By Peter Laird, MD
A well respected member of nephrology contacted me a few days ago about a recent post I wrote and noted that he took issue with my attribution of Japanese survival in dialysis patients due to practice differences alone. He contends that genetic differences in survival explains much of the differences in dialysis outcomes between America and Japan. Indeed, studies have suggested such an analysis:
RESULTS: Adjusting for demographics, diabetes, comorbidities, and nutritional factors, the RR for Asian Americans was 0.75 (P = 0.0001). Race-specific background population death rates accounted for over half of the race-related mortality difference. For whites, mortality decreased as the body mass index (BMI) increased. For Asians, the relationship between BMI and survival was u-shaped. The ratio of Asian American/white dialysis death rates and the ratio of Asian American/white general population death rates both varied by age in a similar pattern. The population death rates of Asian American and Japanese were also similar.
CONCLUSION: Among dialysis patients, Asian Americans had a markedly lower adjusted RR than whites. The effect of BMI on survival differed by race. Compared with the respective general population, dialysis patients had the same relative increase in death rates for both races. The difference in death rates between the United States and Japan does not appear to be primarily treatment related, but rather is related to background death rates.
There is no doubt that the differences in outcomes are dramatic between America and Japan as well as that of Europe. The debate often centers on population differences and mitigates the effects of practice differences despite large areas of differences in practice styles. When evaluating the burden of disease and correcting outcomes with those parameters, the Japan survival is even more striking:
Survival among HD patients in Japan, Europe, and the United States: Data from DOPPS I (1997 through 2001). *Cox proportional hazards model adjusted for age, male gender, black race, coronary artery disease, congestive heart failure, other cardiac disease, left ventricular hypertrophy, cardiomegaly by x-ray, hypertension, cardiovascular disease, peripheral vascular disease, diabetes, lung disease, dyspnea, smoking, cancer, HIV/AIDS, gastrointestinal bleed, peptic ulcer disease, hepatitis B, hepatitis C, neurologic disorder, psychiatric disease, recurrent cellulitis or gangrene, and vision problems. **P
DOPPS has evaluated the international differences in outcomes in several well done papers. One of the most important practice differences is that of time on dialysis. An important article that all should be familiar with in this debate is the Saran article from 2006 that found that for every increased thirty minute increment of dialysis times, outcomes improved dramatically:
Abstract: Longer treatment time (TT) and slower ultrafiltration rate (UFR) are considered advantageous for hemodialysis (HD) patients. The study included 22,000 HD patients from seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Logistic regression was used to study predictors of TT > 240 min and UFR > 10 ml/h/kg bodyweight. Cox regression was used for survival analyses. Statistical adjustments were made for patient demographics, comorbidities, dose of dialysis (Kt/V), and body size. Europe and Japan had significantly longer (P < 0.0001) average TT than the US (232 and 244 min vs 211 in DOPPS I; 235 and 240 min vs 221 in DOPPS II). Kt/V increased concomitantly with TT in all three regions with the largest absolute difference observed in Japan. TT > 240 min was independently associated with significantly lower relative risk (RR) of mortality (RR = 0.81; P = 0.0005). Every 30 min longer on HD was associated with a 7% lower RR of mortality (RR = 0.93; P < 0.0001). The RR reduction with longer TT was greatest in Japan. A synergistic interaction occurred between Kt/V and TT (P = 0.007) toward mortality reduction. UFR > 10 ml/h/kg was associated with higher odds of intradialytic hypotension (odds ratio = 1.30; P = 0.045) and a higher risk of mortality (RR = 1.09; P = 0.02). Longer TT and higher Kt/V were independently as well as synergistically associated with lower mortality. Rapid UFR during HD was also associated with higher mortality risk. These results warrant a randomized clinical trial of longer dialysis sessions in thrice-weekly HD.
