Cannabinoid receptor 1 is a major mediator of renal fibrosis.

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-ß1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Successful Kidney Transplantation Using Elderly Living Donor with Extremely Large Renal Cyst and Double Arteries.

The authors describe a kidney transplant procedure using a living donor with a large cyst and double arteries. Due to the lack of regular transplant activity from a deceased donors, we decided to use the, so called, expanded criteria living donors, which means older age (more than 65 years), hypertension, some structural anomalies of the kidneys (cysts, multiple renal arteries), ABO incompatible kidney transplant, etc. The surgical procedure was the unroofing of a large cyst and wadding with perirenal fat. The 10 years survival rate is quite successful and we can recommend it.

Pathohistomorphometric and Immuno-Histologic Changes in Early Arteriovenous Fistula Failure in Patients with Chronic Kidney Disease.

BACKGROUND: Hemodialysis is a prevalent treatment for the end-stage chronic kidney disease (CKD) worldwide. The primary arteriovenous fistula (AVF), widely considered the optimal hemodialysis access method, fails to mature in up to two-thirds of the cases. The etiology of the early AVF failure, defined as thrombosis or inability to use within three months post-creation remains less understood, and is influenced by various factors including patient demographics, surgical techniques, and genetic predispositions. Neointimal hyperplasia is a primary histological finding in stenotic lesions leading to the AVF failure. However, there are insufficient data on the cellular phenotypes and the impact of the preexisting CKD-related factors. This study aims to investigate the histological, morphometric, and immunohistochemical alterations in the fistula vein, pre-, peri-, and post-early failure. MATERIALS AND METHODS: Eighty-nine stage 4-5 CKD patients underwent standard preoperative assessment, including the Doppler ultrasound, before a typical radio-cephalic AVF creation. Post-failure, a new AVF was created proximally. The vein specimens were collected during the surgery, processed, and analyzed for morphometric analyses and various cellular markers, including Vimentin, TGF, and Ki 67. RESULTS: The study enrolled 89 CKD patients, analyzing various aspects of their condition and AVF failures. The histomorphometric analysis revealed substantial venous luminal stenosis and varied endothelial changes. The immunohistologic analysis showed differential marker expressions pre- and post-AVF creation. CONCLUSION: This study highlights the complexity of the early AVF failures in CKD patients. The medial hypertrophy emerged as a significant preexisting lesion, while the postoperative analyses indicated a shift towards neointimal hyperplasia. The research underscores the nuanced interplay of vascular remodeling, endothelial damage, and cellular proliferation in the AVF outcomes.

Celiac-Like Duodenopathy Associated With Enteric-Coated Mycophenolate Sodium Immunosuppression in Renal Transplant Recipients: Report of 4 Cases.

Celiac-like disease and celiac sprue associated with widespread use of mycophenolic acid are among the most frequent complications of renal transplant. Most cases have been observed in patients receiving mycophenolate mofetil; however, there have been rare instance after administration of enteric-coated mycophenolate sodium. Here, we describe 4 renal transplant recipients with celiac-like duodenopathy that occurred in association with enteric-coated mycophenolate sodium treatment in a time period of 14 to 19 years after living donor kidney transplant. Three of 4 patients had diarrhea, and all 4 patients had marked loss of body weight. Esophago-gastroduodenoscopy was not diagnostically helpful; however, randomly performed duodenal biopsies showed mild villous atrophy and intraepithelial lymphocytosis. Replacement of enteric-coated mycophenolate sodium with azathioprine was successful with stopping diarrhea, allowing regained body weight, and stabilization of renal function. This potential complication in kidney transplant recipients can occur more than a decade after transplant. Diagnosis and treatment initiation are urgent to cure this disease.

The outcome of commercial kidney transplant tourism in Pakistan.

The lack of cadaver organs for transplantation motivates some Balkan patients to go to developing countries to buy a kidney. We have followed 36 patients who received kidney transplants in Lahore and Rawalpindi, Pakistan. The patients had not been cleared for transplantation with a standard pre-transplant work-up: 80% were hepatitis-C virus (HCV) or HBsAg positive. During follow-up, seven patients died. Sixteen patients experienced wound infections with post-operative hernias, and three patients developed peri-renal hematomas. Six abscesses and four lymphoceles occurred, and four urinary fistulas were surgically treated. Nephrectomy was performed in three patients because of renal artery thrombosis. Nine patients developed active hepatitis C, and four patients manifested cytomegalovirus disease. Three patients developed steroid diabetes, and three patients experienced acute myocardial infarction. Nine patients had one or more rejection episodes. Urinary tract infection with Pseudomonas or Escherichia occurred frequently. The one-yr patient and graft survival rates were 80% and 68%, respectively. Paid unregulated renal transplantation is not recommended for both ethical reasons and because of an association with excessive morbidity and mortality.

