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Diabetes kidney disease (DKD) defined as the presence of albuminuria and/or chronic renal disease in patients with diabetes,1 is the most important cause of end-stage renal failure (ESRF) in developed countries. About half the patients starting dialysis in New Zealand suffer from type 2 diabetes and DKD.2 Established risk factors such as obesity,3 smoking,4 hyperglycaemia5,6 and hypertension,7,8 are important targets in slowing the progression of DKD. Attaining remission of albuminuria is also an important treatment goal: remission of albuminuria (variously defined) is associated with a substantial reduction in morbidity and mortality.9–11 However, achieving this is challenging, with only about 25% of type 2 diabetic patients with proteinuric renal disease attaining and maintaining remission.10,11 Specific combinations of antihypertensive treatment (with blockade of the renin-angiotensin system being first-line therapy) have been shown to be more effective than others in reducing albuminuria, slowing the progression of diabetic nephropathy and reducing cardiovascular events and death.8,12,13 However, it is often difficult to reduce blood pressure (BP) down to target levels particularly in patients with diabetes, raising the question as to whether more intensive antihypertensive therapy might be more effective in inducing remission of albuminuria and preserving renal function. The incidence of end-stage renal failure (ESRF) is the greatest in Māori and Pasifika people.14 This is largely attributed to a higher prevalence of obesity, earlier onset of type 2 diabetes, poorer glycaemic control, higher levels of albuminuria, and smoking.15,16 Cultural and language differences and socioeconomic disadvantage are also significant barriers to accessing health care. The DEFEND study was a randomised-controlled trial which studied the effectiveness of 12-month community-based intervention in achieving BP target <130/80 mmHg in Māori and Pasifika patients with type 2 diabetes and DKD. It demonstrated that a community-based intervention of regular BP monitoring and titration of antihypertensive agents using ethnic-concordant health care assistants and supervised by nurses, was more effective than routine primary care in lowering systolic BP after 1 year, with the prospect of improved cardio-renal outcomes.17 These results were likely a result of improved patient adherence. Community-based interventions through primary care play a crucial role in modifying risk factors at a population level, and at managing chronic diseases. For example, Russell et al18 demonstrated that integrated medical care with a specialist and general practitioner (GP) in a primary care setting was successful in achieving improvements in BP, glycaemic and lipid profile in patients with complex type 2 diabetes. Such models of care highlight that a systematic and well-supported practice in primary care may be effective and efficient in complex chronic disease management. Furthermore, primary care is well-positioned to overcome barriers to health care through easier accessibility, providing a supportive, culturally-appropriate environment and continuity of care.19 We undertook our study at the Langimalie Tongan Health Centre. This primary care practice serves a large proportion of the Tongan community living in Auckland and is well-connected to the community through its Tongan-speaking staff. Our intervention utilised an integrated model of care involving a primary care physician and nurses and a diabetologist to provide intensive BP management in this high-risk group. We evaluated the effectiveness of this intervention, delivered through a community-based team, on the remission of albuminuria and on DKD progression. Methods and study design We conducted a 2-year prospective uncontrolled cohort study of 47 Pasifika patients who had type 2 diabetes and DKD as defined by the presence of substantial albuminuria. The intervention followed an algorithm which directed a stepwise escalation of antihypertensive therapies to achieve and maintain BP ≤125/80 mmHg. The first-line therapy included an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) if intolerant. The second-line therapy was the addition of a thiazide; third-line, a calcium-channel blocker and, if necessary, fourth to sixth-line agents were added: loop diuretic, beta-blocker, alpha-blocker or aldosterone-receptor antagonist. The choice of the latter agents was individualised according to cardiac and fluid status, residual renal function and serum potassium. Antihypertensive treatment was adjusted based on 2–6 weekly office BP readings and regular laboratory results and was predominantly directed by nurses following consultation with the study doctors. Doses of individual drugs were titrated up to maximal recommended doses, unless there was intolerance or side effects. We devised a cumulative scoring system based on the number of different agents and prescribed doses to measure the intensity of therapy (Table 1). The nurses at the Langimalie Tongan Health Centre leading the programme particularly focused on improving medication adherence. This included a close working relationship with the local pharmacy to provide patients with updated and free medication blister packs. Home visits were made to those unable to visit the clinic (usually because of work commitments) to measure BP, deliver prescriptions and monitor adherence by reviewing medication blister packs. Lifestyle, dietary and self-care education were provided for all study patients. Patients who had a more complex medical history or required closer medical attention were reviewed regularly at the health centre by the diabetologist or GP, in addition to nurses' home visits. Table 1. Antihypertensive scoring based on class and dosage of antihypertensive agents Score ACEi ARB Thiazide Loop diuretic Aldoseterone receptor antagonist Calcium channel blocker Beta-blocker Alpha-blocker Alpha & beta-blocker Cilazapril Quinapril Losartan HCT Frusemide Spironolactone Felodipine/ Amlodipine Isradipine Metoprolol Doxazsoin Carvedilol 0 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 1 ≤2.5mg ≤10mg ≤25mg 12.5mg ≤20mg ≤12.5mg ≤5mg ≤2.5mg ≤23.75mg 1mg ≤12.5mg 2 5mg 20mg 50mg 25mg 40mg 25mg 10mg 5mg 47.5mg 2mg 25mg 3 ≥10mg 40mg ≥100mg ≥60mg ≥50mg ≥20mg ≥10mg ≥95mg ≥4mg ≥50mg ACEi: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin 2 receptor blockade, HCT: Hydrochlorothiazide Data source and patients—Patients were included in this study if they were 18 to 65 years of age, had a history of type 2 diabetes, a urinary albumin/creatinine ratio (ACR) ≥40 mg/mmol from 2 of 3 consecutive sterile casual urine specimens (normal range 0 – 3.5 mg/mmol), an estimated glomerular filtration rate (eGFR) ≥40 ml/min/1.73m2, and who had a life expectancy of at least 2 years. Patients were recruited after they were flagged at the Centre's triage who fulfilled the study inclusion criteria. Patients were recruited between October and November 2011. The study was fully explained in Tongan language and informed consent received from all participants.We recorded patient demographics and clinical data including the duration of type 2 diabetes, hypertension and albuminuria, retinopathy and smoking status, and comorbidities. The severity of retinopathy was collected from the national retinal screening database which have been graded by a trained operator as none, minimal, mild/moderate or severe. Patients were reviewed at the clinics 2–6 weekly for optimisation of BP to a target of ≤125/80 mmHg with titration of antihypertensive medications. Seated systolic and diastolic BP measurements, urinary ACR, serum creatinine, weight, and details of prescribed antihypertensive therapies were documented 4-6 weekly and glycated haemoglobin (HbA1c), 3-monthly. We reported the mean of repeated BP measurements taken over 3 months at baseline, and 4 – 6 weekly nurse-facilitated measurements over the study period. The study was completed in November 2013.Outcome measures—The main outcome measures were change in BP, eGFR and remission of urinary ACR at the end of the 2-year intervention. Remission of ACR was defined as ≥70% reduction from the peak ACR in the 6 months before the study that was sustained till the end of follow up.11 Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease (MDRD) equation;20 and annualised eGFR loss was calculated.Secondary outcomes included change in HbA1c, non-fatal cardiovascular (acute myocardial infarction (AMI) or congestive heart failure (CHF)), cerebrovascular (ischemic stroke or transient ischemic attack), peripheral vascular (foot ulcers or amputation) events, ESRF (eGFR ≤10 ml/min/1.73m2 or dialysis) and death.We explored the relationship between baseline characteristics and eGFR decline. Intergroup comparison of baseline characteristics between patients who achieved remission of albuminuria, and those who did not, was performed to identify variables associated with remission of albuminuria.Statistical analysis—Statistical analysis was performed using STATA software (version 13.1). Results are expressed as mean±SD unless otherwise stated and were compared using Student's t-test or ANOVA. Median values were compared using Mann-Whitney test or Wilcoxon matched-pairs signed rank test. Proportions were compared using χ2-test (Chi-squared test). Regression analyses was performed for baseline variables and both eGFR decline, and remission of albuminuria. P<0.05 was considered significant. All tests were two-tailed.ResultsForty-seven patients were enrolled into the programme: 45 were Tongan, one Niuean and one Cook Islander. Of these 47 patients, four withdrew from (2 opted out before commencement, 1 transferred to different GP and 1 moved overseas). The baseline characteristics of the remaining 43 patients is recorded in Table 2.At the commencement, 30% of patients had no evidence of diabetic retinopathy, in spite of the presence of macroalbuminuria. The median (IQR) eGFR was 68 (50 – 81) ml/min/1.73m2, including 4 patients with eGFR ≤40ml/min/1.73m2. All 43 patients were already on ACEi or ARB treatment.Six patients (14%) had a previous history of vascular events: 2 had both an AMI and CHF as separate events, the other 4 had previous single events—1 AMI, 1 CHF and 2 amputations due to peripheral vascular disease (Table 2).Patients were followed for up to 2 years. Two patients were referred to Renal Services for worsening renal impairment at 4 months and 18 months, respectively. Thirty-nine patients had 17 – 24 months of intervention. The mean±SD duration of follow-up was 21±5 months. Table 2. Baseline characteristics of 43 patients Baseline characteristics Male, n (%) 33 (77) Age (years) 53±8 Residence in New Zealand (years) 23±11 Smoking status, n (%) None Previous Current 13 (30) 21 (49) 9 (21) Retinopathy status, n (%) None Minimal Mild/moderate Severe 12 (30) 7 (17.5) 12 (30) 9 (22.5) Duration of type 2 diabetes (years)* 8 (4–12.5) Patients on insulin, n (%) 20 (47) Duration of macroalbuminuria (years)* 3 (2–6) Duration of hypertension* 6 (2–9) Median eGFR (MDRD equation)* (ml/min/1.72m2) 68 (50 – 81) Previous events, n (%) Cardiovascular/CHF Cerebrovascular events Peripheral vascular disease 4 (9%) 0 (0%) 2 (5%) *median (IQR). Primary outcomes—At the final follow up, the antihypertensive score was higher than baseline (p<0.05) and mean systolic and diastolic BP were significantly lower. The mean number of classes of antihypertensive agents used at baseline and at 21 months were 2.7±1.1 and 3.5± 0.9 (p<0.05) respectively. The proportion of patients achieving the BP target of ≤125/85 mmHg had doubled by the two years. Mean HbA1c values were also significantly lower.Median (IQR) urinary ACR was significantly reduced at final follow up compared to that at baseline (51 (20–97) vs. 126 (65–194), p=0.003) and a higher proportion of patients achieved remission of urinary ACR to ≤30mg/mmol as the study progressed (19% at 6 months, 25% at 12 months and 33% at end). The number of patients with urinary ACR ≥100mg/mmol was halved (56% at 0 months vs 26% at 21 months, p=0.001) (Table 3).The median (IQR) eGFR at baseline was 68 ml/min/1.73m2. At 12 months and at study end it was significantly lower at 59 and 57 ml/min/1.73m2, respectively (p<0.05) (Figure 1). The median (IQR) eGFR loss was 4.6 (0.4–13.6) ml/min/1.73m2 over the first year and 6.7 (-2.4–12.6) ml/min/1.73m2 over the second year (p=NS). At baseline there were four patients with eGFR ≤40ml/min/1.73m2, and at the end there were eight (p<0.05).Secondary outcomes—Four cardiovascular events occurred (1 AMI and 3 episodes of CHF) during the 2 years of follow up. Two patients reached ESRF – one was referred to the renal service 4 months into the study and was established on dialysis 14 months later. The other patient was referred to the renal service at 18 months and reached eGFR <10ml/min/1.73m2 3 months later: both patients had low renal reserve at baseline with eGFR of 29 and 37 ml/min/1.73m2, respectively. There were no reported deaths. The change in eGFR was not related to baseline urinary ACR or eGFR, or duration of diabetes. Table 3. Blood pressure and renal outcomes during the 2-year follow up Variables Baseline N=43 6months N=43 12 months N=39 End N=39 HbA1c (mmol/mol) 81±24 77±33 75±37b 71±20c BMI (kg/m2) 37.6±5.9 38.3±16.5 37.8±11.3 38.4±13.4 SBP (mmHg) 137±17 133±31 129±25b 126±16c DBP (mmHg) 84±13 80±20a 76±17b 74±13c Patients with BP ≤ 125/80 mmHg; n (%) 11 (26%) 9 (22%) 15 (39%) 22c (56%) Antihypertensive score* 5 (3–7) 6 (4–9)a 7 (5–11)b 9 (6–11)c,d ACR (mg/mmol)* 126 (65–194) 85 (33–154)a 67 (29–114)b 51 (20–97)c Serum creatinine (µmol/L)* 104 (82–135) 107 (82–135) 116b (81–142) 118c,d (91–155) Estimated GFR† (ml/min/1.73m2) 68 (50–81) 65 (51–82) 59 b (46–78) 57 c,d (42–73) ACR, n (%)‡ <3 mg/mmol 3–30 mg/mmol 31–50 mg/mmol 51–100 mg/mmol >100mg/mmol 0 0 3 (7) 16 (37) 24 (56) 0 7 (19) 5 (14) 11 (30) 14 (38) 0 8 (25) 5 (16) 10 (31) 9 (28) 2 (5) 11 (28) 6 (15) 10 (26) 10 (26) ACR: Albumin creatinine ratio; BMI: body mass index; HbA1c: glycated haemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressureMean±SD except *median (IQR)† eGFR calculated using MDRD equation20‡ At 6 months and 12 months, there were 37 and 32 available urinary ACR measurementsa p<0.05 comparing baseline and 6 months; b p< 0.05 comparing baseline and 12 monthsc p< 0.05 comparing baseline and 24 months; d p< 0.05 comparing 12 months and 24 months Remission of albuminuria—Twelve (28%) of 43 patients achieved and sustained remission of urine ACR, to a median (IQR) 10.2 (6.1–18.4). Remission was not related to duration of type 2 diabetes, duration or level of albuminuria, HbA1c, eGFR or BP at baseline, or a higher antihypertensive score.In the first year, eGFR fell more rapidly in the group that achieved remission of albuminuria compared to the group which did not (13.6 (4.0–16.6) vs. 3.5 (-0.97–7.5) ml/min/1.73m2/year, p=0.02), but in the second year it was significantly slower than in the first (p=0.03). The rate of decline of eGFR in the second year was slower in those achieving remission compared to the non-remitting group (1.7(-2.0–9.7) vs. 8.2(-0.55–14.5) ml/min/1.73m2/year, p=0.21).Adverse events—Mild hyponatraemia (serum sodium 130–135 mmol/L), was the most common electrolyte abnormality and affected 12(28%) patients in this study. Severe hyponatraemia (<130 mmol/l) occurred in 2 patients during a period of hospitalisation for concurrent illnesses, which resolved on cessation of diuretics. Mild hypokalaemia was observed in one patient. Figure 1. Change of systolic and diastolic BP, urinary ACR and eGFR‡ACR: albumin creatinine ratio; eGFR: estimated glomerular filtration rate; DBP: diastolic blood pressure; SBP: systolic blood pressure; *p<0.05 comparing baseline and 12 months; †p<0.05 comparing 12 and 24 months; ‡ eGFR calculated using MDRD equation20 DiscussionIn this 2-year prospective cohort study of Pasifika patients with type 2 diabetes and macroalbuminuria, we found that a significant reduction of BP to clinical targets can be achieved through intensification of antihypertensive treatment and promotion of medication adherence in a primary care setting. Although the main management focus was BP reduction, the success of this intervention also extended to reduction in albuminuria and improved HbA1c.A multi-risk approach targeting BP, glycaemia, dyslipidaemia and weight reduction plays an important role in survival outcomes in patients with type 2 diabetes with metabolic syndrome – with adequate BP lowering BP having the major effect.21 Blood pressure optimisation delays the progression of cardiovascular and renal diseases,22 and reduces albuminuria which is an independent factor of premature death.8While it has been debated as to the lowest threshold for BP targets, the general consensus is that a goal <130/80 mmHg should be aimed in patients with DKD without concomitant cardiovascular disease.23 In a subgroup of patients with overt albuminuria and renal insufficiency however, renal benefits have been observed with lower BP.24,25 Our BP goal was lower compared to most interventional studies as our cohort comprised of a population with heavy albuminuria and minimal cardiac history. The mean systolic and diastolic BP at the end of this study was lower than that observed in similar studies,17,18 with more than half of the group attaining the pre-determined BP goal of <125/80 mmHg by 1 year and sustained to the study's end.These results highlight the importance of patient and provider-specific factors in effective health care delivery. The recognition of these variations allow for meaningful patient-centred management and improved outcomes.19 Langimalie Tongan Health Centre operates with culturally-appropriate staff who understand the unique cultural and economic barriers and can address these with patient education through community events, home visits and co-operation with local pharmacy to ensure medication adherence. An integrated community-based care involving a specialist, primary care physician and nurses, and the patient in complex diabetes care has previously demonstrated clinical and process benefits beyond that of tertiary diabetes outpatient care.18Six new events occurred—two cases of ESRF and four cardiovascular events. The two patients who reached ESRF had low eGFR at recruitment and neither had remission of albuminuria. During the follow-up period, 10% of study patients had non-fatal cardiovascular events. This proportion is lower than that reported in larger studies such as the RENAAL (33%) and IDNT (24%) trials which had similar duration of follow up.8,26 However, the observation period was too short and not sufficiently powered to determine outcome benefit.In spite of the widespread use of RAS inhibitors, only a third of our patients achieved remission of albuminuria, suggesting that current therapies for DKD may not be adequate. The absence of retinal disease in 30% of patients in this cohort emphasises that non-diabetic kidney disease is prevalent in patients with type 2 diabetes in whom obesity and metabolic syndrome are common.27 Furthermore familial clustering of nephropathy occurs in Pasifika people regardless of the presence of diabetes.28Overall, the intensification of antihypertensive management did not appear to compromise renal function. The rate of eGFR decline in this cohort was comparable to the trend seen in recent studies with ranges from 4 to 6.5 ml/min/1.73m2/year.29 In the group of patients who achieved remission of albuminuria the rate of eGFR decline in the first year was more rapid, but it plateaued and was significantly slower in the second year. This finding is consistent with the notion that aggressive antihypertensive treatment reduces renal function primarily through early haemodynamic effects. A slower progression to ESRF has been reported in diabetic patients who had greater initial GFR decline,30 hence such an intervention is more likely to benefit patients with higher renal reserve at baseline.Our findings have limitations. First, the study was small, and a number of our outcomes were surrogates. However, studies in Pacific Island patients are scarce, and collection of medical data is challenging due to infrequent presentations and the lack of continuity of care. The nurse-led programme succeeded in achieving regular follow up for ≥ 22 months in 70% of our patients. There are 849 type 2 diabetic patients (aged 18 to 65) registered at the Langimalie Tongan Health Centre. Our study population of 47 patients indicates a minimal prevalence of macroalbuminuric DKD of 5.5%, similar to the prevalence observed in other population-based studies.1Secondly, eGFR was calculated using the four-variable MDRD study formula which has limitations, particularly in overweight subjects. This was chosen over the Cockcroft-Gault equation as this has been shown to be superior in estimating eGFR in patients with diabetes and chronic kidney disease.31 Thirdly, BP measurements in this study were based on both clinic and home readings instead of the gold-standard 24-hour automated BP monitoring. The trend in BP however, corresponded closely with the change in antihypertensive score.Attaining BP targets in clinical practice has often been difficult, with a greater rate of failure in patients with diabetes,19 notwithstanding the challenges of other clinical and patient factors. This study has shown that a systematic approach of monitored intensification of antihypertensive therapy coupled with promotion of medication adherence, provides a model of care which can be effectively and safely applied in primary care. It also provides a framework for specialist support and up-skilling of primary care practitioners in the management of complex chronic diseases. A longer term follow up is necessary to accurately assess the sustainability, effectiveness and safety of such an intervention on slowing the progression of DKD with specific attention to important clinical outcomes.

