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The Nephrology Blog has an interesting post on early nephrology referral of CKD patients and outcome on dialysis. I pulled all the references from that paper which have looked at the subject. I’ll be adding my thouhts on these references over next few pages so that this post becomes a quasi review article or annotated reference list.

Hasegawa et al. Greater First-Year Survival on Hemodialysis in Facilities in Which Patients Are Provided Earlier and More Frequent Pre-nephrology Visits. Clin J Am Soc Nephrol (2009) 4 595-602. (PDF)

• DOPPS I and II databases
• 8500 new starts to dialysis
• Pre-ESRD Nephrology contact defined as at least one visit prior to HD
• PNV associated with adjusted odds ratio of 0.57! (half the risk of death for one visit! what a bargain!) p<0.001
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• adjusted for age, sex, race, primary cause of ESRD, 14 summary comorbidities (CAD, CHF, other cardiac disease, htn, dm, cerebroVD, PAD, cancer, HIV/AIDS, lung disease, neurologic disorders, GI bleeding, recurrent cellulitis/gangrene)
• Facility level data is consistent with the individual patient data. DOPPS always tries to show this because it controls for some of the biases inherent in a retrospective study. From the ESRD NephSap:

• When we choose to examine facility practice using statistical models, patients are assigned not to the individual treatment received but to the facility’s practice (e.g., percentage of patients receiving vitamin D or having phosphorus within guideline range). Patient- or facility-level outcomes can be used. The rationale for this method is fundamental to the DOPPS and merits additional emphasis here. In standard observational analyses, the true effect of a treatment of interest may be distorted analytically by the effect of the indication to receive that treatment (treatment-by-indication bias). This bias is a fundamental challenge to inferring the causal effect of a treatment from observational data. The DOPPS facility practice-based analytic approach is conceptually similar to instrumental variable analysis, a method embraced for decades in econometrics and now used more commonly in clinical studies to address treatment-by-indication bias (9,10). The approach seeks to identify natural experiments in which patients are nearly “randomly” assigned to a particular facility practice by factors independent of clinical characteristics, such as proximity to the patient’s residence. Ideally, this mimics randomized treatment assignment in a clinical trial. Recent publications discussed theoretical considerations and provided examples in clinical medicine outside nephrology (9 –17).

• They found a dose effect of frequency of seeing a nephrologist. seeing a nephro doc 5 times had 28% lower mortality than if they saw one once or less.
• The people with nephrology care were more likely to be diabetic and hypertensive but were less likely to have CHF, lung disease or cancer
• Nephrology care was also linked to marriage, employment and college educated
• The creatinine at initiation of dialysis was lower with CKD care 7.2 versus 7.6. [Of note: with creatinines that high, a change of 0.4 only represents a difference of 1 mL/min (9 mL/min with predialysis care, 8 mL/min without)]

Innes et al. Early deaths on renal replacement therapy: the need for early nephrological referral. Nephrol Dial Transplant (1992) vol. 7 (6) pp. 467-71.

Forty-four patients who commenced renal replacement therapy between January 1983 and January 1988 died within 1 year of starting treatment. To examine the factors influencing early mortality of patients on renal replacement therapy these patients (group A) were compared with a group of 44 age- and sex-matched subjects who started dialysis over the same period and who survived more than 1 year (group B). The interval between first presentation and dialysis was significantly shorter in group A (median 36 days) than group B (median 30 months) patients. Plasma urea and creatinine were significantly greater in group A than group B at the time of first presentation to a nephrologist but not at first dialysis. Patients in group A were more often treated first by hemodialysis. Systemic disease as the cause of renal failure did not appear to influence early death. Early death on renal replacement therapy appears to be associated with late referral to a nephrologist. Early referral may be beneficial because it allows for planning of dialysis and treatment of the complications of progressive uremia.

• 44 patients who died in the first year of dialysis (group A)
• Compared to 44 patients (age and sex matched) who survived the first year of dialysis (group B)
• Association found with early death and late referral to a nephrologist. Average time between first visit to nephrologist and initiation of dialysis 36 days in group A and 30 months in group B.
• no difference in BUN or Cr at initiation of dialysis

Sesso et al. Late diagnosis of chronic renal failure. Braz J Med Biol Res (1996) vol. 29 (11) pp. 1473-8.

