Intraduodenal Fecal Microbiota Transplantation Ameliorates Gut Atrophy and Cholestasis in a Novel Parenteral Nutrition Piglet Model.

BACKGROUND: Total parenteral nutrition (TPN) provides lifesaving nutritional support intravenously; however it is associated with significant side effects. Given gut microbial alterations noted with TPN, we hypothesized that transferring fecal microbiota from healthy controls would restore gut-systemic signaling in TPN and mitigate injury. METHODS: Using our novel ambulatory model (US Patent: US 63/136,165), 31 piglets were randomly allocated to enteral nutrition (EN), TPN only, TPN + antibiotics (TPN-A) or TPN + intraduodenal fecal microbiota transplant (TPN-FMT) for 14 days. Gut, liver, and serum were assessed through histology, biochemistry, and qPCR. Stool samples underwent 16s rRNA sequencing. PERMANOVA, Jaccard and Bray-Curtis metrics were performed. RESULTS: Significant bilirubin elevation in TPN and TPN-A vs EN (p<0.0001) was prevented with FMT. IFN-G, TNF-alpha, IL-beta, IL-8 and LPS were significantly higher in TPN (p=0.009/0.001/0.043/0.011/<0.0001), with preservation upon FMT. Significant gut-atrophy by villous/crypt ratio in TPN (p<0.0001) and TPN-A (p=0.0001) vs EN was prevented by FMT (p=0.426 vs EN). Microbiota profiles using Principal Coordinate Analysis demonstrated significant FMT and EN overlap, with the largest separation in TPN-A followed by TPN, driven primarily by Firmicutes and Fusobacteria. TPN altered gut barrier was preserved upon FMT. Upregulated CYP7A1 and BSEP in TPN and TPN-A, and downregulatedFGFR4, EGF, FXR and TGR5 vs EN was prevented by FMT. CONCLUSION: This study provides novel evidence of prevention of gut atrophy, liver injury and microbial dysbiosis with intraduodenal FMT, challenging current paradigms into TPN injury mechanisms and underscores importance of gut microbes as prime targets for therapeutics and drug discovery.

Water/fluid intake in Kidney transplant recipients: An underrated topic.

Although kidney transplantation (KT) is the best treatment option for end-stage kidney disease, long-term complications such as chronic kidney allograft dysfunction and cardiovascular disorders are observed. To decrease these complications, preventive measures must be applied in kidney transplant recipients (KTRs). One of these common measures is the increase of water/fluid intake although this is not evidence-based practice. Indeed, surprisingly very limited studies evaluated the impact of increased water/fluid intake on graft function, with small number of KTRs and short term follow-up. We suggest that the water/fluid intake should be personalized based on baseline graft function, time onset after KT (which water homeostasis changes), presence of hyponatremia and hypervolemia, concomitant medications, and patient willingness. Methods for estimating water/fluid intake (direct measurement, 24-h urine volume measurement, urine osmolarity) has both advantages and drawbacks and the best method has not been identified. Increase of water/fluid intake in specific conditions (in hot, and humid weather, before exercise, during Ramadan fasting) or in distinct KTRs (KTRs with de novo nephrolithiasis, frequent urinary tract infections) is not tested. Furthermore, the relationship between water/fluid intake and major cardiovascular adverse events are not known. There is no doubt that minimum amount of water/fluid intake is necessary for graft function (the amount is not known) but there is no evidence for a particular target level of water/fluid intake. In the current review, we summarize the studies assessing fluid/water intake in KTR, explained the pathophysiologic basis of water disorders in early period of KT and late after KT, elucidate conflicts and unknown issues of water intake in KTRs and suggest future research needs.

The Relationship between Sclerostin and Kidney Transplantation Mineral Bone Disorders: A Molecule of Controversies.