Primary Renal Squamous Cell Carcinoma in Native Polycystic Kidney and Ureter 16 Years After Living Donor Kidney Transplant.

We describe a case of a 55-year-old woman with polycystic kidney disease who received a living donor kidney transplant 16 years earlier and was on immunosuppressive therapy with satisfactory renal function. The donor was her mother. The patient presented with flank pain on the right side and macrohematuria, and noncontrast computed tomography and magnetic resonance imaging led to the diagnosis of tumors in the remaining right native polycystic kidney and ureter, as well as secondary retroperitoneal dissemination. We performed right radical nephrectomy and ureterectomy with extirpation of 2 metastases; the left native kidney remained intact. Histology showed squamous metaplastic changes and invasive epithelial neoplasm in the lumen of the renal pelvis and ureter with extensive squamous differentiation positive for nuclear p63 as squamous cell immunohistochemical marker. After surgery, an immunosuppressive therapy with methylprednisolone was administered, without calcineurin inhibitors and mycophenolate mofetil. Twelve months later the patient was still alive, with a glomerular filtration rate of 29 mL/min. Needs remain for further treatment modalities in patients with primary squamous cell carcinoma in nonfunctioning kidneys and improvements in imaging technique accuracy.

Impact of preoperative arterial and venous diameter on achievement of the adequate blood flow in arteriovenous fistula for hemodialysis.

An arteriovenous fistula (AVF) remains the best choice of vascular access (VA) for hemodialysis (HD). The aim of the study was to determine the factors associated with the achievement of adequate blood flow (BF) of AVFs at the 4th week after creation. Created AVFs in 63 patients with chronic kidney disease (CKD) stage 4/5 and CKD stage 5 on hemodialysis (CKD5D) were analyzed in a prospective study. Doppler ultrasound (DUS) was used for measuring the diameter of the radial artery, the brachial artery and the cephalic vein before AVF creation. The BF of AVF was calculated by DUS at the 4th week after creation and adequate BF was defined as ≥ 600 mL/min. The average age of patients was 61.31 ± 12.9 years. An adequate BF of AVF at the 4th week after creation was achieved in 43.54% of patients. The BF of AVF measured in male patients was significantly higher compared to the BF of AVF obtained in females (576.03 mL/min vs 375.12 mL/min, P = 0.004). The diameter of the blood vessels with achieved adequate BF was significantly larger compared to the diameter of the blood vessels without adequate BF (radial artery: 2.45 mm vs 2.03 mm, P = 0.000; brachial artery: 4.78 mm vs 4.06 mm, P = 0.001 and cephalic vein: 3.12 mm vs 2.83 mm P = 0.018). The gender and the diameter of the blood vessels before AVF creation were significantly associated with achievement of adequate BF of AVF at the 4th week of creation.

Management of Multiple Renal Arteries and Unusual Venous Anatomy During Kidney Transplant: From a Simple Technical Problem to a Graft-Saving Procedure.

