Conn´s syndrome after kidney transplantation.

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least a triple combination of antihypertensives, including a diuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control.In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on a cross-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium.We present the case of a patient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from a deceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with a dual combination of antihypertensives (amlodipine at a daily dose of 5 mg and carvedilol at a daily dose of 50 mg), without the need for a diuretics.We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome (Fig. 3, Ref. 19). Text in PDF www.elis.sk Keywords: kidney transplantation, primary hyperaldosteronism, hypokalaemia, metabolic alkalosis, secondary arterial hypertension.

The impact of different induction immunosuppression protocols on patient survival, graft survival and acute graft rejection after kidney transplantation.

OBJECTIVES: The aim of the study was to stratify the immunological risk based on the presence of risk factors using different induction immunosuppressive protocols. BACKGROUND: The path to successful kidney transplantation reflects the accuracy of immunological risk assessment and choice of correct induction and maintenance of immunosuppression to avoid acute kidney rejection. METHODS: We performed a multicentre prospective analysis consisting of patients after kidney transplantation with a 12-month follow-up. RESULTS: In total, 152 kidney transplant recipients were included, of whom 100 were males (66.4 %). We divided patients according to the induction immunosuppression as follows: no induction (n = 19), induction with basiliximab (n = 60), and induction with ATG at cumulative doses of 3.5 mg/kg (n = 42) and 6 mg/kg (n = 31). In our study, we demonstrated a shorter survival of patients without induction immunosuppression. In the basiliximab group, the duration of dialysis ≥ 3 years (p = 0.0191), cold ischaemia time ≥ 1,020 minutes or expected delayed graft function (p < 0.0001) are independent risk factors for graft loss (p = 0.0097). CONCLUSIONS: Risk of no induction immunosuppression significantly exceeds the risks associated with its administration and is desirable even in patients at low immunological risk. Induction immunosuppression should be tailored individually and thus differ from patient to patient (Tab. 6, Fig. 1, Ref. 15).

Early recurrence of focal segmental glomerulosclerosis as an unusual cause of primary kidney transplant malfunction.

Recurrence of the primary disease is one of the most common causes of graft failure in the first decade after kidney transplantation. We present a case of a patient with an unusually rapid recurrence of focal segmental glomerulonephritis in the graft, the recognition of its occurrence was hampered by the primary graft affection and oligoanuria and by insignificant histological changes in the first two biopsy samples in the early post-transplant period, as well as by unawareness of the disease leading to terminal renal failure, as no renal biopsy was performed due to grade 3 obesity. Only worsening of hypoalbuminemia and finding of massive proteinuria despite oligoanuria were crucial for further management. Disease recurrence in the graft was confirmed by electron microscopy. However, complex targeted therapy did not result in restoration of graft function and decrease in proteinuria. This case history was aimed to draw attention to the knowledge of the importance of the primary disease confirmed by renal biopsy and early (so called pre-emptive) treatment in case of diseases with a high potential of recurrence (Fig. 7, Ref. 10). Text in PDF www.elis.sk Keywords: kidney transplantation, recurrence, minimal changes in glomeruli, focal segmental glomerulosclerosis.

Overview of urological complications before, during and after kidney transplantation.

The result of a kidney transplantation may be affected by certain congenital or acquired urological diseases that need to be addressed before, during or after the kidney transplant. Complications accompanying kidney transplantation are not fundamentally different from the events that accompany other difficult surgical procedures. However, their course is usually modified by adverse circumstances in the recipient - uremia, dialysis treatment, immunosuppression. The incidence of urological complications is reported in the range of 1 to 30 % of the transplants, and they represent up to one half of all surgical complications. They can cause a significant morbidity and mortality and can lead to a delayed onset of the function and even to a loss of the transplanted kidney.Urological complications that need to be addressed before kidney transplantation include anomalies or pathological changes in the lower urinary tract, pelvic involvement in atherosclerosis or previous kidney transplants, infectious foci in lithiasis or pyonephrosis, large polycystic kidneys and malignancies. During the kidney transplantation itself, vascular complications, and complications connected with the reconstruction of the lower urinary tract can occur. Other complications are bacterial and viral infections and malignancies. All these complications require a rapid and accurate diagnosis and subsequent targeted treatment with intention to maintain a functional kidney transplant (Fig. 11, Ref. 36). Text in PDF www.elis.sk Keywords: kidney transplantation, urological, vascular, infectious, bleeding, complications.

