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Patients with chronic kidney disease (CKD) present to their healthcare providers an array of problems with ever deepening complexity. It has become apparent ...
Peritoneal Dialysis International, Vol. 28, pp. 343–346 Printed in Canada. All rights reserved.

0896-8608/08 $3.00 + .00 Copyright © 2008 International Society for Peritoneal Dialysis

REFERRAL OF PATIENTS WITH CHRONIC KIDNEY DISEASE TO THE NEPHROLOGIST: WHY AND WHEN

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REPORTED BENEFITS OF REFERRAL OF CKD PATIENTS TO NEPHROLOGISTS

The benefits of nephrologic care have been studied in terms of patient survival and management according to existing guidelines of various adverse clinical entities resulting from CKD comorbidities. In univariate and multivariate methods, longer post dialysis initiation survival of CKD patients with “early” referral to nephrologists than those referred at end-stage renal disease (ESRD) was noted in several studies (1–7). That these studies were performed in patients from several countries provides a partial reply to the question of external validity. However, the main external validity question, whether or not the patients studied are representative of the CKD populations in the respective countries, remains open.

A number of studies compared the CKD care provided by generalists and specialists and concluded that early referral to nephrologists is needed to avoid complications of the CKD (8–13). Specific benefits of early referral to the nephrologist include achieving target blood hemoglobin, correction of metabolic acidosis, control of hyperphosphatemia and hyperparathyroidism, use of appropriate drugs to manage hypertension and thereby retard the progression of renal failure, prevention of late initiation of dialysis, and lowering of hospitalization rate after initiation of dialysis (8–11). Differences in awareness of clinical practice guidelines contribute to the differences in CKD care provided by generalists and nephrologists (12). Delayed referral to the nephrologist has adverse effects on the choice of home dialysis programs (14,15) and referral for renal transplantation (15,16). One item that needs to be stressed, however, is that awareness of guidelines for the management of CKD by nephrologists has substantial room for improvement (17). Barriers to timely referral to the nephrologist can be many. The barriers caused by advanced age (18) and poor socioeconomic status of CKD patients (19) have been stressed. WHAT CAN NEPHROLOGISTS OFFER TO PATIENTS WITH CKD?

There are three major areas where nephrologists can provide substantial help to patients with CKD prior to the stage of ESRD: identification of the etiology of kidney disease, slowing of the progression of renal failure, and recognition and management of the diverse complications of CKD involving multiple organ systems. These conditions lead to increased morbidity and mortality. Accurate diagnosis of the cause of renal failure is critical, particularly if that cause is reversible. That specialists trained in the diagnosis of renal disease can provide a real service in this area is self-evident; however, there is a paucity of studies of this topic. Nephrologists relate to each other their anecdotal experiences of missed diagnoses. The authors have come across a delayed — until the visit to the nephrologist — diagnosis of a reversible cause of the renal failure in two broad categories, relatively rare diseases that may mimic other diseases and relatively common conditions with 343

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atients with chronic kidney disease (CKD) present to their healthcare providers an array of problems with ever deepening complexity. It has become apparent that primary care providers, who are burdened with a host of new developments in the vast spectrum of diseases that they manage, need help in managing patients with CKD some time prior to its final end stage. This assistance is provided in the form of referral for consultation and follow-up to either a nephrologist or a multidisciplinary chronic disease (CKD) care unit, usually consisting of, in addition to the nephrologist, a specialized nurse educator/manager, a renal dietician, a renal pharmacist, a social worker, and a clinical psychologist. Continuous cooperation of the primary care provider, who often has had a relationship with the patient over many years, and the nephrologist or the multidisciplinary CKD care team is imperative for the best care of the patient. In recent years, several published studies have addressed various aspects of the referral of CKD patients to nephrologists. In this report, we will discuss the reported benefits and timing of this referral. One item that should be emphasized is that the evidence level of the published studies is not the highest. While several studies were prospective, all of the studies were observational. Limitations common to all the studies are external validity issues and referral bias.

