Chronic kidney disease occurs in more than half of adults with sickle cell disease (SCD) [1] and is an independent predictor for early death.[2] SCD patients that progress to end-stage renal disease (ESRD) have an especially poor prognosis, with 26% mortality within the 1st year of initiating renal replacement therapy.[3] In non-SCD ESRD patients, high rates of cardiovascular, infectious, and nutritional complications are observed,[4, 5] but the morbidity of ESRD in SCD patients is unclear. We conducted a retrospective analysis comparing these complications among SCD patients with versus without ESRD. We also analyzed the morbidity of ESRD in a cohort of SCD patients from the Truven Health MarketScan® Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases.
Thirty-two SCD patients, all Hb SS genotype, were treated for ESRD at the University of Illinois at Chicago (UIC) between January 1998 and December 2018. Clinical and laboratory data within 12 months of initiating renal replacement therapy and clinical complications during renal replacement therapy were obtained from the electronic medical charting system. Thirty-two age, sex, hemoglobin genotype, and hydroxyurea therapy-matched SCD patients without ESRD were randomly selected from a prospective registry at UIC. The protocol was approved by the Institutional Review Board prior to data collection. Linear and categorical variables were compared using the Kruskal-Wallis and Chi square test, respectively. Survival patterns were compared using the log-rank test and the Cox proportional hazards models adjusting for age and sex. Median and interquartile ranges (IQR) are provided.
Of the 32 SCD patients with ESRD, 21 were treated with hemodialysis, six with peritoneal dialysis, and five with kidney transplantation. The median age at the time renal replacement therapy was initiated was 44 years old and 59% were male. Twenty-two of 30 (73%) patients with medical records available pre-ESRD had established nephrology care prior to progressing to ESRD. At the time renal replacement therapy was initiated, 21 (70%) had hemodialysis performed through a central venous catheter, 6 (20%) had peritoneal dialysis performed through a peritoneal catheter, 2 (7%) had hemodialysis performed through an AV fistula, and 1 (3%) went directly to a living related-donor kidney transplantation.
SCD patients with ESRD had a greater proportion diagnosed with hypertension, a higher serum ferritin concentration and systolic blood pressure, and lower hemoglobin F%, platelet count, and reticulocyte percentage at the time renal replacement therapy was initiated compared to matched non-ESRD SCD patients at the time of entry into the registry (P≤0.008) (Supplementary Table 1). Greater prevalences of an elevated tricuspid regurgitant jet velocity (defined as >3.0 m/s) and left ventricular dysfunction (defined as ejection fraction <50%) were observed in the ESRD SCD patients (P≤0.03) (Figure 1A). Phosphorous levels, which rise due to a reduction in the filtered phosphate load and then lead to secondary hyperparathyroidism in kidney disease,[5] were higher in the ESRD SCD patients (ESRD: 6.0 mg/dL, IQR 5.1–7.3 mg/dL vs. non-ESRD: 4.3 mg/dL, IQR 3.7–4.9 mg/dL) (P<0.0001). Parathyroid hormone levels were also significantly higher in the ESRD SCD patients (P=0.0003) (Figure 1B).
Figure 1A: Cardiac abnormalities in patients with sickle cell disease by ESRD status.
Higher rates of an elevated tricuspid regurgitant jet velocity (TRJV) and reduce ejection fraction (EF) were observed in the ESRD versus non-ESRD SCD patients.
Figure 1B: Parathyroid hormone (PTH) levels in patients with sickle cell disease.
PTH levels were significantly higher in those SCD patients with ESRD (711 pg/mL, IQR 428 – 1073 pg/mL) versus non-ESRD (70 pg/mL, IQR 54 – 110 pg/mL).
During renal replacement therapy, greater rates of atrial flutter/fibrillation, congestive heart failure exacerbation, bacteremia, and sepsis were observed in the ESRD SCD patients compared to rates observed in the non-ESRD SCD patients during longitudinal follow up (Table 1A). Higher rates of deep vein thrombosis and hemorrhage requiring red blood cell (RBC) transfusion and lower rates of acute chest syndrome were also observed in the ESRD patients (Table 1A). A higher annual RBC transfusion requirement was observed in the ESRD patients after starting renal replacement therapy (8.7 units/year, IQR 2.5–17.8 units/year) versus non-ESRD (1.1 units/year, IQR 0–7.0 units/year) SCD patients (P=0.005). The RBC transfusion burden was highest in ESRD patients not treated with an erythroid stimulating agent (ESA) and lowest in those treated with an ESA and hydroxyurea (Figure 1C).
