De novo CMV-associated collapsing focal segmental glomerulosclerosis in a kidney transplant recipient.

Collapsing focal segmental glomerulosclerosis (FSGS) is a variant of FSGS and is associated with severe nephrotic syndrome and acute kidney injury and can occur after kidney transplantation. The exact mechanism of collapsing FSGS after kidney transplantation is unknown, but potential causes include autoimmune diseases, certain malignancies, bisphosphonates, m-TOR inhibitors, interferon-alpha, HIV infection, and other viruses. We describe a case of de novo Cytomegalovirus (CMV)-associated collapsing FSGS in a kidney transplant recipient with a UL97 phosphotransferase mutation that was successfully treated with intravenous ganciclovir, intravenous immunoglobulin, and steroids.

Cyclosporine induces endothelial cell release of complement-activating microparticles.

Defective control of the alternative pathway of complement is an important risk factor for several renal diseases, including atypical hemolytic uremic syndrome. Infections, drugs, pregnancy, and hemodynamic insults can trigger episodes of atypical hemolytic uremic syndrome in susceptible patients. Although the mechanisms linking these clinical events with disease flares are unknown, recent work has revealed that each of these clinical conditions causes cells to release microparticles. We hypothesized that microparticles released from injured endothelial cells promote intrarenal complement activation. Calcineurin inhibitors cause vascular and renal injury and can trigger hemolytic uremic syndrome. Here, we show that endothelial cells exposed to cyclosporine in vitro and in vivo release microparticles that activate the alternative pathway of complement. Cyclosporine-induced microparticles caused injury to bystander endothelial cells and are associated with complement-mediated injury of the kidneys and vasculature in cyclosporine-treated mice. Cyclosporine-induced microparticles did not bind factor H, an alternative pathway regulatory protein present in plasma, explaining their complement-activating phenotype. Finally, we found that in renal transplant patients, the number of endothelial microparticles in plasma increases 2 weeks after starting tacrolimus, and treatment with tacrolimus associated with increased C3 deposition on endothelial microparticles in the plasma of some patients. These results suggest that injury-associated release of endothelial microparticles is an important mechanism by which systemic insults trigger intravascular complement activation and complement-dependent renal diseases.

Treatment of De Novo Renal Transplant Recipients With Calcineurin Inhibitor-free, Belatacept Plus Everolimus-based Immunosuppression.

Compared with calcineurin inhibitor-based immunosuppression, belatacept (BELA)-based treatment has been associated with better renal function but higher acute rejection rates. This phase 2 study (NCT02137239) compared the antirejection efficacy of BELA plus everolimus (EVL) with tacrolimus (TAC) plus mycophenolate mofetil (MMF), each following lymphocyte-depleting induction and rapid corticosteroid withdrawal. Methods: Patients who were de novo renal transplant recipients seropositive for Epstein-Barr virus were randomized to receive BELA+EVL or TAC+MMF maintenance therapy after rabbit antithymocyte globulin induction and up to 7 d of corticosteroids. The primary endpoint was the rate of biopsy-proven acute rejection at month 6. Results: Because of an unanticipated BELA supply constraint, enrollment was prematurely terminated at 68 patients, of whom 58 were randomized and transplanted (intention-to-treat [ITT] population: n = 26, BELA+EVL; n = 32, TAC+MMF). However, 25 patients received BELA+EVL' and 33 received TAC+MMF (modified ITT population). In the ITT population, the 6-mo biopsy-proven acute rejection rates were 7.7% versus 9.4% in the BELA+EVL versus TAC+MMF group. The corresponding 24-mo biopsy-proven acute rejection rates were 19.2% versus 12.5% in the ITT population and 16.0% versus 15.2% in the mITT population; all events were Banff severity grade ≤IIA and similar between groups. One patient in each group experienced graft loss unrelated to acute rejection. The 24-mo mean unadjusted estimated glomerular filtration rates were 71.8 versus 68.7 mL/min/1.73 m2 in the BELA+EVL versus TAC+MMF groups. Posttransplant lymphoproliferative disorder was reported for 1 patient in each group. No deaths or unexpected adverse events were observed. Conclusions: A steroid-free maintenance regimen of BELA+EVL may be associated with biopsy-proven acute rejection rates comparable to TAC+MMF.

The complement inhibitors Crry and factor H are critical for preventing autologous complement activation on renal tubular epithelial cells.