TZAMALOUKAS and RAJ

DEFINING EARLY AND LATE REFERRAL TO THE NEPHROLOGIST

In this topic there is no agreement in the literature. Studies have made the distinction between early and late referral by time from the ESRD stage or by serum creatinine and CKD stage. In the case of time from ESRD, the referral was characterized as early if the patient was seen by a nephrologist 3 months or longer (8,16), 4 months or longer (4), and 6 months or longer (5,7,25,26) prior to ESRD. These definitions of early referral have a strong arbitrary component. In addition, they can be applied only to retrospective studies. Several studies have defined early referral in terms of serum creatinine, glomerular filtration rate, or CKD stage 344

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(1,27–29). One of these studies (29) showed a clear survival benefit of nephrology referral for patients with CKD stage III, but not those with CKD stages I or II. On the basis of this evidence, the optimal time to refer CKD patients to a nephrologist would be CKD stage III (earlier when there are questions about the nature of the renal disease). Defining early and late referral to the nephrologist by CKD stage is applicable to both retrospective and prospective studies. EFFECTS OF EARLY REFERRAL TO A NEPHROLOGIST ON PATIENTS TREATED WITH PERITONEAL DIALYSIS (PD)

Most published studies of the benefits of early nephrology care were conducted in patients on hemodialysis. Timely placement of arteriovenous fistulas or grafts with avoidance of central vein catheters is a major factor in avoiding morbidity and mortality in hemodialysis and is related to timely referral of patients to the specialist. This and several other issues affecting outcomes and potential action by nephrologists are different between patients on hemodialysis and those on PD. Few reports address timely nephrologic referral in patients on PD. Lin and co-authors reported significantly longer survival in continuous ambulatory PD patients that were referred to the nephrologist 6 months or more prior to ESRD than those that were referred less than 6 months prior to ESRD (5). More studies on this topic are clearly needed. In this regard, the paper by Chow and collaborators, published in this issue of Peritoneal Dialysis International (30), represents an important addition. Chow and his colleagues (30) studied in a retrospective study the survival of 102 incident ESRD patients for whom PD was the only treatment and who were followed for a median of 37 months. These patients were divided in an early nephrology referral group, with 61 patients, and a late nephrology referral group, with 41 patients. The two groups were comparable. The cutoff value for classifying the patients was a first visit to a multidisciplinary clinic staffed by nephrologists, specialized nurses, dieticians, and social workers, at 3 months prior to ESRD. The clinic paid special attention to control of blood pressure and calcium–phosphorus balance, and maintenance of nutrition and residual renal function. The main findings of the study were a lower mortality in the early referral group from all causes and from cardiovascular causes. The finding that early referral to a multidisciplinary CKD group leads to improvement in the cardiovascular mortality rate of PD patients is important. Chow’s article should be noted for this finding. Along with this contribution, the article has some limitations and has created

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specific symptomatology, when patients do not relate their symptoms or the physicians fail to ask specific questions. Two patients with CKD secondary to Wegener’s represent the first category, and a host of patients with lower urinary obstruction represent the second category. After identification of the cause of renal failure, specific treatment for the causative condition, if available, avoidance of all nephrotoxic influences, and specific management of conditions accompanying the renal failure that can worsen renal function can slow the development of ESRD and even prevent it in certain instances. The field is extensively studied. Reviews providing the scope of measures to prevent progression of CKD have been published (20,21). Studies have provided evidence of superiority of nephrology care over generalist care in slowing the progression of CKD (22,23). One of the most exiting and evolving fields in nephrology is the recognition that known and unknown factors related to the early stages of CKD have major impact on patient well-being and survival. The association between early CKD and cardiovascular mortality is an example of a CKD-related morbid condition. Several factors operating in CKD patients can lead to adverse outcomes. These factors include abnormalities in extracellular volume, water balance, potassium balance, calcium–phosphate– parathyroid hormone balance, acid–base balance, serum lipids, nutrition, blood pressure, anemia, economic pressures, and psychological balance, among others. Nephrologists and multidisciplinary teams for CKD care are best prepared and equipped to manage these conditions. Benefits for survival from the appropriate management of certain of these conditions, such as blood hemoglobin level (24), have been documented. Much more work is needed to identify which of the CKD-associated morbid conditions have the greatest influence on patient well-being and survival and will need to be managed aggressively.