BACKGROUND: Recent observations in our country have shown that late diagnosis of chronic renal failure (CRF) is an important cause of late referral and late commencement of maintenance dialysis. We prospectively investigated the influence of late diagnosis of CRF on patient mortality during dialysis therapy. METHODS: Among 184 consecutive patients with nondiabetic end-stage renal disease starting chronic dialysis at the Federal University Hospital in the city of São Paulo, 106 had a late diagnosis of CRF (less than 1 month before starting dialysis) and 78 had an early diagnosis. During the first 6 months of dialysis treatment, patient survival was compared in the two groups, using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Six-month patient survival rate was lower in the late than in the early diagnosis group (69% versus 87%, P less than 0.01). In the late diagnosis group, the hazard ratio of mortality was 2.77 (95% CI, 1.36-5.66) times that of the early diagnosis group. In a multivariate analysis, after adjusting for age, comorbid illness, and serum biochemical measurements, time of diagnosis did not remain significantly associated with mortality risk. In this analysis, age, pulmonary infection, and low serum albumin were significant predictors of mortality. CONCLUSIONS: Patients with a late diagnosis have a higher mortality risk during the first 6 months of maintenance dialysis. This increased risk is related to comorbid conditions, some of which could be prevented by predialysis care. Interventions to promote early diagnosis of CRF and adequate predialysis follow-up need to be evaluated if the survival of patients with chronic renal failure is to improve.

• 184 new dialysis patients
• Lack of pre-ESRD CKD care defined as initiation of dialysis within 1 month of the first visit to the nephrologist
• 6-month rather than 1 year analysis
• raw mortality was 31% for late dx and 13% for early diagnosis
• HR for death in the first 6 months of dialysis with late diagnosis was 2.77
• Despite a very high hazard ratio with late diagnosis, this was not an independent association such that after controlling for age, comorbid illness and biochemical measurments the time of diagnosis was not significant.

Jungers et al. Longer duration of predialysis nephrological care is associated with improved long-term survival of dialysis patients. Nephrol Dial Transplant (2001) vol. 16 (12) pp. 2357-64. (PDF)

• 1057 consecutive patients
• pre-dialysis nephrology care less than 6 months in 258 patients (193 of them initiated within a month of the first nephro encounter.)
• 6-35 months in 267 patients
• 36-71 months in 227 patients
• over 71 months in 307 patients
• mean age 54
• only 13% diabetics (French study), little hypertension
• half of the late presentation group had been referred earlier but had neglected or refused nephrological care
• DM, PVD, HTN, CVD all were more prevelant with late referral
• Cr was higher in late referral [We need to worry about systemic lead time bias]
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• Dramatic changes in the rates of catheter use and the length of hospital stay associate dwith the initiation of dialysis. Importantly the authors excluded 60 patients who had either AKI or RPGN which precluded prolonged pre-dialysis care.
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• one-year mortality was 13.6% for less than 6 months pre-dialysis nephrocare and 7.4% (6-35 mo), 7.2% (36-71 mo) and 2.5% (over 71 mo) for longer care
• With multivariate analysis only the longest duration of care (over 71 mo) was significantly and independantly associated with survival with a RR of death of 0.56 p=0.002.
• The two shorter periods barely missed signifigance: 6-35 mo RR=0.73, p=0.058 and 36-71 mo RR=0.71, p=0.066.
• Age, DM and prior CVD were each significant with multivariate analysis

Kinchen et al. The timing of specialist evaluation in chronic kidney disease and mortality. Annals of Internal Medicine (2002) vol. 137 (6) pp. 479-86. (PDF)

• 828 new on-set ESRD from 81 centers
• time from first visit to initiation of dialysis
• Late: less than 4 months
• Intermediate: 4-12 months
• Early: over 12 months
• 213 patients were eliminated because of a lack of definitive medical records

• Significantly associated with late referral was Black ethnicity, not attending college, not having insurance, PD, not having DM, less urine output, lower renal function, less exercise, more anemia, lower albumin, less ESA, less vascular access.
• Late referral was associated with death
• 
• Notice how quickly the Late and Early curves digress. By 10 months it looks like the association is maximal and the curves are roughly parallel after that.
• The association with timing of referral and mortality was robust and remained significant when examined with 5 recipes for controlling different factors:

• An interesting finding was that late referral was worse for patients with diabetes and hypertension, growing segments of the ESRD population
• Sicker patients were referred later begging the question does the sickness prevent the consultation or does lack of nephrologic care cause other co-morbid diseases to become more severe (i.e. better use of diuretics in a heart failure patient, sometimes the nephrologist is the only one still willing to use ACEi with a GFR of 18)

