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Family clustering of secondary chronic kidney disease with hypertension or diabetes mellitus. A case-control study/Agregacao familiar da doenca renal cronica secundaria a hipertensao arterial ou diabetes mellitus: estudo caso-controle.

Introduction

Chronic Kidney Disease (CKD) is a worldwide public health problem (1-3). Renal Replacement Therapies (RRT) in the end-stage of the disease (glomerular filtration rate < 15 ml/min/1.73[m.sup.2]) include haemodialysis, peritoneal dialysis and kidney transplant (1, 3). The causes of end-stage CKD are multiple. However, the most common causes over the last two decades have been hypertension and type 2 diabetes mellitus which are responsible for 63.5% of cases in Brazil and over 70% of cases in the United States (2, 3). When these diseases are associated with CKD they present a common ethiopatogenetic link that increases the chances of cardiovascular complications, which in turn are the main causes of hospitalisations and death in individuals undergoing RRT (2, 4). The prevalence of patients in Brazil undergoing dialysis increased from 333 patients per million population (pmp) in 2004 to 483 pmp in 2010 and is expected to continue to increase at an annual rate of 6.5%5. Over 85% of Brazil's RRT patients are treated under the Unified Health System which is currently on the verge of saturation point and experiencing difficulties in meeting the demand of patients with end-stage CKD. The total estimated cost to the health system of meeting this demand in 2008 was R$200 million (3, 5, 6). For these reasons, individuals with incipient renal lesions, hypertension and diabetes mellitus are targeted by CKD prevention campaigns in Brazil and worldwide (7, 8).

Certain primary renal diseases, such as renal autosomal dominant polycystic kidney disease, Alport syndrome and primary glomerulopathies, are clearly genetically transmitted, which in some ways facilitates their prevention (9, 10).

However, the association between predisposition to renal lesion and diseases that show familial aggregation, such as hypertension and type 2 diabetes mellitus, but whose hereditary determinants are multigenetical, remains unclear. Studies carried out in states on the West Coast of the United States identified familial aggregation of chronic kidney disease, regardless of the cause disease, and observed that it is was more common in African Americans (11-13): around 23% of CKD patients undergoing RRT in this population had positive family history of the disease (12). Furthermore, the prevalence of hypertension, diabetes mellitus, proteinuria or renal insufficiency was greater among family members of CKD patients (13). The only study to date on this topic in Brazil, carried out in Rio de Janeiro, observed familial aggregation of CKD among patients undergoing RRT. However, the study did not identify any association with skin colour (14).

Where familial aggregation of a disease is confirmed, direct family members of CKD patients should also be preferential targets of research and intervention measures directed towards primary and secondary prevention of CKD.

The objective of this study is therefore to determine the existence of familial aggregation of CKD among individuals with hypertension and/ or type 2 diabetes in the municipalities of Sorocaba and Votorantim in the State of Sao Paulo, which have a combined population of 800,000 inhabitants. The evaluation parameter used was prevalence of CKD in family members of CKD patients undergoing RRT using individuals with hypertension or type 2 diabetes with normal kidney function as a control.

Methods

Study type

This research project consists of a case-control study using frequency pairing in a sample of CKD patients undergoing RRT ("cases") in Sorocaba, Sao Paulo. The cause of CKD in these patients was confirmed by the assistant nephrologist as being hypertension or type 2 diabetes. Patients with hypertension and/or type 2 diabetes mellitus but with normal kidney function and treated under the Hypertension and Diabetes Programme at primary health care units (HCUs) in Sorocaba and Votorantim were used as "control cases".

Patient selection

The interview team comprised medical students taking a scientific initiation fellowship at the Faculty of Medical and Health Sciences of the Pontifical Catholic University of Sao Paulo-PUC/ SP (authors' initials--GSC, ALB, MMJ, GVS and EAB). The case patients were selected using up to date records from the dialysis centers frequented by the patients. To be included in the study patients had to: be over 18 years of age, have end-stage CKD, have been undergoing RRT for at least three months, and have had hypertension or type 2 diabetes mellitus for at least five years before beginning RRT. It is important to note that the diagnosis of the causes of end-stage CKD is invariably assumption-based. Patients with the following medical history or diagnosis were excluded: polycystic kidney disease, primary glomerulopathies, tubulo-interstitial diseases, reflux and obstructive nephropathy, and unknown causes.

The control cases were selected from patients diagnosed with hypertension and/or type 2 diabetes mellitus who had been under treatment in a HCU for at least six months prior to the study and whose medical records showed normal levels of creatinine in the blood (< 1.4 mg/dl in men and < 1.2 mg/dl in women) for the six months prior to the study. All patients answered a questionnaire in order to obtain the following information: personal information (age, sex, skin colour); relevant medical history (CKD cause and length of time after hypertension and/or diabetes mellitus diagnosis); anthropometric data (weight and height); clinical and laboratory test information (blood pressure, plasma creatinine) taken from the last monthly control registered in the patient medical chart; and family history of CKD and RRT. Skin colour categories were defined based on the Brazilian Institute of Geography and Statistics classification: "white", "black", "brown", "yellow" or "indigenous" (15).

Sample size calculation and pairing

Using an alpha error of 5% and beta error of 20% (power of 80%) and an odds ratio of 5.7 based on the above mentioned study in Rio de Janeiro, we calculated a sample size of 304 "cases" and 304 "control cases" (14). A final sample size of 335 was defined assuming a loss rate of 10%. "Cases" and "control cases" with type 2 diabetes mellitus and/or hypertension were paired based on the cause disease (hypertension or type 2 diabetes mellitus), sex and age. The control cases were paired based on the frequency of cases to ensure a balanced distribution in each sample (16).

Research location

Patients undergoing RRT (cases) were selected and evaluated in the following RRT centers in Sorocaba: the Dialysis and Kidney Transplant Center in the Santa Lucinda Hospital (belonging to the Pontifical Catholic University of Sao Paulo), the RRT unit of the Leonor Mendes de Barros Hospital (belonging to the State of Sao Paulo Secretary of Health), the Sorocaba Institute of Haemodialysis (an independent unit associated to the Sorocaba Evangelic Hospital) and the RRT unit of the UNIMED Sorocaba Hospital. The control cases were selected and evaluated from eight HCUs in Sorocaba and four HCUs in Votorantim. These units were chosen to ensure a proportionally representative sample of the population respecting the population distribution of both cities.

Ethical considerations

The study was carried out in accordance with the principles of the Declaration of Helsinki and was approved by the Research Ethics Committee of the Faculty of Medical and Health Sciences of the Pontifical Catholic University of Sao Paulo. All participants read and signed an informed consent form and agreed to participate in the study before procedures commenced.

Statistical analysis

Data was inputted into an Excel spread sheet and later exported to the software program STATA 10.0. The continuous variables of the "cases" and "control cases" were compared using the Student's t-test. The categorical variables were compared using the odds ratios based on a 95% confidence interval. Statistical significance (p-value) is shown below and in the tables. A statistical analysis of the association between prevalence of end-stage CKD/RRT and specific risk factors was carried out using the Mantel-Haenszel method and multiple logistic regression analysis. Conditional logistic regression was not used since it is not necessary in frequency pairing (16).

Results

The group "cases" comprised 336 CKD patients undergoing RRT and living in Sorocaba or Votorantim. The proportion of cases with type 2 diabetes mellitus and hypertension was 50.9% and 49.1%, respectively, while the proportion of control cases (n = 389) with these diseases was 46,5% and 53.5%, respectively. Table 1 shows the results of pairing. No major differences were found between the two groups regarding the pairing criteria used. Statistically significant differences were observed only with the variables diastolic blood pressure and plasma creatinine, which was expected given the inclusion criteria.

