End stage renal disease (ESRD) is a complex disorder encompassing a large variety of phenotypes. Each phenotype is a result of an underline kidney disease and superimposing environmental and genetic factors. The complexity of the phenotypic makeup of renal diseases makes it difficult to diagnose and predict their progression and to decide on the optimal treatment for each patient. ESRD is an advanced form of chronic renal failure where renal function has declined to approximately 10% of normal prior to initiation of dialysis or transplantation. The impact of genetic variability on the development of renal failure is becoming clearer and emphasizes the need to elucidate the genetic basis for renal diseases and its complications. This would lead to the better understanding of different phenotypes observed in ESRD and would enable us to determine whether a patient is genetically predisposed to such complications.

Renal functions and blood pressure are tightly linked. Physiologically, kidneys provide a key mechanism of chronic blood pressure control via their infinite gain mechanism 1, whereas elevated blood pressure affects renal function via pressure natriuresis mechanism 23. Pathophysiologically, long standing hypertension attenuates pressure natriuresis 4 and can cause or at least contribute to renal damage 5. Therefore, hypertension is one of the imperative contributing factors associated with both causation and progression of renal failure 6. It is a common, polygenic and complex disorder resulting from interaction of several genes with each other and with environmental factors 7.

The Renin-Angiotensin system (RAS) is a key regulator of both blood pressure and kidney functions and may play a role in their interaction. Its role in the pathogenesis of hypertension is well documented but its contribution to chronic renal failure and progression of kidney nephropathy is still debated 8. It has been seen that RAS blockers i.e. both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers lower blood pressure and can also attenuate or prevent renal damage 9. However, major inter individual treatment responses to RAS inhibitors have been noted 10 and it remains difficult to predict responders based on known pathophysiological characteristics 11. In such a situation, genetic variability in the genes of different components of RAS is likely to contribute for its heterogeneous association in the renal disease patients.

Angiotensin converting enzyme-1 (ACE-1) is an important component of RAS and it determines the vasoactive peptide Angiotensin-II. Its inhibition reduces the pace of progression of majority of chronic nephropathies 1213. The gene coding for ACE is subjected to an insertion/deletion (I/D) polymorphism that is a main determinant of plasma and tissue ACE levels 14. Presence (insertion-I) or absence (deletion -D) of a 287 bp fragment in the 16^th intron of ACE gene has been linked to high prevalence of renal disorders among hypertensives and has been studied extensively 15. Furthermore, the D allele has been linked to a failure of the renoprotective action of ACE inhibitors to retard the development of end stage renal disease (ESRD) 1617. Despite of the fact that most of the recent studies have suggested high prevalence of D allele among hypertensive individuals 1318, still there are contradictory reports available 19. This inconsistency could be in part due to the genetic and environmental heterogeneity among different ethnic groups 20.

In the present study, we have investigated the association between ACE gene polymorphism and the causation of renal disease in 127 end stage renal disease patients from north India. The major aim of the study was to explore whether the limited observations of association of ACE genotypes and renal function in patients of different ethnicities can be extended to all patients with primary renal disease among North Indians.

The data presented in this study is the first report from north India regarding the role of genetic variants of ACE gene in causation and progression of renal diseases. The findings clearly establish the association of ACE I/D gene polymorphism with the renal failure. The DD genotype was found to be a major risk determinants of ESRD among north Indians (OR = 5.74). Simultaneously, it was also observed that the hypertensive state is an important physiological state that affects the causation or progression of renal diseases.

Hypertension being a complex polygenic disorder is often regarded as a physiological state affected by "Genetic Predisposition", which highlights the presence of heritable allelic differences in the genes coding/associated with different components of RAS. Such differences result into differential transcript and protein expression accounting for different rates of progression of hypertension and other related diseases mainly, renal failures 22. Among different RAS genes like angiotensin (AGT), angiotensin II type-1 receptor (AGTR1), rennin and ACE, the I/D polymorphism of ACE has been reported as a crucial determinant. The DD genotype have unanimously been shown to have increased serum ACE production and activity while II and ID genotypes produces low and intermediate levels of proteins respectively 22.

