|Year : 2014 | Volume
| Issue : 1 | Page : 14-20
Early referral to nephrologist is required for improving outcome of chronic kidney disease patients
Mohamed F.T. Almaghraby
Department of Nephrology, Faculty of Medicine, Benha University, Egypt
|Date of Submission||23-Oct-2013|
|Date of Acceptance||19-Dec-2013|
|Date of Web Publication||7-Apr-2014|
Mohamed F.T. Almaghraby
Department of Nephrology, Faculty of Medicine, Benha University, Benha
The aim of our study was to evaluate the impact of late referral (LR) on health parameters and mortality rate of chronic kidney disease (CKD) patients.
Patients and methods
This retrospective study includes patients referred to the Renal Replacement Therapy Unit. Patients were classified as early referrals (ERs) if their first encounter with a nephrologist occurred within 16 weeks before initiation of dialysis and all others patients were considered LRs. Collected data included constitutional data, data on underlying kidney diseases, clinical and laboratory data, and the modified Charlson comorbidity index (CCI). The outcomes of the study are presented as the follow-up mortality rates in both groups and their relationship with the timing of referral and collected data.
The study included 370 CKD patients: 140 ERs and 230 LRs. Patients of the LR group had significantly higher blood pressure (BP) and CCI scores compared with those of the ER group. Laboratory data showed significantly lower hemoglobin concentration and estimated glomerular filtration rate (eGFR) with significantly higher serum phosphate, total cholesterol, and low-density lipoprotein levels in the LR group compared with the ER group. Thirty-one patients (8.4%) died: six from the ER group and 25 from the LR group, with a significantly higher mortality rate in the LR group compared with the ER group. Survival was negatively correlated with time till referral, age, CCI, BP, and multiplicity of associated comorbidities, whereas it was positively correlated with female sex and high eGFR. Statistical analyses showed that high CCI and low eGFR were significant specific predictors, whereas old age, LR, and high systolic BP were significant sensitive predictors for mortality. In the Cox regression analysis, the survival rate in ER patients was significantly better than that in LR patients after adjusting for several risk factors.
ER of CKD patients to a nephrologist significantly minimizes morbidities and improves the chances of survival, which is significantly affected by age, multiplicity of associated comorbidities, and GFR. Improving the knowledge of patients and general physicians on the hazards of LR to nephrologists will definitely improve the outcome of patients with CKD.
Keywords: Chronic kidney disease, mortality rate, predictors, time of referral
|How to cite this article:|
Almaghraby MF. Early referral to nephrologist is required for improving outcome of chronic kidney disease patients. Tanta Med J 2014;42:14-20
|How to cite this URL:|
Almaghraby MF. Early referral to nephrologist is required for improving outcome of chronic kidney disease patients. Tanta Med J [serial online] 2014 [cited 2020 Aug 15];42:14-20. Available from: http://www.tdj.eg.net/text.asp?2014/42/1/14/130092
| Introduction|| |
The burden of chronic kidney diseases (CKD) is increasing and has been linked to an epidemic. The number of patients with end-stage renal disease (ESRD) in Europe and the USA has doubled in the last two decades because of the ageing population and the epidemic of type 2 diabetes. It is estimated that the number will not plateau for the next two decades . CKD carries with it not only the risk for progression to ESRD but also the risk for increased morbidity and mortality from cardiovascular disease. Indeed, it is more likely that a patient with CKD of stages 3-5 will die of cardiovascular disease rather than progress to dialysis. CKD does not affect all sectors of the population equally, with a higher prevalence among the elderly .
Observational studies and their meta-analysis have shown that late referral (LR) of patients with CKD to nephrologists is associated with poor clinical outcomes. Longer predialysis care by nephrologists may result in a reduction in the rate of hospitalization and mortality There is no universally accepted definition for 'late referral' of patients with CKD. Several inconsistent criteria including the number of months before the initiation of dialysis (1, 3, or 6 months) or the stage of CKD have been used to define LR of patients with CKD ,. The National Kidney Foundation - Kidney Disease Outcomes Quality Initiatives guidelines recommend that patients with CKD be referred to nephrologists when the glomerular filtration rates (GFRs) fall below 30 ml/min (stage 4 CKD), and earlier if possible .
