Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Histopathologic and Clinical Features in Patients with Diabetes and Kidney Disease.

Background: The discovery of nondiabetic kidney disease (NDKD) in an individual patient with diabetes may have significant treatment implications. Extensive histopathologic data in this population are lacking, but they may provide insights into the complex pathogenesis of diabetic nephropathy (DN) and reveal specific phenotypes for the development of targeted therapies. This study seeks to elucidate the clinical and laboratory parameters associated with the spectrum of kidney histopathologic features in patients with diabetes. Methods: This study is a retrospective analysis of 399 kidney biopsies assessed from 2014 to 2016 at the University of Washington among patients with diabetes. More comprehensive clinical data were evaluated in a subset of 79 participants. Results: Of the 399 biopsies reviewed, 192 (48%) had a primary diagnosis of DN (including 26 with an additional diagnosis), and 207 (52%) had a primary diagnosis of NDKD (including 67 who also had DN). Retinopathy (sensitivity: 0.86; specificity: 0.81; OR, 27.1; 95% CI, 6.8 to 107.7) and higher levels of proteinuria (7.6 versus 4.1 g/d; P=0.004) were associated with DN, whereas a physician description of AKI was associated with a lower risk of DN (OR, 0.13; 95% CI, 0.04 to 0.38). The four most prevalent diagnoses in participants with NDKD were FSGS in 39, nephrosclerosis in 29, IgA nephropathy in 27, and acute tubular injury in 21. Conclusions: Among patients with diabetes who undergo kidney biopsy in the Pacific Northwest, approximately half have DN, and half have NDKD. Retinopathy and more severe proteinuria were associated with DN, and AKI was a more common descriptor in NDKD.Podcast: This article contains a podcast at https://www.asnonline.org/media/podcast/K360/2020_11_25_KID0003962020.mp3.

Albumin in Cirrhosis: More Than a Colloid.

PURPOSE OF REVIEW: Albumin has repeatedly been shown to be beneficial in treating patients with decompensated cirrhosis. We reviewed the medical literature regarding indications for the use of intravenous albumin in cirrhosis, with particular focus on the ways in which albumin can help mitigate hepatorenal physiology. RECENT FINDINGS: Albumin has long been used as the preferred agent for volume expansion in patients with decompensated cirrhosis. It is used in conjunction with vasoconstrictors for the treatment of type 1 hepatorenal syndrome, and in combination with antibiotics for the treatment of spontaneous bacterial peritonitis. When given at the time of large volume paracentesis, albumin is known to help reduce the incidence of post-paracentesis circulatory dysfunction. Recently, albumin has been shown to improve outcomes in hospitalized patients with cirrhosis and hyponatremia, and has also shown promise in reducing mortality and hospitalizations in outpatients with both diuretic resistant and uncomplicated ascites. It is increasingly clear that these benefits derive from a combination of the oncotic and non-oncotic properties of albumin, and from the effects of albumin administration on effective arterial blood volume. Albumin is an effective treatment for multiple complications encountered in patients with decompensated cirrhosis.

Protecting kidneys in liver transplant patients: A pathway to preventive interventions.

Acute kidney injury (AKI) is a frequent postoperative complication after liver transplantation. The etiology is multifactorial, including perioperative renal status, surgery related events, and postoperative immunosuppression therapy. The role of renal hypoperfusion and hepatic ischemia-reperfusion injury as causes of early AKI are now being increasingly recognized. Further studies should focus on therapies that would attenuate this injury.

Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets.

Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.

Kidney Biopsies May Help Predict Renal Function After Liver Transplantation.

BACKGROUND: Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population. METHODS: We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed. RESULTS: Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK. CONCLUSIONS: Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates.

Primary Care Team Members Report Greater Individual Benefits from Long- Versus Short-Term Specialty Telemedicine Mentorship.