OBJECTIVES: Incidence of vascular anomalies in donor kidneys varies from 18% to 30% and presents a challenge for a transplant surgeon in kidney transplant. Here we present our personal experience for man - agement of the complicated and unexpected cases. MATERIALS AND METHODS: A total of 250 kidney transplants (226 living, 24 deceased) were performed in a period of 24 years; mean donor age was 55 years (range, 25-86 years), and mean recipient age was 38.6 years (range, 14-66 years). We analyzed the surgical techniques, complications and outcomes, rejection episodes, kidney function, and graft and patient survival rates. RESULTS: Of 250 nephrectomies, 209 had a single artery (83.6%), 34 had 2 arteries (13.6%), and 7 had 3 arteries (2.8%). Of 34 double arteries, 14 had 2 main arteries, 15 had a main and a polar artery, and 5 had an aortic Carrel patch after deceased donation. According to the size, type, and position, the anastomoses were performed with branches of hypogastric, epigastric inferior, iliac external, and main renal artery, intracorporeally or in bench surgery. Regarding veins, 1 double inferior vena cava, 1 left-side inferior vena cava, 4 retroaortic, 2 circumaortic, 10 large lumbar veins draining into the left renal veins, and 8 cases with 2 or more different size renal veins were managed. In 9 cases with short right renal vein, an extension with vena cava (a "Barry cavoplasty") was performed in deceased donor organs. No serious surgical complications related to vascular anomalies were observed. There were no statistical differences in 1-, 6-, and 12-month graft survival rates between the groups with or without vascular anomalies. CONCLUSIONS: Vascular anomalies should no longer be considered a contraindication for transplant, if careful anastomosis is performed in every case to avoid ischemia and further complications. Therefore, management of vascular anomalies could be a graftsaving procedure.

Hypertension after Kidney Transplantation: Clinical Significance and Therapeutical Aspects.

Most of the kidney transplanted patients develop arterial hypertension after renal transplantation. Together with very well-known and usual risk factors, post-transplant hypertension contributes to the whole cardiovascular morbidity and mortality in the kidney transplant population. The reasons of post-transplant hypertension are factors related to donors and recipients, immunosuppressive therapy like Calcineurin Inhibitors (CNI) and surgery procedures (stenosis and kinking of the renal artery and ureteral obstruction). According to Eighth National Committee (JNC 8) recommendations, blood pressure > 140/90 mmHg is considered as hypertension. The usual antihypertensive drugs used for the control of hypertension are Calcium channel blockers (CCB), Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin -II receptor blockers (ARB), B- blockers and diuretics. Follow the KDIGO guidelines the target blood pressure < 140/90 mmHg for patients without proteinuria and < 125/75 mmHg in patients with proteinuria is recommended. Better control of post-transplant hypertension improves the long-term graft and patient's survival.

Primary Failure of the Arteriovenous Fistula in Patients with Chronic Kidney Disease Stage 4/5.

BACKGROUND: An Arteriovenous fistula (AVF) is a creation of the natural blood vessels. It is a "gate of life" for the patients on hemodialysis. AIM: The study aimed to analyze the predictors for primary failure of AVF such as gender, age, number and location of AVF, and primary renal disease in patients with chronic kidney disease (CKD) stage 4/5. MATERIAL AND METHODS: The medical records of 178 created arteriovenous fistulae in patients with CKD stage 4/5, were retrospectively studied. Primary failure of AVF was defined as thrombosis or inability for cannulation of AVF within 3 months. Adequate maturation of AVF was defined as successful cannulation of AVF treatment and blood flow of > 600 ml/min. RESULTS: The mean age of the patients was 59.75 ± 14.65 years, and 65.16% (116/178) were men. Adequate maturation of AVF was achieved in 83.71% (149/178). Primary failure of AVF occurred in 16.29% (29/178) of the created fistulae, while 10.11% (18/178) had early thrombosis. The distal arteriovenous fistulae were significantly more frequently created in male patients (51 vs 18; p = 0.015). The female patients were significantly older than the male patients (63.27 vs 57.86 years; p = 0.018). CONCLUSION: Male gender was associated with better maturation of AVF. The age, number and location of AVF, and primary renal disease in patients with CKD stage 4/5 were not associated with primary failure of AVF.

The Spectrum of Histopathological Changes in the Renal Allograft - a 12 Months Protocol Biopsy Study.