How COVID-19 crisis influenced kidney transplant recipients in Slovakia.

OBJECTIVES: The aim of our analysis was to evaluate the impact of the COVID-19 pandemic on the procurement program and kidney transplantation in Slovakia and to identify the risk factors for a severe course of COVID-19 disease, as well as the risk factors for COVID-19 fatalities, with the focus on the parameters preceding the infection. We compared morbidity and mortality from COVID-19 before and after the spread of the alpha variant of the virus and the same among transplant (KTRs) and haemodialysis patients in Slovakia. METHODS: 305 KTRs (68.8 % males) with confirmed SARS-CoV-2 positivity were included in the multicentric retrospective analysis. The patients were split into subgroups based on the time of falling ill and their clinical course. RESULTS: The procurement program and kidney transplants in Slovakia dropped in the observed period by 28.6 % (p<0.0001) and by 33.5 % (p<0.0001) respectively. Age over 59 years (p=0.0088) and diabetes mellitus (p=0.0106) were identified as independent risk factors for severe course of the disease. Risk factors for death were the age over 59 years (p=0.0003) and graft dysfunction with CKD-EPI<0.5 mL/s (p=0.0029). The prevalence of the alpha variant in Slovakia was associated with a severe course in KTRs treated with corticoids (p=0.0273) and in graft dysfunction with CKD-EPI<0.5 mL/s (p=0.0076); the risk of death was higher in KTRs over 59 years (p=0.0173) and again with CKD-EPI<0.5 mL/s (p=0.0393). KTRs had a 3.7 times lower risk of infection compared to the haemodialysis patients (p<0.0001), with mortality of 9.8 % vs 30 % (p<0.0001). CONCLUSION: The procurement and transplant program is sustainable even during a pandemic, provided that measures are set up quickly. Morbidity and mortality from COVID-19 in KTRs was comparable to the situation in EU countries. Patients in the haemodialysis program had a worse prognosis (Tab. 5, Fig. 1, Ref. 21) Keywords: COVID-19, kidney transplantation, dialysis, immunosuppression, obesity, diabetes mellitus.

Improvement in cardiovascular risk markers by the combined effect of natural polyphenols and vitamins in patients after kidney transplantation.

OBJECTIVES: The aim of this study was to evaluate the potential of supportive therapy by natural polyphenols combined with vitamins C and E on kidney function and risk factors of cardiovascular diseases in renal transplant recipients (RTR). BACKGROUND: Transplant patients have an altered lipid profile associated with the development of cardiovascular disease, which is a major cause of graft loss and mortality in patients. METHODS: The study included 29 renal transplant recipients with mean graft function levels. The lipoprotein (atherogenic and non-atherogenic) subfractions were identified and quantified in plasma by polyacrylamide gel electrophoresis. RESULTS: After supplementation, glomerular filtration rate (GFR) was increased by 8 %, serum creatinine was decreased by 6.7 % and significant changes were found in atherogenic LDL subfractions. The effect of supplementation was observed in arylesterase and lactonase activities of paraoxonase 1 which increased by 9.3 % and 8.1 %, respectively. In addition, significantly decreased levels of neopterin (by 16 %) and asymmetric dimethylarginine (ADMA) (by 7.9 %) were found. CONCLUSION: We could summarize that supportive therapy improves the renal function (GFR, serum creatinine), and reduces the risk of cardiovascular disease by affecting important risk markers of atherosclerosis (lipid profile, paraoxonase 1 activity, neopterin and ADMA) in RTR (Tab. 4, Fig. 1, Ref. 53).

The Role of HLA Antigens and Steroid Dose on the Course of COVID-19 of Patients After Kidney Transplantation.

Background: Kidney transplant recipients appear to be at higher risk for critical COVID-19. Our analysis aimed to identify the possible risk factors for a severe course of the COVID-19 disease and to determine the influence of selected human leukocyte antigens (HLAs) on the course of the disease. Methods: This is a retrospective, multicenter analysis that included patients that were confirmed to be severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive after kidney transplantation (KT). The group of patients was divided into two subgroups according to the course of the infection, as follows: non-hospitalized and hospitalized. Results: A total of 186 patients (men, 69.4%) with confirmed SARS-CoV-2 positivity were included in the group. The following independent risk factors for the outcome of hospitalization were identified: the age at the time of infection [odds ratio (OR) = 1.19, P < 0.0001], a body mass index (BMI) >29.9 kg/m2 (OR = 7.21, P < 0.0001), <7.5-mg prednisone dose/day (OR = 2.29, P = 0.0008), and HLA-DQ2 with a protective nature (OR = 0.05, P = 0.0034). Conclusions: Higher doses of corticosteroids (>7.5 mg/kg) in standard immunosuppressive regimes and HLA-DQ2 appear to be protective factors in our analysis.