BACKGROUND: Primary care providers who participate in structured specialty telemedicine mentorship report improvements in clinical content mastery, professional satisfaction, and specialist communication. INTRODUCTION: Although these programs require investments of infrastructure resources and time, the duration of participation required to accrue optimal benefits is not known. We aimed to assess whether duration of participation is related to improved benefits of a longitudinal telemedicine-based mentorship program, specifically regarding perceived specialty care access, acquisition of new knowledge and skills, team integration, and overall job satisfaction. MATERIALS AND METHODS: We conducted an e-mail survey of Veterans Affairs-based primary care team members in the United States' Pacific Northwest region who engaged in a longitudinal telemedicine mentorship program (n = 78). RESULTS: After adjustment for potential confounding factors, respondents who engaged in telemedicine mentorship for ≥1 year were significantly more likely to strongly agree that telemedicine mentorship improved patient access to specialty care (adjusted odds ratio [AOR] = 9.3, p < 0.005) and was useful in treating other patients on their panels (AOR = 3.7, p = 0.04). Participation ≥1 year was also associated with higher self-reported knowledge and competencies (AOR = 4.0, p = 0.03) and with perception of integration into a clinical team (AOR = 5.6, p = 0.01), but not with overall job satisfaction. CONCLUSION: Telemedicine-based specialty mentorship programs are highly valued by primary care-based participants, and self-reported benefits accumulate beyond 1 year of participation.

A unique way to treat Goodpasture's disease.

A 21-year-old man with no medical history presented to the emergency department with fatigue, oliguria and lower extremity oedema. Initial laboratory tests showed that the patient was in acute renal failure with a creatinine of 12.8 mg/dL (normal 0.51-1.18 mg/dL). Further work up showed crescentic glomerulonephritis on renal biopsy, and serology was positive for antiglomerular basement antibody (titre 191 U/mL, normal 0-0.7 U/mL). Shortly after diagnosis he developed haemoptysis and chest imaging was consistent with pulmonary haemorrhage. The standard immunotherapy for Goodpasture's disease is cyclophosphamide, but due to known reproductive toxicities associated with cyclophosphamide and the patient's age, it was decided to use alternate but less studied therapies for treatment. At discharge, the patient had undergone five plasmapheresis treatments, had received two doses of Rituximab with a steroid taper, and his antiglomerular basement membrane level had decreased significantly.

Minimal-change disease secondary to etanercept.

Etanercept is a soluble tumor necrosis factor alpha (TNFα) receptor which is widely used in the treatment of rheumatoid arthritis, psoriasis and other autoimmune inflammatory disorders. It is known for its relative lack of nephrotoxicity; however, there are reports on the development of nephrotic syndrome associated with the treatment with TNFα antagonists. Here, we describe a patient with psoriasis who developed biopsy-proven minimal-change disease (MCD) shortly after initiating etanercept. Our case is unique in that the MCD resolved after discontinuation of this medication, notably without the use of corticosteroids, strongly suggesting a drug-related phenomenon.

Collapsing glomerulopathy associated with natural killer cell leukemia: a case report and review of the literature.

We report a case of collapsing glomerulopathy associated with natural killer cell leukemia in a previously healthy 27-year-old African American man. An initial kidney biopsy showed findings concordant with the cellular variant of focal segmental glomerulosclerosis. A repeated biopsy 3 months later showed collapsing glomerulopathy, likely representing a morphologic evolution from a cellular variant into the collapsing glomerulopathy variant of focal segmental glomerulosclerosis. Collapsing glomerulopathy has been described in connection with a number of disparate disorders in which podocyte injury seems to be the common denominator. The close temporal association between clinical presentation and the development of nephropathy provides support for a direct pathogenic link between the underlying lymphoproliferative disorder and the glomerular lesions. We hypothesize that dysregulated cytokine production by the neoplastic cells led to podocyte alterations and eventually to the development of collapsing glomerulopathy.

