Thromboembolism is a life-threatening complication of nephrotic syndrome with variable reported incidence for deep venous thrombosis (approximately 15%), pulmonary embolus (10%–30%), and renal vein thrombosis (25%–37%). Complications after the initial event include recurrent thromboembolism, post-thrombotic syndrome, and chronic thromboembolic pulmonary hypertension. Thromboembolism is more common in adults (25%) compared with children (3%), with higher childhood incidence in congenital (10%) and secondary nephrotic syndrome (17.1%).1 Patients with pulmonary emboli or renal vein thrombosis may be asymptomatic or present with the acute onset of symptoms. Younger adult patients with renal vein thrombosis often develop sudden flank pain and gross hematuria, whereas older adults tend to be asymptomatic. In adults, thromboembolism usually occurs within 6 months after nephrotic syndrome is initially diagnosed.2 The incidence of arterial thromboembolism is less than venous thromboembolism, but it remains significant. Mahmoodi and colleagues found an eight-fold higher risk of arterial thrombi in 298 patients with primary and secondary nephrotic syndrome compared with the general population over a 10-year time frame. Traditional risk factors of atherosclerotic disease were predictors of arterial thrombi.2 Membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, membranous lupus nephritis with antiphospholipid antibody, and amyloidosis are glomerular diseases with particularly high rates of venous thromboemboli. Studies have shown hypoalbuminemia to be the strongest predictor of risk for venous thromboembolism. A serum albumin level of <2.8 g/dl was associated with a 2.5-fold higher risk of venous thromboembolism compared with lower values in a cohort of 898 patients with membranous nephropathy.3 Each 1.0 g/dl reduction in serum albumin resulted in doubling the risk of venous thromboembolism. A ratio of proteinuria to serum albumin has been found to be more predictive of venous thromboembolic events than serum albumin alone.2 The hypercoagulable state in nephrotic syndrome is postulated to stem from multiple factors, including genetic predisposition; increased number, activation, and aggregability of platelets; and localized clotting activation in the kidney. It is generally accepted that the increased hypercoagulability in nephrotic syndrome is largely due to glomerular loss of anticoagulant and profibrinolytic proteins coupled with increased liver synthesis of procoagulant proteins (fibrinogen, factor V, factor VIII). Marked urinary loss of antithrombin III has been postulated to be an important cause of the imbalance of anticoagulants and procoagulants1. However, studies have shown both decreased and normal levels of antithrombin III in patients with nephrotic syndrome. In this issue of CJASN, Abdelghani and colleagues4 examine the contribution of antithrombin III deficiency to the hypercoagulable state of nephrotic syndrome in 208 patient samples. Patient samples were collected from three incident nephrotic syndrome cohorts: the Nephrotic Syndrome Study Network (NEPTUNE [n=147]), the Pediatric Nephrology Research Consortium (PNRC [n=38]), and the Columbus cohort (n=23). The authors measured both antithrombin III antigen levels using two immunoassays and antithrombin activity by a functional assay. Clinically relevant antithrombin deficiency has been previously defined as <70% of antigen level or activity, and this was used as the threshold for deficiency.5 These authors previously demonstrated in rat models that antithrombin activity, but not antigen levels, correlated with proteinuria and thrombin generation,6 indicating thrombotic risk may correlate with decreased qualitative antithrombin activity rather than increased urinary loss. Hypercoagulopathy was measured by endogenous thrombin potential (ETP), a thrombin generation assay. ETP was previously used by these authors to estimate nephrotic syndrome hypercoagulopathy, and prior results demonstrated correlation with nephrotic syndrome severity.7 In addition, this study also included meta-analyses of 27 studies of nephrotic syndrome that measured antithrombin III antigen levels, activity, or both. These meta-analyses assessed whether antithrombin III deficiency (<70% antigen or activity) was associated with active nephrotic syndrome in adult and pediatric cohorts. The authors found that antithrombin antigen and activity levels were not consistently related to plasma albumin or proteinuria, which are established clinical markers of higher risk of thromboembolism, as mentioned above. Antithrombin antigen level, but not activity, was related to the hypercoagulopathy in adult nephrotic syndrome. Antithrombin activity was not consistently associated with hypercoagulability in childhood nephrotic syndrome. No difference in hypercoagulopathy, measured by ETP, was seen in the plasma of those with normal versus deficient antithrombin III levels. Even lower antithrombin III levels divided by quartile failed to show correlation with hypercoagulopathy. In addition, ex vivo supplementation of antithrombin to severely antithrombin III