Association of HLA-G Polymorphisms in the 3'UTR Region and Soluble HLA-G with Kidney Graft Outcome.

Background: Human leukocyte antigen G (HLA-G) belongs to nonclassical HLA I molecule involving in the suppression of immune response. Besides its profound effect to induce fetal tolerance, HLA-G expression has been associated with allograft acceptance. For the regulation of HLA-G levels, polymorphic sites within the 3' untranslated region (3'UTR) are of crucial importance. The aim of the study was to analyze the association between several HLA-G 3'UTR variants (+3003T/C, +3010C/G, +3027C/A, +3035C/T, +3142G/C, +3187A/G, and +3196C/G), soluble HLA-G (sHLA-G) level, and kidney graft outcome in the Slovak Caucasian population. Methods: We investigated 69 kidney transplant recipients (45 males, 24 females) of age 27-65 years. Out of this group, 37 recipients developed acute rejection that was biopsy proven. Recipient's plasma was obtained at 1 day before transplantation and analyzed by ELISA. The HLA-G 3'UTR polymorphisms were typed by direct sequencing. Results: In the recipients with stable allograft function, significantly higher values of sHLA-G were found in the homozygous +3010GG, +3142CC, +3187GG, and +3196CC carriers in comparison to the acute rejection recipients (P = 0.01-0.05). Conclusion: The study demonstrated genetic association between HLA-G 3'UTR variants and sHLA-G level in kidney recipients leading to graft acceptance. We suggest to monitor the pretransplantation sHLA-G level as additional marker to predict kidney graft outcome. Abbreviations: AMR: Antibody-mediated rejection; APC: antigen-presenting cell; CD: cluster of designation; del: deletion; HLA: human leukocyte antigen; ILT: immunoglobulin-like transcript; ins: insertion; KIR: killer-cell immunoglobulin-like receptor; NK: natural killer; sHLA-G: soluble HLA-G; SNP: single nucleotide polymorphism; TCMR: T cell-mediated rejection; URR: upstream regulatory region; UTR: untranslated region.

Effect of Paricalcitol on Bone Density After Kidney Transplantation: Analysis of 2 Transplant Centers.

INTRODUCTION: The Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines on the management of bone disease in patients with chronic kidney disease recommend periodic measurement of serum calcium, phosphorus, vitamin D, and parathyroid hormone levels after kidney transplantation, with the frequencies that will vary according to the severity of bone disease and graft function. Paricalcitol, a selective vitamin D receptor activator, is indicated in the prevention and treatment of secondary hyperparathyroidism. MATERIALS AND METHODS: We retrospectively evaluated the effect of treatment with paricalcitol among our kidney transplant recipients. We monitored the effect of paricalcitol on bone density; the plasma levels of parathyroid hormone, calcium, and phosphorus; and proteinuria and calciuria. Comparisons were made between these parameters before treatment and 12 months after treatment. RESULTS: Eighty-eight kidney transplant recipients with a mean age at the time of transplantation of 47.1 ± 10.5 years were receiving paricalcitol. On average, paricalcitol was included into the treatment for 48 months from transplantation (median, 27 months). The patients had significantly improved bone density (P < .001), significantly lower parathyroid hormone levels (P < .001), and significantly decreased proteinuria (P = .02) after 12 months of treatment. During the treatment with paricalcitol, the immunosuppressive therapy, dose of prednisone, body mass index, and vitamin D levels had not significantly changed. Nor had any significant change occurred to graft function. CONCLUSIONS: Paricalcitol is an effective therapy for secondary hyperparathyroidism in kidney transplant recipients.

Clinical experience of conversion from cyclosporine to tacrolimus prolonged-release in stabilized kidney transplant patients.