Summary

Abstract

Background Chronic kidney disease is common in Pasifika people with type 2 diabetes. Lowering blood pressure (BP) and reducing proteinuria may slow the rate of progression of renal disease.-Method We conducted a 2-year study in patients with type 2 diabetes with estimated glomerular filtration rate (eGFR) \u226540ml/mmin/1.73m2 and urinary albumin-creatinine ratio (ACR) \u226540 mg/mmol to evaluate a community-based programme aimed at optimising BP. Primary outcomes included BP reduction, remission of albuminuria and change in eGFR.-Results Thirty-nine of 47 patients completed \u226517 months of intervention. The mean age was 53\u00b18 years; 77% were male. An increase in antihypertensive therapy intensity was accompanied by a median (IQR) reduction in BP of 13[-1.5-22.5)/ 12(1-19) mmHg p

Aim

Method

Results

Conclusion

Author Information

Jasmine Tan, Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Auckland; Fifita McCready, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; Fiona Noovao, Primary Care Physician, Langimalie Tongan Health Centre, Onehunga, Auckland; Oketi Tepueluelu, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; John Collins, Transplant Nephrologist, Department of Renal Medicine, Auckland City Hospital, Auckland; Tim Cundy, Endocrinologist, Auckland Diabetes Centre, Green Lane Clinical Centre, Auckland

Acknowledgements

This study was funded by Sector Capability and Implementation Directorate at the Ministry of Health, and we thank Nick Polaschek and Ailsa Jacobson for their support. Dr Noovao was supported by the Eli Lilly Diabetes Research Grant and Dr Tan was a New Zealand Diabetes Foundation Research Fellow. The authors also thank Zena Mubarak and Ross Mudafar (Vaiola Pharmacy, Onehunga) and Stephanie Emma (Mangere Community Health Trust) for their assistance.

Correspondence

Dr Jasmine Tan, Auckland Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Level 1, Building 4, 214 Greenlane Road, Auckland 1023, New Zealand.

Correspondence Email

jasmineta@adhb.govt.nz

Competing Interests

Nil.