Table 2 compares the prevalence of CKD and RRT among family members. A total of 51 cases (15.2%) had at least one first-degree or second-degree relative that had CKD and was undergoing RRT, compared to only 27 control cases (6.9%) (OR 2.40; CI 95% 1.47-3.92; p < 0,001). Prevalence of CKD undergoing RRT was greater among family members of the cases regardless of degree of relationship (first-degree: parents, brothers and sisters, or second-degree: grandparents, uncles and aunties and nieces and nephews). Since the disease is more common in individuals over the age of forty, only one younger family member was undergoing RRT among the cases (the child of one of the participants), which was not sufficient for statistical analysis. Ten cases had two relatives that were undergoing RRT and two cases had three relatives undergoing RRT, while none of the control cases had more than one family member undergoing RRT.

Table 3 shows prevalence of CKD undergoing RRT among family members of both groups by skin colour (white and non white) and cause disease. A separate analysis of whites and non whites resulted in a statistically significant odds ratio: 2.06 (CI 95% 1.12-3.79; p < 0.05) and 2.87 (CI 95% 1.20-6.90; p < 0.01), respectively. A joint analysis of black and brown skin colour showed resulted in an OR of 3.01 (IC 95% 1.23-7.32; p < 0,01). The results showed that people in the black and brown skin colour category were not more likely to have family members with CKD undergoing RRT (OR = 1.11; CI 95% 0.60-2.06) than white individuals (OR = 1.0). The same can be said of the yellow skin colour group, which showed a high OR (3.04) but was not statistically significant (CI 95% 0.72-12.88). It should be noted however that the proportion of individuals in this category was low in both groups (cases n = 9; controls n = 2).

Hypertension and type 2 diabetes mellitus remained statistically significant as cause diseases after a separate analysis of these two variables. The OR of the variable type 2 diabetes mellitus was slightly lower than that of hypertension (Table 3). Although type 2 diabetes mellitus was shown to be the most common cause disease, the likelihood of this disease causing end-stage CKD among relatives of patients undergoing RRT was not greater than that of hypertension (OR = 1.10; CI 95% 0.61-2.01).

The likelihood of case family members having end-stage CKD undergoing RTT was still greater after carrying out multiple logistic regression analysis adjusted by sex, age, skin colour, cause disease, and length of time after diagnosis of hypertension and diabetes mellitus (OR = 2.35; CI 95% 1.42-3.89; p < 0,001). This association was statistically significant showing that familial predisposition is an independent risk factor for kidney failure related to hypertension and type 2 diabetes mellitus even after controlling for known end-stage CKD risk factors.

Discussion

This case-control study identified that members of the case group were twice as likely to have family members with CKD undergoing RRT than members of the control group, showing familial aggregation and familial predisposition to renal lesion in this representative sample of individuals with end-stage CKD associated with hypertension or type 2 diabetes mellitus. Similar studies carried out in the southeast of the United States have demonstrated familial aggregation of CKD among a predominantly African American population (11-13). The present study only included cases where the cause disease was type 2 diabetes mellitus or hypertension, thereby excluding individuals with diseases that show a Mendelian pattern of inheritance, such as autosomal dominant polycystic kidney disease in adults, or for which familial aggregation is documented, such as some hereditary glomerulopathies (Alport syndrome) or focal segmental glomerulosclerosis (9, 10). A recent studied carried out in China observed a 29.7% prevalence rate for urinary alterations and renal insufficiency in first-degree relatives of CKD patients; however, this study included all renal diseases, including glomerulopathies (16). The present investigation is the first study in Brazil to show that familial predisposition is an independent risk factor for end-stage CKD associated with both hypertension and type 2 diabetes mellitus, regardless of skin colour.

This is the second study of this type to be carried out with a sample of the Brazilian population. The first study, also a case-control study, was carried out in Rio de Janeiro a decade ago. The control group comprised inpatients with normal levels of plasma creatinine but the study did not select the cause diseases for CKD (14). The study showed that the likelihood of family members of case patients having CKD and RRT was 5.7 greater than among control patients (14). The likelihood observed by the present study was lower (OR = 2.4) but still significant. The most reasonable explanation for this difference is the fact that the present study selected cases where the cause disease was type 2 diabetes mellitus or hypertension, making it possible to choose an appropriate control sample comprised of individuals with the same cause diseases paired by gender, age and cause disease. In the afore mentioned study, the cause disease was glomerulonephritis in 12.1% of the cases and unknown in 32.9% of the cases. In the control group, hypertension or diabetes mellitus was the cause disease in 26.7% of hospitalized patients (14).

Case-control studies are subject to assessment and selection bias. However, the risk of assessment bias and recall bias was limited in this study due to the specific characteristics of CKD and the cause diseases whose selection was based on sound criteria which ensured that all sample members, including the control sample, were participating in treatment programmes for these diseases. It is important to highlight that the etiological diagnosis of hypertension and type 2 diabetes mellitus related to end-stage CKD is invariably assumption-based since a renal biopsy is not carried out during this stage of the disease. Furthermore, reverse causality is not uncommon in this type of study because family members of known CKD patients are often more likely to be examined for renal lesions, even in initial stages. This does not apply to this study, since we considered patients with end-stage CKD undergoing RRT.

The greater likelihood of CKD and RRT among case family members remained significant even after a separate analysis of patients by disease cause (type 2 diabetes mellitus or hypertension) and after carrying out a multiple logistic regression analysis to adjust for known risk factors for end-stage CKD (sex, age, skin colour, cause disease, length of time after hypertension and/or diabetes mellitus diagnosis). In other words, the results indicate that familial predisposition to both hypertension and type 2 diabetes mellitus is an independent risk factor for kidney failure. This is yet another explanation for the high prevalence of these diseases as worldwide causes of end-stage CKD (1-6). A number of studies produced over the last two decades regarding the common physiopathological features of these diseases, including its genetic features, have shown that they are frequently concomitant and commonly diagnosed as a metabolic syndrome (18).

Contrary to the findings of the aforementioned study carried out in the United States, we did not find a greater predisposition to end-stage CKD associated with black or brown skin colour (11, 12, 20). A possible explanation is that the segregation of the genes linked to hypertension and type 2 diabetes may not be related to race, which makes it impossible to identify their importance.

The authors do not discard the possibility that cultural habits and socioeconomic conditions may also explain familial aggregation. Publications show divergent findings regarding this issue. While some studies suggest that low socioeconomic status and lack of access to adequate health facilities are associated with greater prevalence of end-stage CKD, others did not observe such an association and reinforce that a genetic predisposition in the family is the main contributing factor to familial aggregation (20-23). In this respect, recent studies have discovered certain genes which explain familial predisposition to chronic kidney disease associated with both hypertension and diabetes mellitus (24-26).

Previous studies show that periodic monitoring of arterial pressure, blood glucose levels, levels of plasma creatinine, albuminuria and proteinuria are strategic preventative interventions for this risk group (27-31).

This study confirms our initial hypothesis of the existence of familial aggregation of CKD in individuals with hypertension and/or type 2 diabetes mellitus, indicating that familial predisposition to these diseases is an independent risk factor for kidney failure within this sample of the Brazilian population. This information is very important for those individuals with hypertension and/or type 2 diabetes mellitus and for health professionals that treat these patients, because it means that the immediate family of CKD patients should be preferential targets of diagnostic investigation and primary and secondary prevention interventions of end-stage CKD. Apart from family links, it is therefore important to identify whether other risk factors for CKD are present in first and second-degree relatives of CKD patients in order to establish appropriate control and prevention measures. The main limitation of this research, apart from the selection biases mentioned above which are common to case-control studies, is the regional nature of this study. Brazil is a country with continental proportions and therefore epidemiological characteristics vary enormously meaning that results cannot be extrapolated to other regions. However, we hope that the results of this study will stimulate the implementation of correlative studies in other regions in Brazil.