Congenital and acquired deficiencies of complement regulatory proteins are associated with pathologic complement activation in several renal diseases. To elucidate the mechanisms by which renal tubular epithelial cells (TECs) control the complement system, we examined the expression of complement regulatory proteins by the cells. We found that Crry is the only membrane-bound complement regulator expressed by murine TECs, and its expression is concentrated on the basolateral surface. Consistent with the polarized localization of Crry, less complement activation was observed when the basolateral surface of TECs was exposed to serum than when the apical surface was exposed. Furthermore, greater complement activation occurred when the basolateral surface of TECs from Crry(-/-)fB(-/-) mice was exposed to normal serum compared with TECs from wild-type mice. Complement activation on the apical and basolateral surfaces was also greater when factor H, an alternative pathway regulatory protein found in serum, was blocked from interacting with the cells. Finally, we injected Crry(-/-)fB(-/-) and Crry(+/+)fB(-/-) mice with purified factor B (an essential protein of the alternative pathway). Spontaneous complement activation was seen on the tubules of Crry(-/-)fB(-/-) mice after injection with factor B, and the mice developed acute tubular injury. These studies indicate that factor H and Crry regulate complement activation on the basolateral surface of TECs and that factor H regulates complement activation on the apical surface. However, congenital deficiency of Crry or reduced expression of the protein on the basolateral surface of injured cells permits spontaneous complement activation and tubular injury.

Binding of factor H to tubular epithelial cells limits interstitial complement activation in ischemic injury.

Factor H is a regulator of the alternative pathway of complement, and genetic studies have shown that patients with mutations in factor H are at increased risk for several types of renal disease. Pathogenic activation of the alternative pathway in acquired diseases, such as ischemic acute kidney injury, suggests that native factor H has a limited capacity to control the alternative pathway in the kidney. Here we found that an absolute deficiency of factor H produced by gene deletion prevented complement activation on tubulointerstitial cells after ischemia/reperfusion (I/R) injury, likely because alternative pathway proteins were consumed in the fluid phase. In contrast, when fluid-phase regulation by factor H was maintained while the interaction of factor H with cell surfaces was blocked by a recombinant inhibitor protein, complement activation after renal I/R increased. Finally, a recombinant form of factor H, specifically targeted to sites of C3 deposition, reduced complement activation in the tubulointerstitium after ischemic injury. Thus, although factor H does not fully prevent activation of the alternative pathway of complement on ischemic tubules, its interaction with the tubule epithelial cell surface is critical for limiting complement activation and attenuating renal injury after ischemia.

The role of endothelial cell injury in thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) refers to a clinical and pathologic syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury. A host of causes may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor-cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Many persons with hereditary causes may remain disease free for years or may never develop disease. Others with acute inciting events, such as Escherichia coli O157 enteritis, never manifest TMA. Experimental studies document the importance of specific factors, such as endothelial nitric oxide levels, in helping protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather at general measures that may improve overall endothelial health. We propose studies to determine whether interventions that improve endothelial health, such as the administration of angiotensin-converting enzyme inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs, may be able to prevent TMA, even in persons with underlying hereditary conditions that otherwise would predispose them to these diseases.

Acute and Chronic Allograft Dysfunction in Kidney Transplant Recipients.

Allograft dysfunction after a kidney transplant is often clinically asymptomatic and is usually detected as an increase in serum creatinine level with corresponding decrease in glomerular filtration rate. The diagnostic evaluation may include blood tests, urinalysis, transplant ultrasonography, radionuclide imaging, and allograft biopsy. Whether it occurs early or later after transplant, allograft dysfunction requires prompt evaluation to determine its cause and subsequent management. Acute rejection, medication toxicity from calcineurin inhibitors, and BK virus nephropathy can occur early or later. Other later causes include transplant glomerulopathy, recurrent glomerulonephritis, and renal artery stenosis.

Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes.