1. Reutens AT. Epidemiology of Diabetic Kidney Disease. Med Clin North Am. 2013;97:1-18. 2. Grace B, Hurst K, McDonald S. New patients commencing on treatment in 2011. In: The Australia New Zealand dialysis and transplant (ANZDATA) Registry, in the Thirty-fifth Annual Report of the ANZDATA Registry. Adelaide, South Australia: 2012, 10. 3. Praga M, Morales E. obesity, proteinuria and progression of renal failure. Curr Opin Nephrol Hypertens. 2006;15(5):481-6. 4. Chakkarwar VA. Smoking in diabetic nephropathy: sparks in the fuel tank? World J Diabetes. 2012;3(12):186-95. 5. UK Prospective Diabetes Study (UKPDS) group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352(9131):837-53. 6. Agrawal L, Azad N, Emanuele NV, et al. Observation on renal outcomes in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011;34:2090-94. 7. UK Prospective Diabetes Study (UKPDS) group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-13. 8. Brenner B, Cooper M, de Zeeuw D. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. 9. de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309-20. 10. Rossing K, Christensen PK, Hovind P, Parving HH. Remission of nephrotic-range albuminuria reduces risk of end-stage renal disease and improves survival in type 2 diabetic patients. Diabetologia. 2005;48:2241-7. 11. Tan J, Jaung R, Gamble G, Cundy T. Proteinuric renal disease in type 2 diabetes - Is remission of proteinuria associated with improved morbidity and mortality? Diab Res Clin Pract. 2014;103:63-7. 12. Jamerson K, Weber MA, Bakris GL, Dahl\u00f6f B, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28. 13. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542-51. 14. Stewart JH, McCredie MRE, McDonald SP. The incidence of treated end-stage renal disease in New Zealand Mori and Pacific Island people and in Indigenous Australians. Nephrol Dial Transplant. 2004;19(3):678-85. 15. Kenealy T, Elley CR, Collins JF, Moyes SA, et al. Increased prevalence of albuminuria among non-European peoples with type 2 diabetes. Nephrol Dial Transplant. 2012;27:1840-6. 16. Scott A, Toomath R, Bouchier D, et al. First national audit of outcomes of care in young people with diabetes in New Zealand: high prevalence of nephropathy in Mori and Pacific Islanders. N Z Med J. 2006;119(1235):U2015. 17. Hotu C, Bagg W, Collins J, et al. A community-based model of care improves blood pressure control and delays progression of proteinuria, left ventricular hypertrophy and diastolic dysfunction in Mori and Pacific patients with type 2 diabetes and chronic kidney disease: a randomised controlled trial. Nephrol Dial Transplant. 2010;25:3260-6. 18. Russell AW, Baxter KA, Askew DA, et al. Model of care for the management of complex Type 2 diabetes managed in the community by primary care physicians with specialist support: an open controlled trial. Diabet Med. 2013;30:1112-21. 19. Chopra I, Kamal KM. Variations in blood pressure and lipid goal attainment in primary care. Curr Med Res Opin. 2013;29:1115-25. 20. Levey AS, Bosch JP, Lewis JB, et al. 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;16:461-70. 21. Gaede P, Tarnow L, Vedel P, Parving HH, et al. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbumuminuria. Nephrol Dial Transplant. 2004;19:2784-88. 22. Drury PL, Ting R, Zannino D, et al. Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia. 2011;54:32-43. 23. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(S2):S3-21. 24. Lazarus JM, Bourgoignie JJ, Buckalew VM, Greene T, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension. 1997;29:641-50. 25. Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical implications and limitations J Am Soc Nephrol. 2004;16:3027-37. 26. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and over nephropathy. Ann Intern Med. 2003;138:542-9. 27. Kambham N, Markowitz GS, Valeri AM, et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498-509. 28. Thompson CF, Simmons D, Collins JF, Cecil A. Predisposition to nephropathy in Polynesians is associated with family history of renal disease, not diabetes mellitus. Diabetic Medicine. 2001;18:40-6. 29. Leehey DJ, Kramer HJ, Daud TM, et al. Progression of kidney diseases in type 2 diabetes - beyond blood pressure control: an observational study. BMC Nephrol. 2005;6:8. 30. Holtkamp FA, de Zeeuw D, Thomas MC, et al. 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Diabetes kidney disease (DKD) defined as the presence of albuminuria and/or chronic renal disease in patients with diabetes,1 is the most important cause of end-stage renal failure (ESRF) in developed countries. About half the patients starting dialysis in New Zealand suffer from type 2 diabetes and DKD.2 Established risk factors such as obesity,3 smoking,4 hyperglycaemia5,6 and hypertension,7,8 are important targets in slowing the progression of DKD. Attaining remission of albuminuria is also an important treatment goal: remission of albuminuria (variously defined) is associated with a substantial reduction in morbidity and mortality.9–11 However, achieving this is challenging, with only about 25% of type 2 diabetic patients with proteinuric renal disease attaining and maintaining remission.10,11 Specific combinations of antihypertensive treatment (with blockade of the renin-angiotensin system being first-line therapy) have been shown to be more effective than others in reducing albuminuria, slowing the progression of diabetic nephropathy and reducing cardiovascular events and death.8,12,13 However, it is often difficult to reduce blood pressure (BP) down to target levels particularly in patients with diabetes, raising the question as to whether more intensive antihypertensive therapy might be more effective in inducing remission of albuminuria and preserving renal function. The incidence of end-stage renal failure (ESRF) is the greatest in Māori and Pasifika people.14 This is largely attributed to a higher prevalence of obesity, earlier onset of type 2 diabetes, poorer glycaemic control, higher levels of albuminuria, and smoking.15,16 Cultural and language differences and socioeconomic disadvantage are also significant barriers to accessing health care. The DEFEND study was a randomised-controlled trial which studied the effectiveness of 12-month community-based intervention in achieving BP target <130/80 mmHg in Māori and Pasifika patients with type 2 diabetes and DKD. It demonstrated that a community-based intervention of regular BP monitoring and titration of antihypertensive agents using ethnic-concordant health care assistants and supervised by nurses, was more effective than routine primary care in lowering systolic BP after 1 year, with the prospect of improved cardio-renal outcomes.17 These results were likely a result of improved patient adherence. Community-based interventions through primary care play a crucial role in modifying risk factors at a population level, and at managing chronic diseases. For example, Russell et al18 demonstrated that integrated medical care with a specialist and general practitioner (GP) in a primary care setting was successful in achieving improvements in BP, glycaemic and lipid profile in patients with complex type 2 diabetes. Such models of care highlight that a systematic and well-supported practice in primary care may be effective and efficient in complex chronic disease management. Furthermore, primary care is well-positioned to overcome barriers to health care through easier accessibility, providing a supportive, culturally-appropriate environment and continuity of care.19 We undertook our study at the Langimalie Tongan Health Centre. This primary care practice serves a large proportion of the Tongan community living in Auckland and is well-connected to the community through its Tongan-speaking staff. Our intervention utilised an integrated model of care involving a primary care physician and nurses and a diabetologist to provide intensive BP management in this high-risk group. We evaluated the effectiveness of this intervention, delivered through a community-based team, on the remission of albuminuria and on DKD progression. Methods and study design We conducted a 2-year prospective uncontrolled cohort study of 47 Pasifika patients who had type 2 diabetes and DKD as defined by the presence of substantial albuminuria. The intervention followed an algorithm which directed a stepwise escalation of antihypertensive therapies to achieve and maintain BP ≤125/80 mmHg. The first-line therapy included an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) if intolerant. The second-line therapy was the addition of a thiazide; third-line, a calcium-channel blocker and, if necessary, fourth to sixth-line agents were added: loop diuretic, beta-blocker, alpha-blocker or aldosterone-receptor antagonist. The choice of the latter agents was individualised according to cardiac and fluid status, residual renal function and serum potassium. Antihypertensive treatment was adjusted based on 2–6 weekly office BP readings and regular laboratory results and was predominantly directed by nurses following consultation with the study doctors. Doses of individual drugs were titrated up to maximal recommended doses, unless there was intolerance or side effects. We devised a cumulative scoring system based on the number of different agents and prescribed doses to measure the intensity of therapy (Table 1). The nurses at the Langimalie Tongan Health Centre leading the programme particularly focused on improving medication adherence. This included a close working relationship with the local pharmacy to provide patients with updated and free medication blister packs. Home visits were made to those unable to visit the clinic (usually because of work commitments) to measure BP, deliver prescriptions and monitor adherence by reviewing medication blister packs. Lifestyle, dietary and self-care education were provided for all study patients. Patients who had a more complex medical history or required closer medical attention were reviewed regularly at the health centre by the diabetologist or GP, in addition to nurses' home visits. Table 1. Antihypertensive scoring based on class and dosage of antihypertensive agents Score ACEi ARB Thiazide Loop diuretic Aldoseterone receptor antagonist Calcium channel blocker Beta-blocker Alpha-blocker Alpha & beta-blocker Cilazapril Quinapril Losartan HCT Frusemide Spironolactone Felodipine/ Amlodipine Isradipine Metoprolol Doxazsoin Carvedilol 0 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 1 ≤2.5mg ≤10mg ≤25mg 12.5mg ≤20mg ≤12.5mg ≤5mg ≤2.5mg ≤23.75mg 1mg ≤12.5mg 2 5mg 20mg 50mg 25mg 40mg 25mg 10mg 5mg 47.5mg 2mg 25mg 3 ≥10mg 40mg ≥100mg ≥60mg ≥50mg ≥20mg ≥10mg ≥95mg ≥4mg ≥50mg ACEi: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin 2 receptor blockade, HCT: Hydrochlorothiazide Data source and patients—Patients were included in this study if they were 18 to 65 years of age, had a history of type 2 diabetes, a urinary albumin/creatinine ratio (ACR) ≥40 mg/mmol from 2 of 3 consecutive sterile casual urine specimens (normal range 0 – 3.5 mg/mmol), an estimated glomerular filtration rate (eGFR) ≥40 ml/min/1.73m2, and who had a life expectancy of at least 2 years. Patients were recruited after they were flagged at the Centre's triage who fulfilled the study inclusion criteria. Patients were recruited between October and November 2011. The study was fully explained in Tongan language and informed consent received from all participants.We recorded patient demographics and clinical data including the duration of type 2 diabetes, hypertension and albuminuria, retinopathy and smoking status, and comorbidities. The severity of retinopathy was collected from the national retinal screening database which have been graded by a trained operator as none, minimal, mild/moderate or severe. Patients were reviewed at the clinics 2–6 weekly for optimisation of BP to a target of ≤125/80 mmHg with titration of antihypertensive medications. Seated systolic and diastolic BP measurements, urinary ACR, serum creatinine, weight, and details of prescribed antihypertensive therapies were documented 4-6 weekly and glycated haemoglobin (HbA1c), 3-monthly. We reported the mean of repeated BP measurements taken over 3 months at baseline, and 4 – 6 weekly nurse-facilitated measurements over the study period. The study was completed in November 2013.Outcome measures—The main outcome measures were change in BP, eGFR and remission of urinary ACR at the end of the 2-year intervention. Remission of ACR was defined as ≥70% reduction from the peak ACR in the 6 months before the study that was sustained till the end of follow up.11 Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease (MDRD) equation;20 and annualised eGFR loss was calculated.Secondary outcomes included change in HbA1c, non-fatal cardiovascular (acute myocardial infarction (AMI) or congestive heart failure (CHF)), cerebrovascular (ischemic stroke or transient ischemic attack), peripheral vascular (foot ulcers or amputation) events, ESRF (eGFR ≤10 ml/min/1.73m2 or dialysis) and death.We explored the relationship between baseline characteristics and eGFR decline. Intergroup comparison of baseline