Outcomes of Bladder Washout for the Treatment of Recurrent Urinary Tract Infections After Renal Transplantation.

Background Current literature suggests that anywhere from 2.9-27% of renal transplant recipients (RTR) will develop recurrent urinary tract infections (UTIs) (≥2 UTIs over six months or ≥3 UTIs over 12 months). Recurrent UTIs are of particular importance to RTR given its increased risk for allograft fibrosis and overall patient survival. Alternative solutions are needed for the management of recurrent UTIs, especially given the vulnerability of RTR to UTIs. We hypothesize that bladder washout (BW) reduces the incidence and recurrence of UTIs in RTR. Methods This is a retrospective study evaluating the utility of BW procedures on RTR diagnosed with recurrent UTIs between December 2013 and July 2021 at a single center. Results A total of 106 patients were included in the study with a total of 118 BW performed. 69% of patients were successfully treated with BW, meaning they no longer met the criteria for recurrent UTIs (<1 UTI) in the six-month post-BW period. The mean number of UTIs was 2.76 (range 2-7) before the BW and 1.16 (range 0-5) after the BW. On average, there were 1.60 fewer UTIs in the post-BW period compared to the pre-BW period (p<0.0001). There is no statistically significant difference in success rates stratified by bacterial class (p=1) or antimicrobial resistance class (p=0.6937). Conclusion BW decreased the incidence of UTIs in the six-month post-operative period as nearly 70% of patients did not have UTI recurrence. This data provides evidence that BW may have utility in transplant recipients with recurrent UTIs. We hope this will stimulate further prospective randomized studies in this area.

Comparative incidence and outcomes of COVID-19 in kidney or kidney-pancreas transplant recipients versus kidney or kidney-pancreas waitlisted patients: A single-center study.

BACKGROUND: COVID-19 epidemiologic studies comparing immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressants on outcomes. METHODS: In this retrospective cohort study, we assembled kidney or kidney-pancreas transplant recipients who underwent transplant from January 1, 2010, to June 30, 2020, and kidney or kidney-pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020. We identified laboratory-confirmed COVID-19 until January 31, 2021, and tracked its outcomes by leveraging informatics infrastructure developed for an outcomes research network. RESULTS: COVID-19 was identified in 62 of 887 kidney or kidney-pancreas transplant recipients and 20 of 434 kidney or kidney-pancreas waitlisted patients (7.0% vs. 4.6%, p = .092). Of these patients with COVID-19, hospitalization occurred in 48 of 62 transplant recipients and 8 of 20 waitlisted patients (77% vs. 40%, p = .002); intensive care unit admission occurred in 18 of 62 transplant recipients and 2 of 20 waitlisted patients (29% vs. 10%, p = .085); and 7 transplant recipients were mechanically ventilated and died, whereas no waitlisted patients were mechanically ventilated or died (11% vs. 0%, p = .116). CONCLUSIONS: Our study provides single-center data and an informatics approach that can be used to inform the design of multicenter studies.

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.

PURPOSE: Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). METHODS: We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO2/FiO2 < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model. RESULTS: Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO2/FiO2 prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO2/FiO2 < 80 (HR 0.55; 95% CI 0.40-0.77). CONCLUSION: In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality.

Percutaneous Renal Biopsy Using an 18-Gauge Automated Needle Is Not Optimal.

BACKGROUND: As percutaneous renal biopsies (PRBs) are increasingly performed by radiologists, an increase in the use of 18-gauge automated needle stands to compromise adequacy. We compare the adequacy and safety of PRB with 14-, 16-, and 18-gauge automated needles. METHODS: PRB of native (N-592) and transplant (T-1,023) kidneys was performed from January 2002 to December 2019 using real-time ultrasound. Baseline clinical and laboratory data, biopsy data (number of cores, total glomeruli, and total glomeruli per core), and outcome (hematoma on renal US at 1-h, complications, and transfusion) were collected prospectively. PRB with N14g (337) versus N16g (255) and T16g (892) versus T18g (131) needles were compared. A p value of <0.05 was significant. RESULTS: PRB with an 18-g needle yielded the lowest number of total glomeruli per biopsy (N14g vs. N16g: 33 ± 13 vs. 29 ± 12, p < 0.01 and T16g vs. T18g: 34 ± 16 vs. 21 ± 11, p < 0.0001), significantly fewer total glomeruli per core (T16g vs. T18g: 12.7 ± 6.4 vs. 9.6 ± 5.0, p < 0.001 and N16g vs. T18g: 14.2 ± 6.3 vs. 9.6 ± 5.0, p < 0.001). A hematoma by renal US 1-h post-PRB was similar for native (14g-35% vs. 16g-29%, p = 0.2), and transplant biopsies (16g-10% vs. 18g-9%, p = 0.9) and the complication rate for native (14g-8.9% vs. 16g-7.1%, p = 0.5), transplant biopsies (16g-4.6% vs. 18g-1.5%, p = 0.2) and transfusion rate for native (14g-7.7% vs. 16g-5.8%, p = 0.4), and transplant biopsies (16g-3.8% vs. 18g-0.8%, p = 0.1) were similar irrespective of needle size. CONCLUSIONS: PRB of native and transplant kidneys with the use of a 16-gauge needle provides an optimal sample. However, our experience in transplant biopsies suggests the use of an 18-gauge needle stands to jeopardize the diagnostic accuracy of the PRB while not improving safety.