This inconsistency in the definition of LR is attributable to changing practice patterns among physicians, changes in the definition of CKD, and increasing awareness among physicians and patients. The optimal timing of referral varies depending on the physicians' characteristics and preferences, practice setting, comfort level of the treating physician, and the availability of nephrologists. However, later referral to nephrology care could be defined as referral occurring within 4 months of ESRD and in terms of the proportion of patients starting hemodialysis with a mature arteriovenous fistula and starting dialysis in the outpatient setting ,,.
LR of patients with advanced renal disease is associated with significant morbidity and mortality and compromises preparations for dialysis. It also incurs greater costs than more timely referral ,,. The current single-center retrospective study aimed to evaluate the impact of LR on health parameters and concomitant mortality rate of CKD patients.
| Patients and methods|| |
The current study was conducted at the Nephrology Department of Ibn Sina College of Medicine, Jeddah, KSA, from January 2009 to December 2012. Data were collected from the files of patients referred to the Renal Replacement Therapy (RRT) Unit. Patients were classified as early referrals (ERs) if their first encounter with a nephrologist was within 16 weeks before initiation of dialysis, and all others patients were considered LRs .
Estimated GFR (eGFR) was calculated using the modified Modification of Diet in Renal Disease equation , as follows:
eGFR (ml/min/1.73m 2 ) = 186.3 × (serum creatinine in mg/dl)−1.154 × (ageinyear)−0.203 (×0.742 for female individuals)
Evaluated parameters included age, sex, BMI measures - that is, weight and height - and calculated BMI. Underlying kidney diseases including diabetes mellitus, hypertension, glomerulonephritis, polycystic kidney disease, and other known or unknown kidney diseases were evaluated for. The modified Charlson comorbidity index (CCI) was calculated . Data from clinical examination were verified with special reference to associated comorbidities and determination of blood pressure measures. Laboratory data including hemoglobin concentration; lipid profile; and uric acid, calcium, and phosphate levels were revised. The outcome of the study is presented as the follow-up mortality rate in both ER and LR groups and its relationship with the timing of referral and collected data.
Obtained data are presented as mean ± SD, ranges, numbers, percentages, and ratios. Results were analyzed using Wilcoxon's ranked test for unrelated data (Z-test) and c2 -test. Possible relationships were investigated using Pearson's linear regression. The receiver operating characteristic curve was used to evaluate various parameters as predictors for survival. Analysis was judged by the area under the curve (AUC) compared versus the null hypothesis that AUC = 0.05 and was assured using Regression analysis (Stepwise method). Cox regression analysis was used for evaluation of timing of referral as a predictor of mortality. Statistical analysis was carried out using SPSS (version 15, 2006; SPSS Inc., Chicago, Illinois, USA) for Windows statistical package. A P-value of less than 0.05 was considered statistically significant.
| Results|| |
The study included 370 CKD patients: 161 male (43.5%) and 209 female (56.5%), with a mean age of 61.7 ± 6.7 years (range: 45-77 years). ER was reported in 140 patients with a mean duration since the first nephrologist visit of 3.3 ± 0.8 months (range: 2-4 months), whereas LR was reported in 230 patients with a mean duration since the first nephrologist visit of 8.2 ± 1.5 months (range: 5-11 months). The mean BMI of the studied patients was 31.7 ± 2.4 kg/m 2 (range: 26.3-39.1 kg/m 2 ). Among the patients, 130 (35.1%) were of average weight, 215 (58.1%) were obese, and 25 (6.8%) were morbidly obese. Diabetic nephropathy was the most frequent underlying cause of CKD and was reported in 114 patients, hypertension was detected in 73 patients, and 26 patients were diabetic and hypertensive. Glomerulonephritis was the underlying disease in 50 patients and 117 patients had other diseases or an unknown underlying disease. There was a nonsignificant (P > 0.05) difference between the ER and LR groups as regards enrollment data [Table 1]. Patients of LR group had significantly higher blood pressure measures compared those of the ER group [Table 1], [Figure 1].
|Table 1: Enrollment data of studied patients categorized according to time of referral to a nephrologist|
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All patients had associated comorbidities with varying distributions; however, only 11 patients had comorbidities of 6 points on CCI, 23 patients had comorbidities of 3 points on CCI, 60 patients had comorbidities of 2 points on CCI, and the remaining patients had comorbidities of 1 point on CCI. There was a nonsignificant difference (χ2 = 0.975, P > 0.05) between the studied groups as regards the differential frequency of associated comorbidities. Forty-one patients had more than one associated morbidity: five (3.6%) in the ER group and 36 (15.7%) in the LR group, with a significantly higher (χ2 = 3.885, P < 0.05) frequency of patients with more than one comorbidity in the LR group [Table 2].
|Table 2: Patient distribution according to the frequency of associated comorbidities differentiated according to the Charlson comorbidity index scores|
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Despite the non-significantly (χ2 = 1.783, P > 0.05) higher number of patients had high CCI score in LR group, the calculated collective mean CCI score was significantly higher (Z = 2.811, P = 0.005) in the LR group (3.8 ± 1; range: 2-8) compared with the ER group (3.6 ± 0.8; range: 2-6, [Figure 2].
