Renal hemodynamic effect of tacrolimus in renal transplanted children

Like cyclosporine (CsA), tacrolimus acts through the inhibition of renal phosphatase calcineurin. CsA induces reversible vasoconstriction, causing a transient reduction of renal plasma flow in patients with renal transplantation. The aim of this study was to determine the effect of tacrolimus on renal plasma flow in renal transplanted children. Eight children were studied with a median age of 10.6 years, a mean glomerular filtration rate (inulin clearance) of 55 ml/min per 1.73 m² (range 29–95), and a mean follow-up after transplantation of 5.6 months. Effective renal plasma flow (ERPF) was studied in each patient for 12 h after tacrolimus administration. Clearan- ces were obtained every 2 h for 12 h after drug administration. Tacrolimus pharmacokinetics was also studied. Average ERPF at the start of the test was 289 ml/min per 1.73 m² (range 177–404, SD±106). Variation in each of the 2-h periods was not significant, although a mild reduction of plasma flow was observed in three of the eight children. No correlation was found between tacrolimus AUC, peak, or trough levels and renal blood flow variations. Despite the relatively small number of patients studied, these data suggest that, in vivo, a therapeutic oral dose of tacrolimus is not necessarily followed by a significant reduction of ERPF in renal transplanted children. Received: 15 November 2000 / Revised: 3 April 2001 / Accepted: 16 May 2001     

Renal functional reserve after acute poststreptococcal glomerulonephritis

 We evaluated renal functional reserve (RFR) in 36 patients aged 5 – 21 years, who had recovered from an acute episode of poststreptococcal glomerulonephritis (PSGN) 1 – 16 years previously, without apparent sequelae, as evidenced by normal serum creatinine, blood pressure, and urinary sediment. The control group consisted of 12 children aged 2 – 12 years with recurrent urinary tract infections or nocturnal enuresis, without active infection or anatomical anomalies. The basal creatinine clearance was similar in the PSGN and control groups: 140.0±27.4 ml/min per 1.73 m² and 142.9±15.5 ml/min per 1.73 m², respectively. The RFR in the PSGN group was significantly reduced compared with that of the control group: 18.6±12.9 ml/min per 1.73 m² and 41.1±25.3 ml/min per 1.73 m², respectively (P <0.02). In 7 PSGN patients (19.4%), no RFR was found. In 69% of patients who had recovered from PSGN more than 10 years before the protein loading tests, a significantly reduced RFR (less than 10% of baseline) was found. The same degree of reduction in RFR was found in only 26% of patients who had suffered from PSGN less than 10 years ago. Received May 23, 1996; received in revised form November 11, 1996; accepted November 27, 1996     

Renal transplantation in children with emphasis on young patients

We report the results of 41 consecutive renal transplantations performed on 39 children (median age 2.7 years). Twenty-six recipients were less than 5 years old. Twenty-one recipients (13 under the age of 5 years) received cadaver (CAD) grafts. All grafts except 2 were from adult donors and were placed extraperitoneally. Patients were on triple immunosuppression (cyclosporine plus azathioprine plus methylprednisolone). Mean followup time was 2.3 years. No vascular and only one ureteral complication was seen. Acute tubular necrosis occurred in 3 patients (7.3%). No grafts were lost due to acute rejection. Three-year patient survival and 1-year graft survival were 100%. The overall 3-year actuarial graft survival was 86%. Three-year survival of grafts from living-related donors (LRD) was 92% and that of CAD grafts 75%. In recipients younger than 5 years, 3-year LRD graft survival was 89% and CAD graft survival 73%. No significant differences in graft survival between recipients of different age groups or between LRD and CAD grafts were found. We conclude that results of renal transplantation in children under 5 years of age are comparable to those of older children, even using CAD grafts, when adult donors and triple immunosuppression are used.     

Renal functional reserve in children with a previous episode of haemolytic-uraemic syndrome

