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.

Crocus sativus L. Extract (Saffron) Effectively Reduces Arthritic and Inflammatory Parameters in Monotherapy and in Combination with Methotrexate in Adjuvant Arthritis.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by inflammation that affects not only the liver but also other organs and the musculoskeletal system. The standard therapy for RA is methotrexate (MTX), which has safety limitations. The extract from Crocus sativus L. (saffron-SF) is also known for its anti-inflammatory effects. Therefore, we decided to investigate the potential benefit of SF in monotherapy via two doses (SF1-25 mg/kg of b.w.; SF2-50 mg/kg of b.w.) and in combination with MTX (0.3 mg/kg of b.w., twice a week) using adjuvant arthritis in rats. To evaluate these therapeutic settings, we used biometric, immunological, and biochemical parameters, as well as the relative gene expression of the mRNA in the liver. Our results showed a statistically significant increase in the experimental animals' body weight and the arthritic score (AS) on day 14 for monotherapy with SF1 and SF2. The change of hind paw volume (CHPV) was significant only for SF2 monotherapy on the 14th day of the experiment. A combination of SF1 and SF2 with MTX significantly modulated all the biometric parameters during the experimental period. Additionally, AS and CHPV improved considerably compared to MTX monotherapy on day 21. Furthermore, all monotherapies and combination therapies were significant for the biochemical parameter γ-glutamyl transferase (GGT) in the joint. GGT activity in the spleen was less pronounced; only MTX in combination with SF1 significantly modified this parameter. The higher dose of SF monotherapy (SF2) was similarly significant with respect to immunological parameters, such as plasmatic IL-17A, IL-1ß, and MMP-9 on day 21. The combination of both doses of SF with MTX significantly improved these immunological parameters, except for C-reactive protein (CRP), which was influenced only by the higher dose of SF2 in combination with MTX in plasma at the end of the experiment. A different effect was found for the relative expression of CD36 mRNA, where only SF1 significantly decreased gene expression in the liver. However, the relative gene mRNA expression of IL-1ß in the liver was significantly reduced by the SF monotherapies and the combination of both SF doses with MTX. Our findings showed SF's partial antiarthritic and anti-inflammatory potential in monotherapy, but the effect was stronger in combination with MTX.

Rhodiola rosea L. Extract, a Known Adaptogen, Evaluated in Experimental Arthritis.

Rhodiola rosea L. extract (RSE) is mostly known for its adaptogen properties, but not for its antiarthritic activities, therefore monotherapy and combination with low-dose methotrexate (MTX) was studied. The collagen-induced arthritis (CIA) model was used to measure the functional score, and the change in hind paw volume (HPV). Both parameters had significant antiarthritic effects. Based on these preliminary results, an adjuvant arthritis (AA) model was further applied to assess another parameters. The experiment included these animal groups: healthy controls, untreated AA, AA administered with RSE (150 mg/kg b.w. daily, p.o.), AA administered by MTX (0.3 mg/kg b.w. twice a week, p.o.), and AA treated with the combination of RSE+MTX. The combination of RSE+MTX significantly reduced the HPV and increased the body weight. The combination significantly decreased HPV when compared to MTX monotherapy. The plasmatic levels of inflammatory markers (IL-6, IL-17A, MMP-9 and CRP) were significantly decreased by MTX+RSE treatment. The RSE monotherapy didn't influence any of the inflammatory parameters studied. In CIA, the RSE monotherapy significantly decreased the arthritic parameters studied. In summary, the combination of RSE and sub-therapeutic MTX was significantly effective in AA by improving inflammatory and arthritic parameters.

Combination Therapy of Carnosic Acid and Methotrexate Effectively Suppressed the Inflammatory Markers and Oxidative Stress in Experimental Arthritis.

BACKGROUND: Combination therapy with methotrexate (MTX) is the most common therapeutic strategy used for the treatment of patients with rheumatoid arthritis (RA). In this study, we combined the natural compound carnosic acid (CA) with MTX to reduce inflammation and oxidative stress in adjuvant arthritis (AA). METHODS: AA was induced in 6-8 rats per group. MTX was administrated twice a week at a dose of 0.3 mg/kg b.w., while CA was administered daily at a dose of 100 mg/kg both in monotherapy and in combination with MTX. Plasma samples were collected on the 14th, 21st, and 28th day. Body weight and hind paw volume were measured once a week. RESULTS: We found that, mainly, the CA + MTX combination significantly reduced the hind paw swelling, the levels of IL-17A, MMP-9, and MCP-1 in plasma, and GGT activity in joint homogenates. The mRNA expression of HO-1, catalase, and IL-1ß in the liver were significantly improved by CA + MTX only. Our results indicate that adding CA to MTX treatment could be a good therapeutic option for patients suffering from RA. CONCLUSIONS: The addition of CA to methotrexate treatment significantly improved its efficacy in decreasing the development of AA by inhibiting the markers of inflammation and oxidative stress.

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.

Enhanced Anti-Inflammatory Effect of the Combination of Lactiplantibacillus plantarum LS/07 with Methotrexate Compared to Their Monotherapies Studied in Experimental Arthritis.

The gut microbiome (GM) of rheumatic arthritis (RA) patients is often altered in composition and function. Moreover, methotrexate (MTX), one of the most frequently used disease-modifying antirheumatic drugs, is known to negatively affect GM composition. The modulation of immune system activity is one of the therapeutic benefits of probiotics. The aim of the current investigation was to determine the impact of MTX therapy combined with one of the Lactobacillus strains, Lactoplantibacillus plantarum LS/07 (LB), on adjuvant arthritis (AA) in rats. Methods focused on biometric and inflammatory parameters in AA, particularly on plasmatic levels of IL-17A, MMP-9, and MCP-1, and the activities of gamma-glutamyl transferase in the spleen and joints were applied. Enhancing the effect of MTX, LB positively influenced all biometric and inflammatory parameters. The findings of the present study may be of help in proposing novel therapeutic strategies for RA patients.

Bioflavonoid Robinin from Astragalus falcatus Lam. Mildly Improves the Effect of Metothrexate in Rats with Adjuvant Arthritis.

Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.

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.