Dual renin-angiotensin-aldosterone system blockade for diabetic kidney disease.

Blockade of the renin-angiotensin-aldosterone system (RAAS) prevents the development and progression of diabetic kidney disease (DKD). It is controversial whether the simultaneous use of two RAAS inhibitors (ie, dual RAAS blockade) further improves renal outcomes. This review examines the scientific rationale and current clinical evidence addressing the use of dual RAAS blockade to prevent and treat DKD. It is concluded that dual RAAS blockade should not be routinely applied to patients with low or moderate risk of progressive kidney disease (normoalbuminuria or microalbuminuria with preserved glomerular filtration rate). For patients with high risk of progressive kidney disease (substantial albuminuria or impaired glomerular filtration rate), clinicians should carefully weigh the potential risks and benefits of dual RAAS blockade on an individual basis until ongoing clinical trials provide further insight.

Donor-recipient size matching influences early but not late graft function after pediatric en-bloc kidney transplantation.

BACKGROUND: Pediatric en-bloc kidney transplantation into adult recipients is an accepted technique to expand the donor pool. Concerns about adequate "nephron dosing" have traditionally favored placing these kidneys into smaller recipients. METHODS: We reviewed 20 pediatric en-bloc transplants performed at our institution between 2002 and 2008. We examined the impact of donor age, donor weight, recipient sex, combined kidney length, recipient weight, recipient-to-donor weight ratio, and recipient weight gain on serum creatinine over time using regression analysis. RESULTS: Patient survival was 100%. Two grafts were lost early from vascular thrombosis. Of the remaining 18 recipients, all had immediate and excellent long-term function with average creatinine of 0.91+/-0.38 mg/dL at a mean follow-up of 1257+/-656 days. For 17 patients with 1 year follow-up, recipient weight, recipient-to-donor weight ratio, and recipient male sex negatively influenced renal function at 1 month. However, this relationship was lost by 1 year with increasing function in the smallest donors and largest size mismatches. Between 1 month and 1 year posttransplant, estimated creatinine clearance improved from 59+/-13 mL/min at 1 month posttransplant to 88+/-41 mL/min (P<0.015). Weight gain after transplant was associated with improved creatinine clearance, suggesting continued adaptation over time. CONCLUSIONS: We conclude that donor or recipient size matching up to a recipient-to-donor weight ratio of 7.5 does not significantly impact later renal function after pediatric en-bloc kidney transplantation into adults.

Higher levels of leflunomide are associated with hemolysis and are not superior to lower levels for BK virus clearance in renal transplant patients.

BACKGROUND AND OBJECTIVES: Leflunomide use in renal transplantation has been increasing. Outcome correlation and safety data are still to be refined. The goals of this study were to report one center's experience with leflunomide, specifically the correlation of leflunomide levels with the outcomes of BK nephropathy and the observed toxic effects during the treatment with leflunomide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Leflunomide was used in 21 patients with BK nephropathy. These patients were divided into two groups on the basis of the leflunomide levels achieved: Low-level group (<40 microg/ml) and high-level group (>40 microg/ml). RESULTS: During 13 mo of follow-up, there was no difference in the rate of serum BK viral clearance between the groups. There were three graft losses in the low-level group and one in the high-level group; however, creatinine levels were higher at the time of starting leflunomide in the low-level group. Leflunomide was also used in six patients with chronic allograft injury. No graft loss was observed during the follow-up period of 16 mo. Treatment with leflunomide seemed to be associated with a new toxicity, hemolysis, seen in four of the 27 patients so treated. Patients with hemolysis had high leflunomide levels (81.4 +/- 14 microg/ml) and worsening allograft function. Two patients had histologic evidence of thrombotic microangiopathy, which led to graft loss in one patient. CONCLUSIONS: The clinical correlation between leflunomide levels and outcomes needs to be further refined. This study described a possible association of leflunomide with thrombotic microangiopathy, especially at higher levels.