Renal function [creatinine clearance (C _Cr)] and renal functional reserve (RFR) was measured in 16 children who had had haemolytic-uraemic syndrome (HUS) an average of 6.6±0.72 years previously. All patients had normal plasma creatinine and blood pressure and only 3 had proteinuria, which was mild in every instance. Patients were studied whilst ingesting three diets which provided an average of 1.5, 2.1 and 3.1 g protein/kg body weight per day, respectively. Diets were administered over three consecutive periods of 7 days each andC _Cr was measured on the 7th day of each diet. Values tended to correlate with protein intake. They were in the normal range when patients were taking 1.5 and 2.1 g protein diets and increased markedly in 13 of the 16 patients (P<0.001) when they ingested the high-protein diet (3.1 g). The effect on glomerular filtration rate (GFR)-measured byC _Cr and inulin clearance (C _in)-of an acute oral protein load was studied in 12 of the HUS patients and four control subjects. In the control periods, prior to the protein load, values forC _Cr were similar in the HUS and control subjects (104.0±11.0 vs 121.6±10.1 ml/min per 1.73 m², NS). HoweverC _in values were significantly reduced in HUS patients (59.5±9.2 vs 102.7±12.4 ml/min per 1.73 m², (P<0.025). TheC _Cr/C _in ratio in the patients averaged 2.10 compared with 1.13 in controls. Acute protein loading was accompanied by an increase inC _in in all controls but in only 8 of the 12 patients. Baseline values forC _in did not correlate with the presence or absence of protein-stimulated enhancement ofC _in. TheC _Cr/C _in ratios after protein loading remained twice as high in HUS patients as in controls. The data indicate thatC _Cr is not an accurate indicator of GFR in children who have had acute renal injury. Tubular secretion of creatinine represents a greater proportion of excreted creatinine in these children, may maintain serum creatinine in the normal range and mask the decrease in GFR. The study also emphasizes the problems of measuring RFR in these children.     

Long-term clinical outcome of paediatric kidneys transplanted to adults.

BACKGROUND: We have earlier shown an increase in the size and excellent graft function of paediatric kidneys transplanted to adults up to 1 year following transplantation. This study was performed to assess the long-term outcome of these transplants. METHODS: From a primary cohort of 19 adults, receiving a first kidney transplant from a paediatric donor <10 years of age, 16 patients were available for a complete long-term follow-up, 5-9 years post-transplant. Of these, eight patients were transplanted with a donor of <5 years. All medical files and registry data of the cohort, from the time of transplantation to the follow-up time point, were recalled and events were registered. The patients' general condition, body weight, blood and urine tests, blood pressure (BP), use of antihypertensive agents and GFR were recorded. To explore the temporal increment in the size of paediatric donor kidneys transplanted to adults, the maximal cranio-caudal length of the kidneys from the time of transplantation to follow-up was established by ultrasound. Volumes (length x width x thickness x pi/6) of en bloc kidneys versus single paediatric kidneys and adult-to-adult transplants were compared. RESULTS: Long-term (7 years, median) patient and graft survival was 95% and 89%, respectively. Mean serum creatinine was 85 micromol/l (range, 32-131). The mean estimated GFR was 84 ml/min/1.73 m(2). The mean BP was 134/79 mmHg (range, 120-185/70-90). The number of antihypertensive agents used was not statistically different from the number used at 1 year post-transplant. None of the patients had significant proteinuria as a sign of hyperfiltration injury of the graft. There were no statistically significant increases in the maximal cranio-caudal length of the transplanted kidney(s) from 1 year post-transplant to follow-up; however, the en bloc kidneys tended to be larger than single paediatric grafts (240 ml and 204 ml) and adult-to-adult grafts (170 ml). CONCLUSION: Paediatric kidneys transplanted to adults should be considered as excellent for transplantation on a long-term basis.     

Renal functional reserve in children with reduced renal mass: study by two dietary periods

It has been suggested that the renal functional reserve (RFR) defined by the rise in glomerular filtration rate (GFR) after a protein load could disappear in patients with severe nephron loss but with a normal GFR. This study compared, in 17 children, inulin clearance (C _in) measured by the plasma inulin plateau at the end of two 14-day randomized periods differing in protein intake: 100% (low protein, LP), or 200% (high protein, HP) of recommended dictary allowances (RDA). Diets were aimed at maintaining food habits and energy intake. Compliance was assessed by records of the last 3–4 days, an interview with the dietician and by urinary nitrogen measurements. Mean actual protein intake was 109% (56%–139%) RDA for the LP period and 220% (163%–319%) RDA for the HP period.C _in did not change in 14 children with GFR below (n=7) or within (n=7) the normal range.C _in was higher in the HP period than in the LP period (+32, 50, 63%) in 3 children who had a 50% (single kidneys) or a 25% (sclerosed glomeruli) nephron loss. Non-responding children had a GFR below 105 ml/min per 1.73 m². Nephron loss (70% sclerosed glomeruli) was estimated in only 1 child with no RFR. The results suggest that GFR measurement after prolonged dietary stimulation could help in evaluating the severity of nephron loss in children with normal or borderline GFR. The prognostic value of this test has to be confirmed by long-term follow-up.     

