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.

The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review.

Studies consistently showed that sodium-glucose cotransporter inhibitors (SGLTi) have cardiovascular and renal benefits, independent of their glucose lowering effects. Recent studies showed that SGLTi might influence gut microbiota. We performed a narrative review of publications focusing on use of SGLTi and changes in gut microbiota. Most studies showed that use of SGLTi re-shapes gut microbiota. These studies are heterogeneous regarding in study designs, doses and types of drugs used (SGLT1i vs. SGLT2i, or SGLT1/2i in combination) and the methods used to determine gut microbiota. However, existing data showed that SGLTi might alter food fermentation and gut permeability, which might translate into clinical outcomes. Thus the objective of this review is to summarize and discuss the updated data regarding SGLTi and changes in gut microbiota for the first time and suggest further study points that needs to be discovered.

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.

Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

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.

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.

A Case of Hypernatremia in a Newly Diagnosed Patient With Acute Myeloid Leukemia: Lessons for Nephrologists.

Arginine vasopressin deficiency (AVP-D), formerly known as central diabetes insipidus, is a disease characterized by polyuria, polydipsia, and hypernatremia. The concomitant diagnosis of acute myeloid leukemia (AML) is an underappreciated event that requires prompt recognition and treatment by practicing nephrologists and hematologists. This report highlights this importance by describing the case of a 39-year-old patient newly diagnosed with AML who developed severe hypernatremia. The role of diagnostic testing through desmopressin (DDAVP) challenge and copeptin testing to confirm the diagnosis of AVP-D in this context and the use of DDVAP for treatment are discussed. Practicing nephrologists and primary care providers taking care of patients with similar symptoms will benefit from understanding the pathophysiology of AVP-D, its relationship with AML, and the prognosis in this patient cohort.

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.

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.

Indications, Techniques, and Barriers for Pancreas Transplant Biopsy: A Consensus Perspective From a Survey of US Centers.

BACKGROUND: Pancreas transplant biopsy practices for the diagnosis of rejection or other pathologies are not well described. METHODS: We conducted a survey of staff at US pancreas transplant programs (March 22, 2022, to August 22, 2022) to assess current program practices and perceptions about the utility and challenges in the performance and interpretation of pancreas allograft biopsies. RESULTS: Respondents represented 65% (76/117) of active adult pancreas transplant programs, capturing 66% of recent pancreas transplant volume in the United States. Participants were most often nephrologists (52%), followed by surgeons (46%), and other staff (4%). Pancreas allograft biopsies were performed mostly by interventional radiologists (74%), followed by surgeons (11%), nephrologists (8%), and gastroenterologists (1%). Limitations in the radiologist's or biopsy performer's comfort level or expertise to safely perform a biopsy, or to obtain sufficient/adequate samples were the two most common challenges with pancreas transplant biopsies. Pancreas transplant biopsies were read by local pathologists at a majority (86%) of centers. Challenges reported with pancreas biopsy interpretation included poor reliability, lack of reporting of C4d staining, lack of reporting of rejection grading, and inconclusive interpretation of the biopsy. Staff at a third of responding programs (34%) stated that they rarely or never perform pancreas allograft biopsies and treat presumed rejection empirically. CONCLUSIONS: This national survey identified significant variation in clinical practices related to pancreas allograft biopsies and potential barriers to pancreas transplant utilization across the United States. Consideration of strategies to improve program experience with percutaneous pancreas biopsy and to support optimal management of pancreas allograft rejection informed by histology is warranted.

Generating strategies for a national comeback in pancreas transplantation: A Delphi survey and US conference report.

In the United States, potential transplant candidates with insulin-dependent diabetes mellitus are inconsistently offered pancreas transplantation (PTx), contributing to a dramatic decline in pancreas allograft utilization over the past 2 decades. The American Society of Transplantation organized a workshop to identify barriers inhibiting PTx and to develop strategies for a national comeback. The 2-day workshop focused on 4 main topics: (1) referral/candidate selection, (2) organ recovery/utilization, (3) program performance/patient outcomes, and (4) enhanced education/research. Topics were explored through expert presentations, patient testimonials, breakout sessions, and strategic planning, including the identification of tasks for immediate focus. Additionally, a modified-Delphi survey was conducted among workshop members to develop and rate the importance of barriers, and the impact and feasibility of workgroup-identified improvement strategies. The panelists identified 16 barriers to progress and 44 strategies for consideration. The steps for a national comeback in PTx involve greater emphasis on efficient referral and candidate selection, better donor pancreas utilization practices, eliminating financial barriers to procurement and transplant, improving collaboration between transplant and diabetes societies and professionals, and increasing focus on PTx training, education, and research. Partnership between national societies, patient advocacy groups, and professionals will be essential to realizing this critical agenda.

OPTN/SRTR 2022 Annual Data Report: Kidney.