Table 1A:
Complications in adults with sickle cell disease and end stage renal disease vs. non-end-stage renal disease from the University of Illinois at Chicago cohort.
| Clinical Complications | ESRD |
non-ESRD |
||
|---|---|---|---|---|
| Event Rate (per 100 person years) | Proportion of Patients Affected | Event Rate (per 100 person years) | Proportion of Patients Affected | |
| Infectious | ||||
| Bacteremia | 1.72* | 24/32 (75%)* | 0.24 | 7/32 (22%) |
| SBP | 0.08 | 3/32 (9%) | 0 | 0/32 (0%) |
| Endocarditis | 0.08 | 3/32 (9%) | 0 | 0/32 (0%) |
| Sepsis | 0.61* | 17/32 (53%)* | 0.15 | 4/32 (13%) |
| Thrombotic | ||||
| Deep vein thrombosis | 0.40* | 13/32 (41%) | 0.09 | 6/32 (19%) |
| Pulmonary Embolus | 0.20 | 6/32 (19%) | 0.07 | 5/32 (16%) |
| Cardiac | ||||
| Atrial flutter/fibrillation | 0.43* | 7/32 (22%)* | 0 | 0/32 (0%) |
| CHF exacerbation | 0.96* | 13/32 (41%) | 0.10 | 6/32 (19%) |
| Neurologic | ||||
| Seizures | 0.38 | 6/32 (19%) | 0.01 | 1/32 (3%) |
| Stroke | 0.23 | 9/32 (28%) | 0.03 | 2/32 (6%) |
| Hematologic | ||||
| HIT | 0.05 | 2/32 (6%) | 0 | 0/32 (0%) |
| Major hemorrhage | 0.33* | 11/32 (34%)* | 0.06 | 3/32 (9%) |
| Sickle Cell Disease-Specific | ||||
| Vaso-occlusive crises | 10.24 | 26/32 (81%) | 5.29 | 24/32 (75%) |
| Acute chest syndrome | 0.68 | 13/32 (41%) | 1.42* | 22/32 (69%) |
SBP, spontaneous bacterial peritonitis; CHF, congestive heart failure; HIT, heparin induced thrombocytopenia
P value ≤ 0.01
Figure 1C: Annual red blood cell transfusion requirements.
Annual red blood cell transfusion rates were highest in sickle cell disease patients with ESRD not treated with an erythroid stimulating agent (ESA) (13 units/year, IQR 5 – 29 units/year) compared to those on ESA alone (9 units/year, IQR 3 – 18 units/year), ESA + hydroxyurea (6 units/year, IQR 0 – 17 units/year), or non-ESRD patients (1 unit/year, IQR 0 – 7 units/year). Median and interquartile ranges (IQR) are provided.
With a median follow up of 6.8 years (IQR, 2.2–7.7 years), 24 (75%) deaths were observed in the ESRD group versus 5 (16%) deaths in the non-ESRD group (log-rank P<0.0001; age and sex-adjusted HR 8.4, 95% CI: 3.2–23.5). Survival was improved in those ESRD patients that went on to kidney transplantation compared to the non-transplanted ESRD group (log-rank P=0.02; age and sex-adjusted HR 0.1, 95% CI: 0.03–0.6) (Figure 1D).
Figure 1D: Survival in sickle cell disease patients.
Survival was lowest in SCD patients treated with hemodialysis or peritoneal dialysis (21/27 deceased, mean survival 3.9 years) compared to those that received a kidney transplant (3/5 deceased, mean survival 8.8 years) or in the non-ESRD group (5/32 deceased, mean survival not reached) (log-rank P < 0.0001).
To further evaluate the morbidity of ESRD in SCD, we analyzed data from the Truven Health MarketScan® Research Databases between January 2009 through December 2014. Detailed cohort selection criteria are provided in Supplementary Table 2. Seventy-eight SCD patients with ESRD (hemodialysis: n=54, peritoneal dialysis: n=17, kidney transplantation: n=7) were identified. The median age of this cohort was 48 years and 42% were male. Consistent with the UIC cohort, a higher prevalence of hypertension, iron overload, and heart failure were observed in the ESRD SCD patients compared to age- and sex-matched non-ESRD SCD patients (P≤0.002) (Supplementary Table 3). During the follow up period, greater rates of congestive heart failure exacerbation, bacteremia, and sepsis were observed in the patients with ESRD relative to non-ESRD controls (Table 1B). Also consistent with the UIC cohort, higher rates of thromboembolic events (deep vein thrombosis, pulmonary embolus, and stroke) were observed in the ESRD versus non-ESRD SCD patients.