Ultrafiltration rates also differ in Japan. Several studies have outlined the effects of UFR higher than 10 ml/h/kg and their adverse effects on survival. However, America has chosen to ignore these profound results as noted in The Expert Panel which concluded the following recommendation contrary to evidence based medicine: Utilization of High Ultrafiltration Rate for Fluid Removal measures the proportion of patients who received an ultrafiltration (UF) rate greater than or equal to 15 ml/kg/hr in the reporting month. (here on page 143)
Cubic spline analysis of the associations between ultrafiltration rate (UFR) and cardiovascular (CV) (solid line) and all-cause (dashed line) mortality. Hazard ratios were adjusted for age, sex, interdialytic weight gain, race (black, non-black), smoking status (never, past, current), vintage (<1, 1–2, 2–4, 4 years), access type (graft, fistula, catheter), systolic blood pressure (<120, 120–140, 140–160, 160–180, 180 mm Hg), residual urine output ( versus >200 ml/day), diabetes, congestive heart failure, peripheral vascular disease, ischemic heart disease, cerebrovascular disease, serum albumin, creatinine, hematocrit (<30, 30–33, 33–36, 36%), and phosphorus, and use of α-adrenergic blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, β-blocker, calcium channel blocker, nitrates, and other antihypertensives. Estimates are presented for UFRs between 5.8 ml/h/kg (the 5th percentile of observed UFR in the study sample) and 20.4 ml/h/kg (the 95th percentile).
One issue in practice differences that has not recieve the attention it is due is that of the significantly lower endotoxin levels in Japanese dialysate preparations.
The Japanese Society for Dialysis Therapy (JSDT) surveyed all dialysis facilities for bacteriological quality of dialysis fluid and quality controls for dialysis fluid in 2006 and 2007. The JSDT collected the data for endotoxin (ET) levels, bacterial count and usage of ET retentive filters (ETRF). The JSDT standard for ET level in dialysis fluid (<0.050 EU/ml) was achieved in 89.0% in 2006 and in 93.6% in 2007. The JSDT standard for bacterial cell counts in dialysis fluid (<100 cfu/ml) was achieved in 96.9% in 2006 and in 97.4% in 2007. The central dialysis fluid delivery system (CDDS) is a unique system developed in Japan which has easy handling for daily maintenance of delivery systems, but it has been pointed out that CDDS has a weak point for the protection of biofilms. However, the bacteriological water qualities of dialysis fluid in CDDS were proven to be extremely high in most Japanese dialysis facilities by JSDT surveys. Bacteriological water quality has a strong impact on the patient outcome. The acceptable level of ET of dialysis fluid should be <0.1 EU/ml based on the results of JSDT survey. The excellent water quality in CDDS might be one of the important factors which help good patient survival in chronic dialysis in Japan.
There are many factors in the great Japanese survival debate here in America but what is missing is the sense that despite the fact that there are intrinsic differences in the American vs. Japanese population demographics, what is the same is the need to maximize outcomes in whatever population nephrologists treat. There is no doubt that the missing ingredient is the willingness to admit to a need to improve upon our current outcomes. What I often see instead is intense debate to justify the status quo and to leave everyone with a message of we are really doing well here in America when instead, American dialysis practices do result in death and misery every day in the standard American dialysis unit that has the shortest treatment times and the highest blood flow rates and ultrafiltration rates as well as the highest levels of endotoxins of any developed nation.
The real debate should be how can we improve upon the status quo and embrace cost effective practices that mitigate the devastating effects of not only renal disease, but of the adverse clinical dialyiss practices brought on by for-profit dialysis business motivations that maim and harm patients daily as study after study elucidates. There is much more at work in Japan that basic alleged genetic and demographic factors in my opinion. Ignoring the many clinical practice differences and improvements on outcomes by alleging improved survival based on genetics and demographics misses the entire issue completely. It is time for nephrology to engage in real world practice improvements as all of their colleagues in other specialties have accomplished for decades and stop the blame game of poor patient population protoplasm to work with. We can do better and we should do better.