Laboratory data showed a significantly (Z = 4.029, P = 0.001) lower hemoglobin concentration [Figure 3] and significantly higher serum phosphate (Z = 2.796, P = 0.005; [Figure 4], total cholesterol (Z = 4.134, P = 0.001), and low-density lipoprotein (Z = 2.885, P = 0.004; [Figure 5] levels in the LR group compared with the ER group. Other parameters were nonsignificantly different between both groups but were in favor of the ER group [Table 3]. eGFR was significantly higher (Z = 9.325, P < 0.001) in the ER group (21.2 ± 7.5, range: 15-55 ml/min/1.73 m 2 ) compared with the LR group (14.5 ± 2.1, range: 11-21 ml/min/1.73 m 2 ).
During the entire study period, 31 patients died, yielding a total mortality rate of 8.4%: six from the ER group and 25 from the LR group, with mortality rates of 4.3 and 10.9%, respectively. The mortality rate was significantly higher (χ2 = 3.78, P < 0.05) in the LR group compared with the ER group. Infection was the most frequent cause of death and was reported in 13 patients (mortality rate of 41.9%), followed by cardiovascular accidents in eight patients (mortality rate of 25.8%), an underlying malignant disease in four patients (mortality rate of 12.9%), development of hepatic coma in three patients, uncontrollable gastrointestinal bleeding in one patient, and acute pulmonary embolism in one patient.
Survival was found to be negatively correlated with time until referral to a nephrologist, age, CCI, systolic blood pressure (SBP), and multiplicity of associated comorbidities, whereas it was found to be positively correlated with female sex and high eGFR [Table 4].
|Table 4: Correlation coefficient between survival, constitutional, and disease-related data|
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Verification of these parameters as predictors for mortality by ROC curve analysis showed that high CCI and low eGFR were significant specific predictors for mortality, whereas old age, LR, and high SBP were significant sensitive predictors for mortality [Table 5], [Figure 6].
|Table 5: ROC analysis of constitutional and disease-related data as predictors for mortality as judged by AUC|
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Regression analysis defined LR as the significant predictor for mortality in four models, old age in three models, low eGFR in two models, and high CCI in one model, [Table 6]. In the Cox regression analysis, the survival rate among ER patients was significantly better than that among LR patients after adjusting for several risk factors [Figure 7].
|Table 6: Regression analysis of constitutional and disease-related data as predictors for mortality|
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| Discussion|| |
The current study detected significantly lower eGFR and hemoglobin concentration; significantly higher serum levels of total cholesterol, low-density lipoprotein, and phosphate; and higher blood pressure measures in LR patients compared with ER patients. Concomitantly, throughout the follow-up period, the LR group showed a significantly higher mortality rate compared with the ER group. These data illustrate the burden of LR on CKD patients, who were mostly compromised as manifested by the finding that all patients had at least one associated comorbidity, despite the significantly higher total CCI score in the LR group compared with the ER group.
Moreover, survival was found to be negatively correlated with time until referral to nephrologist, age, CCI, SBP, and multiplicity of associated comorbidities, whereas it was positively correlated with female sex and high eGFR. Regression analysis defined LR as the persistently significant predictor for mortality, followed by old age, low eGFR, and high CCI. Cox regression analysis showed that survival rate in ER patients was significantly better than that in LR patients after adjusting for several risk factors.
The reported data is in accordance with previously reported literature on the impact of referral timing on outcome in CKD patients. Chen et al.  reported that nephrology referral was the most significant factor associated with slowing of renal disease progression, followed by younger age and female sex, and patients had better control of diastolic blood pressure and sugar and lipid levels; more frequent use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins; less frequent use of NSAIDs; and more serum creatinine measurements after nephrology referral. Chen et al.  found ER to be significantly associated with better clinical outcome and prolonged survival.