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Antonios H. Tzamaloukas1,2* Dominic S.C. Raj2 Renal Section1 New Mexico Veterans Affairs Health Care System Division of Nephrology2 Department of Medicine University of New Mexico School of Medicine Albuquerque, New Mexico, USA

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*e-mail: [email protected] REFERENCES 1. Kessler M, Frimat L, Panescu V, Briancon S. Impact of nephrology referral on early and midterm outcomes in ESRD: EPidemiologie de l’Insuffissance REnale chronique terminale en Lorraine (EPIREL): results of a 2-year prospective, community-based study. Am J Kidney Dis 2003; 42:474–85. 2. Ravani P, Marinangeli G, Tancredi M, Malberti F. Multidisciplinary chronic kidney disease management improves survival on dialysis. J Nephrol 2003; 16:870–7. 3. Frimat L, Loos-Ayav C, Panescu V, Cordebar N, Biancon S, Kessler M. Early referral to a nephrologist is associated with better outcomes in type 2 diabetes patients with endstage renal disease. Diabetes Metab 2004; 30:67–74. 4. Kazmi WH, Obrador GT, Khan SS, Pereira BJ, Krausz AT. Late nephrology referral and mortality among patients

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with end-stage renal disease: a propensity score analysis. Nephrol Dial Transplant 2004; 19:1808–14. Lin CL, Chuang FR, Wu CF, Yang CT. Early referral as an independent predictor of clinical outcome in end-stage renal disease on hemodialysis and continuous ambulatory peritoneal dialysis. Ren Fail 2004; 26:531–7. Lorenzo V, Martín M, Rufino M, Hernandez D, Torres A, Ayus JC. Predialysis nephrologic care and a functioning arteriovenous fistula at entry are associated with better survival in incident hemodialysis patients: an observational cohort study. Am J Kidney Dis 2004; 43:999–1007. Khan SS, Xue JL, Kazmi WH, Gilbertson DT, Obrador GT, Pereira BJ, et al. Does predialysis nephrology care influence patient survival after initiation of dialysis? Kidney Int 2005; 67:1038–46. Dogan E, Erkoc R, Sayarlioglu H, Durmus A, Topal C. Effects of late referral to a nephrologist in patients with chronic renal failure. Nephrology (Carlton) 2005; 10: 516–19. Wavamunno MD, Harris DC. The need for early nephrology referral. Kidney Int Suppl 2005; 94:S128–32. Lenz O, Fornoni A. Chronic kidney disease care delivered by US family medicine and internal medicine trainees: results from an online survey. BMC Med 2006; 4:30. Jander A, Nowicki M, Tkaczyk M, Roszowska-Blaim M, Jarmalinski T, Marczak E, et al. Does a late referral to a nephrologist constitute a problem in children starting renal replacement in Poland? A nationwide study. Nephrol Dial Transplant 2006; 21:957–61. Boulware LE, Troll MM, Jaar BG, Myers DI, Powe NR. Identification and referral of patients with progressive CKD: a national study. Am J Kidney Dis 2006; 48:192–204. Thilly N, Boini S, Kessler M, Biancon S, Frimat L. Nephrology referral and appropriateness of therapeutic drug care in chronic kidney disease. J Nephrol 2006; 19:303–11. Piccoli GB, Mezza E, Burdese M, Consiglio V, Vaggione S, Mastella C. Dialysis choice in the context of early referral policy: there is room for self care. J Nephrol 2005; 18: 267–75. Mehrotra R, Marsh D, Vonesh E, Peters V, Nissenson A. Patient education and access of ESRD patients to renal replacement therapies beyond in-center hemodialysis. Kidney Int 2005; 68:378–90. Cass A, Cunningham J, Snelling P, Ayanian R. Late referral to a nephrologist reduces access to renal transplantation. Am J Kidney Dis 2003; 42:1043–9. Curtis BM, Barrett BJ, Djurdjev O, Singer J, Levin A. Evaluation and treatment of CKD patients before and at their first nephrologist encounter in Canada. Am J Kidney Dis 2007; 50:733–42. Arora P, Mustafa RA, Karam J, Khalil P, Wilding G, Rangan R, et al. Care of elderly patients with chronic kidney disease. Int Urol Nephrol 2006; 38:363–70. Obialo CI, Ofili CO, Quarshie A, Martin PC. Ultralate referral and presentation for renal replacement therapy: socioeconomic implications. Am J Kidney Dis 2005; 46:81–6. 345