Collaborations

FA Almeida and RJ Gianini participated in project conception, data analysis and interpretation, and the writing of this article and approved the final submitted version of this article. GS Ciambelli, AL Bertoco, MM Jurado, GV Siqueira e EA Bernardo participated in project conception, data collection, analysis and interpretation, and in the critical revision and approval of the final submitted version of this article. MV Pavan participated in project conception, data analysis and interpretation, and in the critical revision and approval of the final submitted version of this article.

DOI: 10.1590/1413-81232015202.03572014

Acknowledgements

We are grateful to the Institutional Scientific Initiation Grant Programme of the Pontifical Catholic University of Sao Paulo (PIBIC-PUC/ SP) and to the National Council for Scientific and Technological Development (CNPq) for the grants for scientific initiation awarded to the students that participated in this study.

References

(1.) KDIGO. Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Definition, identification, and prediction of CKD progression. Kidney Int 2012; (Supl. 3):63-72.

(2.) U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2013. [acessado 2013 out 9]. Disponivel em: http://www.usrds.org/ reference.aspx

(3.) Sesso RC, Lopes AA, Thome FS, Lugon JR, Santos DR. Dialise cronica no Brasil--Relatorio do censo brasileiro de dialise, 2011. J Bras Nefrol 2012; 34(3):272-277.

(4.) KDIGO. Clinical Practice Guidline for the Evaluation and Management of Chronic Kidney Disease. Other complications of CKD: CVD, medication dosage, patient safety, infections, hospitalizations, and caveats for investigating complications of CKD. Kidney Int 2012; (Supl. 3):91-111.

(5.) Sesso R, Gordon P Dados disponiveis sobre a doenca renal cronica no Brasil. J Bras Nefrol 2007; 29(Supl. 1):9-12.

(6.) Sesso RC, Lopes AA, Thome FS, Lugon JR, Santos DR. Relatorio do censo brasileiro de dialise de 2010. J Bras Nefrol 2011; 33(4):442-447.

(7.) World Kidney Day. [acessado 2013 out 8]. Disponivel em: http://www.worldkidneyday.org

(8.) Dia Mundial do Rim 2013. [acessado 2013 out 8]. Disponivel em: http://www.sbn.org.br/index.php?Noticia &pagina=&dado_id=1420

(9.) Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med 2009; 60:321-337.

(10.) Zunino D. Glomerulopatias hereditarias. In: Riella MC, organizador. Principios de nefrologia e disturbios hidroeletroliticos. Rio de Janeiro: Guanabara-Koogan; 2010. p. 754-764.

(11.) Freedman BI, Soucie JM, McClellan WM. Family history of end-stage renal disease among incident dialysis patients. J Am Soc Nephrol 1997; 8(12):1942-1945.

(12.) Freedman BI, Volkova NV, Satko SG, Krisher J, Jurkovitz C, Soucie JM, McClellan WM. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 2005; 25(6):529-535.

(13.) Lei HH, Perneger TV, Klag MJ, Whelton PK, Coresh J. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998; 9(7):1270-1276.

(14.) Madeira EPQ, Santos OR, Santos SFF, Silva LA, Innocenzi AM, Santoro-Lopes G. Familial aggregation of end-stage kidney disease in Brazil. Nephron 2002; 91(4):666-670.

(15.) Instituto Brasileiro de Geografia e Estatistica (IBGE). Conceitos. [acessado 2013 out 6]. Disponivel em: http:// www.ibge.gov.br/home/estatistica/populacao/condicaodevida/indicadoresminimos/conceitos.shtm

(16.) Schlesselman JJ. Case-control studies. Oxford: Oxford University Press Inc; 1982.

(17.) Wei X, Li Z, Chen W, Mao H, Li Z, Dong X, Tan J, Ling L, Chen A, Guo N, Yu X. Prevalence and risk factors of chronic kidney disease in first-degree relatives of chronic kidney disease patients in Southern China. Nephrology (Carlton) 2012; 17(2):123-130.

(18.) Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16):1640-1645.

(19.) Bergman S, Key BO, Kirk KA, Warnock DG, Rostant SG. Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease. Am J Kidney Dis 1996; 27(3):341-346.

(20.) Byrne C, Nedelman J, Luke RG. Race, socioeconomic status, and the development of end-stage renal disease. Am J Kidney Dis 1994; 23(1):16-22.

(21.) Perneger TV, Whelton PK, Klag MJ. Race and end-stage renal disease (socioeconomic status and access to health care as mediating factors). Arch Intern Med 1995; 155(11):1201-1208.

(22.) Ward MM. Socioeconomic status and the incidence of ESRD. Am J Kidney Dis 2008; 51(4):563-572.

(23.) Song EY, McClellan WM, McClellan A, Gadi R, Hadley AC, Krisher J, Clay M, Freedman BI. Effect of community characteristics on familial clustering of end-stage renal disease. Am J Nephrol 2009; 30(6):499-504.

(24.) Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS; Family Investigation of Nephropathy and Diabetes Research Group. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40(10):1185-1192.

(25.) Freedman BI, Parekh RS, Linda Kao WH. Genetic basis of nondiabetic end-stage renal disease. Semin Nephrol 2010; 30(2):101-110.

(26.) Bowden DW, Freedman BI. The challenging search for diabetic nephropathy genes. Diabetes 2012; 61(8):1923-1924.

(27.) de Jong PE, Brenner BM. From secondary to primary prevention of progressive renal disease: the case for screening for albuminuria. Kidney Int 2004; 66(6):2109-2018.

(28.) Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, Jong PE, Coresh J; Chronic Kidney Disease Prognosis Consortium, Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, de Jong PE, Coresh J, El-Nahas M, Eckardt KU, Kasiske BL, Wright J, Appel L, Greene T, Levin A, Djurdjev O, Wheeler DC, Landray MJ, Townend JN, Emberson J, Clark LE, Macleod A, Marks A, Ali T, Fluck N, Prescott G, Smith DH, Weinstein JR, Johnson ES, Thorp ML, Wetzels JF, Blankestijn PJ, van Zuilen AD, Menon V, Sarnak M, Beck G, Kronenberg F, Kollerits B, Froissart M, Stengel B, Metzger M, Remuzzi G, Ruggenenti P, Perna A, Heerspink HJ, Brenner B, de Zeeuw D, Rossing P, Parving HH, Auguste P, Veldhuis K, Wang Y, Camarata L, Thomas B, Manley T. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int 2011; 79(12):1331-1340.

(29.) Hellemons ME, Denig P, de Zeeuw D, Voorham J, Lambers Heerspink HJ. Is albuminuria screening and treatment optimal in patients with type 2 diabetes in primary care? Observational data of the GIANTT cohort. Nephrol Dial Transplant 2013; 28():706-715.

(30.) Hoerger TJ, Wittenborn JS, Zhuo X, Pavkov ME, Burrows NR, Eggers P, Jordan R, Saydah S, Williams DE. Cost-effectiveness of screening for microalbuminuria among African Americans. J Am Soc Nephrol 2012; 23(12):2035-2041.

(31.) Low eGFR and high albuminuria predict end stage kidney disease and death at all ages. BMJ 2012; 345:e7478.

Article submitted 09/04/2014

Approved 19/06/2014

Final version submitted 21/06/2014

Fernando Antonio de Almeida [1] Giuliano Serafino Ciambelli [1] Andre Luz Bertoco [1] Marcelo Mai Jurado [1] Guilherme Vasconcelos Siqueira [1] Eder Augusto Bernardo [1] Maria Valeria Pavan [1] Reinaldo Jose Gianini [1]

[1] Faculdade de Ciencias Medicas e da Saude, Pontificia Universidade Catolica de Sao Paulo. faalmeida@globo.com
Table 1. Demographic characteristics and results of pairing by
cause disease, sex, age, clinical and laboratory parameters.