The year 2022 had continued successes and challenges for the field of kidney transplantation, as the community adapted to ongoing surges of the COVID-19 pandemic and broader geographic organ distribution. The total number of kidney transplants in the United States reached a record count of 26,309, driven by continued growth in deceased donor kidney transplants (DDKTs). The total number of candidates listed for DDKT rose slightly in 2022 but remained below 2019 listing levels, with 12.4% of candidates having been waiting 5 years or longer. Following the height of the COVID-19 pandemic, pretransplant mortality in 2022 declined across age, race and ethnicity, sex, and blood type groups. Pretransplant mortality continued to vary substantially by donation service area. The proportion of deceased donor kidneys recovered but not used for transplant (nonuse rate) rose to a high of 26.7% overall, with greater nonuse of biopsied kidneys (39.8%), kidneys from donors aged 55 years or older (54.7%), and kidneys with a kidney donor profile index (KDPI) of 85% or greater (71.3%). Nonuse of kidneys from donors who are hepatitis C virus (HCV) antibody positive rose to 30.2% but only slightly exceeded that of HCV antibody-negative donors. Disparities in access to living donor kidney transplant (LDKT) persist, especially for non-White and publicly insured patients. Delayed graft function continues an upward trend and occurred in 26.3% of adult kidney transplants in 2022. Five-year graft survival after LDKT compared with DDKT was 90.0% versus 81.4% for recipients aged 18-34 years and 80.8% versus 67.8% for recipients aged 65 years or older, respectively. The total number of pediatric kidney transplants performed in 2022 decreased to 705, its lowest point in the past decade; 502 (71.2%) were DDKTs and 203 (28.8%) were LDKTs. Among pediatric recipients, LDKT remains low, with continued racial disparities. The rate of DDKT among pediatric candidates has decreased by almost 25% since 2011. Congenital anomalies of the kidney and urinary tract remain the leading primary kidney disease diagnosis among pediatric candidates with a reported diagnosis. Most pediatric deceased donor recipients received a kidney from a donor with a KDPI of less than 35%. The rate of delayed graft function was 5.8% in 2022 and has been stable over the past decade. Long-term graft survival continues to improve, with superior outcomes for living donor transplant recipients.

Risk Factors for Developing Low Estimated Glomerular Filtration Rate and Albuminuria in Living Kidney Donors.

Rationale & Objective: Chronic kidney disease is associated with significant morbidity and mortality in the general population, but little is known about the incidence and risk factors associated with developing low estimated glomerular filtration rate (eGFR) and moderate-severe albuminuria in living kidney donors following nephrectomy. Study Design: Retrospective, population-based cohort study. Setting & Participants: Kidney donors in Alberta, Canada. Exposure: Donor nephrectomy between May 2001 and December 2017. Outcome: Two eGFR measurements <45 mL/min/1.73 m2 or 2 measurements of moderate or severe albuminuria from 1-year postdonation onwards that were at least 90 days apart. Analytical Approach: Associations between potential risk factors and the primary outcome were assessed using Cox proportional hazard regression analyses. Results: Over a median follow-up period of 8.6 years (IQR, 4.7-12.6 years), 47 of 590 donors (8.0%) developed sustained low eGFR or moderate-severe albuminuria with an incidence rate of 9.2 per 1,000 person-years (95% confidence interval, 6.6-11.8). The median time for development of this outcome beyond the first year after nephrectomy was 2.9 years (IQR, 1.4-8.0 years). Within the first 4 years of follow-up, a 5 mL/min/1.73 m2 lower predonation eGFR increased the hazard of developing postdonation low eGFR or moderate-severe albuminuria by 26% (adjusted HR, 1.26; 95% CI, 1.10-1.44). Furthermore, donors were at higher risk of developing low eGFR or albuminuria if they had evidence of predonation hypertension (adjusted HR, 2.52; 95% CI, 1.28-4.96) or postdonation diabetes (adjusted HR, 4.72; 95% CI, 1.54-14.50). Limitations: We lacked data on certain donor characteristics that may affect long-term kidney function, such as race, smoking history, and transplant-related characteristics. Conclusions: A proportion of kidney donors at an incidence rate of 9.2 per 1,000 person-years will develop low eGFR or albuminuria after donation. Donors with lower predonation eGFR, predonation hypertension, and postdonation diabetes are at increased risk of developing this outcome.

The purpose of this study was to understand the risk of developing kidney disease in living kidney donors after donation. We followed 590 donors in Alberta, Canada for almost 9 years. Approximately 8% of donors developed reduced kidney function (low estimated glomerular filtration rate) or increased protein in the urine (albuminuria). Donors with lower kidney function before donation, hypertension before donation, or diabetes after donation had a higher likelihood of experiencing these kidney outcomes. This research provides important insights to patients and health care providers to better support the long-term kidney health of living kidney donors.