characteristics between patients who achieved remission of albuminuria, and those who did not, was performed to identify variables associated with remission of albuminuria.Statistical analysis—Statistical analysis was performed using STATA software (version 13.1). Results are expressed as mean±SD unless otherwise stated and were compared using Student's t-test or ANOVA. Median values were compared using Mann-Whitney test or Wilcoxon matched-pairs signed rank test. Proportions were compared using χ2-test (Chi-squared test). Regression analyses was performed for baseline variables and both eGFR decline, and remission of albuminuria. P<0.05 was considered significant. All tests were two-tailed.ResultsForty-seven patients were enrolled into the programme: 45 were Tongan, one Niuean and one Cook Islander. Of these 47 patients, four withdrew from (2 opted out before commencement, 1 transferred to different GP and 1 moved overseas). The baseline characteristics of the remaining 43 patients is recorded in Table 2.At the commencement, 30% of patients had no evidence of diabetic retinopathy, in spite of the presence of macroalbuminuria. The median (IQR) eGFR was 68 (50 – 81) ml/min/1.73m2, including 4 patients with eGFR ≤40ml/min/1.73m2. All 43 patients were already on ACEi or ARB treatment.Six patients (14%) had a previous history of vascular events: 2 had both an AMI and CHF as separate events, the other 4 had previous single events—1 AMI, 1 CHF and 2 amputations due to peripheral vascular disease (Table 2).Patients were followed for up to 2 years. Two patients were referred to Renal Services for worsening renal impairment at 4 months and 18 months, respectively. Thirty-nine patients had 17 – 24 months of intervention. The mean±SD duration of follow-up was 21±5 months. Table 2. Baseline characteristics of 43 patients Baseline characteristics Male, n (%) 33 (77) Age (years) 53±8 Residence in New Zealand (years) 23±11 Smoking status, n (%) None Previous Current 13 (30) 21 (49) 9 (21) Retinopathy status, n (%) None Minimal Mild/moderate Severe 12 (30) 7 (17.5) 12 (30) 9 (22.5) Duration of type 2 diabetes (years)* 8 (4–12.5) Patients on insulin, n (%) 20 (47) Duration of macroalbuminuria (years)* 3 (2–6) Duration of hypertension* 6 (2–9) Median eGFR (MDRD equation)* (ml/min/1.72m2) 68 (50 – 81) Previous events, n (%) Cardiovascular/CHF Cerebrovascular events Peripheral vascular disease 4 (9%) 0 (0%) 2 (5%) *median (IQR). Primary outcomes—At the final follow up, the antihypertensive score was higher than baseline (p<0.05) and mean systolic and diastolic BP were significantly lower. The mean number of classes of antihypertensive agents used at baseline and at 21 months were 2.7±1.1 and 3.5± 0.9 (p<0.05) respectively. The proportion of patients achieving the BP target of ≤125/85 mmHg had doubled by the two years. Mean HbA1c values were also significantly lower.Median (IQR) urinary ACR was significantly reduced at final follow up compared to that at baseline (51 (20–97) vs. 126 (65–194), p=0.003) and a higher proportion of patients achieved remission of urinary ACR to ≤30mg/mmol as the study progressed (19% at 6 months, 25% at 12 months and 33% at end). The number of patients with urinary ACR ≥100mg/mmol was halved (56% at 0 months vs 26% at 21 months, p=0.001) (Table 3).The median (IQR) eGFR at baseline was 68 ml/min/1.73m2. At 12 months and at study end it was significantly lower at 59 and 57 ml/min/1.73m2, respectively (p<0.05) (Figure 1). The median (IQR) eGFR loss was 4.6 (0.4–13.6) ml/min/1.73m2 over the first year and 6.7 (-2.4–12.6) ml/min/1.73m2 over the second year (p=NS). At baseline there were four patients with eGFR ≤40ml/min/1.73m2, and at the end there were eight (p<0.05).Secondary outcomes—Four cardiovascular events occurred (1 AMI and 3 episodes of CHF) during the 2 years of follow up. Two patients reached ESRF – one was referred to the renal service 4 months into the study and was established on dialysis 14 months later. The other patient was referred to the renal service at 18 months and reached eGFR <10ml/min/1.73m2 3 months later: both patients had low renal reserve at baseline with eGFR of 29 and 37 ml/min/1.73m2, respectively. There were no reported deaths. The change in eGFR was not related to baseline urinary ACR or eGFR, or duration of diabetes. Table 3. Blood pressure and renal outcomes during the 2-year follow up Variables Baseline N=43 6months N=43 12 months N=39 End N=39 HbA1c (mmol/mol) 81±24 77±33 75±37b 71±20c BMI (kg/m2) 37.6±5.9 38.3±16.5 37.8±11.3 38.4±13.4 SBP (mmHg) 137±17 133±31 129±25b 126±16c DBP (mmHg) 84±13 80±20a 76±17b 74±13c Patients with BP ≤ 125/80 mmHg; n (%) 11 (26%) 9 (22%) 15 (39%) 22c (56%) Antihypertensive score* 5 (3–7) 6 (4–9)a 7 (5–11)b 9 (6–11)c,d ACR (mg/mmol)* 126 (65–194) 85 (33–154)a 67 (29–114)b 51 (20–97)c Serum creatinine (µmol/L)* 104 (82–135) 107 (82–135) 116b (81–142) 118c,d (91–155) Estimated GFR† (ml/min/1.73m2) 68 (50–81) 65 (51–82) 59 b (46–78) 57 c,d (42–73) ACR, n (%)‡ <3 mg/mmol 3–30 mg/mmol 31–50 mg/mmol 51–100 mg/mmol >100mg/mmol 0 0 3 (7) 16 (37) 24 (56) 0 7 (19) 5 (14) 11 (30) 14 (38) 0 8 (25) 5 (16) 10 (31) 9 (28) 2 (5) 11 (28) 6 (15) 10 (26) 10 (26) ACR: Albumin creatinine ratio; BMI: body mass index; HbA1c: glycated haemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressureMean±SD except *median (IQR)† eGFR calculated using MDRD equation20‡ At 6 months and 12 months, there were 37 and 32 available urinary ACR measurementsa p<0.05 comparing baseline and 6 months; b p< 0.05 comparing baseline and 12 monthsc p< 0.05 comparing baseline and 24 months; d p< 0.05 comparing 12 months and 24 months Remission of albuminuria—Twelve (28%) of 43 patients achieved and sustained remission of urine ACR, to a median (IQR) 10.2 (6.1–18.4). Remission was not related to duration of type 2 diabetes, duration or level of albuminuria, HbA1c, eGFR or BP at baseline, or a higher antihypertensive score.In the first year, eGFR fell more rapidly in the group that achieved remission of albuminuria compared to the group which did not (13.6 (4.0–16.6) vs. 3.5 (-0.97–7.5) ml/min/1.73m2/year, p=0.02), but in the second year it was significantly slower than in the first (p=0.03). The rate of decline of eGFR in the second year was slower in those achieving remission compared to the non-remitting group (1.7(-2.0–9.7) vs. 8.2(-0.55–14.5) ml/min/1.73m2/year, p=0.21).Adverse events—Mild hyponatraemia (serum sodium 130–135 mmol/L), was the most common electrolyte abnormality and affected 12(28%) patients in this study. Severe hyponatraemia (<130 mmol/l) occurred in 2 patients during a period of hospitalisation for concurrent illnesses, which resolved on cessation of diuretics. Mild hypokalaemia was observed in one patient. Figure 1. Change of systolic and diastolic BP, urinary ACR and eGFR‡ACR: albumin creatinine ratio; eGFR: estimated glomerular filtration rate; DBP: diastolic blood pressure; SBP: systolic blood pressure; *p<0.05 comparing baseline and 12 months; †p<0.05 comparing 12 and 24 months; ‡ eGFR calculated using MDRD equation20 DiscussionIn this 2-year prospective cohort study of Pasifika patients with type 2 diabetes and macroalbuminuria, we found that a significant reduction of BP to clinical targets can be achieved through intensification of antihypertensive treatment and promotion of medication adherence in a primary care setting. Although the main management focus was BP reduction, the success of this intervention also extended to reduction in albuminuria and improved HbA1c.A multi-risk approach targeting BP, glycaemia, dyslipidaemia and weight reduction plays an important role in survival outcomes in patients with type 2 diabetes with metabolic syndrome – with adequate BP lowering BP having the major effect.21 Blood pressure optimisation delays the progression of cardiovascular and renal diseases,22 and reduces albuminuria which is an independent factor of premature death.8While it has been debated as to the lowest threshold for BP targets, the general consensus is that a goal <130/80 mmHg should be aimed in patients with DKD without concomitant cardiovascular disease.23 In a subgroup of patients with overt albuminuria and renal insufficiency however, renal benefits have been observed with lower BP.24,25 Our BP goal was lower compared to most interventional studies as our cohort comprised of a population with heavy albuminuria and minimal cardiac history. The mean systolic and diastolic BP at the end of this study was lower than that observed in similar studies,17,18 with more than half of the group attaining the pre-determined BP goal of <125/80 mmHg by 1 year and sustained to the study's end.These results highlight the importance of patient and provider-specific factors in effective health care delivery. The recognition of these variations allow for meaningful patient-centred management and improved outcomes.19 Langimalie Tongan Health Centre operates with culturally-appropriate staff who understand the unique cultural and economic barriers and can address these with patient education through community events, home visits and co-operation with local pharmacy to ensure medication adherence. An integrated community-based care involving a specialist, primary care physician and nurses, and the patient in complex diabetes care has previously demonstrated clinical and process benefits beyond that of tertiary diabetes outpatient care.18Six new events occurred—two cases of ESRF and four cardiovascular events. The two patients who reached ESRF had low eGFR at recruitment and neither had remission of albuminuria. During the follow-up period, 10% of study patients had non-fatal cardiovascular events. This proportion is lower than that reported in larger studies such as the RENAAL (33%) and IDNT (24%) trials which had similar duration of follow up.8,26 However, the observation period was too short and not sufficiently powered to determine outcome benefit.In spite of the widespread use of RAS inhibitors, only a third of our patients achieved remission of albuminuria, suggesting that current therapies for DKD may not be adequate. The absence of retinal disease in 30% of patients in this cohort emphasises that non-diabetic kidney disease is prevalent in patients with type 2 diabetes in whom obesity and metabolic syndrome are common.27 Furthermore familial clustering of nephropathy occurs in Pasifika people regardless of the presence of diabetes.28Overall, the intensification of antihypertensive management did not appear to compromise renal function. The rate of eGFR decline in this cohort was comparable to the trend seen in recent studies with ranges from 4 to 6.5 ml/min/1.73m2/year.29 In the group of patients who achieved remission of albuminuria the rate of eGFR decline in the first year was more rapid, but it plateaued and was significantly slower in the second year. This finding is consistent with the notion that aggressive antihypertensive treatment reduces renal function primarily through early haemodynamic effects. A slower progression to ESRF has been reported in diabetic patients who had greater initial GFR decline,30 hence such an intervention is more likely to benefit patients with higher renal reserve at baseline.Our findings have limitations. First, the study was small, and a number of our outcomes were surrogates. However, studies in Pacific Island patients are scarce, and collection of medical data is challenging due to infrequent presentations and the lack of continuity of care. The nurse-led programme succeeded in achieving regular follow up for ≥ 22 months in 70% of our patients. There are 849 type 2 diabetic patients (aged 18 to 65) registered at the Langimalie Tongan Health Centre. Our study population of 47 patients indicates a minimal prevalence of macroalbuminuric DKD of 5.5%, similar to the prevalence observed in other population-based studies.1Secondly, eGFR was calculated using the four-variable MDRD study formula which has limitations, particularly in overweight subjects. This was chosen over the Cockcroft-Gault equation as this has been shown to be superior in estimating eGFR in patients with diabetes and chronic kidney disease.31 Thirdly, BP measurements in this study were based on both clinic and home readings instead of the gold-standard 24-hour automated BP monitoring. The trend in BP however, corresponded closely with the change in antihypertensive score.Attaining BP targets in clinical practice has often been difficult, with a greater rate of failure in patients with diabetes,19 notwithstanding the challenges of other clinical and patient factors. This study has shown that a systematic approach of monitored intensification of antihypertensive therapy coupled with promotion of medication adherence, provides a model of care which can be effectively and safely applied in primary care. It also provides a framework for specialist support and up-skilling of primary care practitioners in the management of complex chronic diseases. A longer term follow up is necessary to accurately assess the sustainability, effectiveness and safety of such an intervention on slowing the progression of DKD with specific attention to important clinical outcomes.