BACKGROUND: Donor-specific antibodies (DSAs) after kidney transplantation have been associated with poor graft outcomes in multiple studies. However, these studies have generally used stored sera or a single cross sectional screening test to identify patients with DSA. We evaluated the effectiveness of a prospective DSA screening protocol in identifying kidney and kidney/pancreas recipients at risk for poor graft outcomes. METHODS: From September 2007 through September 2009, 244 consecutively transplanted kidney and kidney/pancreas recipients without pretransplant DSA were screened for de novo DSA at 1, 6, 12, and 24 months and when clinically indicated. RESULTS: DSA was detected in 27% of all patients by protocol or indication screening. Patients with DSA (DSA+) were significantly more likely to have experienced acute rejection (AR) compared with no DSA (DSA-) (29% vs. 9.5%, P<0.001), and lower estimated 2-year graft survival (83% vs. 98%, P<0.001). Only 3 of 19 DSA (+) patients with AR had DSA detected before the AR episode. When excluding patients with AR, 2-year graft survival was similar between DSA (+) and DSA (-) patients (100% vs. 99%) as was estimated glomerular filtration rate. Patients with DSA detected by protocol screening had similar outcomes compared with DSA (-), whereas those with DSA detected by indication experienced significantly worse outcomes. CONCLUSIONS: Patients with de novo DSA experience worse graft outcomes due to previous/concurrent episodes of AR. A prospective DSA screening protocol failed to identify patients at risk for AR or poor short-term graft outcomes.

Long-term impact of donor-recipient size mismatching in deceased donor kidney transplantation and in expanded criteria donor recipients.

BACKGROUND: The degree to which recipient/donor (R/D) size mismatching leads to nephron underdosing and worse kidney allograft survival remains poorly defined, particularly in the setting of preexisting nephron loss such as the expanded criteria donor (ECD). METHODS: We performed a retrospective analysis of 69,737 deceased donor transplants followed by a subset analysis of ECD transplants using data from the Scientific Registry of Transplant Recipients from 1992 to 2005. Ratios of R/D body surface area (BSA) were used to estimate nephron disparity and segregate pairs. RESULTS: In the entire cohort, severe BSA disparity (R/D BSA>1.38 m) was associated with slightly worse 10-year unadjusted graft survival (35% for severe BSA disparity vs. 39% in pairs of comparable size, P<0.0001). In multivariate analysis, BSA disparity was associated with a 15% increased risk of graft loss (hazard ratio 1.15, P<0.0001). Within ECD cohorts, severe BSA disparity was associated with a decrease in 10-year unadjusted graft survival of greater magnitude than the overall cohort (10% for severe BSA disparity vs. 22% in pairs of comparable size, P<0.0004). On multivariate analysis, severe R/D BSA disparity was associated with worse allograft survival similar to the entire cohort (hazard ratio 1.18, P=0.04). CONCLUSIONS: Recipients receiving kidneys from substantially smaller donors have a statistically higher rate of graft loss that is more pronounced in ECD kidneys. Although severe R/D size disparity is an independent risk factor for graft loss, the magnitude of this risk requires consideration in the context of other risk factors for the graft loss and the hazards of dialysis.

Adequacy of peritoneal dialysis: beyond small solute clearance.

Peritoneal dialysis adequacy is monitored primarily by indices of small solute clearance, Kt/V(urea) and creatinine clearance (C(cr)). Once a threshold of adequacy has been obtained, however, increasing small solute clearance does not result in improved long-term outcomes of PD patients. There are several other factors that may affect optimal dialysis outcomes. These include, but are not limited to: ultrafiltration, inflammation, malnutrition, and mineral metabolism. In this article, we will briefly review data regarding the relationships between these factors and survival on PD.

Long-term outcomes of acute kidney injury.

Acute kidney injury (AKI) is common in the intensive care unit and is associated with significant morbidity and mortality. Based on the RIFLE criteria, AKI occurs in up to 67% of patients in the intensive care unit (ICU), with approximately 4% of critically ill patients requiring renal replacement therapy (RRT). It is well known that this subset of AKI patients who require RRT have an in-hospital mortality rate exceeding 50%. However, long-term outcomes of survivors of AKI requiring RRT remain poorly described. Long-term mortality is greater in those patients who survived AKI when compared with critically ill patients without AKI. Long-term morbidity, renal and extrarenal, is a frequent and underappreciated complication of AKI. Among survivors of AKI at long-term follow-up (1-10 years), approximately 12.5% are dialysis dependent (wide range of 1%-64%, depending on the patient population) and 19% to 31% have chronic kidney disease. According to the United States Renal Data System, "acute tubular necrosis without recovery" as a cause of end-stage kidney disease increased from 1.2% in 1994 to 1998 to 1.7% in 1999 to 2003. The incidence will likely continue to rise with the aging population, increase in comorbidities, and expansion of intensive care unit capabilities. AKI is an underrecognized cause of chronic kidney disease (CKD) and patients who survive should be followed closely for new CKD and/or progression of underlying CKD.