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some questions for further research. The limitations of external validity and referral bias, common to all studies in this area, extend to this study. Another important limitation is the inability to infer causality to the early connection with the multidisciplinary clinic. This inability is enhanced by two characteristics of the study: the low number of deaths, particularly the cardiovascular deaths, which poses also questions about the statistical significance of the findings, and the relatively short interval of 3 months prior to referral to the CKD clinic. More important than the limitations of Chow’s study are the questions it has created. Assuming one or more of the very brief (within 3 months or a little longer) interventions by the specialists was able to substantially reduce cardiovascular mortality in PD patients, finding which interventions had the major impact is of critical importance. Further studies analyzing larger numbers of PD patients, and with specialist intervention starting at CKD stage III, are needed to dissect the effects of each of the nephrologic techniques for managing the comorbidities of CKD on the cardiovascular mortality of PD patients and, in the long run, to reduce this mortality to much lower rates.

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of patients with chronic kidney disease: no time to waste [Published erratum appears in Mayo Clin Proc 2007; 82: 253]. Mayo Clin Proc 2006; 81:1487–94. Navaneethan SD, Nigwekar S, Sandogan M, Anand E, Kadam S, Jeevanatham V, et al. Referral to nephrologists for chronic kidney disease care: is non-diabetic kidney disease ignored? Nephron Clin Pract 2007; 106:c113–18. Lhotta K, Zoebl M, Mayer G, Kronenberg F. Late referral defined by renal function: association with morbidity and mortality. J Nephrol 2003; 16:855–61. Kee F, Reaney EA, Maxwell AP, Fogarty DG, Savage G, Patterson CC. Late referral for assessment of renal failure. J Epidemiol Community Health 2005; 59:386–8. Orlando LA, Owen WF, Matchar DB. Relationship between nephrologist care and progression of chronic kidney disease. N C Med J 2007; 68:9–16. Chow KM, Szeto CC, Law MC, Kwan BCH, Leung CB, Li PKT. Impact of early nephrology referral on mortality and hospitalization in peritoneal dialysis patients. Perit Dial Int 2008; 28:371–6.

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20. Pereira BJG. Optimization of pre-ESRD care: the key to improved dialysis outcomes. Kidney Int 2000; 57:351–65. 21. Jaber BL, Madias NE. Progression of chronic kidney disease: can it be prevented or arrested? Am J Med 2005; 118: 1323–30. 22. Martinez-Ramirez HR, Jalomo-Martinez R, CortezSanabria L, Rojas-Campos E, Barragan G, Alfaro G, et al. Renal function preservation in type 2 diabetes mellitus patients with early nephropathy: a comparative prospective cohort study between primary health care doctors and a nephrologist. Am J Kidney Dis 2006; 47:78–87. 23. Jones C, Roderick P, Harris S, Rogerson M. Decline in kidney function before and after nephrology referral and the effect on survival in moderate to advanced chronic kidney disease. Nephrol Dial Transplant 2006; 21:2133–43. 24. Levin A, Djurdjev O, Duncan H, Rosembaum D, Werb R. Haemoglobin at time of referral prior to dialysis predicts survival: an association of haemoglobin with long-term outcomes. Nephrol Dial Transplant 2006; 21:370–7. 25. Sprangers B, Evenepoel P, Vanrenterghem Y. Late referral

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