INTRODUCTION: Renal transplantation became a routine and successful medical treatment for Chronic Kidney Disease in the last 30 years all over the world. Introduction of Luminex based Single Antigen Beads (SAB) and recent BANFF consensus of histopathological phenotypes of different forms of rejection enables more precise diagnosis and changes the therapeutic approach. The graft biopsies, protocol or cause, indicated, remain a golden diagnostic tool for clinical follow up of kidney transplant recipients (KTR). AIM: The study aimed to analyse the histopathological changes in renal grafts 12 months after the surgery in KTR with satisfactory kidney function. MATERIAL AND METHODS: A 12-month protocol biopsy study was performed in a cohort of 50 Kidney transplant recipients (42 from living and 8 from deceased donors). Usual work-up for suitable donors and recipients, standard surgical procedure, basic principles of peri and postoperative care and follow up were done in all KTR. Sequential quadruple immunosuppression including induction with Anti-thymocyte globulin (ATG) or Interleukin-2R antagonist (IL-2R), and triple drug maintenance therapy with Calcineurin Inhibitors (CNI), Mycophenolate Mofetil (MMF) and Steroids were prescribed to all pts. Different forms of Glomerulonephritis (16), Hypertension (10), End Stage Renal Disease (13), Hereditary Nephropathies (6), Diabetes (3) and Vesicoureteral Reflux (2) were the underlying diseases. All biopsies were performed under ultrasound guidance. The 16 gauge needles with automated "gun" were used to take 2 cores of tissue. The samples were stained with HE, PAS, Trichrome Masson and Silver and reviewed by the same pathologist. A revised and uploaded BANFF 2013 classification in 6 categories (Cat) was used. RESULTS: Out of 48 biopsies, 15 (31%) were considered as normal, 4 (8%), Borderline (BL-Cat 3), 5 (10%) as Interstitial Fibrosis/Tubular Atrophy (IF/TA-Cat 5), 5 (10%) were classified as non-immunological (Cat 6), 2 as a pure antibody-mediated rejection (ABMR-Cat 2) and T-cell Mediated Rejection (TCMR-Cat 4). The remaining 17 samples were classified as a "mixed" rejection: 7 (41%) ABMR + IF/TA, 5 (29%) ABMR + BL + IF/TA, 2 (11%) BL + IF/TA, 1 (5%) ABMR + BL, 1 (5%) ABMR + TCMR and 1 (5%) TCMR + IF/TA. The mean serum creatinine at the time of the biopsy was 126.7 ± 23.4 µmol/L, while GFR-MDRD 63.4 ± 20.7 ml/min, which means that the majority of the findings were subclinical. Among the non-immunological histological findings (Cat 6), 3 cases belonged to CNI toxicity, 1 to BK nephropathy and 1 to recurrence of the primary disease. CONCLUSION: Our 12-month protocol biopsy study revealed the presence of different forms of mixed subclinical rejection. Use of recent BANFF classification and scoring system enables more precise diagnosis and subsequently different approach to the further treatment of the KTR. More correlative long-term studies including Anti HLA antibodies and Endothelial Cell Activation- Associated Transcripts (ENDAT) are needed.

Trafficking in Human Beings for the Purpose of Organ Removal and the Ethical and Legal Obligations of Healthcare Providers.

Physicians and other health care professionals seem well placed to play a role in the monitoring and, perhaps, in the curtailment of the trafficking in human beings for the purpose of organ removal. They serve as important sources of information for patients and may have access to information that can be used to gain a greater understanding of organ trafficking networks. However, well-established legal and ethical obligations owed to their patients can create challenging policy tensions that can make it difficult to implement policy action at the level of the physician/patient. In this article, we explore the role-and legal and ethical obligations-of physicians at 3 key stages of patient interaction: the information phase, the pretransplant phase, and the posttransplant phase. Although policy challenges remain, physicians can still play a vital role by, for example, providing patients with a frank disclosure of the relevant risks and harms associated with the illegal organ trade and an honest account of the physician's own moral objections. They can also report colleagues involved in the illegal trade to an appropriate regulatory authority. Existing legal and ethical obligations likely prohibit physicians from reporting patients who have received an illegal organ. However, given the potential benefits that may accrue from the collection of more information about the illegal transactions, this is an area where legal reform should be considered.

Severe Endothelial Damage in Chronic Kidney Disease Patients Prior to Haemodialysis Vascular Access Surgery.