                                           Cases
                                          (n=336)

Sex
  Male                                       198 (58,9%)
  Female                                     138 (41,1%)
Cause disease
  Type 2 diabetes mellitus                   171 (50,9%)
  Hypertension                               165 (49,1%)
Skin colour
  White                                      191 (56,8%)
  Black                                       70 (20,8%)
  Brown                                       66 (19,7%)
  Yellow                                        9 (2,7%)
Age (years)                       58,8 [+ or -] 12,3 (b)
  < 50 years                                  68 (20,2%)
  50-59 years                                 97 (28,9%)
  60-69 years                                107 (31,8%)
  70-79 years                                 57 (17,0%)
  80 or + years                                 7 (2,1%)
Systolic Blood Pressure (mmHg)       142 [+ or -] 26 (b)
Diastolic blood pressure (mmHg)       80 [+ or -] 15 (b)
Plasma creatinine (mg/dL)         9,47 [+ or -] 3,25 (b)

                                       Controls           P
                                        (n=389)

Sex                                                      0,356
  Male                                   216 (55,5%)
  Female                                 173 (44,5%)
Cause disease                                            0,240
  Type 2 diabetes mellitus               181 (46,5%)
  Hypertension                           208 (53,5%)
Skin colour                                              0,904
  White                                  270 (69,4%)
  Black                                   50 (12,9%)
  Brown                                   67 (17,2%)
  Yellow                                    2 (0,5%)
Age (years)                       59,3 [+ or -] 12,0     0,603
  < 50 years                              73 (18,8%)
  50-59 years                            118 (30,3%)
  60-69 years                            119 (30,6%)
  70-79 years                             65 (16,7%)
  80 or + years                            14 (3,6%)
Systolic Blood Pressure (mmHg)       141 [+ or -] 19      0,33
Diastolic blood pressure (mmHg)       88 [+ or -] 12   < 0,001
Plasma creatinine (mg/dL)         0,94 [+ or -] 0,25   < 0,001

(a) = based on the Brazilian Institute of Geography and Statistics
classification; (b) = mean [+ or -] standard deviation.

Table 2. Prevalence of chronic kidney disease undergoing renal
replacement therapy among cases and controls and association with
degree of relationship.

Variable                             Cases      Controls       Odds
                                   (n = 336)    (n = 389)    Ratio (1)
                                     N (%)        N (%)

No relative undergoing RRT3       285 (84,8)   362 (93,1)
Parents undergoing RRT              15 (4,5)       7(1,8)      2,55
Brothers or sisters undergoing      27 (8,0)     13 (3,3)      2,53
  RRT
Son or daughter undergoing RRT       1 (0,3)      0 (0,0)
Second-degree relatives (4)         22 (6,6)       7(1,8)      3,82
  undergoing RRT
Total number of family members     51 (15,2)     27 (6,9)      2,40
Undergoing RRT5

Variable                          CI 95% (2)      P

No relative undergoing RRT3
Parents undergoing RRT            1,03-6,33    < 0,05
Brothers or sisters undergoing    1,28-4,98    < 0,01
  RRT
Son or daughter undergoing RRT
Second-degree relatives (4)       1,61-9,07    < 0,01
  undergoing RRT
Total number of family members    1,47-3,92    < 0,001
Undergoing RRT5

(1) = Likelihood; (2) = 95% confidence interval; p = level of
statistical significance; (3) = RRT/Renal Replacement Therapy
(haemodialysis or peritoneal dialysis); (4) = Second/degree
relatives were considered grandparents, uncles/aunties or
nieces/nephews; (5) = Total number of individuals with at least
one family member undergoing RRT.

Table 3. Prevalence of chronic kidney disease in family members
undergoing renal replacement therapy among cases and controls
stratified by skin colour and cause disease.

Variable                     Cases (n)   Controls (n)     Odds
                              Yes/ No      Yes / No     Ratio (1)

Skin Colour 3
  White                      27 / 191      20 / 270       2,06
  Non-white                  24 / 142       7 / 119       2,87
Cause disease
  Hypertension               24 / 141      12 / 196       2,75
  Type 2 diabetes mellitus   27 / 144      15 / 166       2,08

Variable                     CI 95% (2)     P

Skin Colour 3
  White                      1,12-3,79    < 0,05
  Non-white                  1,20-6,90    < 0,01
Cause disease
  Hypertension               1,33-5,69    < 0,01
  Type 2 diabetes mellitus   1,06-4,05    < 0,05

(1) = Likelihood; (2) = 95% confidence interval; p = level of
statistical significance, (3) = skin colour based on the Brazilian
Institute of Geography and Statistics classification 15.


Introducao

A doenca renal cronica (DRC) e um problema de saude publica em todo o mundo (1-3). Em seu estagio terminal (filtracao glomerular < 15 mL/ min/1,73[m.sup.2]) tem como terapia renal substitutiva (TRS) a hemodialise, a dialise peritoneal e o transplante renal (1, 3). As causas de DRC terminal sao multiplas, porem, a hipertensao arterial e o diabetes mellitus tipo 2 sao, ha decadas, as mais comuns e respondem a 63, 5% dos casos de DRC terminal no Brasil e mais de 70% dos casos nos Estados Unidos (2, 3). Essas doencas que tem laco etiopatogenico comum, quando associadas a DRC, aumentam ainda mais as complicacoes cardiovasculares que sao as principais causas de internacoes e morte nos individuos em TRS (2, 4). No Brasil, a prevalencia de pacientes em dialise desenha uma curva ascendente. Em 2004 tinhamos 333 pacientes em TRS por milhao da populacao (pmp) e, em 2010, 483 pmp, com taxa de incidencia de 99, 5 pacientes pmp e o crescimento anual estimado na prevalencia de 6,5% (5). Por esta razao, o Sistema Unico de Saude (SUS), responsavel pelo financiamento de 85,8% dos pacientes em TRS, tem dado expressivas mostras de saturacao e dificuldades em atender os individuos portadores de DRC terminal, a um custo estimado em 2008 de 200 milhoes de reais (3, 5, 6). Assim, os individuos portadores de lesao renal incipiente, hipertensao arterial e diabetes mellitus tem sido os alvos de campanhas de prevencao da DRC no Brasil e no mundo (7, 8).

Algumas doencas renais primarias, como e o caso da doenca renal policistica autossomica dominante, a doenca de Alport e algumas glomerulopatias primarias tem clara transmissao genetica, o que de certa forma pode facilitar sua prevencao (9, 10).

Entretanto, em doencas que apresentam agregacao familiar, como a hipertensao arterial e o diabetes mellitus tipo 2, mas cujos determinantes hereditarios sao multigenicos, a predisposicao para a lesao renal nao esta claramente estabelecida. Alguns estudos identificaram em estados da Costa Leste nos Estados Unidos a agregacao familiar da doenca renal cronica, independente da doenca de base, sendo ainda mais comum em individuos afrodescendentes (11-13). Nesta populacao especifica, cerca de 23% dos pacientes com DRC em TRS tem historia familiar positiva (12). Alem disso, familiares de pacientes com DRC tem maior prevalencia de hipertensao arterial, diabetes mellitus, proteinuria ou deficit de funcao renal (13). No Brasil ha um unico estudo realiza do no Rio de Janeiro, onde se observou a agregacao familiar da DRC em pacientes submetidos a TRS, porem, o estudo nao identificou diferencas raciais (14).

Se a agregacao familiar se confirmar como verdadeira em nosso meio, os familiares diretos de individuos com DRC devem ser os alvos preferenciais para a investigacao e intervencao visando a prevencao primaria e secundaria da DRC. Assim, o objetivo deste estudo foi avaliar se existe agregacao familiar da DRC entre os individuos com hipertensao arterial e/ou diabetes tipo 2 da regiao dos municipios de Sorocaba e Votorantim, Estado de Sao Paulo, cuja populacao conjunta estimada e de 800.000 habitantes. Utilizamos como parametro de avaliacao a prevalencia de DRC em familiares de pacientes com DRC submetidos a TRS comparando-os aos controles apropriados, individuos portadores de hipertensao arterial ou diabetes tipo 2 com funcao renal normal.