Kidney transplantation is the most effective treatment option for most patients with end-stage kidney disease due to reduced mortality, decreased cardiovascular events and increased quality of life compared to patients treated with dialysis. However, kidney transplantation is not devoid of both acute and chronic complications including mineral bone disorders (MBD) which are already present in patients with chronic kidney disease (CKD) before kidney transplantation. The natural history of MBD after kidney transplantation is variable and new markers are needed to define MBD after kidney transplantation. One of these promising molecules is sclerostin. The main action of sclerostin is to inhibit bone formation and mineralization by blocking osteoblast differentiation and function. In kidney transplant recipients (KTRs), various studies have shown that sclerostin is associated with graft function, bone parameters, vascular calcification, and arterial stiffness although non-uniformly. Furthermore, data for inhibition of sclerostin with monoclonal antibody romosozumab for treatment of osteoporosis is available for general population but not in KTRs which osteoporosis is highly prevalent. In this narrative review, we have summarized the studies investigating the change of sclerostin before and after kidney transplantation, the relationship between sclerostin and laboratory parameters, bone metabolism and vascular calcification in the context of kidney transplantation. We also pointed out the uncertainties, explained the causes of divergent findings and suggest further potential study topics regarding sclerostin in kidney transplantation.

LIM Zinc Finger Domain Containing 1 Risk Genotype of Recipient Is Associated with Renal Tubular Inflammation in Kidney Transplantation.

BACKGROUND: Homozygosity for LIMS1 rs893403-GG genotype is linked to an increased risk of allograft rejection after kidney transplantation. Ischemia-reperfusion of the kidney allograft leads to long term infiltration of activated and effector-memory T lymphocytes and resulting in rejection and long-term fibrosis. However, the genotype, LIMS1 expression under ischemic conditions and the long-term histopathological relationships remain ill-defined. METHODS: We examined the impact of the recipient's LIMS1-rs893403 genotype with transplant kidney histopathology. The association of the LIMS1-rs893403 genotype and LIMS1 and GCC2 mRNA expression in ischemic donor kidneys were also examined. Recipients who underwent transplant kidney biopsy were genotyped for the LIMS1-rs893403 variant and associated deletion. Histopathological findings were compared between recipients with LIMS1 risk and non-risk genotypes. Real-time PCR and immunofluorescence staining for LIMS1 and GCC2 expression were performed in non-utilized donor kidneys. RESULTS: Demographic, clinical, and treatment characteristics and the histopathological diagnosis were similar between recipients with rs893403 GG and AA/AG genotype. The Banff tubulitis score was higher in GG recipients (n = 24) compared to AA/AG (n = 86) recipients (1.42 ± 0.65 vs. 1.12 ± 0.66, p = 0.03). Ischemic kidneys with GG showed higher LIMS1 and GCC2 mRNA expression than kidneys with AG. Kidneys with rs893403-GG had higher tubular LIMS1 and GCC2 immunohistochemical staining compared to kidneys with rs893403-AG. CONCLUSIONS: Our data supports the role of the LIMS1 locus in kidney transplant rejection, particularly in lymphocyte infiltration into the internal aspect of the tubular basement membranes. Increased LIMS1 and GCC2 expression in ischemic donor kidneys with the GG genotype require further studies.

Brain natriuretic peptide and N-terminal pro b-type natriuretic peptide in kidney transplantation: More than just cardiac markers.

Although kidney transplantation (KT) is the best treatment option for most patients with end-stage kidney disease (ESKD) due to reduced mortality, morbidity and increased quality of life, long- term complications such as chronic kidney allograft dysfunction (CKAD) and increased cardiovascular disease burden are still major challenges. Thus, routine screening of KT recipients (KTRs) is very important to identify and quantify risks and guide preventative measures. However, no screening parameter has perfect sensitivity and specificity, and there is unmet need for new markers. In this review, we evaluate brain natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) as promising markers for risk stratification in the kidney transplant recipients (KTRs). The usefulness of these markers are already proven in heart failure, hypertension, coronary artery disease. In the context of KT, evidence is emerging. BNP and NT-proBNP has shown to be associated with kidney function, graft failure, echocardiographic parameters, major cardiovascular events and mortality but the underlying mechanisms are not known. Although BNP and NT-proBNP interact with immune system, renin angiotensin system and sympathetic system; it is not known whether these interactions are responsible for the clinical findings observed in KTRs. Future studies are needed whether these biomarkers show clinical efficacy, especially with regard to hard outcomes such as major adverse cardiovascular events and graft dysfunction and whether routine implementation of these markers are cost effective in KTRs.

Renin angiotensin system-induced muscle wasting: putative mechanisms and implications for clinicians.