BACKGROUND: Hemodialysis as an efficient therapy for advanced CKD is the most used treatment modality all over the world. Even though primary AVF is widely accepted as a best permanent vascular access in hemodialysis patients, up to 60% of all fistulas fail to mature. The pathogenesis of early fistula failure is not very well understood. Many general and local factors are involved: patient's age, sex, primary renal disease, small vessel's diameter, presence of accessory veins, prior venipunctures, surgical skill, genetics, etc. Histological investigations have confirmed the neointimal venous hyperplasia as a major pathological finding in stenotic lesions of AVF failure, due to local inflammation, oxidative stress and migration and proliferation of myofibroblasts, fibroblasts and endothelial cells. MATERIALS AND METHODS: A total of 89 patients with stadium 4-5 of CKD are involved in the study. A typical radio-cephalic AVF is created in all patients. Part of the fistula vein was taken for histological, immunohistochemical (Vimentin, TGF ß and KI67) and morphometric analysis. Appriopriate statistical method was applied. RESULTS: Up to 80% of the patients showed some degree of endothelial changes at the time of creation of AVF, among them 19 pts with substantial intimal hyperplasia, 51 with medial hypertrophy and 19 pts with normal histology. Almost two thirds of the patients did not have expression of TGFß. More than 95% had some expression of Vimentin. None of the patients had expression of the marker KI 67. CONCLUSION: Medial hypertrophy is predominant preexisting pathohistological lesion prior the AVF creation, despite the presence of neointimal hyperplasia. The absence of TGFß expression in majority of our patients could suggest that inflammation and oxidative stress are developing later, after vascular access surgery. The dominant cells within the stenosis in the veins are myofibroblasts. Their increased presence maybe a reason why some patients are prone to developing venous endothelial changes as a results of exaggerated vascular endothelial response to the effect of uremia, hypertension and other insults.

Use of expanded criteria in living kidney donors - the crucial factor for improvement of the kidney transplant programme in Republic of Macedonia.

Renal transplantation is surely the best treatment for Chronic Kidney Disease (CKD) patients in both developed and developing countries. Due to the tragic events in former Yugoslavia at the beginning of the nineties, it was not possible to develop a really good clinical practice in the field of transplantation. Facing the lack of Deceased Donor Donation Transplantation and any organ-sharing among the Balkan countries, we introduced a large and very ambitious living donor transplant programme including what were called expanded criteria living donors. In the period of the past 20 years elderly (above 65 years), unrelated (emotionally related), marginal and ABO incompatible living donors were accepted. Due to the skilled surgical team, powerful immunosupression and HLA compatibility testing, the results were promising and the number of complications very low. The authors concluded that use of an expanded criteria living donor is fully acceptable, especially in developing countries, and could ameliorate the severe organ shortage in the region.

Cyclosporine nephrotoxicity and early posttransplant hyperkalemia in living-donor renal recipients: report of 4 cases.

OBJECTIVES: Hyperkalemia is an electrolyte disorder that may occur during the first few months after a renal transplant, in patients undergoing cyclosporine immunosuppression. We present our experience with cyclosporine-associated hyperkalemia in living-donor renal transplant recipients, with isolated clinically relevant hyperkalemia soon after surgery. MATERIALS AND METHODS: We report 4 living-donor renal recipients with hyperkalemia soon after transplant. RESULTS: Severe unexpected hyperkalemia (7.5- 9.4 mmol/L) was noted in our patients 12, 20, 22, and 34 days after transplant. The C2 cyclosporine concentration was within recommended range or slightly greater than 1200 ng/mL. The hypertonic glucose/insulin treatment along with potassium diet was without results. A reduction in daily cyclosporine dosages, along with 1- to 2-week administration of fludrocortisone was effective. The patients became normokalemic taking a standard, triple-drug immunosuppression protocol, and were discharged home with normal renal function. There were no repeat episodes of hyperkalemia in any of the patients during 12 months of follow-up. CONCLUSIONS: Cyclosporine should be considered a cause of hyperkalemia in renal transplant recipients. Successful treatment with fludrocortisone confirms that transitional pseudohypoaldosteronism has a potential nephrotoxic effect of cyclosporine. We recommend close monitoring of the cyclosporine concentration and administering fludrocortisone when treating hyperkalemia in renal transplant recipients.

Protocol for performing nephrological activity in the Republic of Macedonia.

The fast development of nephrology in the world, especially in the second half of the 20 th century demanded protocol (guidelines) for nephrological activity for all levels of medical care, of doctors and specialists. The International Society of Nephrology, the European Renal Association and other national associations created their own protocol (guidelines) for nephrological activity. The Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) proclaimed the First Protocol for Performing Nephrological Activity in the Republic of Macedonia at the First Congress of the MSNDTAO, held in Ohrid 1993, and it was published in the Macedonian Medical Review, 1994; Supplement 14: 397-406 [1]. The update of the Protocol for Performing Nephrological Activity in the Republic of Macedonia was proclaimed at the Fourth Congress of MSNDTAO, held in Ohrid 2012 and it presented in this text.