Metodos

Tipo de Estudo

Trata-se de um estudo "caso-controle" com pareamento por frequencia tendo como "casos" os individuos portadores de DRC em TRS no Municipio de Sorocaba/SP, cuja etiologia da DRC foi considerada pelo nefrologista assistente como hipertensao arterial ou diabetes tipo 2 e, como "controles", pacientes portadores de hipertensao arterial e/ou diabetes mellitus tipo 2 atendidos no Programa de Hipertensao e Diabetes das Unidades Basicas de Saude (UBS) ou Unidades de Saude da Familia (USF) dos municipios de Sorocaba e Votorantim.

Selecao dos Pacientes

A equipe de entrevistadores era formada por alunos de iniciacao cientifica do curso de medicina da Faculdade de Ciencias Medicas e da Saude da PUC/SP (iniciais dos autores: GSC, ALB, MMJ, GVS e EAB). Os pacientes foram selecionados a partir dos registros atualizados dos centros de dialise participantes. Os criterios de inclusao para os "casos" foram: ter idade superior a 18 anos, ter DRC terminal e estar em programa de TRS ha pelo menos 3 meses e ter hipertensao arterial ou diabetes mellitus tipo 2 ha pelo menos 5 anos antes do inicio da TRS. Lembramos que o diagnostico etiologico da DRC terminal por hipertensao arterial e diabetes mellitus tipo 2 e, quase que invariavelmente, presuntivo. Foram excluidos os pacientes com DRC cuja historia medica e etiologia documentada fosse glomerulopatias primarias, doenca renal policistica, doencas tubulo-intersticiais, nefropatia de refluxo ou obstrutiva ou de causa desconhecida. Foram incluidos como "controles" pacientes em tratamento nas UBS ou USF ha pelo menos 6 meses com diagnosticos de hipertensao arterial e/ou diabetes mellitus tipo 2 e que tivessem documentado em prontuario valores normais de creatinina (< 1, 4 mg/dL para homens e < 1, 2 mg/dL para mulheres) nos ultimos 6 meses. Todos os pacientes responderam um questionario que tinha por objetivo coletar as informacoes pessoais (idade, sexo, raca), pontos relevantes da historia medica (doenca de base causadora da DRC e o tempo do diagnostico da hipertensao arterial e/ou diabetes mellitus), dados antropometricos (peso e altura) e algumas informacoes clinicas (pressao arterial) e laboratoriais (creatinina plasmatica) extraidas do ultimo controle mensal registrado no prontuario do paciente e a historia familiar de prevalencia de DRC com necessidade de TRS. A categorizacao por raca dos participantes foi feita de acordo com a definicao do Instituto Brasileiro de Geografia e Estatistica em "branco", "preto", "pardo", "amarelo" ou "indigena" (15).

Calculo do tamanho da amostra e pareamento

Assumindo o erro alfa de 5% e o erro beta de 20% (poder de 80%) e considerando o odds ratio de 5, 7 observado no estudo realizado no Rio de Janeiro, calculamos o numero de individuos para participarem do estudo em 304 "casos" e 304 "controles" (14). Considerando a perda habitual de dados de aproximadamente 10%, estabelecemos que as amostras de "casos" e "controles" fossem de 335 sujeitos. Os pacientes pertencentes ao grupo "casos" e "controles" portadores de diabetes mellitus tipo 2 e/ou hipertensao arterial foram pareados de acordo com a doenca de base (hipertensao arterial ou diabetes mellitus tipo 2), sexo e idade. O pareamento dos controles foi feito por frequencia dos casos de modo a ter uma distribuicao equilibrada nas duas amostras (16).

Locais da Pesquisa

Os pacientes em TRS (casos) foram identificados e avaliados nos quatro centros de TRS existentes no municipio de Sorocaba, o Centro de Dialise e Transplante Renal localizado no Hospital Santa Lucinda (hospital proprio da Pontificia Universidade Catolica de Sao Paulo), a unidade de TRS do Hospital Leonor Mendes de Barros (hospital proprio da Secretaria da Saude do Estado de Sao Paulo), o Instituto de Hemodialise de Sorocaba (unidade autonoma ligada ao Hospital Evangelico de Sorocaba) e a unidade de TRS do Hospital da UNIMED Sorocaba. Os individuos "controles" foram identificados e avaliados em oito UBS ou USF no municipio de Sorocaba e quatro UBS no municipio de Votorantim. As UBS e USF foram escolhidas de forma a garantir a distribuicao proporcional da populacao atendida nos dois municipios e respeitando a distribuicao populacional nas diferentes regioes de ambas as cidades.

Consideracoes Eticas

O estudo foi realizado em acordo com os preceitos eticos presentes na Declaracao de Helsinki e foi aprovado pelo Comite de Etica em Pesquisa da Faculdade de Ciencias Medicas e da Saude da Pontificia Universidade Catolica de Sao Paulo. Todos os participantes do estudo leram e assinaram o TCLE e concordaram em participar do estudo antes que qualquer procedimento fosse realizado.

Analise Estatistica

Os dados foram tabulados em planilha Excel sendo posteriormente exportados para o programa STATA 10.0. As variaveis continuas foram comparadas entre os grupos de "casos" e "controles" atraves do teste "t" de Student. As variaveis categoricas foram comparadas pelos valores de odds ratio e foram considerados significantes quando dentro do intervalo de confianca de 95%, e os niveis de significancia estatistica (p) sao apresentados nas tabelas e no texto. A analise estatistica da associacao entre a prevalencia de DRC terminal e TRS e determinados fatores de risco pesquisados foi realizada atraves do metodo de Matel-Haenszel e regressao logistica multipla, tendo sido dispensada a regressao logistica condicional por se tratar de pareamento por frequencia (16).

Resultados

No grupo "casos" avaliamos 336 pacientes portadores de DRC em TRS residentes nos municipios de Sorocaba e Votorantim. As causas da DRC terminal dos participantes incluidos foram diabetes mellitus tipo 2 (50, 9%) e hipertensao arterial (49, 1%). No grupo "controles" (n = 389) os individuos portadores de hipertensao arterial corresponderam a 53,5% e de diabetes mellitus tipo 2 a 46,5%. A Tabela 1 mostra a distribuicao dos criterios de pareamento dos pacientes nos grupos "casos" e "controles". Observa-se que nao houve diferenca na distribuicao entre os criterios utilizados para o pareamento entre os grupos, sendo significantes apenas as diferencas dos valores de pressao arterial diastolica e de creatinina plasmatica, esta esperada pelos criterios de inclusao.

A Tabela 2 compara entre "casos" e "controles" a prevalencia de familiares com DRC necessitando de TRS. No grupo "casos" encontramos o total de 51 individuos (15, 2%) que tinham pelo menos 1 familiar de primeiro ou segundo graus com DRC submetido a TRS contra apenas 27 individuos (6, 9%) no grupo controle, com um odds ratio (OR) de 2, 40 (IC95% 1, 47-3, 92; p < 0, 001). Ao discriminar o grau de parentesco, observamos que os individuos submetidos a TRS (casos) tem maior frequencia de familiares que vieram a desenvolver DRC terminal com necessidade de TRS, independente do grau de parentesco, ou seja, pais, irmaos ou familiares de segundo grau (avos, tios ou sobrinhos). Por se tratar de doenca que usualmente compromete individuos da quinta decada de vida em diante, tivemos apenas um caso de filho necessitando de TRS no grupo "casos", o que nao permite a analise estatistica. Entre os casos havia 10 individuos que tinham 2 familiares com DRC necessitando TRS e dois individuos com 3 familiares em TRS. Ja entre os controles, todos relataram apenas um familiar em TRS.