Comparison of palpation-guided and ultrasound-guided biopsies in transplanted kidneys

Biopsy is the gold standard for the diagnosis of conditions affecting the function of renal allografts. Obtaining representative tissue in biopsies is critical but these procedures are associated with up to 9% of complications and 20% of inadequate material. Although ultrasound guidance allows perfect control of depth and location of the graft, there is controversy regarding the cost-benefit of its use and reports of unsuitable material in ultrasound-guided biopsies are still high. PURPOSE: To compare ultrasound with the palpation method to guide biopsies in order to see if there is any difference between both methods and which one is better. PATIENTS AND METHODS: The casuistic consisted of 82 renal transplant patients (32 female and 50 male patients, age ranging between 5 and 64 yr; m=31.2 yr) randomized into two groups: GI, palpation-guided; GII, ultrasound-guided. Fifty-six biopsies were performed in GI and 66 in GII. RESULTS: Number of glomeruli, arcuate, and interlobar arteries and arterioles were compared in the two groups and were 503 (m=10) vs. 801 (m=12.9), 24 (m=0.5) vs. 38 (m=0.6), 104 (m=2.1) vs. 154 (m=2.5), and 174 (m=3.5) vs. 264 (4.3), respectively (p<0.05). Inadequate material for analysis in GI and GII was 7.1 and 7.6%, respectively (p=0.72). CONCLUSIONS: Although ultrasound guidance improves the number of glomeruli, arcuate, and interlobar arteries, as well as arterioles, compared with palpation-guided biopsies, there is no difference in the rate of adequate material between the two methods.     

Renal functional reserve and renal hemodynamics in hypertensive patients

The renal functional reserve (RFR) is the ability of the kidneys to increase renal plasma flow and glomerular filtration rate (GFR) in response to protein intake. It is a measure of functional and anatomic integrity of nephrons. It is not known what relation between RFR and kidney Doppler parameters. We aimed to study the relation between the RFR and renal hemodynamic parameters in hypertensive patients with and without nephropathy who had normal kidney function. Twenty-four hypertensive subjects with nephropathy (HTN-n, n?=?10) and hypertension without nephropathy (HTN, n?=?14) were included in the study. Control group included 11 healthy subjects. Baseline GFR (GFR1) and GFR after intake of egg protein 1?mg/kg of body weight were determined (GFR2). RFR was calculated by the following formula: (GFR2-GFR1)/GFR1?×?100%. Doppler ultrasonography was performed. Arterial blood pressure (BP), body mass index (BMI), and estimated GFR were also recorded. HTN and HTN-n groups had impaired levels of RFR compared with controls (p?<?0.05), significantly decreased value of flow velocity parameters (Vmax, Vmin), and increased RRI compared with controls. There was significant negative correlation of RFR with blood pressure levels (sBP, r?=??0.435, p?=?0.009; dBP, r?=??0.504, p?=?0.002), RRI (r?=??0.456, p?=?0.008), micro albuminuria (MAU, r?=??0.366, p?=?0.031) and positive correlation with Vmax and Vmin (r?=?0.556, p?=?0.001 and r?=?0.643, respectively, p?<?0.001). Linear regression showed that RRI and MAU were independent predictors of decreased RFR. RFR is lower in hypertensive patients despite near-normal level of kidney function and is related to particular level of BP. RRI and MAU were independent predictors of decreased RFR.     

Renal length and inulin clearance in the radiologically normal single kidney

Compensatory hypertrophy of a single functioning kidney is well described and has been shown to occur in utero. The long-term effects of hypertrophy and hyperfiltration in this situation are unknown. This study defined the growth parameters for single kidneys during childhood and correlated them with inulin clearance. Patients were those who had a radiologically "normal" single kidney, where the contralateral kidney was known to be non-functioning from infancy. Data were obtained from 74 children (40 boys and 34 girls) drawn from a registry of cases with a single kidney, and in whom simultaneous measurements of inulin clearance and renal length had been made at around 5, 10, and 16 years of age. Renal length was taken as the maximal bipolar measurement using real-time ultrasound scan. Inulin clearance was by continuous infusion technique. Nomograms for single kidney growth were determined against age, height, weight, and body surface area. Renal growth was correlated with inulin clearance. Renal length was found to correlate best with body surface area (r=0.85, P<0.001), but this was not significantly superior to correlations with age, height, or weight separately. Inulin clearance per body surface area correlated positively with standardized renal length, i.e., Z score for renal length normalized for body surface area (r=0.53, P<0.001). The larger kidneys have a higher glomerular filtration rate. Provided that the nephron number in the single kidney is similar to that in a paired kidney, single kidneys are hypertrophied and the single nephron glomerular filtration rate is likely to be abnormally high in these children.     