antigen-deficient (33.8±0.78%) plasma samples did not change nephrotic syndrome hypercoagulopathy. The meta-analyses of studies showed that antithrombin III deficiency using antigen or activity of <70% was not a uniform feature for nephrotic syndrome. It was more common in children than adults. The authors concluded that antithrombin does not play a significant role in the hypercoagulopathy of nephrotic syndrome. It is worth mentioning that samples from the pediatric cohort PNRC did show correlations between antithrombin activity and plasma albumin and ETP, but this was not demonstrated in the pediatric NEPTUNE subcohort. One possible reason was a difference in storage of plasma in the PNRC cohort that could have resulted in lower antithrombin III levels in this cohort. Of note, most of the patient samples (70.7%) in this study were from the NEPTUNE cohort, and 37% of these patients were on immunosuppression compared with none of the patients in the PNRC or Columbus cohorts. This might have been one reason for the large difference in median baseline proteinuria of 1.9 (0.3–3.6) g/g in NEPTUNE versus 9.84 (5.43–18.49) g/g in the PNRC cohort and 5.2 (1.2–13.9) g/g in the Columbus cohort. The median serum albumin levels were 3.2 (2.4–3.7) g/dl, 2.21 (1.85–2.84) g/dl, and 3.8 (3.5–4.4) g/dl in the NEPTUNE, PNRC, and Columbus cohorts, respectively. It is possible there would have been a stronger correlation between antithrombin deficiency with hypercoagulopathy if samples from NEPTUNE patients treated with immunosuppression were excluded. Importantly, the study uses ETP to estimate the risk of hypercoagulopathy rather than measuring antithrombin III levels in actual thromboembolic events. Antithrombin III deficiency, measured by either antigen levels or activity, does not appear to be the major cause of higher risk of thromboembolism in nephrotic syndrome. Studies are inconsistent when measuring levels of procoagulants and anticoagulants in nephrotic syndrome.1 Protein S deficiency has been postulated to play a role, but measurements of levels are not straight forward. Protein S is bound to C4b-binding protein, a large protein (570 kd) that is part of the complement system. Free protein S is a cofactor for protein C. Loss of free protein S in the urine coupled with preserved C4b-binding protein may lead to low free protein S levels, although studies do not consistently demonstrate this finding. Platelet number, activation, and aggregability through elevations of von Willebrand factor, hyperfibrinogenemia, hypercholesterolemia, and hypoalbuminemia in nephrotic syndrome may be increased and likely contribute to the hypercoagulable state.8 Genetic predisposition to venous thromboembolism may play a role in higher risk of patients with nephrotic syndrome. Nephrotic patients have been identified with mutations in Factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase, and other genes that increase thrombotic risk. Other factors leading to increased thromboembolic events include inflammation and the presence of central venous catheters. Finally, alterations in the fibrinolytic system in nephrotic syndrome may lead to a reduced capacity to dissolve thrombi. Plasminogen and tissue plasminogen activator may be reduced, whereas alpha 2 macroglobulin and lipoprotein A, which inhibit fibrinolytic activity, are increased.1 In addition, experiments using plasma from animal models of nephrotic syndrome and nephrotic patients demonstrated thrombi with a denser fibrin network that had increased resistance to fibrinolysis compared with typical thrombi. The density of the fibrin network was proportional to disease severity being increased by higher levels of proteinuria and lower levels of serum albumin.9 One unanswered question is why membranous nephropathy is associated with the highest risk for developing venous thromboembolism.1,9 In 1313 patients with nephrotic syndrome, the adjusted hazard ratio for venous thromboembolism was 10.8 for membranous nephropathy compared with IgA nephropathy.10 There is presently no identifiable role for anti–phospholipase A2 receptor antibody in the development of thromboemboli. The authors point to the potential role of endothelial damage from antithrombin deficiency.4 Cytokine profiles of some membranous nephropathy patients in China exposed to fine air particulate matter demonstrated high IL-17A levels after in vitro stimulation.11 Elevated IL-17 A levels have been associated with thromboemboli in animal models, and membranous patients with higher levels IL-17A in this study had more thromboembolic events (P=0.03) compared with those with lower levels.11 One could speculate anti-PLA2R, or antibodies to other membranous antigens such thrombospondin type-1 domain-containing 7A, neural epidermal growth factor-like 1 protein, or Exostosin 1/Exostosin 2 disrupt vascular quiescence, leading to a prothrombogenic state via intermediary pathways. Hopefully, future research will help further clarify the pathophysiology of the hypercoagulable state in nephrotic syndrome to increase the accuracy of predicting thromboembolic risk of prophylactic anticoagulation.
