Actions Of Angiotensin Ii
Inhibition of Angiotensin II might be the main issue in the diabetes patient with hypertension, nephropathy or both conditions in coexistence. The effects of this active metabolite are potentially damaging to an extent superior to many other peptides and metabolites. This makes inhibition and control of Angiotensin II essential. The renin-Angiotensin system can be stimulated by stress, high sodium intake, or an increase in sympathetic activity. This stimulation results in increased renin...
Microalbuminuria In The Non Diabetic Population
Several population based studies have suggested a link between microalbuminuria , blood pressure and cardiovascular disease 29, 30 . In the Islington heart study an elevated AER was found in 9 of non - diabetic patients over 40 years of age. Those with an elevated AER had more coronary disease OR 5.7 , more peripheral vascular disease OR 7.45 and an increased mortality after 3.6 years OR 24.3 31 . Microalbuminuria is associated with rising blood pressure particularly systolic BP and increased...
Longitudinal Studies Of Gfr In Microalbuminuric Patients With Type Diabetes
There are at least 3 reasons why the rate of decline of GFR may differ in microalbuminuric patients with type 2 diabetes compared with type 1 diabetes. Firstly, there is an age related GFR decline of approximately 1 ml min 1.73m2 year after the age of 40 years 74, 75 . Secondly, there is a higher prevalence of hypertension in type 2 diabetes, which may accelerate renal injury 81 . Thirdly, a proportion of microalbuminuric patients with minimal or no detectable renal structural lesions may never...
The Relation To Clinic Bp
We have found a markedly lower day time BP 147 85 mmHg than clinic BP 163 95 mmHg in 102 consecutive NIDDM and IDDM patients referred to ambulatory BP measurement because of repeated clinic BP gt 140 90 mmHg 124 . The frequency of white coat hypertension in normoalbuminuric diabetic patients is about 25 124,125 . If patients are selected for the presence of organ lesions related to hypertension diabetic nephropathy the proportion of white coat hypertension may be reduced 125 . One study...
Definition Of Microalbuminuria
Microalbuminuria has been defined using a variety of screening procedures for urine sampling 18-26 Urinary albumin excretion rate UAE 20-200 g min overnight urine collection or 30-300 mg 24 h 24 h urine collection . Albumin creatinine ratio A C ratio 2.5-25 mg mmol spot urine Europe . Note that a lower limit of 3.5 mg mmol has been proposed in females because of lower creatinine excretion. Albumin creatinine ratio A C ratio 30-300 mg g spot urine . North America . Albumin concentration AC...
Alternative Hypothesis For The Hspg Alterations Findings From The
The role of PGs in atherosclerosis has been the subject of intense investigations largely owing to the observation that chondroitin sulfate CS and dermatan sulfate DS PGs manly versican and decorin associate with apoB-containing lipoproteins 50 , which are major components of the atherosclerotic plaque. The increase in CS DS-PGs in the intima of atherosclerotic vessels might therefore explain an increased retention of lipoprotein. On the other hand, HS-PGs mainly perlecan are reduced in the...
The Relevance Of The Problem
Nephropathy is a major cause of illness and death of patients with type 2 diabetes mellitus DM , the excess being confined to proteinuric patients due to complications of end-stage renal disease ESRD and particularly due to cardiovascular events 1 . Diabetic nephropathy is the single most common cause of ESRD in the United States and more than one third of all patients enrolled in the Medicare ESRD program are actually diabetics 2 . It derives that costs of renal replacement therapy for...
REFERENCES Uxa
1. Mogensen CE, Christensen CK. Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 1984 311 89-93. 2. Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey. Lancet 1988 2 530-533. 3. Lane PH, Steffes MW, Mauer SM. Glomerular structure in IDDM women with low glomerular filtration rate and normal urinary albumin excretion. Diabetes 1992 41 581586. 4. Tsalamandris C, Allen TJ, Gilbert RE, et...