Renal funtional reserve in kidney transplant recipients

In the last few years different authors have observed that kidney transplant recipients with good organ function do not have a renal functional reserve (RFR). This condition is accompained by a high glomerular filtration rate (GFR) [2–6]. We studied RFR in patients with very good organ function under different immunosuppressive therapies, who were divided into groups based on the presence or absence of RFR.     

Renal function following kidney transplantation in children treated with cyclosporine

The study was performed to evaluate the longterm renal function of children treated with cyclosporine after kidney transplantation. Renal function was determined with clearances of inulin and aminohippurate sodium for evaluating glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Thirty-six children aged 0.4–16.2 (median 6.9) years at transplantation were examined within 5 months of transplantation and then yearly over 0.3–7.1 years. Twenty-five children and young adults, 1.5–20 (median 7.7) years of age, with solitary kidneys because of renal agenesis or nephrectomy, served as controls. The GFR and ERPF within 1 year of transplantation were significantly lower than those of controls (65±19 and 345±88 vs 96±12 and 474±91 ml/min per 1.73 m², respectively). GFR remained constant 4 years after transplantation, but ERPF decreased significantly. Significant inverse correlations were found between GFR within 5 months of transplantation and the mean cyclosporine concentration and the number of rejection episodes. The frequency of hypertension decreased from 82% within 5 months of transplantation to 0% after 4 years. The absolute GFR increased during follow-up. In conclusion, kidney transplantation results in a reduced renal function compared with that of solitary native kidneys. The reduction in renal function correlated with the number of rejection episodes and the cyclosporine load. The increase in absolute GFR during follow-up suggests a remaining capacity for growth and/or compensatory hypertrophy.     

盐酸小檗碱对肾移植受者环孢素A血浓度的影响

目的研究盐酸小檗碱(Ber)对肾移植受者环孢素A(CsA)血浓度的影响.方法33例肾移植后口服CsA+Ber的受者为试验组,27例单纯口服CsA的受者为对照组,以CsA全血浓度及肝、肾功能生化检测指标作为临床评价指标.结果试验组受者CsA全血浓度与合用Ber前比较,增幅达66.9%,与对照组比较差异有显著性(P<0.001),停用Ber后,CsA全血浓度显著下降.Ber与CsA合用对肝、肾功能无明显影响.结论Ber能显著升高肾移植受者CsA血浓度.在升高CsA血浓度的同时,Ber并不增加CsA的毒性反应.Ber与CsA合用有望成为一种节省CsA费用的方法.     

A prospective study on size and function of paediatric kidneys (<10 years) transplanted to adults

BACKGROUND: There is increasing evidence that paediatric kidneys transplanted to adults have good graft function and satisfactory graft survival. The relationship between size increment and functional potential of paediatric kidneys following transplantation is not defined in detail. We therefore initiated a prospective single centre study, comprising detailed and repeated measurements of size and function of paediatric kidneys transplanted to adults. METHODS: Nineteen adults receiving a first kidney transplant from a paediatric donor (<10 years of age) were included in the study. All patients were followed for 12 months post-transplant. Increment in size and function of the transplanted kidneys were assessed by ultrasound, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). All tests were performed during the first week, post-transplant and subsequently repeated at 1, 3, 6 and 12 months. RESULTS: Kidney volume increased 2.6-fold at 12 months (P < 0.001). GFR and ERPF showed a slightly more moderate increase, 1.8-fold and 1.6-fold, respectively. Patient and graft survival at 1 year were 100% and serum creatinine was 91 micromol/l (66-169). CONCLUSION: The study indicates that paediatric kidneys for transplantation may be considered as excellent rather than being referred to as suboptimal for adult recipients, at least the first year after transplantation.     

Arterial abnormalities identified in kidneys transplanted into children during the COVID-19 pandemic

Graft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic.     