Summary

Abstract

Background Chronic kidney disease is common in Pasifika people with type 2 diabetes. Lowering blood pressure (BP) and reducing proteinuria may slow the rate of progression of renal disease.-Method We conducted a 2-year study in patients with type 2 diabetes with estimated glomerular filtration rate (eGFR) \u226540ml/mmin/1.73m2 and urinary albumin-creatinine ratio (ACR) \u226540 mg/mmol to evaluate a community-based programme aimed at optimising BP. Primary outcomes included BP reduction, remission of albuminuria and change in eGFR.-Results Thirty-nine of 47 patients completed \u226517 months of intervention. The mean age was 53\u00b18 years; 77% were male. An increase in antihypertensive therapy intensity was accompanied by a median (IQR) reduction in BP of 13[-1.5-22.5)/ 12(1-19) mmHg p

Aim

Method

Results

Conclusion

Author Information

Jasmine Tan, Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Auckland; Fifita McCready, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; Fiona Noovao, Primary Care Physician, Langimalie Tongan Health Centre, Onehunga, Auckland; Oketi Tepueluelu, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; John Collins, Transplant Nephrologist, Department of Renal Medicine, Auckland City Hospital, Auckland; Tim Cundy, Endocrinologist, Auckland Diabetes Centre, Green Lane Clinical Centre, Auckland

Acknowledgements

This study was funded by Sector Capability and Implementation Directorate at the Ministry of Health, and we thank Nick Polaschek and Ailsa Jacobson for their support. Dr Noovao was supported by the Eli Lilly Diabetes Research Grant and Dr Tan was a New Zealand Diabetes Foundation Research Fellow. The authors also thank Zena Mubarak and Ross Mudafar (Vaiola Pharmacy, Onehunga) and Stephanie Emma (Mangere Community Health Trust) for their assistance.