Nonimmune cell-derived ICOS ligand functions as a renoprotective αvß3 integrin-selective antagonist.

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvß3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvß3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvß3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvß3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvß3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvß3-selective antagonist to maintain glomerular filtration.

uPAR isoform 2 forms a dimer and induces severe kidney disease in mice.

Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding ß3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin ß3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for ß3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.

Soluble Urokinase Receptor and the Kidney Response in Diabetes Mellitus.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. DN typically manifests by glomerular hyperfiltration and microalbuminuria; then, the disease progresses to impaired glomerular filtration rate, which leads to ESRD. Treatment options for DN include the strict control of blood glucose levels and pressure (e.g., intraglomerular hypertension). However, the search for novel therapeutic strategies is ongoing. These include seeking specific molecules that contribute to the development and progression of DN to potentially interfere with these "molecular targets" as well as with the cellular targets within the kidney such as podocytes, which play a major role in the pathogenesis of DN. Recently, podocyte membrane protein urokinase receptor (uPAR) and its circulating form (suPAR) are found to be significantly induced in glomeruli and sera of DN patients, respectively, and elevated suPAR levels predicted diabetic kidney disease years before the occurrence of microalbuminuria. The intent of this review is to summarize the emerging evidence of uPAR and suPAR in the clinical manifestations of DN. The identification of specific pathways that govern DN will help us build a more comprehensive molecular model for the pathogenesis of the disease that can inform new opportunities for treatment.

Extrarenal determinants of kidney filter function.

The kidney is an organ involved in cross talk with many human organs. The link between the immune system and the kidney has been studied in some detail, although data precisely elucidating their interaction are sparse, in particular with regard to the function of the kidney filter apparatus. Current research suggests that an understanding of the impairment of this cross talk between the bone marrow, as a fundament of the immune system and the kidney will provide meaningful insights into the pathophysiological mechanisms of impaired kidney filter function. Circulating factors have long been implicated in the pathogenesis of idiopathic nephrotic syndrome, particularly focal segmental glomerulosclerosis (FSGS) and its recurrence. Soluble urokinase receptor (suPAR) has emerged as a circulating factor responsible for FSGS and also as an early predictive marker for the development of various renal diseases. The bone marrow has recently been revealed as a predominant source of suPAR with deleterious effects on the kidney filter. These new findings have led to bone marrow or hematopoietic stem cell transplants being considered as potential therapeutic options for preventing the post-transplantation recurrence of FSGS or even as a treatment for the original disease associated with high suPAR levels. Whereas bone marrow transplantation for patients with pre-existing chronic kidney disease is challenging, recent clinical trials have demonstrated the promising outcome of combined bone marrow and kidney transplantation in patients with kidney failure. In this review, with its brief update on suPAR, we describe the critical new role of the bone marrow in the pathogenesis of the kidney disease process and the functional connection between these two organs through the soluble mediator, suPAR. We also comment on the feasibility of bone marrow transplants for the treatment of patients with chronic renal failure arising from recurrent FSGS.

A tripartite complex of suPAR, APOL1 risk variants and αvß3 integrin on podocytes mediates chronic kidney disease.

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvß3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvß3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvß3 integrin activation is a mechanism for CKD.