Renin angiotensin system (RAS) alters various mechanisms related to muscle wasting. The RAS system consists of classical and non-classical pathways, which mostly function differently. Classical RAS pathway, operates through angiotensin II (AngII) and angiotensin type 1 receptors, is associated with muscle wasting and sarcopenia. On the other hand, the non-classical RAS pathway, which operates through angiotensin 1-7 and Mas receptor, is protective against sarcopenia. The classical RAS pathway might induce muscle wasting by variety of mechanisms. AngII reduces body weight, via reduction in food intake, possibly by decreasing hypothalamic expression of orexin and neuropeptide Y, insulin like growth factor-1 (IGF-1) and mammalian target of rapamycin (mTOR), signaling, AngII increases skeletal muscle proteolysis by forkhead box transcription factors (FOXO), caspase activation and muscle RING-finger protein-1 transcription. Furthermore, AngII infusion in skeletal muscle reduces phospho-Bad (Ser136) expression and induces apoptosis through increased cytochrome c release and DNA fragmentation. Additionally, Renin angiotensin system activation through AT1R and AngII stimulates tumor necrosis factor-α, and interleukin-6 which induces muscle wasting, Last but not least classical RAS pathway, induce oxidative stress, disturb mitochondrial energy metabolism, and muscle satellite cells which all lead to muscle wasting and decrease muscle regeneration. On the contrary, the non-classical RAS pathway functions oppositely to mitigate these mechanisms and protects against muscle wasting. In this review, we summarize the mechanisms of RAS-induced muscle wasting and putative implications for clinical practice. We also emphasize the areas of uncertainties and suggest potential research areas.

A holistic review of sodium intake in kidney transplant patients: More questions than answers.

Kidney transplantation (KT) is the best treatment option for end-stage kidney disease (ESKD). Acute rejection rates have decreased drastically in recent years but chronic kidney allograft disease (CKAD) is still an important cause of allograft failure and return to dialysis. Thus, there is unmet need to identify and reverse the cause of CKAD. Additionally, cardiovascular events after KT are still leading causes of morbidity and mortality. One overlooked potential contributor to CKAD and adverse cardiovascular events is increased sodium/salt intake in kidney transplant recipients (KTRs). In general population, the adverse effects of high sodium intake are well known but in KTRs, there is a paucity of evidence despite decades of experience with KT. Limited research showed that sodium intake is high in most KTRs. Moreover, excess sodium intake is associated with elevated blood pressure and albuminuria in some studies involving KTRs. There is also experimental evidence suggesting that increased sodium intake is associated with histologic graft damage. Critical knowledge gaps still remain, including the exact amount of sodium restriction needed in KTRs to optimize outcomes and allograft survival. Additionally, best methods to measure sodium intake and practices to follow-up are not clarified in KTRs. To meet these deficits, prospective long term studies are warranted in KTRs. Moreover, preventive measures must be determined and implemented both at individual and societal levels to achieve sodium restriction in KTRs.

Sociodemographic disparities in sodium-glucose cotransporter-2 inhibitor use among US kidney transplant recipients: An observational study of real-world pharmacy records.

BACKGROUND: Recent clinical trials demonstrate benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with chronic kidney disease, but data on use in kidney transplant (KTx) recipients are limited. METHODS: We examined a novel database linking SRTR registry data for KTx recipients (2000-2021) with outpatient fill records from a large pharmaceutical claims warehouse (2015-2021). Adult (≥18 years) KTx recipients treated with SGLT2i were compared to those who received other noninsulin diabetes medications without SGLT2i. Characteristics associated with SGLT2i use were quantified by multivariable logistic regression (adjusted odds ratio, 95%LCLaOR95%UCL). RESULTS: Among 18 988 KTx recipients treated with noninsulin diabetes agents in the study period, 2224 filled an SGLT2i. Mean time from KTx to prescription was 6.7 years for SGLT2i versus 4.7 years for non-SGLT2i medications. SGLT2i use was more common in Asian adults (aOR, 1.091.311.58) and those aged > 30-59 years (compared with 18-30 years) or with BMI > 35 kg/m2 (aOR, 1.191.411.67), and trended higher with self-pay status. SGLT2i use was lower among KTx recipients who were women (aOR, .79.87.96), Black (aOR, .77.881.00) and other (aOR, .52.751.07) race, publicly insured (aOR, .82.921.03), or with less than college education (aOR, .78.87.96), and trended lower in those age 75 years and older. SGLT2i use in KTx patients increased dramatically in 2019-2021 (aOR, 5.015.636.33 vs. prior years). CONCLUSION: SGLT2i use is increasing in KTx recipients but varies with factors including race, education, and insurance. While ongoing study is needed to define risks and benefits of SGLT2i use in KTx patients, attention should also focus on reducing treatment disparities related to sociodemographic traits.