Contents
1. Rationale for early screening for diabetic renal disease 1 2. Pressure-induced and metabolic alterations in the glomerulus cytoskeletal 13 changes 3. The Steno hypothesis for cardiovascular and renal disease revisited 27 Giovanni Gambaro, Monica Ceol and Augusto Antonello 4. Microalbuminuria and cardiovascular disease 45 Stephen M. Thomas and GianCarlo Viberti 5. The heart in diabetes results of trials 63 Giulio Zuanetti and Elena Sarugeri 6. Microalbuminuria and GFR in type 1 and type 2...
Concluding Remarks
The characteristic lesions of diabetic nephropathy such as renal hypertrophy, increased glomerular hypertension, and altered extracellular matrix metabolism may be intimately related to the effects of high ambient glucose on various growth factors and cytokines that are increased locally or in the circulation. Recent studies using cell culture techniques and experimental animal models have provided important insights into the pathogenetic mechanisms of diabetic nephropathy Table 1 . Much...
REFERENCES Eso
1. Viberti G-C, Walker J, Pinto J. Diabetic Nephropathy. In Alberti K, Defronzo R, Keen H and Zimmet P, eds. The International Textbook of Diabetes. 1992 Vol 2 1267 - 1328. John Wiley amp Sons, Chichester. 2. Barker D, Bull A, Osmond C, Simmonds S. Fetal and placental size and risk of hypertension in adult life. Br Med J 1990 302 259 - 262 3. Barker D, Hales C, Fall C, Osmond C, Phipps K, Clark P. Type 2 non-insulin dependent diabetes mellitus, hypertension and hyperlipidaemia syndrome X...
Evolution Of Diabetic Nephropathy
Diabetic renal disease is characterised by changes in both AER and GFR in predisposed patients. The usual sequence starts with an increase in GFR hyperfiltration , followed by an increase in AER leading to microalbuminuria. Hyperfiltration may persist through the phase of microalbuminuria or it may normalise prior to the onset of overt nephropathy macroalbuminuria , which is accompanied by further increases in AER and a declining GFR. In parallel with these changes, there is a rise in blood...
REFERENCES Bmj
1. Dorman JS, Laporte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE, Drash AL. The Pittsburgh insulin-dependent diabetes mellitus IDDM . Morbidity and mortality study. Mortality results. Diabetes l984 33 271-276. 2. Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in Type 1 insulin dependent diabetes mellitus. Diabetologia 1985 28 590-596. 3. Borch-Johnsen K, Kreiner S. Proteinuria value as predictor of cardiovascular...
REFERENCES Rib
1. Kimmelstiel P, Wilson C. Intercapillary lesions in the glomeruli of the kidney. Am J Pathol 1936 12 83-105. 2. Thomsen AC. The Kidney in Diabetes Mellitus thesis . Copenhagen Munksgaard, 1965. 3. Ditscherlein G. Nierenver nderungen bei Diabetikern. Jena G. Fischer, 1969. 4. Allen AC. So-called intercapillary glomerulosclerosis a lesion associated with diabetes mellitus. Arch Pathol Lab Med 1941 32 33-51. 5. Bell ET. Renal lesions in diabetes mellitus. Am J Pathol 1942 18 744-745. 6. Bell ET....
Glomerular Hyperfunction
From the onset of IDDM, kidney function is characterised by elevation of glomerular filtration rate GFR and renal plasma flow RPF for reviews see 1,2 . Using precise measurements e.g. renal clearance of inulin or iothalamate, it has been found, that mean GFR in groups of short-term IDDM patients is increased by 15-25 - to approximately 135-140 ml min 1.73m2 during 'usual metabolic control' 3-7 . Before start of insulin treatment, but in the absence of ketoacidosis, glomerular hyperfiltration is...
Regulation Of Glomerular Expansion
Cellular mechanical strain is derived from the repetitive stretching and contracting of the cell body as the consequence of cyclic variations in glomerular volume. Therefore the elements opposing distention, i.e., overall glomerular stiffness are important modulators of mechanical strain. The degree of glomerular stiffness is primarily determined by the rigidity of the glomerular scaffold, i.e., peripheral basement membrane and mesangial matrix 19, 36 and by the cellular component. The...