A Tabela 3 apresenta a frequencia de familiares com DRC necessitando TRS entre "casos" e "controles" categorizando-os segundo a raca (brancos e nao brancos) e a doenca de base que provocou a DRC terminal. Observa-se que quando analisados separadamente, os individuos brancos mantem um OR significante de 2, 06 (IC 95% 1, 12-3, 79; p < 0, 05) e os nao brancos um OR tambem significante de 2, 87 (IC 95% 1, 20-6, 90; p < 0, 01). Pretos e pardos agrupados apresentam o OR de 3, 01 (IC 95% 1, 23-7, 32; p < 0, 01). Se tomarmos os individuos brancos como referencia (OR = 1, 0), os renais cronicos pretos e pardos em conjunto nao tem maior chance de terem familiares com DRC em TRS (OR = 1, 11 com IC 95% 0,60-2,06). Da mesma forma, os renais cronicos amarelos se comparados aos brancos, embora tenham um OR elevado (3,04), nao atingem significancia estatistica (IC 95% 0,7212,88), mas estao representados na amostra em pequeno numero (n = 9, casos e n = 2, controles).

Quando a hipertensao arterial e o diabetes mellitus tipo 2 foram analisados separadamente como doencas de base causadoras da DRC terminal necessitando TRS, ambas mantem a significancia estatistica com OR ligeiramente inferior para o diabetes mellitus tipo2 (Tabela 3). Ao compararmos entre si estas doencas de base, embora o diabetes mellitus tipo 2 seja a causa mais comum de DRC terminal na amostra, nao ha risco adicional em relacao a hipertensao arterial de provocar DCR terminal (OR = 1, 10 com IC 95% 0, 61-2,01).

Apos a analise de regressao logistica multipla ajustada por sexo, idade, raca, doenca de base, tempo de hipertensao e tempo de diabetes mellitus, os "casos" mantiveram maior razao de chance de terem familiares com DRC terminal e TRS, OR = 2, 35 (IC 95% 1, 42-3, 89; p < 0, 001), indicando que mesmo balanceando-se para os fatores de risco conhecidos para a DRC terminal, ainda permanece significante a predisposicao familiar como um fator de risco independente para o comprometimento renal na hipertensao arterial e no diabetes mellitus tipo 2.

Discussao

Neste estudo "caso-controle", identificamos que os participantes do grupo "casos", quando comparados aos seus controles apropriados, tem pelo menos duas vezes mais chance de terem familiares com DRC necessitando TRS. Isto significa que ha agregacao e predisposicao familiar para a lesao renal nesta amostra representativa da populacao de individuos com DRC terminal por hipertensao arterial ou diabetes mellitus tipo 2 desta regiao de aproximadamente 800.000 habitantes. Estudos semelhantes no sudoeste dos Estados Unidos ja demonstraram, em populacoes predominantemente de afrodescendentes, a agregacao familiar da DRC (11-13). No presente estudo foram incluidos apenas individuos que tinham como causa da DRC o diabetes mellitus tipo 2 ou a hipertensao arterial, tendo sido excluidos os individuos com doencas que reconhecidamente tem heranca genetica Mendeliana, como e o caso da doenca renal policistica autossomica do adulto, ou que tem agregacao familiar documentada, tal como algumas glomerulopatias hereditarias (Doenca de Alport) ou glomeruloesclerose segmentar e focal (9, 10). Mais recentemente, foi tambem descrito em chineses com DRC a prevalencia de familiares de primeiro grau com presenca de alteracoes urinarias e deficit de funcao renal, atingindo 29,7% dos familiares, mas nesta amostra foram incluidos individuos com qualquer doenca renal, inclusive as gloemrulopatias (17). O presente estudo documentou pela primeira vez no Brasil que tanto na hipertensao arterial como no diabetes mellitus tipo 2 a predisposicao familiar e um fator de risco independente para a DRC terminal, independente da raca.

Este e o segundo estudo desta natureza realizado na populacao brasileira. O primeiro foi tambem um estudo "caso-controle" realizado na cidade do Rio de Janeiro ha uma decada, no qual nao houve selecao da doenca de base entre os "casos" e foram tomados como "controles" pacientes internados com valores normais de creatinina plasmatica (14). Naquele estudo os autores encontraram uma razao de chance para doenca renal cronica e terapia renal substitutiva de 5, 7 na comparacao entre "casos" e "controles" (14). Ja no presente estudo, foram selecionados como "casos" individuos com DRC que tinham como doenca de base o diabetes mellitus tipo 2 ou a hipertensao arterial. Isto nos possibilitou escolher o grupo controle apropriado, formado por individuos com as mesmas doencas de base pareando-os por frequencia quanto ao genero, idade e doenca de base. Esta e a explicacao mais aceitavel para termos observado em nossa amostra populacional uma razao de chance menor (OR = 2, 4), porem significante, para a ocorrencia de DRC e TRS quando comparada ao estudo brasileiro anterior (14). Naquele estudo havia entre os casos 12, 1% de individuos com glomerulonefrites como doenca de base e 32, 9% com DRC terminal de causa desconhecida e, entre os controles, apenas 26, 7% de individuos com hipertensao arterial ou diabetes mellitus (14).

Os estudos do tipo "caso-controle" estao sujeitos a vieses de afericao ou de selecao. Entretanto, a natureza da DCR e a necessidade de tratamento dialitico nao permitem o vies de afericao ou de lembranca. Com relacao a selecao, esta foi feita baseada em criterios bem definidos, pois as doencas de base causadoras da DRC (hipertensao e diabetes) tambem nao permitem vieses de selecao e todos os participantes, inclusive os controles, estavam em programa de tratamento destas doencas. Ressaltamos que na pratica clinica o diagnostico etiologico de hipertensao arterial e diabetes mellitus tipo 2 para a DRC terminal e feito, quase que invariavelmente, de forma presuntiva, pois a biopsia renal nesta fase da doenca nao e feita. Tambem, nao e incomum em estudos desta natureza a causacao reversa, ou seja, a possibilidade de parentes de pacientes sabidamente com DRC serem mais frequentemente investigados para a presenca de lesao renal, mesmo em estagios iniciais. Isto nao se aplica ao presente estudo, pois o evento considerado (endpoint) foi a DRC terminal com necessidade de TRS, um estagio da doenca que nao permite desconhecimento do individuo ou de familiares, pois o comprometimento e intenso e causa a morte.

Ao se analisar separadamente os pacientes que tinham como causa da DRC terminal o diabetes mellitus tipo 2 ou hipertensao arterial, a razao de chance de ocorrencia de familiares com necessidade de TRS manteve-se significante. Alem disso, a analise de regressao logistica multipla ajustada para os fatores de risco conhecidos para a DRC terminal (sexo, idade, raca, doenca de base, tempo de hipertensao e tempo de diabetes mellitus), confirmam a analise dos dados crus, mantendo maior razao de chance de DRC terminal e TRS entre os "casos", mesmo apos o balanceamento para estes fatores de risco. Em outras palavras, os dados do presente estudo indicam que tanto na hipertensao arterial como no diabetes mellitus tipo 2 a predisposicao familiar e um fator de risco independente para que ocorra comprometimento renal. Esta e mais uma explicacao para a grande prevalencia destas doencas como causas de DRC terminal em todo o mundo (1-6). Ha pelo menos duas decadas sao descritas varias caracteristicas fisiopatologicas comuns a estas doencas, inclusive geneticas, sendo frequente a concomitancia de ambas, comumente diagnosticada como sindrome metabolica (18).