Mechanical stretch induces podocyte hypertrophy in vitro.

BACKGROUND: Increased intraglomerular pressure is a final pathway toward glomerulosclerosis in systemic hypertension, diabetes, and focal segmental glomerulosclerosis (FSGS). Increased intraglomerular pressure causes stress-tension, or stretch, on resident glomerular cells. However, the effects of stretch on podocyte growth, and the mechanisms that underlie this, have not been elucidated. METHODS: To test the hypothesis that stretch alters podocyte growth, cultured mouse podocytes were exposed to cyclic mechanical stretch created by vacuum; control cells were grown under similar conditions, but not exposed to stretch. Proliferation (cell cycle phases) and hypertrophy (forward light scatter) were measured in stretched and control podocytes by flow cytometry. The role of the cyclin-dependent kinase (CDK) inhibitors, p21 and p27, was examined by stretching podocytes isolated from p21 and p27 knockout (-/-) mice, and the role of specific signaling pathways was assessed by Western blot analysis and blocking studies. RESULTS: Our results showed that stretch reduced cell cycle progression in wild-type and single p27-/- podocytes and induced hypertrophy in these cells in all phases of the cell cycle at 24, 48, and 72 hours. In contrast, stretch did not induce hypertrophy in single p21-/- and double p21/p27-/- podocytes. Stretch-induced hypertrophy required cell cycle entry, and was prevented by specifically blocking extracellular signal-regulated kinase 1/2 (Erk1/2) or Akt. Although stretch increased p38 activation, inhibition of this pathway had no effect on hypertrophy. CONCLUSION: Mechanical stretch induces hypertrophy in podocytes in vitro in all phases of the cell cycle. This effect is cell cycle dependent, and requires p21, Erk1/2, and Akt. Stretch may play a role in podocyte injury when intraglomerular pressure is increased.

Activation of a local tissue angiotensin system in podocytes by mechanical strain.

BACKGROUND: Glomerular capillary hypertension, a common denominator in various forms of progressive glomerular disease, results in mechanical distention of the capillary tuft, and subsequent injury of the overlying podocyte layer. The mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Angiotensin II plays a central role in the pathogenesis of chronic renal injury, largely through its actions on the subtype 1 receptor. Accordingly, we have tested the hypothesis that mechanical strain up-regulates local angiotensin II in podocytes, thereby resulting in a progressive reduction in podocyte number. METHODS: Conditionally immortalized mouse podocytes were subjected to cyclical stretch of 10% amplitude. Nonstretched podocytes served as controls. Angiotensin II levels were measured in whole cell lysate by competitive enzyme-linked immunosorbent assay (ELISA). Expression of angiotensin II receptors (AT1R, AT2R) was measured by quantitative polymerase chain reaction (PCR) and Western blot analysis. Apoptosis was measured by Hoechst staining. Immunostaining for AT1R was performed in tissue sections from rats with 5/6 remnant kidney disease, a model of glomerular hypertension. RESULTS: Mechanical strain increased angiotensin II production in podocytes at 24, 48, and 72 hours (P < 0.05 vs. nonstretched controls). Stretching podocytes resulted in a fivefold increase in AT1R mRNA expression at 24 hours and a twofold increase in protein levels vs. controls (P < 0.05), and also an increase in transforming growth hormone-beta (TGF-beta) mRNA expression. AT1R staining was increased in a podocyte distribution in the 5/6 remnant kidney, consistent with our in vitro findings. Mechanical strain resulted in a 2.5-fold increase in apoptosis (P < 0.001 vs. nonstretched controls) in an angiotensin II-dependent fashion. CONCLUSION: Mechanical strain leads to up-regulation of the AT1R and increased angiotensin II production in conditionally immortalized podocytes. The resulting activation of a local tissue angiotensin system leads to an increase in podocyte apoptosis, mainly in an AT1R-mediated fashion.