Complexities and outcomes of pulmonary hypertension in kidney transplant patients: a comprehensive review.

Pulmonary hypertension (PH) is often present in patients presenting for kidney transplant listing. While PH can complicate kidney transplant (KTx), with multidisciplinary management that includes both the transplant center and pulmonary hypertension center or experts both pre- and post-transplant. This review summaries the approach and management of PH in KTx candidates and recipients, along with expected outcomes and controversies surrounding arteriovenous fistula and graft management.

Outcomes of kidney, liver, and simultaneous liver and kidney transplants from hepatitis c infected donors to hepatitis c naïve recipients: A large single center experience.

BACKGROUND: With the introduction of direct-acting antiviral therapies (DAAs), the non-use rate of hepatitis C virus (HCV)-positive donor organs (D+) has decreased significantly. We present the donor, recipient, and transplant allograft characteristics, along with recipient outcomes, in one of the largest cohorts of HCV-D+ transplants into HCV-naïve recipients (R-). METHODS: Charts of HCV D+/R- kidney (KT), liver (LT), and simultaneous liver-kidney (SLKT) transplant recipients between January 2019 and July 2022 were reviewed. Primary outcomes of interest included waitlist times and 1-year graft failure. Secondary outcomes included hospital and intensive care unit length of stay, post-transplant complications, effectiveness of DAA therapy, and characteristics of patients who relapsed from initial DAA therapy. RESULTS: Fifty-five HCV D+/R- transplants at our center [42 KT (26 nucleic acid testing positive [NAT+], 16 NAT-), 12 LT (eight NAT+, four NAT-), and one SLKT (NAT+)] had a median waitlist time of 69 days for KT, 87 days for LT, and 15 days for SLKT. There were no graft failures at 1 year. All viremic recipients were treated with a 12-week course of DAAs, of which 100% achieved end of treatment response (EOTR)-85.7% (n = 30) achieved sustained virologic response (SVR) and 14.3% relapsed (n = 5; four KT, one LT). All relapsed recipients were retreated and achieved SVR. The most common post-transplantation complications include BK virus infection (n = 9) for KT and non-allograft infections (n = 4) for LT. CONCLUSIONS: Our study has demonstrated no graft failures or recipient deaths at 1 year, and despite a 14.3% relapse rate, we achieved 100% SVR. Complications rates of D+/R- appeared comparable to national D-/R- complication rates. Further studies comparing D+/R- to D-/R- outcomes are needed.

The Effect of a Merit Point Incentive System on the Willingness to Donate Organs.

PURPOSE: Although over 90% of the population of the United States supports organ donation, only 60% of the population is registered as donors. Currently, there is a need for a nonmonetary incentive that will improve willingness to donate. We assessed the young adult population's perspective on their willingness to donate organs when merit points are granted to their family members to prioritize their potential transplant if needed. METHODS: We administered a Qualtrics survey from March 2022 to September 2022 to the undergraduate students volunteering to participate at Saint Louis University, which comprised 10 questions that addressed the attitudes of participants regarding the effects of various factors, including the type of donation and the presence of merit points (vouchers granted to self or a family member to facilitate a potential transplant if needed), on participant's willingness to donate an organ while alive or after death. The responses were analyzed by using SAS software (SAS Institute). RESULTS: A total of 572 participants completed the survey. Overall, only 6.5% of surveyed students were unwilling to donate after death. The willingness to donate while alive to a family member was significantly higher than donating to a stranger (95.8% vs 71.2%, P < .0001). When merit points were added, the unwillingness to donate significantly decreased from 6.5% to 3.8%. However, this change was observed only when the merit points were given to a family member and not to self. When merit points were granted, unwillingness to provide a living donation to a stranger decreased from 28.8% to 16.4% (P < .0001). CONCLUSIONS: Merit points to first-degree family members improve students' expressed willingness to donate organs after death; however, self-merit points did not decrease the rate of "unwillingness to donate after death." When living donation is assessed, offering merit points appears to decrease the "unwillingness to donate to strangers." The adoption of a merit point system in the United States may increase the rates of organ donation.