Patients with kidney failure report a high symptom burden, which likely increases while on dialysis due to physical and mental stressors and decreases after kidney transplantation due to restoration of kidney function.We leveraged a two-center prospective study of 1298 kidney transplant candidates and 521 recipients (May 2014 to March 2020). Symptom scores (0-100) at evaluation and admission for transplantation were calculated using the Kidney Disease Quality of Life Short-Form Survey, where lower scores represent greater burden, and burden was categorized as very high: 0.0-71.0; high: 71.1-81.0; medium: 81.1-91.0; and low: 91.1-100.0. We estimated adjusted waitlist mortality risk (competing risks regression), change in symptoms between evaluation and transplantation (n=190), and post-transplantation symptom score trajectories (mixed effects models).At evaluation, candidates reported being moderately to extremely bothered by fatigue (32%), xeroderma (27%), muscle soreness (26%), and pruritus (25%); 16% reported high and 21% reported very high symptom burden. Candidates with very high symptom burden were at greater waitlist mortality risk (adjusted subdistribution hazard ratio, 1.67; 95% confidence interval, 1.06 to 2.62). By transplantation, 34% experienced an increased symptom burden, whereas 42% remained unchanged. The estimated overall symptom score was 82.3 points at transplantation and 90.6 points at 3 months (10% improvement); the score increased 2.75 points per month (95% confidence interval, 2.38 to 3.13) from 0 to 3 months, and plateaued (-0.06 points per month; 95% confidence interval, -0.30 to 0.18) from 3 to 12 months post-transplantation. There were early (first 3 months) improvements in nine of 11 symptoms; pruritus (23% improvement) and fatigue (21% improvement) had the greatest improvements.Among candidates, very high symptom burden was associated with waitlist mortality, but for those surviving and undergoing kidney transplantation, symptoms improved.
Background and objectives Higher urate levels are associated with higher risk of CKD, but the association between urate and AKI is less established. This study evaluated the risk of hospitalized AKI associated with urate concentrations in a large population-based cohort. To explore whether urate itself causes kidney injury, the study also evaluated the relationship between a genetic urate score and AKI. Design, setting, participants, & measurements A total of 11,011 participants from the Atherosclerosis Risk in Communities study were followed from 1996–1998 (baseline) to 2010. The association between baseline plasma urate and risk of hospitalized AKI, adjusted for known AKI risk factors, was determined using Cox regression. Interactions of urate with gout and CKD were tested. Mendelian randomization was performed using a published genetic urate score among the participants with genetic data (n=7553). Results During 12 years of follow-up, 823 participants were hospitalized with AKI. Overall, mean participant age was 63.3 years, mean eGFR was 86.3 ml/min per 1.73 m2, and mean plasma urate was 5.6 mg/dl. In patients with plasma urate >5.0 mg/dl, there was a 16% higher risk of hospitalized AKI for each 1-mg/dl higher urate (adjusted hazard ratio, 1.16; 95% confidence interval, 1.10 to 1.23; P<0.001). When stratified by history of gout, the association between higher urate and AKI was significant only in participants without a history of gout (P for interaction=0.02). There was no interaction of CKD and urate with AKI, nor was there an association between genetic urate score and AKI. Conclusions Plasma urate >5.0 mg/dl was independently associated with risk of hospitalized AKI; however, Mendelian randomization did not provide evidence for a causal role of urate in AKI. Further research is needed to determine whether lowering plasma urate might reduce AKI risk.
Human immunodeficiency virus (HIV) infection and hepatitis C virus (HCV) infection affect populations worldwide. With the availability of over 35 Food and Drug Administration approved medications for treatment of HIV, the morbidity and mortality associated with HIV has greatly improved. On the other hand, treatment options for HCV have been limited until very recently. While the use of protease inhibitors (such as boceprevir and telaprevir) has become standard of care for treatment of hepatitis C in the general population, data for individuals with impaired kidney function, particularly those on dialysis, are extremely limited. Use of medications in dialysis patients can be challenging given the dose adjustments that must be made for renally cleared molecules, and potentially increased impact of adverse effects such as anemia. Recommendations for dosing of marketed therapies for HIV and HCV are reviewed.