Correspondence

Dr Jasmine Tan, Auckland Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Level 1, Building 4, 214 Greenlane Road, Auckland 1023, New Zealand.

Correspondence Email

jasmineta@adhb.govt.nz

Competing Interests

Nil.

1. Reutens AT. Epidemiology of Diabetic Kidney Disease. Med Clin North Am. 2013;97:1-18. 2. Grace B, Hurst K, McDonald S. New patients commencing on treatment in 2011. In: The Australia New Zealand dialysis and transplant (ANZDATA) Registry, in the Thirty-fifth Annual Report of the ANZDATA Registry. Adelaide, South Australia: 2012, 10. 3. Praga M, Morales E. obesity, proteinuria and progression of renal failure. Curr Opin Nephrol Hypertens. 2006;15(5):481-6. 4. Chakkarwar VA. Smoking in diabetic nephropathy: sparks in the fuel tank? World J Diabetes. 2012;3(12):186-95. 5. UK Prospective Diabetes Study (UKPDS) group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352(9131):837-53. 6. Agrawal L, Azad N, Emanuele NV, et al. Observation on renal outcomes in the Veterans Affairs Diabetes Trial. Diabetes Care. 2011;34:2090-94. 7. UK Prospective Diabetes Study (UKPDS) group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-13. 8. Brenner B, Cooper M, de Zeeuw D. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. 9. de Zeeuw D, Remuzzi G, Parving H-H, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65:2309-20. 10. Rossing K, Christensen PK, Hovind P, Parving HH. Remission of nephrotic-range albuminuria reduces risk of end-stage renal disease and improves survival in type 2 diabetic patients. Diabetologia. 2005;48:2241-7. 11. Tan J, Jaung R, Gamble G, Cundy T. Proteinuric renal disease in type 2 diabetes - Is remission of proteinuria associated with improved morbidity and mortality? Diab Res Clin Pract. 2014;103:63-7. 12. Jamerson K, Weber MA, Bakris GL, Dahl\u00f6f B, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28. 13. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542-51. 14. Stewart JH, McCredie MRE, McDonald SP. The incidence of treated end-stage renal disease in New Zealand Mori and Pacific Island people and in Indigenous Australians. Nephrol Dial Transplant. 2004;19(3):678-85. 15. Kenealy T, Elley CR, Collins JF, Moyes SA, et al. Increased prevalence of albuminuria among non-European peoples with type 2 diabetes. Nephrol Dial Transplant. 2012;27:1840-6. 16. Scott A, Toomath R, Bouchier D, et al. First national audit of outcomes of care in young people with diabetes in New Zealand: high prevalence of nephropathy in Mori and Pacific Islanders. N Z Med J. 2006;119(1235):U2015. 17. Hotu C, Bagg W, Collins J, et al. A community-based model of care improves blood pressure control and delays progression of proteinuria, left ventricular hypertrophy and diastolic dysfunction in Mori and Pacific patients with type 2 diabetes and chronic kidney disease: a randomised controlled trial. Nephrol Dial Transplant. 2010;25:3260-6. 18. Russell AW, Baxter KA, Askew DA, et al. Model of care for the management of complex Type 2 diabetes managed in the community by primary care physicians with specialist support: an open controlled trial. Diabet Med. 2013;30:1112-21. 19. Chopra I, Kamal KM. Variations in blood pressure and lipid goal attainment in primary care. Curr Med Res Opin. 2013;29:1115-25. 20. Levey AS, Bosch JP, Lewis JB, et al. 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;16:461-70. 21. Gaede P, Tarnow L, Vedel P, Parving HH, et al. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbumuminuria. Nephrol Dial Transplant. 2004;19:2784-88. 22. Drury PL, Ting R, Zannino D, et al. Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia. 2011;54:32-43. 23. Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. Am J Kidney Dis. 2014;63(2)(S2):S3-21. 24. Lazarus JM, Bourgoignie JJ, Buckalew VM, Greene T, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension. 1997;29:641-50. 25. Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the Irbesartan Diabetic Nephropathy Trial: Clinical implications and limitations J Am Soc Nephrol. 2004;16:3027-37. 26. Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and over nephropathy. Ann Intern Med. 2003;138:542-9. 27. Kambham N, Markowitz GS, Valeri AM, et al. Obesity-related glomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498-509. 28. Thompson CF, Simmons D, Collins JF, Cecil A. Predisposition to nephropathy in Polynesians is associated with family history of renal disease, not diabetes mellitus. Diabetic Medicine. 2001;18:40-6. 29. Leehey DJ, Kramer HJ, Daud TM, et al. Progression of kidney diseases in type 2 diabetes - beyond blood pressure control: an observational study. BMC Nephrol. 2005;6:8. 30. Holtkamp FA, de Zeeuw D, Thomas MC, et al. 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Diabetes kidney disease (DKD) defined as the presence of albuminuria and/or chronic renal disease in patients with diabetes,1 is the most important cause of end-stage renal failure (ESRF) in developed countries. About half the patients starting dialysis in New Zealand suffer from type 2 diabetes and DKD.2 Established risk factors such as obesity,3 smoking,4 hyperglycaemia5,6 and hypertension,7,8 are important targets in slowing the progression of DKD. Attaining remission of albuminuria is also an important treatment goal: remission of albuminuria (variously defined) is associated with a substantial reduction in morbidity and mortality.9–11 However, achieving this is challenging, with only about 25% of type 2 diabetic patients with proteinuric renal disease attaining and maintaining remission.10,11 Specific combinations of antihypertensive treatment (with blockade of the renin-angiotensin system being first-line therapy) have been shown to be more effective than others in reducing albuminuria, slowing the progression of diabetic nephropathy and reducing cardiovascular events and death.8,12,13 However, it is often difficult to reduce blood pressure (BP) down to target levels particularly in patients with diabetes, raising the question as to whether more intensive antihypertensive therapy might be more effective in inducing remission of albuminuria and preserving renal function. The incidence of end-stage renal failure (ESRF) is the greatest in Māori and Pasifika people.14 This is largely attributed to a higher prevalence of obesity, earlier onset of type 2 diabetes, poorer glycaemic control, higher levels of albuminuria, and smoking.15,16 Cultural and language differences and socioeconomic disadvantage are also significant barriers to accessing health care. The DEFEND study was a randomised-controlled trial which studied the effectiveness of 12-month community-based intervention in achieving BP target <130/80 mmHg in Māori and Pasifika patients with type 2 diabetes and DKD. It demonstrated that a community-based intervention of regular BP monitoring and titration of antihypertensive agents using ethnic-concordant health care assistants and supervised by nurses, was more effective than routine primary care in lowering systolic BP after 1 year, with the prospect of improved cardio-renal outcomes.17 These results were likely a result of improved patient adherence. Community-based interventions through primary care play a crucial role in modifying risk factors at a population level, and at managing chronic diseases. For example, Russell et al18 demonstrated that integrated medical care with a specialist and general practitioner (GP) in a primary care setting was successful in achieving improvements in BP, glycaemic and lipid profile in patients with complex type 2 diabetes. Such models of care highlight that a systematic and well-supported practice in primary care may be effective and efficient in complex chronic disease management. Furthermore, primary care is well-positioned to overcome barriers to health care through easier accessibility, providing a supportive, culturally-appropriate environment and continuity of care.19 We undertook our study at the Langimalie Tongan Health Centre. This primary care practice serves a large proportion of the Tongan community living in Auckland and is well-connected to the community through its Tongan-speaking staff. Our intervention utilised an integrated model of care involving a primary care physician and nurses and a diabetologist to provide intensive BP management in this high-risk group. We evaluated the effectiveness of this intervention, delivered through a community-based team, on the remission of albuminuria and on DKD progression. Methods and study design We conducted a 2-year prospective uncontrolled cohort study of 47 Pasifika patients who had type 2 diabetes and DKD as defined by the presence of substantial albuminuria. The intervention followed an algorithm which directed a stepwise escalation of antihypertensive therapies to achieve and maintain BP ≤125/80 mmHg. The first-line therapy included an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) if intolerant. The second-line therapy was the addition of a thiazide; third-line, a calcium-channel blocker and, if necessary, fourth to sixth-line agents were added: loop diuretic, beta-blocker, alpha-blocker or aldosterone-receptor antagonist. The choice of the latter agents was individualised according to cardiac and fluid status, residual renal function and serum potassium. Antihypertensive treatment was adjusted based on 2–6 weekly office BP readings and regular laboratory results and was predominantly directed by nurses following consultation with the study doctors. Doses of individual drugs were titrated up to maximal recommended doses, unless there was intolerance or side effects. We devised a cumulative scoring system based on the number of different agents and prescribed doses to measure the intensity of therapy (Table 1). The nurses at the Langimalie Tongan Health Centre leading the programme particularly focused on improving medication adherence. This included a close working relationship with the local pharmacy to provide patients with updated and free medication blister packs. Home visits were made to those unable to visit the clinic (usually because of work commitments) to measure BP, deliver prescriptions and monitor adherence by reviewing medication blister packs. Lifestyle, dietary and self-care education were provided for all study patients. Patients who had a more complex medical history or required closer medical attention were reviewed regularly at the health centre by the diabetologist or GP, in addition to nurses' home visits. Table 1. Antihypertensive scoring based on class and dosage of antihypertensive agents Score ACEi ARB Thiazide Loop diuretic Aldoseterone receptor antagonist Calcium channel blocker Beta-blocker Alpha-blocker Alpha & beta-blocker Cilazapril Quinapril Losartan HCT Frusemide Spironolactone Felodipine/ Amlodipine Isradipine Metoprolol Doxazsoin Carvedilol 0 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 0mg 1 ≤2.5mg ≤10mg ≤25mg 12.5mg ≤20mg ≤12.5mg ≤5mg ≤2.5mg ≤23.75mg 1mg ≤12.5mg 2 5mg 20mg 50mg 25mg 40mg 25mg 10mg 5mg 47.5mg 2mg 25mg 3 ≥10mg 40mg ≥100mg ≥60mg ≥50mg ≥20mg ≥10mg ≥95mg ≥4mg ≥50mg ACEi: Angiotensin-converting enzyme inhibitor, ARB: Angiotensin 2 receptor blockade, HCT: Hydrochlorothiazide Data source and patients—Patients were included in this study if they were 18 to 65 years of age, had a history of type 2 diabetes, a urinary albumin/creatinine ratio (ACR) ≥40 mg/mmol from 2 of 3 consecutive sterile casual urine specimens (normal range 0 – 3.5 mg/mmol), an estimated glomerular filtration rate (eGFR) ≥40 ml/min/1.73m2, and who had a life expectancy of at least 2 years. Patients were recruited after they were flagged at the Centre's triage who fulfilled the study inclusion criteria. Patients were recruited between October and November 2011. The study was fully explained in Tongan language and informed consent received from all participants.We recorded patient demographics and clinical data including the duration of type 2 diabetes, hypertension and albuminuria, retinopathy and smoking status, and comorbidities. The severity of retinopathy was collected from the national retinal screening database which have been graded by a trained operator as none, minimal, mild/moderate or severe. Patients were reviewed at the clinics 2–6 weekly for optimisation of BP to a target of ≤125/80 mmHg with titration of antihypertensive medications. Seated systolic and diastolic BP measurements, urinary ACR, serum creatinine, weight, and details of prescribed antihypertensive therapies were documented 4-6 weekly and glycated haemoglobin (HbA1c), 3-monthly. We reported the mean of repeated BP measurements taken over 3 months at baseline, and 4 – 6 weekly nurse-facilitated measurements over the study period. The study was completed in November 2013.Outcome measures—The main outcome measures were change in BP, eGFR and remission of urinary ACR at the end of the 2-year intervention. Remission of ACR was defined as ≥70% reduction from the peak ACR in the 6 months before the study that was sustained till the end of follow up.11 Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease (MDRD) equation;20 and annualised eGFR loss was calculated.Secondary outcomes included change in HbA1c, non-fatal cardiovascular (acute myocardial infarction (AMI) or congestive heart failure (CHF)), cerebrovascular (ischemic stroke or transient ischemic attack), peripheral vascular (foot ulcers or