gland that secretes water, enzymes and electrolytes into the intestinal lumen. These enzymes are needed for the normal digestion of food, and their reduced secretion in cystic fibrosis will cause malabsortion and malnutrition in CF patients. Pancreatic dysfunction in CF begins in uteri. Most patients with CF typically present insufficient pancreatic exocrine function (PI phenotype) and 10-15% of CF patients are pancreatic sufficient (PS phenotype). It has been shown elsewhere that the pancreatic function status in CF could be correlated to mutations in the CFTR gene. To determine the relation between genotype and pancreatic status, we analyzed 32 CF patients in whom both CF gene mutant alleles were identified (Table 1). Patients included in this study attended the Paediatric Department of Mother and Child Health Institute in Belgrade. The diagnosis was based on typical clinical manifestations and high levels of sweat chloride concentration (higher than 60 mmol/L). Of the 32 patients studied, only one (3.12%) was PS and the rest (96.88%) had PI phenotype. For each CF genotype the number of patients who were PI or PS is given in Table 1. The most striking observation was that all given genotypes correlated with either PI or PS, but not with both. On the basis of both preceding hypotheses and our present data (Table 2 and Table 3), it was possible to classify mutations as "severe" or "mild" with respect to pancreatic function (Table 4). This study strengthens the hypothesis that pancreatic function status in CF is genetically determined by specific mutations at the CF locus. Our data also strongly support the hypothesis that, with respect to pancreatic function, "mild" mutant alleles confer a higher residual CFTR activity than do "severe" mutant alleles. Although PS occurs in patients who have one or two "mild" mutations, PI occurs in patients who are homozygous or who are genetic compounds of two "severe" mutant alleles.

[Tumors of the upper urinary tract: results of conservative surgery]. / Tumeurs de la voie excrétrice supérieure: résultats de la chirurgie conservatrice.

OBJECTIVE: To determine the results of conservative surgery for upper urinary tract urothelial tumours. PATIENTS AND METHODS: From 1986 to 1997, 352 patients were treated in the Belgrade urology clinic for upper urinary tract urothelial tumour. 54 patients (15.3%) were treated by conservative surgery. The sex ratio was 1.3 men for 1 woman. The mean age was 63 years. In most cases, the tumour was situated in the ureter. Conservative surgery was performed on principle in 60% of patients for a small isolated lesion (solitary low-stage, low-grade tumour). In contrast, in about 40% of cases, conservative surgery was performed by necessity due to the presence of bilateral tumours, a solitary kidney or renal failure related to Balkan nephropathy. The median follow-up was 67.3 months (range: 6 months-14 years). RESULTS: 15.8% of patients developed a local recurrence during the follow-up period. The risk of recurrence was higher when conservative surgery was performed for indications of necessity than when it was performed on principle (21.7% versus 11.8%), but the difference was not statistically significant (c2 test, t test). The stage and grade of differentiation were identified as the most significant predictive factors for the risk of local recurrence. The overall 5-year survival rate was 67% with more favourable results in the case of conservative surgery performed on principle compared conservative surgery by necessity (72% versus 60%). The difference between these results was not statistically significant, but a statistically significant difference was observed for tumour stage and grade (grade III versus grade I and II, pT3 versus pT1, pT2). The 5-year survival probability was 68.5%. Recurrence was most likely to occur during the early postoperative course, as 81.56% occurred during the first 18 months. CONCLUSION: Urothelial tumours can be managed conservatively. However, the risk of recurrence is directly correlated with the tumour stage and grade, with a high level of statistical significance, and with the type of indication for conservative surgery performed, but with no statistically significant difference.

[Results of kidney transplantation at the Institute of Urology and Nephrology of the Serbian Clinical Center in Belgrade]. / Rezultati transplantacije bubrega u Institutu za urologiju i nefrologiju klinickog centra Srbije u Beogradu. Rezultati Rezultati Rezultati transplantacije bubrega u Institutu za urologiju i nefrologiju Klinickog centra Srbije u Beogradu.