Table 1B:
Complications in adults with sickle cell disease and end stage renal disease vs. non-end-stage renal disease from the Truven cohort.
| Clinical Complications | ESRD | non-ESRD | Absolute Event risk difference (per 100 person years)* | 95%CI** | P-Value | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| N=78 | N=390 | ||||||||||
| Event Rate (per 100 person years)* | Proportion of Patients Affected | Event Rate (per 100 person years)* | Proportion of Patients Affected | Low limit | High limit | Event Rate diff | Proportion diff | ||||
| Infectious event | |||||||||||
| Bacteremia | 5.50 | 7 | 9.0% | 0.65 | 5 | 1.3% | 4.85 | 0.001 | 9.70 | 0.049 | <.0001 |
| SBP | 0 | 0.0% | 0 | 0.0% | NA | ||||||
| Endocarditis | 0.99 | 1 | 1.3% | 0.09 | 1 | 0.3% | 0.90 | −1.06 | 2.859 | 0.4 | 0.2 |
| Sepsis | 5.24 | 5 | 6.4% | 0.19 | 2 | 0.5% | 5.05 | 0.45 | 9.653 | 0.031 | <.0001 |
| Thrombotic events | |||||||||||
| Deep vein thrombosis | 12.13 | 11 | 14.1% | 3.36 | 34 | 8.7% | 8.785 | 1.52 | 16.034 | 0.018 | 0.14 |
| Pulmonary Embolus | 8.22 | 8 | 10.3% | 2.21 | 23 | 5.9% | 6.01 | 0.24 | 11.777 | 0.041 | 0.16 |
| Cardiac event | |||||||||||
| Atrial flutter/fibrillation | 4.21 | 4 | 5.1% | 2.01 | 21 | 5.4% | 2.20 | −2.02 | 6.411 | 0.3 | 0.9 |
| CHF exacerbation | 35.20 | 25 | 32.1% | 3.80 | 39 | 10.0% | 31.40 | 17.55 | 45.255 | <0.0001 | <.0001 |
| Neurologic event | |||||||||||
| Seizures | 2.04 | 2 | 2.6% | 1.13 | 12 | 3.1% | 0.92 | −1.99 | 3.822 | 0.5 | 0.8 |
| Stroke | 18.14 | 15 | 19.2% | 5.42 | 53 | 13.6% | 12.72 | 3.43 | 22.022 | 0.0073 | 0.19 |
| Hematologic event | |||||||||||
| HIT | 0 | 0.0% | 0 | 0.0% | 0.00 | 0.000 | 0.000 | NA | |||
| Major hemorrhage | 16.55 | 15 | 19.2% | 8.29 | 78 | 20.0% | 8.25 | −0.32 | 16.825 | 0.059 | 0.9 |
| Sickle Cell Disease-Specific event | |||||||||||
| Vaso-occlusive crises | 96.32 | 44 | 56.4% | 36.19 | 226 | 57.9% | 60.13 | 31.28 | 88.984 | <0.0001 | 0.8 |
| Acute chest syndrome/Pneumonia | 33.08 | 23 | 29.5% | 6.89 | 66 | 16.9% | 26.19 | 12.57 | 39.809 | 0.0002 | 0.0098 |
In two cohorts, we highlight the morbidity of ESRD in SCD patients. The high rates of cardiovascular complications, infection, and thromboembolism are consistent with what has been observed in other SCD ESRD cohorts [3, 6] and significantly greater than in matched non-ESRD SCD patients. Our findings suggest that initiatives that have been implemented in the general ESRD population, such as establishing nephrology care prior to renal replacement therapy, replacing catheter use with AV fistulas and grafts to reduce thrombosis and infection, nutritional care to prevent hyperphosphatemia and secondary hyperparathyroidism, preemptive kidney transplant evaluation, and cardiovascular risk assessment,[4] are all relevant in SCD patients with advanced kidney disease.
Supplementary Material
Acknowledgements:
This work was supported by the National Heart, Lung, Blood Institute through grants K23-HL125984 (S.L.S).
Footnotes
Disclosure of Financial Interests:
There are no relevant conflicts of interest to disclose.
References
- 1.Saraf SL, et al. , Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br J Haematol, 2014. 164(5): p. 729–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Platt OS, et al. , Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med, 1994. 330(23): p. 1639–44. [DOI] [PubMed] [Google Scholar]
- 3.McClellan AC, et al. , High one year mortality in adults with sickle cell disease and end-stage renal disease. Br J Haematol, 2012. 159(3): p. 360–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Collins AJ, et al. , The state of chronic kidney disease, ESRD, and morbidity and mortality in the first year of dialysis. Clin J Am Soc Nephrol, 2009. 4 Suppl 1: p. S5–11. [DOI] [PubMed] [Google Scholar]
- 5.Delmez JA and Slatopolsky E, Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis, 1992. 19(4): p. 303–17. [DOI] [PubMed] [Google Scholar]
- 6.Nielsen L, et al. , Morbidity and mortality of sickle cell disease patients starting intermittent haemodialysis: a comparative cohort study with non- Sickle dialysis patients. Br J Haematol, 2016. 174(1): p. 148–52. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.