Growth hormone treatment in the pre-transplant period is associated with superior outcome after pediatric kidney transplantation

Background Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant function after KT is yet unknown. Methods Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing KT before the age of 8 years, from two German pediatric nephrology centers, were prospectively investigated with a mean follow-up of 5.56 years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment was assessed by the use of linear mixed-effects models. Results Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared to the non-prior rhGH group but showed similar height z-scores at the time of KT. After KT, steroid exposure was lower and increments in anthropometric z-scores were significantly higher in the rhGH group compared to those in the non-prior rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After adjustment for these confounders, growth outcome did statistically differ for sitting height z-scores only. Conclusions Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney transplant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier maturation after KT. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Deceased donor kidney degradomics indicate cytoskeletal proteolytic alterations impact post-transplant function.

Background. In brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction. Material & Methods. Using mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys. Results. We found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were independent to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, α-actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-β (TGF-β) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in-vitro by Calpain-1 inhibition. Conclusions. Here, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities.

MO587PREVALENCE OF MINERAL AND BONE DISORDERS MAKERS AMONG RECIPIENTS OF KIDNEY TRANSPLANT: SINGLE-CENTER EXPERIENCE

Background and Aims Mineral and bone disorders (MBD) are common after successful kidney transplantation in patients with chronic kidney disease (CKD). We aimed to evaluate the prevalence of biochemical abnormalities among recipients of kidney transplant. Method We performed a cross-sectional study of 236 patients underwent successful kidney transplantation in our clinic between 2007 and 2019. Median age was 49 [Q1-Q3: 39; 58] years, mean estimated glomerular filtration rate (eGFR) was 51,1±21,8 ml/min/1,73 m2. Most of the patients received hemo- or peritoneal dialysis treatment, pre-emptive transplantation was performed in 6% cases. For those previously received dialysis, median duration of any type of dialysis was 21 [Q1-Q3: 11; 36] months. Median time after transplantation reached 42 [Q1-Q3: 19; 75] months. We evaluated serum intact parathyroid hormone (iPTH), total calcium (Ca), phosphorus (P) and alkaline phosphatase (AP) levels. Target ranges were defined according to National guidelines on CKD-MBD as follows: 2,1 - 2,5 mmol/l for total Ca, 0,87 – 1,49 mmol/l for P; normal AP level is defined considering a gender (53-128 Е/l for men, 42-98 Е/l for women). Target iPTH level for optimal and slightly decreased transplant function (corresponding chronic kidney diasease (CKD) stage 3T) was defined as 35-70 pg/ml, for eGFR corresponding CKD 4T – as 70-110 pg/ml, for CKD 5T – as 70-150 pg/ml. Results In our cohort normal iPTH level was observed only in 13% cases, whereas 84% of the patients had hyperparathyroidism. iPTH inversely correlated with eGFR (ρ= -0,454 [95%CI: -0,55; -0,34], р<0,0001 – fig.1) and its level differed significantly between groups with different CKD stage (р<0,0001, Kruskall-Wallis test) – fig.2. However, fraction of patients with target iPTH did not differ in recipient groups with normal and decreased eGFR (p=0,118). Hypercalcaemia was observed in 29% cases; there was a weak correlation of serum total Ca level with iPTH (ρ= 0,282 [95%CI: 0,15; 0,4], р<0,0001) and AP (ρ=0,181 [95%CI: 0,05; 0,31], р=0,006) – fig.3. Hypophosphatemia was seen much more frequently during the first year after transplantation than in long-term period (30,3% vs 6,4% respectively, р=0,0002). Serum P level varied significantly in groups with different eGFR (p<0,0001, Kruskall-Wallis test), increasing in parallel with declining of transplant function – fig.4. The percentage of patients within a target range of AP amounted to 54%, above the target range – 40,7%. In total, only 6,8% of our cohort had all laboratory parameters within the target range. Conclusion We observed a high prevalence of biochemical abnormalities in kidney transplant patients confirming that transplantation itself does not cure mineral and bone disorders in CKD patients.