Unwinding focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) represents the most common primary glomerular disease responsible for the development of end-stage renal disease (ESRD) in the United States (US). The disease progresses from podocyte injury to chronic kidney disease (CKD), ultimately leading to total nephron degeneration. Extensive basic science research has been conducted to unwind the mechanisms of FSGS and, with those insights, understand major contributors of CKD in general. As a result, several putative molecules and pathways have been studied, all implicated in the disease; some serve, in addition, as early biomarkers. The ongoing research is currently focusing on understanding how these molecules and pathways can interplay and be utilized as potential diagnostic and therapeutic targets. Among these molecules, the soluble urokinase plasminogen activating receptor (suPAR) has been studied in detail, both clinically and from a basic science perspective. By now, it has emerged as the earliest and most robust marker of future CKD. Other circulating factors harming podocytes include anti-CD40 auto-antibody and possibly cardiotrophin-like cytokine factor-1. Understanding these factors will aid our efforts to ultimately cure FSGS and possibly treat a larger portion of CKD patients much more effectively.

Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease.

Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic). Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD), such as focal segmental glomerulosclerosis (FSGS). The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.

We Wait Too Long to Refer Patients for Transplantation.

Late referral of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) for evaluation of kidney transplantation is common. Even though renal transplantation offers a clear survival benefit to patients with advanced CKD and ESRD and should be considered the renal replacement therapy of choice, numerous barriers to early renal transplant referral have been observed. Some of these barriers can be overcome by improving the communication between the referring providers and the transplant centers. Furthermore, providing more intensive education to both patients and referring providers with regard to the eligibility of CKD and ESRD patients for a transplant will likely result in higher referral rates. This in turn will lead to improved survival outcomes in this group of patients with otherwise significantly increased morbidity and mortality.

Amyloid A amyloidosis with subcutaneous drug abuse.

INTRODUCTION: Amyloid A (AA) amyloidosis is a systemic form of amyloidosis secondary to chronic infections and inflammatory disorders. An acute-phase protein produced by the liver, serum amyloid A (SAA) is the precursor of AA amyloid fibrils. AA amyloid deposition occurs predominantly in the kidneys, spleen, adrenal glands, liver and gastrointestinal tract. The manifestations of AA amyloidosis involving the kidneys include proteinuria, tubular dysfunction and progressive loss of renal function. CASE: We report a 47-year-old drug addict who developed AA amyloidosis as a result of recurrent suppurative skin infections secondary to subcutaneous drug injection. Elevated C-reactive protein concentrations attested to the presence of a chronic systemic inflammatory state. He suffered from the nephrotic syndrome and insidious loss of renal function. Isosthenuria and glycosuria were indicative of renal tubular dysfunction. Renal biopsy demonstrated AA amyloidosis involving the glomeruli, tubular basement membranes and blood vessel walls. CONCLUSION: Superimposed acute tubular necrosis due to concomitant endocarditis and cocaine use accelerated his renal disease. CASE presentation is followed by a brief discussion of clinical features, natural history and outcome of AA amyloidosis with a particular emphasis on AA amyloidosis as a complication of subcutaneous drug abuse.

Diabetes mellitus in the transplanted kidney.

Diabetes mellitus (DM) is the most common cause of chronic kidney disease and end stage renal disease. New onset diabetes mellitus after transplant (NODAT) has been described in approximately 30% of non-diabetic kidney-transplant recipients many years post transplantation. DM in patients with kidney transplantation constitutes a major comorbidity, and has significant impact on the patients and allografts' outcome. In addition to the major comorbidity and mortality that result from cardiovascular and other DM complications, long standing DM after kidney-transplant has significant pathological injury to the allograft, which results in lowering the allografts and the patients' survivals. In spite of the cumulative body of data on diabetic nephropathy (DN) in the native kidney, there has been very limited data on the DN in the transplanted kidney. In this review, we will shed the light on the risk factors that lead to the development of NODAT. We will also describe the impact of DM on the transplanted kidney, and the outcome of kidney-transplant recipients with NODAT. Additionally, we will present the most acceptable data on management of NODAT.

Dyslipidemia, malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease.

PURPOSE OF REVIEW: Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients. RECENT FINDINGS: Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia. SUMMARY: In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation.

CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival.

Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-ß1-dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-ß1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-ß response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.

Enzymatic disease of the podocyte.

Proteinuria is an early sign of kidney disease and has gained increasing attention over the past decade because of its close association with cardio-vascular and renal morbidity and mortality. Podocytes have emerged as the cell type that is critical in maintaining proper functioning of the kidney filter. A few genes have been identified that explain genetic glomerular failure and recent insights shed light on the pathogenesis of acquired proteinuric diseases. This review highlights the unique role of the cysteine protease cathepsin L as a regulatory rather than a digestive protease and its action on podocyte structure and function. We provide arguments why many glomerular diseases can be regarded as podocyte enzymatic disorders.