UNLABELLED: Over the period 1980-1992 256 kidney transplantations were carried out in the Institute of Urology and Nephrology, Clinical Centre, Belgrade: 105 (41%) from cadaveric and 151 (59%) from alive related donors. The first kidney transplantation was performed in our Institution in 1974; however, in the first decade only 27 kidney transplantations were performed. Since 1987, thanks to an increasing number of living kidney donors, the number of transplantations continually increased, and after that period an average of 30 kidney transplantations are performed annually (Figure 1). The aim of the study was to establish the survival of patients and grafts, and factors influencing this survival, as well as to determine the causes of patients' death and graft loss. All the patients were followed-up in our outpatient department within at least 5 years to maximum 17 years. Drug combination therapies were changed in the observation period. From 1983 cyclosporin A (CyA) was added to azathioprine (Aza) and prednisolone (Pr). An increasing number of patients with high immunological risks necessitated the strongest initial immunosuppressive treatment with ALG in addition to Aza and Pr. CyA in a dose of 8 mg/kg b.w. was introduced when serum creatinine concentration fell below 300 mumol/L. The triple treatment including CyA, Aza and Pr was the most common maintenance immunosuppressive therapy in our patients. RESULTS: One and five years survived 95% and 75% of patients, and 84% and 52% of grafts. In assessing the impact of donor source, the year of transplantation, and age of donors we obtained the following results: Living related grafts survived better than cadaver grafts, especially during the first posttransplantation year (Figure 2). Furthermore, graft survival rates from 1987 to 1992 were significantly better than those from early period i.e. 1980 to 1986 (Figure 3). The significantly worse survival rate for grafts from donors older than 60 was noted than for grafts from younger donors. Searching for factors influencing the survival, non immunological and immunological differences between donors and recipients were analyzed. Our analysis showed that 50 living related donors were older than 60. In addition, the majority of them were 20 years older than their graft recipients. Two and more HLA mismatches were observed in 46% of our transplant patients, and 20 patients were highly sensitized. However, the immunological risks were higher in living related transplantations: different ABO blood groups, historical positive cross match reaction between donors and recipients (Table 1). A multivariate analysis using Cox proportional hazards model was performed to determine the important independent predictors of graft survival, and it revealed the following factors (Table 2): number of acute rejections, graft function at the end of the first month and until the end of the first posttransplant year, donors' age, and age and sex differences between donors and recipients. The occurrence of acute rejection at any time had a significant negative effect on graft survival. Since better HLA matching is likely to mean less early rejection it could be concluded that HLA matching influenced graft function and survival in our patients. Absence of acute rejection and delayed graft function or acute tubular necrosis were associated with an improvement of the graft function based on serum creatinine concentration, indicating that delayed graft function also influenced graft survival. The relative risk of graft loss was 2 times higher for patients receiving graft from donors older than 60. Until December 1997, when our analysis was done, of 256 kidney transplant patients 156 lost their grafts. The major causes of graft loss (Table 3) in the early period from 1980 to 1986 were non immunological such as acute tubular necrosis, vascular thrombosis and patients death with functioning graft. (ABSTRACT TRUNCATED)

[Comparison of upper urinary tract tumors in the region of Balkan nephropathy with those of other regions of Yugoslavia]. / Comparaison des tumeurs du haut appareil urinaire dans la région de la néphropathie balkanique avec celles d'autres régions de Yougoslavie.

OBJECTIVES: To compare the epidemiological and histological characteristics of upper urinary tract tumours in the region of Balkan endemic nephropathy with those of urothelial tumours observed in other regions. MATERIAL AND METHODS: From 1970 to 1997, 766 patients were treated in the Belgrade Department of Urology for an upper urinary tract tumour. These patients were derived from 3 regions: the region of Balkan endemic nephropathy (BEN), the region of probable Balkan endemic nephropathy (PBEN) and the region without Balkan endemic nephropathy (WBEN). The incidence of tumours in BEN + PBEN patients was 68% versus 32% for WBEN patients. The histological and epidemiological characteristics of the tumours in these three groups were compared. RESULTS: Tumours were more frequent in women in the BEN and PBEN groups (1.2:1 and 1.1:1) than in the WBEN group (0.6:1). The tumour was diagnosed an average of 5 years later in the first 2 groups than in the WBEN group (p < 0.05). The BEN and PBEN groups presented a higher incidence of renal failure (45% and 35%), but especially a much higher incidence of bilateral tumours (13% and 6%) than in the WBEN region (2%). CONCLUSION: Our analysis shows that upper urinary tract tumours depend on geographical factors: the incidence of these tumours is significantly higher in regions of BEN and PBEN, women are more frequently affected, tumours are associated with a high incidence of renal failure, bilateral tumours are more frequent, and tumours are more frequent in older patients. Comparison of the histological and pathological characteristics of the tumours did not reveal any significant difference between these three regions.

Markers of oxidative stress after renal transplantation.