Roderick et al. Late referral for end-stage renal disease: a region-wide survey in the south west of England. Nephrol Dial Transplant (2002) vol. 17 (7) pp. 1252-9. (PDF)

• 361 of 411 in England
• Late within 4 months
• Late’ within 1 month
• 35% within 4 months
• 23% within 1 month
• Again late referrals were older, sicker, had less accesses
• 33% Six-month mortality with less than 1 month versus 16% for longer than a month
• A late referral occured in 60% of patients with an established diagnosis of CKD for more than year (preventing the physcian or patinet from excusing themselves by stating “I didn’t know.”)
• Again the cr was higher at initiation (10.7 versus 9.4 mg/dl) for late referrals.
• Time of referral was not an independent predictor of survival at 6 months in regression analysis (p=0.293)
• The only interesting figure comes from the discussion where the authors graph the rates of Late referrals in the medical literature and make a case that it is getting better.

Kessler et al. Impact of nephrology referral on early and midterm outcomes in ESRD: EPidémiologie de l’Insuffisance REnale chronique terminale en Lorraine (EPIREL): results of a 2-year, prospective, community-based study. Am J Kidney Dis (2003) vol. 42 (3) pp. 474-85 (PDF)

Stack. Impact of timing of nephrology referral and pre-ESRD care on mortality risk among new ESRD patients in the United States. Am J Kidney Dis (2003) vol. 41 (2) pp. 310-8. (PDF)

Winkelmayer et al. A propensity analysis of late versus early nephrologist referral and mortality on dialysis. J Am Soc Nephrol (2003) vol. 14 (2) pp. 486-92. (PDF)

Kazmi et al. Late nephrology referral and mortality among patients with end-stage renal disease: a propensity score analysis. Nephrol Dial Transplant (2004) vol. 19 (7) pp. 1808-14. (PDF)

Khan et al. Does predialysis nephrology care influence patient survival after initiation of dialysis?. Kidney Int (2005) vol. 67 (3) pp. 1038-46.

BACKGROUND: Early nephrology referral of patients with chronic kidney disease (CKD) has been suggested to reduce mortality after initiation of dialysis. This retrospective cohort study of incident dialysis patients between 1995 and 1998 was performed to address the association between frequency of nephrology care during the 24 months before initiation of dialysis and first-year mortality after initiation of dialysis. METHODS: Patient data were obtained from the Centers for Medicare & Medicaid Services. Patients who started dialysis between 1995 and 1998, and were Medicare-eligible for at least 24 months before initiation of dialysis, were included. One or more nephrology visits during a month was considered a month of nephrology care (MNC). RESULTS: Of the total 109,321 patients, only 50% had received nephrology care during the 24 months before initiation of dialysis. Overall, first-year mortality after initiation of dialysis was 36%. Cardiac disease was the major cause of mortality (46%). After adjusting for comorbidity, higher mortality was associated with increasing age (HR, 1.04 per year increase; 95% CI, 1.03 to 1.04) and more frequent visits to generalists (HR, 1.009 per visit increase; 95% CI, 1.003 to 1.014) and specialists (HR, 1.012 per visit increase; 95% CI, 1.011 to 1.013). Compared to patients with >/=3 MNC in the six months before initiation of dialysis, higher mortality was observed among those with no MNC during the 24 months before initiation of dialysis (HR, 1.51; 95% CI, 1.45 to 1.58), no MNC during the six months before initiation of dialysis (HR, 1.28; 95% CI, 1.20 to 1.36), and one or two MNC during the six months before initiation of dialysis (HR, 1.23; 95% CI, 1.18 to 1.29). CONCLUSION: Nephrology care before dialysis is important, and consistency of care in the immediate six months before dialysis is a predictor of mortality. Consistent nephrology care may be more important than previously thought, particularly because the frequency and severity of CKD complications increase as patients approach dialysis.

Schwenger et al. Late referral–a major cause of poor outcome in the very elderly dialysis patient. Nephrol Dial Transplant (2006) vol. 21 (4) pp. 962-7. (PDF)

Schmidt et al. Early referral and its impact on emergent first dialyses, health care costs, and outcome. Am J Kidney Dis (1998) vol. 32 (2) pp. 278-83. [negative trial] (PDF)

Roubicek et al. Timing of nephrology referral: influence on mortality and morbidity. Am J Kidney Dis (2000) vol. 36 (1) pp. 35-41. [negative trial] (PDF)

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Zhao et al. Physician access and early nephrology care in elderly patients with end-stage renal disease. Kidney Int (2008) vol. 74 (12) pp. 1596-602 (PDF)