MO952EFFECT OF KIDNEY TRANSPLANTATION ON PARATHYROID GLANDS FUNCTION

Background and Aims The normalization of the function of the parathyroid glands after successful kidney transplantation does not occur in all patients. The aim of our study was to determine of parathyroid function, patient factors that would be predictive of achieving a normal serum PTH in the first months after surgery and prevalence of hyperparathyroidism (HPT) in patients after kidney transplantation (KT) at various stages of the post-transplant period. Method The observational cross-retrospective study included 230 kidney graft recipients. Inclusion criteria: the duration of the post-transplant period is more than 12 months and stable kidney transplant function for 6 months. The median of the pre-transplant stage was 18 months (Q1-Q3: 9; 35), post-transplant period - 42 months (Q1-Q3: 21; 73). Serum concentrations of parathyroid hormone (PTH), calcium, phosphorus, total alkaline phosphatase activity, albumin, and creatinine were determined using standard methods. HPT was diagnosed with PTH>130 pg/ml. Retrospective analysis of parameters in three months after surgery it was performed in 197 patients. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula, stratification of chronic kidney disease (CKD) stages was carried out according to the eGFR. Results Patients had different kidney transplant function: eGFR 117-15 ml/min, median 51 (Q1-Q3: 39;65): CKD 1(КT) st. was in 3.5%, CKD 2(КT) st. - in 33.9%, CKD 3(КT) st. - in 49.1% and CKD 4(КT) st. – in 13.5% patients. Serum PTH levels were 27-670 pg/ml, median 120 pg/ml (Q1-Q3: 87; 182). The median PTH of blood in patients was 99 pg/ml (Q1-Q3: 76; 120), 98 pg/ml (Q1-Q3: 79; 123), 120 pg/ml (Q1-Q3: 89; 180) and 267 pg/ml (Q1-Q3: 170; 328), respectively, with CKD 1(КT), CKD 2(КT), CKD 3(T) and CKD 4(КT) st. The frequency of HPT was 38.7%: 19.8% in patients with eGFR≥60 ml/min, 38.1% and 93.5% in patients with CKD 3(КT) and CKD 4(КT) st. (p<0.001) (Fig. 1). HPT was equally frequently diagnosed in the second, third, fourth and fifth years after kidney transplantation and amounted to 30.3% in the first five years. In patients with a post-transplant period of more than 5 years, HPT was 54.7% (p<0.001). In the same group, the proportion of patients with eGFR<60 ml/min was also higher - 55.5% (p=0.002) (Fig. 2). An inverse relationship was established between serum PTH and eGFR and a direct relationship between serum PTH and serum creatinine (p<0.001). A retrospective analysis showed that 3 months after kidney transplantation, the median PTH was 178 pg/ml (Q1-Q3: 120; 250), HPT was recorded in 65.5% of patients. Serum PTH decreased by 6-92%, median 50%. Kidney graft function was worse in patients with a decrease in serum PTH ≤50% (n = 100) versus patients with a decrease in serum PTH >50% (n = 97). Minimal blood creatinine was recorded in the early postoperative period, respectively, on (median) 7 and 5 days (p = 0.015), the median eGFR by the end of the third month was 59 and 63 ml/min, respectively (p=0.044). We found that preoperative PTH>585 pg/ml (p<0.0001 OR 2.93 95% CI 1.78; 5.05), delayed kidney graft function (p=0.005 OR 1.57 95% CI 1.58; 9.87), and eGFR<60 ml/min (p<0.0005 OR 2.01 95% CI 1.36; 3.09) were predictive of HPT in patients in the early stages after kidney transplantation. Conclusion Hyperparathyroidism in patients after kidney transplantation continues to be an ongoing problem. It occurs in a third of patients in the first five postoperative years and in half patients in subsequent years. Preoperative secondary hyperparathyroidism, delayed and suboptimal kidney graft function prevent the restoration of parathyroid glands function after kidney transplantation.

Bronchial complications after lung transplantation

Bronchial complications are among the main causes of impairing postoperative period and thansplant failure. Severe bronchial complications are very rare but have a high mortality rate. Light forms decrease transplant function and while progressing can leads to life-threatening conditions without required treatment. Nowadays there is a huge necessity in classification of diagnostic and bronchial complications treatment on different terms after lung transplantation. Methods of observation bronchoscopy and interventional bronchology are allowing us to realize prevention, diagnostic and treatment bronchial complications.

Significance of Glomerular Immune Reactivity in Time Zero Biopsies for Allograft Survival Beyond IgA

The quality of a renal transplant can influence the clinical course after transplantation. Glomerular immune reactivity in renal transplants has previously been described, focusing particularly on IgA, and has been shown to disappear in most cases without affecting the outcome. Here, we describe a cohort of time zero biopsies with regard to glomerular immune reactivity and implications for histomorphology and follow-up. 204 Time zero biopsies were analyzed by immunohistochemistry for glomerular immune reactivity. Time zero and 1-year biopsies were evaluated for histomorphological changes, which, together with clinical and follow-up data, were assessed for associations with glomerular immune profiles. Nearly half of the analyzed time zero biopsies showed glomerular immune reactivity with mesangial C3 being the most common (32.9%), followed by IgA (13.7%) and fullhouse patterns (6.9%). Strong C3 deposits (C3high) were only observed in deceased transplants. In the majority of cases immune reactivity was undetectable in follow-up biopsies and had no adverse effect on transplant function in follow-up of 5 years. In kidney pairs transplanted to different recipients a strong concordance of immune profiles in both kidneys was observed. Moreover, an association of male donor sex and deceased donor transplantation with the presence of immune reactivity was observed. In conclusion, glomerular immune reactivity is a very frequent finding in time zero biopsies, which seems to be determined by donor parameters including male sex and deceased donor transplants. It had no adverse impact on transplant function in 5-year follow-up. Glomerular immune reactivity in time zero biopsies, therefore, does not appear to indicate an inferior quality of the transplant.

Determinants of growth after kidney transplantation in prepubertal children

Background Short stature is a frequent complication after pediatric kidney transplantation (KT). Whether the type of transplantation and prior treatment with recombinant human growth hormone (GH) affects post-transplant growth, is unclear. Methods Body height, leg length, sitting height, and sitting height index (as a measure of body proportions) were prospectively investigated in 148 prepubertal patients enrolled in the CKD Growth and Development study with a median follow-up of 5.0 years. We used linear mixed-effects models to identify predictors for body dimensions. Results Pre-transplant Z scores for height (− 2.18), sitting height (− 1.37), and leg length (− 2.30) were reduced, and sitting height index (1.59) was increased compared to healthy children, indicating disproportionate short stature. Catch-up growth in children aged less than 4 years was mainly due to stimulated trunk length, and in older children to improved leg length, resulting in normalization of body height and proportions before puberty in the majority of patients. Use of GH in the pre-transplant period, congenital CKD, birth parameters, parental height, time after KT, steroid exposure, and transplant function were significantly associated with growth outcome. Although, unadjusted growth data suggested superior post-transplant growth after (pre-emptive) living donor KT, this was no longer true after adjusting for the abovementioned confounders. Conclusions Catch-up growth after KT is mainly due to stimulated trunk growth in young children (< 4 years) and improved leg growth in older children. Beside transplant function, steroid exposure and use of GH in the pre-transplant period are the main potentially modifiable factors associated with better growth outcome.