An increased degree of oxidative stress (OS) in chronic renal failure (CRF) and a possible role of free radicals in CRF have already been described. However, data on OS after renal transplantation are scarce. The aim of the present study was to estimate the degree of OS in renal transplant patients. The study included four groups: 1) 15 haemodialysis patients (HD group), 2) 11 renal transplant patients with stable function (SF group), 3) 12 renal transplant patients with chronic biopsy-proven rejection (CR group), and 4) 10 healthy controls (C group). Markers of OS (malondialdehyde and thiol group levels) and antioxidant activity (glutathione peroxidase and Cu,Zn-superoxide dismutase) were determined in plasma and in red blood cells of all examined individuals. After successful renal transplantation a significant improvement, but not normalization, of antioxidant enzyme activities accompanied by significantly reduced lipid peroxidation were found. In the CR group the degree of OS was increased, and our results suggest that OS may be a relevant pathophysiological factor for CR development.

Living related kidney donors over 60 years old.

The lack of available cadaveric organs for transplantation has resulted in an increased number of kidney transplants from living donors. During a period of 6 years, 149 kidney transplantations were performed from living related donors in our institute, 33.5% of whom were older than 60 years of age. In this study we examined the survival of patients and grafts as well as the graft function in 50 patients with transplants from donors over 60 years (mean age 65 years) as compared with those of 99 patients with transplants from donors younger than 60 years (mean age 47 years). There were no significant differences in the course of donor nephrectomy, postoperative complications, or remnant kidney function. However, delayed graft function occurred more frequently in recipients of transplants from older donors. Improvement in graft function was also slower in recipients of kidneys from older donors, with significant differences in serum creatinine levels observed during the first 12 months after transplantation. More frequent acute complications and more progressive chronic graft failure, irrespective of the causes, occurred during the 1st post-transplant year in recipients with grafts from older donors. Five-year patient survival (77% vs 92%) and kidney graft survival differed significantly for the same period with worse results for patients receiving grafts from older donors. It may be concluded that kidney grafts from donors older than 60 years -- and especially those older than 70 years -- may be used for living related kidney transplantation, but with precautions.

[Kidney transplantation in Bombay]. / Transplantacije bubrega u Bombaju.

The paper presents results of renal transplantation from a living unrelated donor in Bombay. Within the past three years 15 patients reported themselves at our Clinic immediately upon renal transplantation from a living unrelated donor, 7 of whom were women and 8 men, 17 to 52 years of age. There were no data on previous pretransplantation processing for the majority of patients, and treatment by repeated hemodialyses in 46.7% of patients lasted less than a year, which increased the risk of transplantation. On admission at our clinic, nine patients had satisfactory renal function, four patients moderate insufficiency and two advanced insufficiency. The most frequent complications occurring in these patients were various forms of infections. A three-year follow-up of these patients showed at the results of renal transplantation in Bombay were unsatisfactory, and the survival rate of the patients and the graft was far too worse that the one in Europe, that is at our Centre.

[Acute renal failure after kidney transplantation]. / Akutna bubrezna insuficijencija posle transplantacije bubrega.

The aim of the study was to establish causes of acute renal failure after renal transplantation and to investigate its influence on subsequent kidney function. Hundred sixty seven renal transplantations were performed at the Institute of Urology and Nephrology, Belgrade, from January 1988 to November 1991. Acute renal failure occurred in 29 patients. Monitoring of serum creatinine levels in acute renal failure patients in the first posttransplant year revealed significantly higher levels than in patients without acute renal failure in the immediate postoperative course. This indicates that acute renal failure significantly influences subsequent function of the transplanted kidney.

[Diagnostic criteria in asthma of children]. / Kriterijumi za procenu oblika bronhijalne astme kod dece.

Actual diagnostic sriteria are represented by a large spectar of data proposed by certain authors, so generally accepted protocole does not exist for similar clinical states i.e. asthmatic bronchitis, recurrent bronchitis and bronchial asthma in childhood, there is a different diagnostic terminology. Our clinical experience, in accordance to the work of Kubos et all., for diagnosis of bronchial asthma the following criteria are needed: 1. general characteristics, 2. immunologic factors and 3. nonspecific precipitating factors. In the primary classification tovextrinsic (atopic), intrinsic (infective) and mixed form of asthma, we consider that the mixed form in pediatric population is the most frequent. In the last form of the disease, attacks are provoked by acute viral respiratory infections, while the role of allergy, metreologic and psychical factors appears by age of children. Classification of asthma on the basis of frewuency of crises, regardless of season, maw be made in the following manner: 1. light form (less than one crise per month), 2. moderate from (about one crise monthly), 3. severe form (several crises during the month) and 4. very severe form (with permanent symptoms). Beside presented criteria, we used data of personal and familly history, climate conditions of environment, as well as the results of previous treatment in climate stations.