Normothermic ex vivo perfusion of deceased donor kidneys and its clinical potential in kidney transplantation outcomes.

In recent years, normothermic machine perfusion (NMP) has emerged in conversation surrounding organ preservation and transplantation techniques with the goal of improving patient and clinical outcomes. This is in great attempt to address the rate of non-utilization and the shortage of available organs in kidney transplantation. This focus in mind, normothermic perfusion presents itself as a potential tool to mimic physiological conditions and improve current preservation methods, such as static cold storage. This review serves to improve understanding of the observed connection between the consequences of ischemia and reperfusion injury and traditional preservation techniques as well as how renal NMP may mitigate these issues. Previous studies suggest that reducing time in static cold storage methods by promoting the normothermic perfusion model results in decreased delayed graft function and post-transplant complications. This review also aims to present the immense clinical potential NMP has on future kidney transplantation success and what this means for the fields of nephrology and transplantation. While great strides have been made to evaluate normothermic perfusion's impact on kidney graft viability and transplant success, future research into unified protocol, clinically relevant biomarkers, cost-utility analysis, and use with associated therapeutic and imaging modalities is paramount.

Long-term Effects of Gastric Acid Prophylaxis in Kidney Transplant Recipients.

Objectives: Prophylactic acid suppression with proton pump inhibitors or H2 receptor antagonists is often administered after kidney transplantation. The Association of proton pump inhibitors or H2 receptor antagonists with acute rejection, hypomagnesemia, and graft loss in kidney transplant recipients is not well established. Material and Methods: We performed a retrospective cohort study of 302 kidney transplant recipients at one center (57% male; mean age 35.5±11.2 years) with more than 6 months post-transplant follow-up. Recipients were grouped according to gastric acid prophylaxis: only proton pump inhibitors (n=179), only H2 receptor antagonists (n=42), proton pump inhibitors and H2 receptor antagonists (n=55), and nonusers (n=26). The primary outcome was biopsy-proven acute rejection. Graft loss and hypomagnesemia were defined as secondary outcomes. Results: Nonusers were younger and mostly under steroid-free immunosuppression compared to other study groups (p=0.030 and p=0.009, respectively). The primary outcome was similar across study groups (p=0.266). Kaplan-Meier analyses also demonstrated similar 10-year graft survival rates: 95.5% for proton pump inhibitors, 97.6% for H2 receptor antagonists, 100% for proton pump inhibitors/H2 receptor antagonists, and 96.2% for nonusers (p=0.275). Conclusions: The use of proton pump inhibitors is not associated with acute rejection or graft loss but may cause mild hypomagnesemia in kidney transplant recipients.

Pregnancy in Living Kidney Donors: An Evidence-Based Review.

Purpose of review: To review the current studies and guidelines on the risk of adverse pregnancy outcomes in female kidney donors. Recent findings: Living kidney donors include a significant amount of young women of child-bearing age. Safety and possible risks of pregnancy after donation are a concern for female kidney donor candidates. Many current studies indicate a higher risk of preeclampsia in women after kidney donation. Considering the increasing number of living kidney donors, the maternal outcomes of living kidney donation is an active area of research. Summary: Guidelines and consensus statements on the risk of pregnancy in living kidney donors recommend close monitoring of blood pressure, weight gain, and proteinuria during pregnancy. Current studies indicate an increased risk of hypertensive disorders of pregnancy in living kidney donors. Counseling and informing donor candidates about the possible risks is important.

Kidney paired donation in developing countries: A global perspective.

Purpose of review: We review the key principles of kidney paired donation (KPD) and discuss the status and unique considerations for KPD in developing countries. Recent findings: Despite the advantages of KPD programs, they remain rare among developing nations, and the programs that exist have many differences with those of in developed countries. There is a paucity of literature and lack of published data on KPD from most of the developing nations. Expanding KPD programs may require the adoption of features and innovations of successful KPD programs. Cooperation with national and international societies should be encouraged to ensure endorsement and sharing of best practices. Summary: KPD is in the initial stages or has not yet started in the majority of the emerging nations. But the logistics and strategies required to implement KPD in developing nations differ from other parts of the world. By learning from the KPD experience in developing countries and adapting to their unique needs, it should be possible to expand access to KPD to allow more transplants to happen for patients in need world-wide.