Diferentemente do que se tem observado nos EUA, nao encontramos em nossa amostra populacional maior predisposicao a DRC terminal em pretos ou pardos (11, 12, 19, 20). Uma possivel explicacao e que a segregacao dos genes ligados a hipertensao arterial e diabetes tipo 2 seja independente da raca, ou ate que sejam segregados em conjunto, impossibilitando a identificacao da importancia deles em separado.

O estudo nao exclui a possibilidade de que habitos culturais comuns ou a situacao socioeconomica possam tambem explicar a agregacao familiar. As publicacoes sao contraditorias neste sentido, pois ha estudos sugerindo que o baixo nivel socioeconomico e a falta de acesso aos cuidados de saude estao associados a maior prevalencia de DRC terminal, enquanto outros nao encontraram tal associacao e reforcam que a predisposicao familiar genetica deve ser o fator mais importante para a agregacao familiar (20-23). Neste contexto, estudos recentes tem procurado identificar e tem encontrado alguns genes candidatos que expliquem a predisposicao familiar a doenca renal cronica, tanto na hipertensao arterial como no diabetes mellitus (24-26).

Estudos anteriores nos permitem eleger como pontos estrategicos da intervencao preventiva nesta populacao de risco, a avaliacao periodica da pressao arterial, da glicemia, da creatinina plasmatica e da proteinuria e, quando esta for negativa, a dosagem da albuminuria (27-31).

Em conclusao, este estudo confirma a hipotese inicial de que existe agregacao familiar da DRC em individuos com hipertensao arterial e/ ou diabetes mellitus tipo 2, indicando, em amostra populacional brasileira, que a predisposicao familiar e um fator de risco independente para o comprometimento renal nestas doencas. Esta informacao e muito importante para os portadores de hipertensao arterial e/ou diabetes mellitus tipo 2, assim como para os profissionais de saude que os atendem, pois os familiares diretos de individuos com DRC devem ser os alvos preferenciais para a investigacao diagnostica e intervencoes visando a prevencao primaria e secundaria da DRC terminal. Nesta linha de atencao e fundamental identificar nos familiares de primeiro e segundo graus de pacientes portadores de DRC se, alem do componente familiar, existem outros fatores de risco para DRC presentes, estabelecendo-se o controle e a prevencao. Alem dos ja discutidos habituais vieses de selecao proprios de estudos do tipo caso-controle, a principal limitacao do presente estudo e seu carater regional, nao se podendo extrapolar os resultados para um pais de dimensoes e caracteristicas epidemiologicas continentais. Entretanto, espera-se que os resultados possam estimular a realizacao de estudos correlatos em outras regioes do Brasil.

Colaboradores

FA Almeida, GS Ciambelli, AL Bertoco, MM Jurado, GV Siqueira, EA Bernardo, MV Pavan e RJ Gianini participaram igualmente de todas as etapas de elaboracao do artigo.

Agradecimentos

Agradecemos ao Programa Institucional de Bolsas de Iniciacao Cientifica da Pontificia Universidade Catolica de Sao Paulo e ao Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (PIBIC-PUC/SP-CNPq) pela concessao de bolsas de iniciacao cientifica aos alunos participantes do estudo.

Referencias

(1.) KDIGO. Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Definition, identification, and prediction of CKD progression. Kidney Int 2012; (Supl. 3):63-72.

(2.) U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2013. [acessado 2013 out 9]. Disponivel em: http://www.usrds.org/ reference.aspx

(3.) Sesso RC, Lopes AA, Thome FS, Lugon JR, Santos DR. Dialise cronica no Brasil--Relatorio do censo brasileiro de dialise, 2011. J Bras Nefrol 2012; 34(3):272-277.

(4.) KDIGO. Clinical Practice Guidline for the Evaluation and Management of Chronic Kidney Disease. Other complications of CKD: CVD, medication dosage, patient safety, infections, hospitalizations, and caveats for investigating complications of CKD. Kidney Int 2012; (Supl. 3):91-111.

(5.) Sesso R, Gordon P Dados disponiveis sobre a doenca renal cronica no Brasil. J Bras Nefrol 2007; 29(Supl. 1):9-12.

(6.) Sesso RC, Lopes AA, Thome FS, Lugon JR, Santos DR. Relatorio do censo brasileiro de dialise de 2010. J Bras Nefrol 2011; 33(4):442-447.

(7.) World Kidney Day. [acessado 2013 out 8]. Disponivel em: http://www.worldkidneyday.org

(8.) Dia Mundial do Rim 2013. [acessado 2013 out 8]. Disponivel em: http://www.sbn.org.br/index.php?Noticia &pagina=&dado_id=1420

(9.) Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med 2009; 60:321-337.

(10.) Zunino D. Glomerulopatias hereditarias. In: Riella MC, organizador. Principios de nefrologia e disturbios hidroeletroliticos. Rio de Janeiro: Guanabara-Koogan; 2010. p. 754-764.

(11.) Freedman BI, Soucie JM, McClellan WM. Family history of end-stage renal disease among incident dialysis patients. J Am Soc Nephrol 1997; 8(12):1942-1945.

(12.) Freedman BI, Volkova NV, Satko SG, Krisher J, Jurkovitz C, Soucie JM, McClellan WM. Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 2005; 25(6):529-535.

(13.) Lei HH, Perneger TV, Klag MJ, Whelton PK, Coresh J. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998; 9(7):1270-1276.

(14.) Madeira EPQ, Santos OR, Santos SFF, Silva LA, Innocenzi AM, Santoro-Lopes G. Familial aggregation of end-stage kidney disease in Brazil. Nephron 2002; 91(4):666-670.

(15.) Instituto Brasileiro de Geografia e Estatistica (IBGE). Conceitos. [acessado 2013 out 6]. Disponivel em: http:// www.ibge.gov.br/home/estatistica/populacao/condicaodevida/indicadoresminimos/conceitos.shtm

(16.) Schlesselman JJ. Case-control studies. Oxford: Oxford University Press Inc; 1982.

(17.) Wei X, Li Z, Chen W, Mao H, Li Z, Dong X, Tan J, Ling L, Chen A, Guo N, Yu X. Prevalence and risk factors of chronic kidney disease in first-degree relatives of chronic kidney disease patients in Southern China. Nephrology (Carlton) 2012; 17(2):123-130.

(18.) Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16):1640-1645.

(19.) Bergman S, Key BO, Kirk KA, Warnock DG, Rostant SG. Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease. Am J Kidney Dis 1996; 27(3):341-346.

(20.) Byrne C, Nedelman J, Luke RG. Race, socioeconomic status, and the development of end-stage renal disease. Am J Kidney Dis 1994; 23(1):16-22.

(21.) Perneger TV, Whelton PK, Klag MJ. Race and end-stage renal disease (socioeconomic status and access to health care as mediating factors). Arch Intern Med 1995; 155(11):1201-1208.

(22.) Ward MM. Socioeconomic status and the incidence of ESRD. Am J Kidney Dis 2008; 51(4):563-572.

(23.) Song EY, McClellan WM, McClellan A, Gadi R, Hadley AC, Krisher J, Clay M, Freedman BI. Effect of community characteristics on familial clustering of end-stage renal disease. Am J Nephrol 2009; 30(6):499-504.

(24.) Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS; Family Investigation of Nephropathy and Diabetes Research Group. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008; 40(10):1185-1192.

(25.) Freedman BI, Parekh RS, Linda Kao WH. Genetic basis of nondiabetic end-stage renal disease. Semin Nephrol 2010; 30(2):101-110.

(26.) Bowden DW, Freedman BI. The challenging search for diabetic nephropathy genes. Diabetes 2012; 61(8):19231924.

(27.) de Jong PE, Brenner BM. From secondary to primary prevention of progressive renal disease: the case for screening for albuminuria. Kidney Int 2004; 66(6):2109-2018.