Renal functional reserve in experimental chronic glomerulonephritis

Loss of renal functional reserve, that is, absence of the glomerularvasodilatory response to amino-acid infusion, has been interpretedas equivalent to glomerular hyperperfusion/hypertension, andthere fore proposed as a marker of high risk for progressiveglomerular sclerosis. To substantiate the validity of this hypothesiswe evaluated the renal response to glycine and the extent ofglomerular damage 10–12 weeks after induction of anti-glomerularbasement membrane glomerulonephritis with or without superimposedclip hypertension. Untreated rats and rats chronically treatedwith quinapril, a converting-enzyme inhibitor, were studied.In untreated groups, loss of renal functional reserve was demonstratedsince GFR, single-nephron GFR (SNGFR) and plasma flow (SNPF)did not increase during glycine infusion. The absence of renalreserve was associated with glomerular hyperfusion/hypertension,and development of proteinuria and glomerulosclerosis. Quinaprilreduced proteinuria and diffuse sclerosis in anti-glomerularbasement membrane GN, and decreased blood pressure and segmentalglomeruloscierosis in anti glomerular basement membrane GN withsuperimposed clip hypertension. Both treated groups demonstrateda restoration of renal functional reserve, as depicted by increasesin GFR, SNGFR, and SNPF after glycine, despite persistence ofglomerular hyperperfusion/hypertension. These data demonstrthat renal functional reserve testing, although it does notdetect glomerular hyperperfusion/hypertension, can provide informationon the progression of glomerular damage.     

Recurrence of SLE in transplanted kidneys: a follow-up transplant biopsy study.

Renal transplant biopsies were obtained from 16 patients with systemic lupus erythematosus 6 months to 11 years post-transplant. Eight biopsies were taken on clinical grounds while eight were elective. Histopathological findings suggesting recurrent lupus nephritis were found in seven biopsies, five of which were taken on clinical indication. By light-microscopy, five graft biopsies showed proliferative glomerulopathy and two glomerulosclerosis. Immunofluorescence was positive for IgM and C3 in a finely granular pattern in all biopsies, for C1q in three, but for IgG in only two. Electron-dense deposits were found in all seven biopsies with predominantly subendothelial location. All but one patient had clinical signs of renal involvement, but only three had extrarenal symptoms and three had serological signs of active SLE. Upon increased immunosuppressive therapy, renal and serological signs improved but one graft was later lost due to recurrent SLE nephritis.     

End-stage disease of native kidneys in a patient with biopsy-proven Arndt-Gottron scleromyxoedema and recurrence in the transplanted kidney.

End-stage renal disease-stage 5 chronic kidney disease (CKD)-of the native kidneys, related to biopsy-proven Arndt-Gottron scleromyxoedema, developed in a male patient. From 1998 until 2001, the patient was treated by haemodialysis. In June 2001, cadaveric kidney transplantation was performed. In January 2004, a kidney biopsy was performed because of deteriorating renal function revealing relapse of scleromyxoedema with typical concentric narrowing of the arterioles due to accumulation of mucopolysaccharides with severe glomerular ischaemia. Arndt-Gottron scleromyxoedema is an as yet unsuspected cause of stage 5 CKD of the native kidneys. Moreover, the disease can relapse in the transplanted kidney, again leading to intractable transplant stage 5 CKD.     

Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis

Atypical haemolytic uraemic syndrome (aHUS) often leads to end‐stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26‐week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event‐free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre‐existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m² in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function.     

Renal hemodynamic changes and renal functional reserve in children with type I diabetes mellitus

Increased glomerular filtration rate (GFR) has been implicated in the development of diabetic nephropathy. Large normal interindividual variations of GFR hamper the diagnosis of renal hemodynamic alterations. We examined renal functional reserve (RFR) in children with type 1 diabetes mellitus to assess whether hyperfiltration occurs. The renal hemodynamic response following dopamine infusion was examined in 51 normoalbuminuric diabetic children (7.7 ± 3.6 years) with a mean duration of diabetes of 6.2 years and compared them with 34 controls. Mean baseline GFR in diabetic children did not differ from the control population (130.7 ± 22.9 vs. 124.8 ± 25 ml/min per 1.73 m²), whereas renal plasma flow was significantly lower (463.7 ± 103.9 vs. 587.2 ± 105 ml/min per 1.73 m², p < 0.001), and filtration fraction was increased (29 ± 8 vs. 21 ± 2%, p < 0.001), compared with controls. The mean RFR was lower (p < 0.001) than in control subjects (−0.77 ± 23 vs. 21 ± 8 ml/min per 1.73 m²). This study documents an increased filtration fraction and reduced or absent RFR in children with type 1 diabetes mellitus in the stage before apparent nephropathy. GFR values were within normal range. Although the reduced RFR and increased filtration fraction indicate the presence of hemodynamic changes, their relevance to the development of hyperfiltration and subsequent diabetic nephropathy remains unknown.