amputation) events, ESRF (eGFR ≤10 ml/min/1.73m2 or dialysis) and death.We explored the relationship between baseline characteristics and eGFR decline. Intergroup comparison of baseline characteristics between patients who achieved remission of albuminuria, and those who did not, was performed to identify variables associated with remission of albuminuria.Statistical analysis—Statistical analysis was performed using STATA software (version 13.1). Results are expressed as mean±SD unless otherwise stated and were compared using Student's t-test or ANOVA. Median values were compared using Mann-Whitney test or Wilcoxon matched-pairs signed rank test. Proportions were compared using χ2-test (Chi-squared test). Regression analyses was performed for baseline variables and both eGFR decline, and remission of albuminuria. P<0.05 was considered significant. All tests were two-tailed.ResultsForty-seven patients were enrolled into the programme: 45 were Tongan, one Niuean and one Cook Islander. Of these 47 patients, four withdrew from (2 opted out before commencement, 1 transferred to different GP and 1 moved overseas). The baseline characteristics of the remaining 43 patients is recorded in Table 2.At the commencement, 30% of patients had no evidence of diabetic retinopathy, in spite of the presence of macroalbuminuria. The median (IQR) eGFR was 68 (50 – 81) ml/min/1.73m2, including 4 patients with eGFR ≤40ml/min/1.73m2. All 43 patients were already on ACEi or ARB treatment.Six patients (14%) had a previous history of vascular events: 2 had both an AMI and CHF as separate events, the other 4 had previous single events—1 AMI, 1 CHF and 2 amputations due to peripheral vascular disease (Table 2).Patients were followed for up to 2 years. Two patients were referred to Renal Services for worsening renal impairment at 4 months and 18 months, respectively. Thirty-nine patients had 17 – 24 months of intervention. The mean±SD duration of follow-up was 21±5 months. Table 2. Baseline characteristics of 43 patients Baseline characteristics Male, n (%) 33 (77) Age (years) 53±8 Residence in New Zealand (years) 23±11 Smoking status, n (%) None Previous Current 13 (30) 21 (49) 9 (21) Retinopathy status, n (%) None Minimal Mild/moderate Severe 12 (30) 7 (17.5) 12 (30) 9 (22.5) Duration of type 2 diabetes (years)* 8 (4–12.5) Patients on insulin, n (%) 20 (47) Duration of macroalbuminuria (years)* 3 (2–6) Duration of hypertension* 6 (2–9) Median eGFR (MDRD equation)* (ml/min/1.72m2) 68 (50 – 81) Previous events, n (%) Cardiovascular/CHF Cerebrovascular events Peripheral vascular disease 4 (9%) 0 (0%) 2 (5%) *median (IQR). Primary outcomes—At the final follow up, the antihypertensive score was higher than baseline (p<0.05) and mean systolic and diastolic BP were significantly lower. The mean number of classes of antihypertensive agents used at baseline and at 21 months were 2.7±1.1 and 3.5± 0.9 (p<0.05) respectively. The proportion of patients achieving the BP target of ≤125/85 mmHg had doubled by the two years. Mean HbA1c values were also significantly lower.Median (IQR) urinary ACR was significantly reduced at final follow up compared to that at baseline (51 (20–97) vs. 126 (65–194), p=0.003) and a higher proportion of patients achieved remission of urinary ACR to ≤30mg/mmol as the study progressed (19% at 6 months, 25% at 12 months and 33% at end). The number of patients with urinary ACR ≥100mg/mmol was halved (56% at 0 months vs 26% at 21 months, p=0.001) (Table 3).The median (IQR) eGFR at baseline was 68 ml/min/1.73m2. At 12 months and at study end it was significantly lower at 59 and 57 ml/min/1.73m2, respectively (p<0.05) (Figure 1). The median (IQR) eGFR loss was 4.6 (0.4–13.6) ml/min/1.73m2 over the first year and 6.7 (-2.4–12.6) ml/min/1.73m2 over the second year (p=NS). At baseline there were four patients with eGFR ≤40ml/min/1.73m2, and at the end there were eight (p<0.05).Secondary outcomes—Four cardiovascular events occurred (1 AMI and 3 episodes of CHF) during the 2 years of follow up. Two patients reached ESRF – one was referred to the renal service 4 months into the study and was established on dialysis 14 months later. The other patient was referred to the renal service at 18 months and reached eGFR <10ml/min/1.73m2 3 months later: both patients had low renal reserve at baseline with eGFR of 29 and 37 ml/min/1.73m2, respectively. There were no reported deaths. The change in eGFR was not related to baseline urinary ACR or eGFR, or duration of diabetes. Table 3. Blood pressure and renal outcomes during the 2-year follow up Variables Baseline N=43 6months N=43 12 months N=39 End N=39 HbA1c (mmol/mol) 81±24 77±33 75±37b 71±20c BMI (kg/m2) 37.6±5.9 38.3±16.5 37.8±11.3 38.4±13.4 SBP (mmHg) 137±17 133±31 129±25b 126±16c DBP (mmHg) 84±13 80±20a 76±17b 74±13c Patients with BP ≤ 125/80 mmHg; n (%) 11 (26%) 9 (22%) 15 (39%) 22c (56%) Antihypertensive score* 5 (3–7) 6 (4–9)a 7 (5–11)b 9 (6–11)c,d ACR (mg/mmol)* 126 (65–194) 85 (33–154)a 67 (29–114)b 51 (20–97)c Serum creatinine (µmol/L)* 104 (82–135) 107 (82–135) 116b (81–142) 118c,d (91–155) Estimated GFR† (ml/min/1.73m2) 68 (50–81) 65 (51–82) 59 b (46–78) 57 c,d (42–73) ACR, n (%)‡ <3 mg/mmol 3–30 mg/mmol 31–50 mg/mmol 51–100 mg/mmol >100mg/mmol 0 0 3 (7) 16 (37) 24 (56) 0 7 (19) 5 (14) 11 (30) 14 (38) 0 8 (25) 5 (16) 10 (31) 9 (28) 2 (5) 11 (28) 6 (15) 10 (26) 10 (26) ACR: Albumin creatinine ratio; BMI: body mass index; HbA1c: glycated haemoglobin; SBP: systolic blood pressure; DBP: diastolic blood pressureMean±SD except *median (IQR)† eGFR calculated using MDRD equation20‡ At 6 months and 12 months, there were 37 and 32 available urinary ACR measurementsa p<0.05 comparing baseline and 6 months; b p< 0.05 comparing baseline and 12 monthsc p< 0.05 comparing baseline and 24 months; d p< 0.05 comparing 12 months and 24 months Remission of albuminuria—Twelve (28%) of 43 patients achieved and sustained remission of urine ACR, to a median (IQR) 10.2 (6.1–18.4). Remission was not related to duration of type 2 diabetes, duration or level of albuminuria, HbA1c, eGFR or BP at baseline, or a higher antihypertensive score.In the first year, eGFR fell more rapidly in the group that achieved remission of albuminuria compared to the group which did not (13.6 (4.0–16.6) vs. 3.5 (-0.97–7.5) ml/min/1.73m2/year, p=0.02), but in the second year it was significantly slower than in the first (p=0.03). The rate of decline of eGFR in the second year was slower in those achieving remission compared to the non-remitting group (1.7(-2.0–9.7) vs. 8.2(-0.55–14.5) ml/min/1.73m2/year, p=0.21).Adverse events—Mild hyponatraemia (serum sodium 130–135 mmol/L), was the most common electrolyte abnormality and affected 12(28%) patients in this study. Severe hyponatraemia (<130 mmol/l) occurred in 2 patients during a period of hospitalisation for concurrent illnesses, which resolved on cessation of diuretics. Mild hypokalaemia was observed in one patient. Figure 1. Change of systolic and diastolic BP, urinary ACR and eGFR‡ACR: albumin creatinine ratio; eGFR: estimated glomerular filtration rate; DBP: diastolic blood pressure; SBP: systolic blood pressure; *p<0.05 comparing baseline and 12 months; †p<0.05 comparing 12 and 24 months; ‡ eGFR calculated using MDRD equation20 DiscussionIn this 2-year prospective cohort study of Pasifika patients with type 2 diabetes and macroalbuminuria, we found that a significant reduction of BP to clinical targets can be achieved through intensification of antihypertensive treatment and promotion of medication adherence in a primary care setting. Although the main management focus was BP reduction, the success of this intervention also extended to reduction in albuminuria and improved HbA1c.A multi-risk approach targeting BP, glycaemia, dyslipidaemia and weight reduction plays an important role in survival outcomes in patients with type 2 diabetes with metabolic syndrome – with adequate BP lowering BP having the major effect.21 Blood pressure optimisation delays the progression of cardiovascular and renal diseases,22 and reduces albuminuria which is an independent factor of premature death.8While it has been debated as to the lowest threshold for BP targets, the general consensus is that a goal <130/80 mmHg should be aimed in patients with DKD without concomitant cardiovascular disease.23 In a subgroup of patients with overt albuminuria and renal insufficiency however, renal benefits have been observed with lower BP.24,25 Our BP goal was lower compared to most interventional studies as our cohort comprised of a population with heavy albuminuria and minimal cardiac history. The mean systolic and diastolic BP at the end of this study was lower than that observed in similar studies,17,18 with more than half of the group attaining the pre-determined BP goal of <125/80 mmHg by 1 year and sustained to the study's end.These results highlight the importance of patient and provider-specific factors in effective health care delivery. The recognition of these variations allow for meaningful patient-centred management and improved outcomes.19 Langimalie Tongan Health Centre operates with culturally-appropriate staff who understand the unique cultural and economic barriers and can address these with patient education through community events, home visits and co-operation with local pharmacy to ensure medication adherence. An integrated community-based care involving a specialist, primary care physician and nurses, and the patient in complex diabetes care has previously demonstrated clinical and process benefits beyond that of tertiary diabetes outpatient care.18Six new events occurred—two cases of ESRF and four cardiovascular events. The two patients who reached ESRF had low eGFR at recruitment and neither had remission of albuminuria. During the follow-up period, 10% of study patients had non-fatal cardiovascular events. This proportion is lower than that reported in larger studies such as the RENAAL (33%) and IDNT (24%) trials which had similar duration of follow up.8,26 However, the observation period was too short and not sufficiently powered to determine outcome benefit.In spite of the widespread use of RAS inhibitors, only a third of our patients achieved remission of albuminuria, suggesting that current therapies for DKD may not be adequate. The absence of retinal disease in 30% of patients in this cohort emphasises that non-diabetic kidney disease is prevalent in patients with type 2 diabetes in whom obesity and metabolic syndrome are common.27 Furthermore familial clustering of nephropathy occurs in Pasifika people regardless of the presence of diabetes.28Overall, the intensification of antihypertensive management did not appear to compromise renal function. The rate of eGFR decline in this cohort was comparable to the trend seen in recent studies with ranges from 4 to 6.5 ml/min/1.73m2/year.29 In the group of patients who achieved remission of albuminuria the rate of eGFR decline in the first year was more rapid, but it plateaued and was significantly slower in the second year. This finding is consistent with the notion that aggressive antihypertensive treatment reduces renal function primarily through early haemodynamic effects. A slower progression to ESRF has been reported in diabetic patients who had greater initial GFR decline,30 hence such an intervention is more likely to benefit patients with higher renal reserve at baseline.Our findings have limitations. First, the study was small, and a number of our outcomes were surrogates. However, studies in Pacific Island patients are scarce, and collection of medical data is challenging due to infrequent presentations and the lack of continuity of care. The nurse-led programme succeeded in achieving regular follow up for ≥ 22 months in 70% of our patients. There are 849 type 2 diabetic patients (aged 18 to 65) registered at the Langimalie Tongan Health Centre. Our study population of 47 patients indicates a minimal prevalence of macroalbuminuric DKD of 5.5%, similar to the prevalence observed in other population-based studies.1Secondly, eGFR was calculated using the four-variable MDRD study formula which has limitations, particularly in overweight subjects. This was chosen over the Cockcroft-Gault equation as this has been shown to be superior in estimating eGFR in patients with diabetes and chronic kidney disease.31 Thirdly, BP measurements in this study were based on both clinic and home readings instead of the gold-standard 24-hour automated BP monitoring. The trend in BP however, corresponded closely with the change in antihypertensive score.Attaining BP targets in clinical practice has often been difficult, with a greater rate of failure in patients with diabetes,19 notwithstanding the challenges of other clinical and patient factors. This study has shown that a systematic approach of monitored intensification of antihypertensive therapy coupled with promotion of medication adherence, provides a model of care which can be effectively and safely applied in primary care. It also provides a framework for specialist support and up-skilling of primary care practitioners in the management of complex chronic diseases. A longer term follow up is necessary to accurately assess the sustainability, effectiveness and safety of such an intervention on slowing the progression of DKD with specific attention to important clinical outcomes.