(28.) Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, Jong PE, Coresh J; Chronic Kidney Disease Prognosis Consortium, Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, de Jong PE, Coresh J, El-Nahas M, Eckardt KU, Kasiske BL, Wright J, Appel L, Greene T, Levin A, Djurdjev O, Wheeler DC, Landray MJ, Townend JN, Emberson J, Clark LE, Macleod A, Marks A, Ali T, Fluck N, Prescott G, Smith DH, Weinstein JR, Johnson ES, Thorp ML, Wetzels JF, Blankestijn PJ, van Zuilen AD, Menon V, Sarnak M, Beck G, Kronenberg F, Kollerits B, Froissart M, Stengel B, Metzger M, Remuzzi G, Ruggenenti P, Perna A, Heerspink HJ, Brenner B, de Zeeuw D, Rossing P, Parving HH, Auguste P, Veldhuis K, Wang Y, Camarata L, Thomas B, Manley T. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int 2011; 79(12):1331-1340.

(29.) Hellemons ME, Denig P, de Zeeuw D, Voorham J, Lambers Heerspink HJ. Is albuminuria screening and treatment optimal in patients with type 2 diabetes in primary care? Observational data of the GIANTT cohort. Nephrol Dial Transplant 2013; 28():706-715.

(30.) Hoerger TJ, Wittenborn JS, Zhuo X, Pavkov ME, Burrows NR, Eggers P, Jordan R, Saydah S, Williams DE. Cost-effectiveness of screening for microalbuminuria among African Americans. J Am Soc Nephrol 2012; 23(12):2035-2041.

(31.) Low eGFR and high albuminuria predict end stage kidney disease and death at all ages. BMJ 2012; 345:e7478.

Artigo apresentado em 09/04/2014

Aprovado em 19/06/2014

Versao final apresentada em 21/06/2014

Fernando Antonio de Almeida [1]

Giuliano Serafino Ciambelli [1]

Andre Luz Bertoco [1]

Marcelo Mai Jurado [1]

Guilherme Vasconcelos Siqueira [1]

Eder Augusto Bernardo [1]

Maria Valeria Pavan [1]

Reinaldo Jose Gianini [1]

[1] Faculdade de Ciencias Medicas e da Saude, Pontificia Universidade Catolica de Sao Paulo. faalmeida@globo.com
Tabela 1. Caracteristicas demograficas, distribuicao dos pacientes
estudados de acordo com o pareamento por doenca de base, sexo e idade
e alguns parametros clinicos e laboratoriais.

                                              Casos
                                             (n=336)

Sexo
  Masculino                                     198 (58,9%)
  Feminino                                      138 (41,1%)
Doenca de Base
  Diabetes Mellitus Tipo 2                      171 (50,9%)
  Hipertensao Arterial                          165 (49,1%)
Raca (a)
  Brancos                                       191 (56,8%)
  Pretos                                         70 (20,8%)
  Pardos                                         66 (19,7%)
  Amarelos                                         9 (2,7%)
Idade (anos)                            58,8 [+ or -] 12,3b
  < 50 anos                                      68 (20,2%)
  50-59 anos                                     97 (28,9%)
  60-69 anos                                    107 (31,8%)
  70-79 anos                                     57 (17,0%)
  80 ou + anos                                     7 (2,1%)
Pressao Arterial Sistolica (mmHg)       142 [+ or -] 26 (b)
Pressao Arterial Diastolica (mmHg)       80 [+ or -] 15 (b)
Creatinina Plasmatica (mg/dL)        9,47 [+ or -] 3,25 (b)

                                          Controles         P
                                           (n=389)

Sexo                                                        0,356
  Masculino                                 216 (55,5%)
  Feminino                                  173 (44,5%)
Doenca de Base                                              0,240
  Diabetes Mellitus Tipo 2                  181 (46,5%)
  Hipertensao Arterial                      208 (53,5%)
Raca (a)                                                    0,904
  Brancos                                   270 (69,4%)
  Pretos                                     50 (12,9%)
  Pardos                                     67 (17,2%)
  Amarelos                                     2 (0,5%)
Idade (anos)                         59,3 [+ or -] 12,0     0,603
  < 50 anos                                  73 (18,8%)
  50-59 anos                                118 (30,3%)
  60-69 anos                                119 (30,6%)
  70-79 anos                                 65 (16,7%)
  80 ou + anos                                14 (3,6%)
Pressao Arterial Sistolica (mmHg)       141 [+ or -] 19      0,33
Pressao Arterial Diastolica (mmHg)       88 [+ or -] 12   < 0,001
Creatinina Plasmatica (mg/dL)        0,94 [+ or -] 0,25   < 0,001

(a) = Raca de acordo com a classificacao do IBGE (15); (b) = media
[+ or -] desvio padrao.

Tabela 2. Prevalencia de Doenca Renal Cronica necessitando Terapia
Renal Substitutiva (TRS) entre casos e controles e a relacao com o
grau de parentesco.

Variavel                             Casos      Controles      Odds
                                   (n = 336)    (n = 389)    Ratio (1)
                                     N (%)        N (%)

Nenhum familiar em TRS (3)        285 (84,8)   362 (93,1)
Pais em TRS                         15 (4,5)      7 (1,8)      2,55
Irmaos em TRS                       27 (8,0)     13 (3,3)      2,53
Filhos em TRS                        1 (0,3)      0 (0,0)
Familiares de segundo grau em       22 (6,6)       7(1,8)      3,82
  TRS (4)
Total com familiares em TRS (5)    51 (15,2)     27 (6,9)      2,40

Variavel                          IC 95% (2)      P

Nenhum familiar em TRS (3)
Pais em TRS                       1,03-6,33     < 0,05
Irmaos em TRS                     1,28-4,98     < 0,01
Filhos em TRS
Familiares de segundo grau em     1,61-9,07     < 0,01
  TRS (4)
Total com familiares em TRS (5)   1,47-3,92    < 0,001

(1) = Razao de chance; (2) = Intervalo de confianca de 95%; p = Nivel
de significancia estatistica; (3) = TRS--Terapia renal substitutiva
(hemodialise ou dialise peritoneal); (4) = Familiares de segundo grau
em TRS foram considerados avos, tios ou sobrinhos; (5) = Total de
individuos com pelo menos um familiar em TRS.

Tabela 3. Prevalencia de Doenca Renal Cronica em familiares
necessitando Terapia Renal Substitutiva entre casos e controles
estratificado por raca e doenca de base.

Variavel                     Casos (n)   Controles (n)     Odds
                             Sim / Nao     Sim / Nao     Ratio (1)

Raca (3)
  Brancos                    27 / 191      20 / 270        2,06
  Nao Brancos                24 / 142       7 / 119        2,87
Doenca de Base
  Hipertensao Arterial       24 / 141      12 / 196        2,75
  Diabetes Mellitus Tipo 2   27 / 144      15 / 166        2,08

Variavel                     IC 95% (2)     p

Raca (3)
  Brancos                    1,12-3,79    < 0,05
  Nao Brancos                1,20-6,90    < 0,01
Doenca de Base
  Hipertensao Arterial       1,33-5,69    < 0,01
  Diabetes Mellitus Tipo 2   1,06-4,05    < 0,05

(1) = Razao de chance; (2) = Intervalo de confianca de 95%; p = Nivel
de significancia estatistica; (3) = Raca de acordo com a conceituacao
do IBGE (15).
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No portion of this article can be reproduced without the express written permission from the copyright holder.
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Article Details
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Title Annotation:FREE THEMES/TEMAS LIVRES; articulo en ingles
Author:de Almeida, Fernando Antonio; Ciambelli, Giuliano Serafino; Bertoco, Andre Luz; Jurado, Marcelo Mai;
Publication:Ciencia & Saude Coletiva
Date:Feb 1, 2015
Words:10020
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