Smart and Titus  reviewed the Cochrane Central Register of Controlled Trials for studies on early versus late nephrology referral in adult patients with CKD and reported that 33% of patients were referred late, comparative mortality was higher among patients referred to a specialist late compared with those referred early, and ER was associated with better preparation and placement of dialysis access.
Boudville et al.  reported that kidney function and anemia were significantly associated with mortality on multivariate analysis, and after 18 months, 8.8% of patients with CKD were referred to a nephrologist; they concluded that despite the high prevalence of CKD among patients attending a geriatric outpatient clinic and its association with anemia and mortality, few of these patients were referred to a nephrologist.
Hommel et al.  reported LR of 38% of incident RRT patients; among these, 72% were treated in non-nephrology hospital departments and 91% in general practice before RRT was commenced, and fewer LRs received recommended pre-RRT treatment as judged by renin-angiotensin-system blockade, 32 versus 57%, or the vitamin-D analog alfacalcidol, 5 versus 30%. The 1-year mortality rate was higher among LRs, and 30% LRs versus 9% ERs had a significantly higher level of plasma creatinine (≤150% of upper reference limit) within 1-2 years before RRT commencement.
Kim et al.  found, after 2 years of follow-up of greater than 1000 Korean ESRD patients in general and patients with diabetes nephropathy, that the survival rate among ER patients was better than that among LR patients, patient survival was also significantly higher among ER patients than among LR patients, and with an increase in age, the risk for mortality was increased. Harel et al.  reported that the incidence of all-cause mortality was lower among severe acute kidney injury patients with early nephrology follow-up compared with those without ER, and they concluded that early nephrology follow-up after hospitalization in patients with acute kidney injury and temporary dialysis were associated with improved survival.
Multiple studies tried to explore the underlying causes for LR. Navaneethan et al.  found that age greater than 75 years, limited life expectancy, patient noncompliance, or refusal to consider dialysis influenced a primary care physician's decision to refer the patient to a nephrologist and may account for the high number of nonreferrals or LRs. Parameswaran et al.  reported that a large majority of patients with ESRD in India seek medical attention late, usually in advanced stages of CKD with uremic complications, and that LR is more frequent among younger patients and those with nondiabetic kidney disease and is associated with poor socioeconomic status, lack of education, and poor outcomes. Mendelssohn et al.  reported that suboptimal initiation of dialysis is common among ER patients and the benefits of ER are lost if dialysis is initiated suboptimally; hence, there is a need to identify factors that lead to suboptimal initiation of dialysis despite ER.
Hughes et al.  blamed not only patients but also nephrologists for initiation of dialysis in a suboptimal manner despite an extended period of predialysis care and ER and reported that factors contributing to suboptimal initiation despite ER included patient-related delays (31.25%), acute kidney disease or CKD (31.25%), surgical delays (16.41%), late decision making (8.59%), and others (12.50%), with the percentage of optimal initiations with ERs among 14 nephrologists ranging from 33 to 72%.
| Conclusion|| |
ER of CKD patients to nephrologists significantly minimizes morbidities and improves the chances of survival, which is significantly affected by age, multiplicity of associated comorbidities, and GFR. Improving the knowledge of patients and general physicians on the hazards of LR to nephrologists will definitely improve the outcome of patients with CKD.
| Acknowledgements|| |
The author thanks all members of the Department of General Medicine and Nephrology, Faculty of Medicine, Benha University, for their assistance until the current article was finalized http://www.bu.edu.eg and http://www.fac.bu.edu.eg
Conflicts of interest
There are no conflicts of interest.