Summary

Abstract

Background Chronic kidney disease is common in Pasifika people with type 2 diabetes. Lowering blood pressure (BP) and reducing proteinuria may slow the rate of progression of renal disease.-Method We conducted a 2-year study in patients with type 2 diabetes with estimated glomerular filtration rate (eGFR) \u226540ml/mmin/1.73m2 and urinary albumin-creatinine ratio (ACR) \u226540 mg/mmol to evaluate a community-based programme aimed at optimising BP. Primary outcomes included BP reduction, remission of albuminuria and change in eGFR.-Results Thirty-nine of 47 patients completed \u226517 months of intervention. The mean age was 53\u00b18 years; 77% were male. An increase in antihypertensive therapy intensity was accompanied by a median (IQR) reduction in BP of 13[-1.5-22.5)/ 12(1-19) mmHg p

Aim

Method

Results

Conclusion

Author Information

Jasmine Tan, Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Auckland; Fifita McCready, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; Fiona Noovao, Primary Care Physician, Langimalie Tongan Health Centre, Onehunga, Auckland; Oketi Tepueluelu, Primary Care Nurse, Langimalie Tongan Health Centre, Onehunga, Auckland; John Collins, Transplant Nephrologist, Department of Renal Medicine, Auckland City Hospital, Auckland; Tim Cundy, Endocrinologist, Auckland Diabetes Centre, Green Lane Clinical Centre, Auckland

Acknowledgements

This study was funded by Sector Capability and Implementation Directorate at the Ministry of Health, and we thank Nick Polaschek and Ailsa Jacobson for their support. Dr Noovao was supported by the Eli Lilly Diabetes Research Grant and Dr Tan was a New Zealand Diabetes Foundation Research Fellow. The authors also thank Zena Mubarak and Ross Mudafar (Vaiola Pharmacy, Onehunga) and Stephanie Emma (Mangere Community Health Trust) for their assistance.

Correspondence

Dr Jasmine Tan, Auckland Diabetes Fellow, Auckland Diabetes Centre, Greenlane Clinical Centre, Level 1, Building 4, 214 Greenlane Road, Auckland 1023, New Zealand.

Correspondence Email

jasmineta@adhb.govt.nz

Competing Interests

Nil.

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