BACKGROUND AND AIMS: The CONCERTO study results showing the beneficial effects of conversion from cyclosporine to tacrolimus prolonged-release (tacrolimus PR) in stabilised patients after kidney transplantation, were first published in 2011. This communication describes our first experience of conversion from cyclosporine to tacrolimus PR in stabilised kidney transplant patients. The aim was to determine whether it could be used in routine clinical practice in the Czech and Slovak Republics. METHODS: Evaluation was carried out at five transplantation centres in the Czech Republic and Slovakia. In all participating Centres, the drug conversion was conducted according to the ICH/GCP guidelines. A total of 104 patients stabilised after kidney transplantation were converted from maintenance therapy with cyclosporine to treatment with tacrolimus PR. The data were collected 26 weeks after the switch. The primary endpoint was change in kidney graft function measured from the estimated glomerular filtration rate (GFR). The effect of conversion on blood pressure, metabolic parameters and cosmetic changes was also recorded. Special attention was paid to the safety and tolerability of treatment with tacrolimus PR. RESULTS: GFR increased after six months by 10 % (P = 0.040). In addition a significant decrease in serum creatinine and triglycerides level was found together with major reduction in the incidence and severity of gingival hyperplasia and hirsutism. 3% of patients developed new onset of diabetes mellitus. Otherwise, the switch was very well-tolerated, without serious adverse events or acute rejections. CONCLUSION: Conversion from cyclosporine to tacrolimus PR was shown to be a safe therapeutic alternative with patient benefits.

Expression of HLA-G transcripts in graft biopsy samples of renal transplant recipients.

BACKGROUND: The HLA-G molecule has a high potential to modulate immune response towards the improvement of graft survival after transplantation. In this work, we have analyzed the total HLA-G mRNA expression in graft tissues of dysfunctional transplanted kidneys. MATERIAL AND METHODS: We examined 84 kidney biopsy samples obtained from 65 renal transplant recipients with dysfunctional graft (50 males, 15 females; average age 46.8 ± 11.9 years). 52 specimens were with signs of acute rejection and 32 without any rejection characteristics (diagnosed as glomerulonephritis, ATN and IFTA). Patients with acute rejection were divided into three groups: antibody-mediated rejection (AMR; n = 23), T cell mediated rejection (TCMR; n = 16) and combined antibody and T cell-mediated rejection (AMR + TCMR; n=13). The biopsy samples were taken from a dysfunctional graft at different time periods after kidney transplantation. The relative expression of total HLA-G mRNA in biopsy specimens was determined by real time RT-PCR. The correlation between HLA-G mRNA expression and dysfunctional graft state was investigated. The impact of different factors (post-transplantation interval, gender,mismatch, induction therapy and cold ischemia time) on relative expression of total HLA-G mRNA was also studied. RESULTS: We have found that the levels of HLA-G transcripts in kidneys with rejection were higher than those in non-rejected but dysfunctional grafts (P = 0.0003). The highest levels of HLA-G mRNA were detected at combined AMR + TCMR rejection (P= 0.005). The time-course analysis of total HLA-G mRNA expression was also studied. In both dysfunctional graft groups (rejected and non-rejected) the lower levels of HLA-G transcripts were detected during early post-transplant period (1­3 months), however a substantial increase of HLA-G mRNA expression was observed after an extended period of time(N3 months). It was also revealed that antibody induction therapy may reduce HLA-G expression (P=0.0004) and in female samples were higher levels of HLAG transcripts than those in male recipients (P=0.003). It was found no significant impact of age, cold ischemic time, PRA (Panel Reactive Antibody) score, and a number of HLA-mismatches on HLA-G mRNA expression. CONCLUSIONS: We have demonstrated that the expression of total HLA-GmRNA in renal grafts can be influenced by different factors such as clinical state of transplanted kidney, elapsed time after transplantation, gender and antibody induction therapy. We have proved that HLA-G mRNA expression was significantly higher in recipients with acute rejection in comparison to patients with dysfunctional but non-rejected grafts.

Waist circumference as an independent risk factor for NODAT.

BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) is a serious and frequent complication of solid organ transplantations. NODAT leads to 2-3 times higher cardiovascular morbidity and mortality. Visceral obesity is a key factor for diabetes mellitus type 2 and metabolic syndrome development, and is an independent risk factor for cardiovascular diseases. MATERIAL AND METHODS: The series consisted of 167 patients after primary kidney transplantation from a dead donor (64 patients had developed NODAT), average age of the series was 46.1±11.6 years. We retrospectively examined waist circumference, body mass index, and weight gain in the 12th month after transplantation. We examined average level of triglycerides, cholesterol, and immunosuppression throughout the 12 monitored months. RESULTS: Patients with NODAT were significantly older (P=0.004) and had greater waist circumference (P<0.0001) and higher average sirolimus level (P=0.0262). We identified the following independent risk factors for NODAT by using multivariate analysis: age at the time of transplantation above 50 years (HR=2.5038, [95% CI: 1.7179 to 3.6492], P<0.0001), waist circumference in men greater than 94 cm (HR=1.9492, [95% CI: 1.1697 to 3.2480], P=0.0104) and in women greater than 80 cm (HR=4.5018, [95% CI: 1.8669 to 10.8553], P=0.009). By using correlation coefficient we have proved that greater waist circumference was related to higher incidence of NODAT (r=0.1935, [95% CI: 0.01156 to 0.3630], P=0.0374). Graft survival (death censored) 12 months after kidney transplantation was 97.1% in the control group and 95.3% in the NODAT group (P=0.5381). Patient survival 12 months after kidney transplantation in the control group was 98.1% and in the NODAT group it was 96.9% (P=0.6113). CONCLUSIONS: We identified waist circumference as an independent risk factor for NODAT in our analysis.

Donor non-specific MICA antibodies in renal transplant recipients.

Despite recent advances in solid organ transplantations, an antibody mediated rejection caused by donor specific antibodies is still a major problem in kidney graft survival. Besides HLA-induced humoral response, antibodies against MICA antigens have recently attracted attention because of their possible role in graft rejection. The aim of our study was to establish whether renal recipients produce antibodies against MICA molecules due to the transplantation and if they are specific for MICA antigens of the donors. MICA antibody screening was performed in 124 kidney recipient sera. 22 sera, that were found to be MICA antibody positive, were further examined for MICA antibody profiles and compared with donor MICA alleles. The analysis of MICA antibody positive sera showed mostly more complex reactivity patterns. A significant fraction of patient sera (59%) reacted not only with the donor MICA antigens, but also with other MICA patterns. A match between antibody specificities and MICA antigens was observed in 41% of renal recipients only. On the other hand, as much as in 36% of recipient sera were detected antibodies against their own MICA molecules. We did not prove a complete correlation between the recipient MICA antibody specificities and MICA antigens of the donor. We assume that MICA antibody induction occurs not only due to the allogeneic stimulation itself but also due to other factors that need to be elucidated.

Pharmacomechanical thrombectomy for treatment of acute transplant renal artery thrombosis.

Acute transplant renal artery thrombosis is a rare complication in kidney transplantation that often leads to renal allograft loss. We present the first case of acute renal artery thrombosis 3 months after kidney transplantation, treated with pharmacomechanical thrombectomy with adjunctive catheter-directed thrombolysis and stent placement. The graft was salvaged with restoration of renal function and renal artery patency at the 3-year follow-up point.

Effects of long-term cholecalciferol supplementation on mineral metabolism and calciotropic hormones in chronic kidney disease.

BACKGROUND: Data on the efficacy and safety of long-term vitamin D supplementation in chronic kidney disease (CKD) are scarce. We assessed the effects of the 12-month vitamin D(3) treatment on mineral metabolism and calciotropic hormones in patients with CKD stages 2-4. METHODS: Eighty-seven patients (mean age 66 years, men/women 33/54) were randomized to cholecalciferol treatment with either 5,000 or 20,000 IU/week. Serum calcium, phosphate, 25(OH)D(3), 1,25(OH)(2)D(3), PTH and urinary mineral concentrations were obtained at baseline and after 4, 8 and 12 months. RESULTS: The median serum mineral concentrations were normal and not changed throughout the study. The number of hypercalciuric patients slightly increased with higher dose, but no sustained rise in calciuria was present. Vitamin D insufficiency/deficiency was revealed in 72 (83%) patients at baseline and 37 (43%) at month 12. The 25(OH)D(3) levels increased more with higher dose; a rise in 1,25(OH)(2)D(3) was less impressive. The parathyroid hormone (PTH) concentrations were reduced, but the number of subjects with PTH below the lower limit for CKD stage 3 increased equally with both doses. CONCLUSIONS: Vitamin D insufficiency/deficiency in CKD significantly improved after the 12-month cholecalciferol treatment, with higher dose being more effective and equally safe. Further studies of vitamin D(3) effects on bone metabolism are warranted.