| References|| |
|1.||Kiberd B. The chronic kidney disease epidemic: stepping back and looking forward. J Am Soc Nephrol 2006; 17:2967-2973. |
|2.||McClellan WM, Wasse H, McClellan AC, Kipp A, Waller LA, Rocco MV. Treatment center and geographic variability in pre-ESRD care associate with increased mortality. J Am Soc Nephrol. 2009; 20:1078-1085. |
|3.||Lhotta K, Zoebl M, Mayer G, Kronenberg F. Late referral defined by renal function: association with morbidity and mortality. J Nephrol 2003; 16:855-861. |
|4.||Chan MR, Dall AT, Fletcher KE, Lu N, Trivedi H. Outcomes in patients with chronic kidney disease referred late to nephrologists: a meta-analysis. Am J Med 2007; 120:1063-1070. |
|5.||National Kidney Foundation K/DOQI. Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 1. Executive summary. Am J Kidney Dis 2002; 39:S1-S266. |
|6.||Lee BJ, Forbes K. The role of specialists in managing the health of populations with chronic illness: the example of chronic kidney disease. BMJ 2009; 339:b2395. |
|7.||Luxton G. CARI: the CARI guidelines. Timing of referral of chronic kidney disease patients to nephrology services (adult). Nephrology (Carlton) 2010; 15:S2-S11. |
|8.||Laris-González A, Madero-Rovalo M, Pérez-Grovas H, Franco-Guevara M, Obrador-Vera GT. Prevalence, risk factors and consequences of late nephrology referral. Rev Invest Clin 2011; 63:31-38. |
|9.||Di Napoli A, Valle S, d′Adamo G, Pezzotti P, Chicca S, Pignocco M, et al.Predialysis Study Group of Lazio Survey of determinants and effects of timing of referral to a nephrologist: the patient′s point of view. J Nephrol 2010; 23:603-613. |
|10.||Padovani CS. Evaluation of profile epidemiologic and the found encountered by patients to the care o the first query in the ambulatory screening of Nephrology UNIFESP. J Bras Nefrol 2012; 34:317-322. |
|11.||Iseki K. Nephrology for the people: Presidential Address at the 42nd Regional Meeting of the Japanese Society of Nephrology in Okinawa 2012. Clin Exp Nephrol 2013; 17:480-487. |
|12.||Winkelmayer WC, Owen WF Jr, Levin R, Avorn J. A propensity analysis of late versus early nephrologist referral and mortality on dialysis. J Am Soc Nephrol 2003; 14:486-492. |
|13.||Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130:461-470. |
|14.||Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373-383. |
|15.||Chen SC, Chang JM, Chou MC, Lin MY, Chen JH, Sun JH, et al. Slowing renal function decline in chronic kidney disease patients after nephrology referral. Nephrology (Carlton) 2008; 13:730-736. |
|16.||Chen SC, Hwang SJ, Tsai JC, Liu WC, Hwang SC, Chou MC, et al. Early nephrology referral is associated with prolonged survival in hemodialysis patients even after exclusion of lead-time bias. Am J Med Sci 2010; 339:123-126. |
|17.||Smart NA, Titus TT. Outcomes of early versus late nephrology referral in chronic kidney disease: a systematic review. Am J Med 2011; 124:1073-1080. |
|18.||Boudville N, Muthucumarana K, Inderjeeth C. Limited referral to nephrologists from a tertiary geriatric outpatient clinic despite a high prevalence of chronic kidney disease and anaemia. BMC Geriatr 2012; 12:43. |
|19.||Hommel K, Madsen M, Kamper AL. The importance of early referral for the treatment of chronic kidney disease: a Danish nationwide cohort study. BMC Nephrol 2012; 13:108. |
|20.||Kim do H, Kim M, Kim H, Kim YL, Kang SW, Yang CW, et al. Early referral to a nephrologist improved patient survival: prospective cohort study for end-stage renal disease in Korea. PLoS One 2013; 8:e55323. |
|21.||Harel Z, Wald R, Bargman JM, Mamdani M, Etchells E, Garg AX, et al. Nephrologist follow-up improves all-cause mortality of severe acute kidney injury survivors. Kidney Int 2013; 83:901-908. |
|22.||Navaneethan SD, Kandula P, Jeevanantham V, Nally JV Jr, Liebman SE. Referral patterns of primary care physicians for chronic kidney disease in general population and geriatric patients. Clin Nephrol 2010; 73:260-267. |
|23.||Parameswaran S, Geda SB, Rathi M, Kohli HS, Gupta KL, Sakhuja V, Jha V. Referral pattern of patients with end-stage renal disease at a public sector hospital and its impact on outcome. Natl Med J India 2011; 24:208-213. |
|24.||Mendelssohn DC, Curtis B, Yeates K, Langlois S, MacRae JM, Semeniuk LM, et al. STARRT Study investigators: suboptimal initiation of dialysis with and without early referral to a nephrologist. Nephrol Dial Transplant 2011; 26:2959-2965. |
|25.||Hughes SA, Mendelssohn JG, Tobe SW, McFarlane PA, Mendelssohn DC. Factors associated with suboptimal initiation of dialysis despite early nephrologist referral. Nephrol Dial Transplant 2013; 28:392-397. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]