Angiotensin II has a potentially important role in the development of Glomerusclerosis 23 through its action as a growth factor and regulator of the cell growth and matrix production 2425. It has also been implicated that the inhibition of its production attenuates the progression of diabetic and non -diabetic nephropathies 2627. In this regard the importance of ACE and its genetic variants becomes more apparent. Although most of the studies on ACE I/D polymorphism have been very encouraging with regard to the role of DD genotype in the pathophysiology and treatment of diabetic nephropathies 28. Similar studies in other types of nephropathies have yielded inconsistent results. For examples studies on autosomal dominant polycystic kidney patients have reported adverse effects of the D allele of the ACE gene in some cases 2930, whereas number of other studies did not confirmed such association 3132. Similarly, an adverse effect of D allele was also found in some studies in IgA nephropathy or ESRD in general 33. In a study of 80 family trios (proband and parents) with interstitial nephritis, the D allele was transmitted significantly and more frequently than would have been expected if no association existed. Further more, the ID and the DD genotypes were associated with a faster rate of renal function decline 34.

Our study revealed a highly significant difference in the presence of DD genotype and D allele of ACE gene among ESRD patients and normal controls validating that the ACE gene polymorphism is an important genetic determinant of non-diabetic nephropathies too. Overall findings were demarcating that D allele of ACE gene confers a high risk of developing renal diseases (OR = 3.36) and this association was highly compounded when D allele was present in homozygous state (OR = 5.74). Even inclusion of the heterozygous ID state known to have intermediate levels of ACE production along with the DD genotype depicted a high risk of renal failures (OR = 3.8). Therefore the finding that ACE DD genotype and D allele is associated with renal ESRD is likely to be true for the north Indian populations.

Furthermore, we postulate that DD genotype confers a greater role in hypertensive state as ~87% of DD genotype patients were hypertensive and this phenomenon could might have been the major factor behind the association of ACE genotypes and ESRD patients from north India. However, no significant differences of the renal function parameters (serum creatinin and protein urea) among the DD and non DD genotypes suggests that this variant might not be a factor involved in the causation of renal damage but could have aggravated or related to the progression of the disease. However, being a referral tertiary care centre, most of the patients reported to us were from outside and had incomplete records of various parameters related to progression of the diseases. Hence due to the non-availability of various data points required for the regression analysis of serum creatinin profile, we have not been able to evaluate the role of different ACE genotypes in the progression of the disease as suggested by McLaughlin et al, 1996. 35.

Various reports are available supporting that how the presence of DD genotype operates at cellular level leading to hypertensive state and renal diseases 28. Caucasians with DD genotype have serum ACE levels and intra-cellular ACE activity twice than those of II genotype 2236. High ACE activity leads to increased Angiotensin II levels that promote expression of growth factors and proliferation of mesanglial cells and matrix leading to glomerusclerosis 27. Incidentally, human genetic variation studies based on autosomal, Y-chromosomal and mt-DNA markers have suggested that north Indians carry high frequency of Caucasian specific mutations and haplotypes 3738. Furthermore, the phylogenetic assessments based on the neutral markers have also shown the clustering of north Indians with other Caucasian populations 3940.

In experimental models of chronic renal disease 41 and in human diabetic nephropathy 42, pharmacological blockade of ACE significantly slows down the rate of decline in renal function. However, the data regarding the relationship between the ACE inhibition and DD genotype has been conflicting. A good correlation was found in IgA nephropathy and diabetic nephropathy 27 but was not confirmed in primary glomerulonephritis 43 and proteinurea 44. In the present study, we have not been able to deduce the association of ACE inhibition and DD genotype due to non-availability of the information of anti-hypertensive therapy.

In addition to the non availability of multiple values of various renal function parameters and information of the anti-hypertensive therapy, the results of the present study may have also been influenced by the study design and composition of the sample population. Regarding study design, it may be possible that being a single centre study, the samples are over representative of a particular genotype secondly it has been widely accepted that the Indian society is fragmented into numerous sub-groups identified by the name of 'caste' and hence there is a high possibility that the social structuring and stringent marital practices since last 3–4 Ky have also resulted into genetic structuring. We suggest that multi centric studies involving a much higher number of subjects and including controls from different socio-cultural strata will lead to validate the strong association found in the present study.

Conclusively, ACE gene polymorphism appears to be an important genetic determinant in causation and progression of renal diseases and ACE DD genotype was found to be strongly associated with ESRD among north Indians. Further studies in this regard will open a plethora of options like timing, type and doses of anti-hypertensive therapy. Incorporation of such approaches will allow an advance anticipation of the clinical outcome and can lead to a shift from "One treatment fits all" approach.

The author(s) declare that they have no competing interests.

GT collected all the samples and has performed experiments. PD has compiled the results and carried out data analysis. FK has interpretated the data and has written the manuscript. RKS and PBV were involved in the patient work up. SA conceptualized the paper and provided important intellectual inputs in the interpretation of the data and preparation of the manuscript. All the authors have read and approved the manuscript.