HEPARIN AND GAGs RENOPROTECTION IN DIABETIC NEPHROPATHY DOES IT SUPPORT THE
A number of reports showed that heparin and more generally GAGs prevent and cure experimental diabetic nephropathy 16,64-67 and decrease albuminuria in type 1 and 2 diabetic patients 68,69 . Because defects in HS-GAG synthesis are believed to be so striking in diabetic nephropathy, the treatment of diabetic nephropathy with HS-GAG like substances can be viewed as an experiment to test the Steno hypothesis. However, the activity of these drugs cannot be explained, by the Steno hypothesis, only...
Hyperglycaemia And The Pathogenesis Of Diabetic Nephropathy
The main metabolic disorder occuring in diabetes is hyperglycaemia. Two landmark studies, the Diabetes Control and Complications Trial DCCT and the United Kingdom Prospective Diabetes Study UKPDS showed that intensive blood glucose control clearly reduces the development or progression of diabetic nephropathy 43,44 . Thus, the impact of extracellular high glucose concentrations on renal cell gene expression was investigated in detail Ayo and coworkers reported that prolonged exposure to high...
Disparity Between Declining Gfr And Increasing Aer
Most patients with diabetic renal disease display a decline in GFR that is preceded or accompanied by an increase in AER. However there is a growing body of evidence to suggest that some patients possibly follow an alternate, non-albuminuric pathway to renal impairment. The combination of impaired renal function in association with normoalbuminuria was first highlighted by Lane et al. 3 who identified eight women with type 1 diabetes who had low creatinine clearance but a normal AER. A recent...
Role Of Combination Therapy
It has been proposed that the combination of two or more antihypertensive agents may be beneficial in the treatment of hypertension in the diabetic patient with or without evidence of renal involvement. The various combinations have been reviewed recently 57 . Brown et al postulated in 1993, that the combination of a calcium antagonist with a converting enzyme inhibitor should result in a greater reduction in urinary protein excretion and slow progression of nephropathy, as assessed...
Emerging Concepts Regarding Albumin Handling By The Kidney
A new understanding of the role of proximal tubular cells in the degradation of filtered proteins including albumin has been reached in the last 5 years. Studies by Comper's group and ourselves have shown that albumin is normally degraded in the kidney and that albumin-derived fragments are not detectable by standard immunological methods 89 . The normal renal handling of albumin involves its degradation through lysosomal uptake from the tubular fluid and subsequent exocytosis of the peptide...
Mechanisms Of Hyperfiltration In Diabetes
The pathogenesis of diabetic hyperfiltration is multifactorial. Numerous mechanisms and mediators for this effect have been proposed Table 1 , and are briefly reviewed here. For better clarity, these mechanisms are divided in five areas separately discussed below. However, the reader should be aware of overlap between these processes, and the fact that they act in concert to promote renal hemodynamic alterations in diabetes. POTENTIAL MEDIATORS OF DIABETIC HYPERFILTRATION 1. Factors affecting...
REFERENCES Fue
1. Hooton TM, Stamm WE. Diagnosis and treatment of uncomplicated urinary tract infection. Infect Dis Clin North Am 1997 Sep 11 3 551-81 2. Barnett BJ, Stephens DS. Urinary tract infection an overview. Am J Med Sci 1997 Oct 314 4 245-9 3. Johnson JR, Roberts PL, Stamm WE. P fimbriae and other virulence factors in Escherichia coli urosepsis Association with patients' characteristics. J Infect Dis 1987 Jul 156 1 225-9 4. Hoepelman AIM, Van Buren M, Van den Broek PJ, et al. Bacteriuria in men...
Molecular Cell Biology Of Endothelial Dysfunction In Diabetes
Endothelial dysfunction in diabetes originates from three main sources 1,3,6876 . Firstly, hyperglycaemia and its immediate biochemical sequelae directly alter endothelial function. Glucose transport into endothelial and vascular smooth muscle cells is insulin-independent and is autoregulated in smooth muscle cells, but not in endothelial cells, in which an increase in blood glucose concentration will thus increase the intracellular accumulation of glucose and its metabolites. Figure 2....
REFERENCES Hub
1. Iversen P, Brun C Aspiration biopsy of the kidney. American Journal of Medicine 11 324330, 1951 2. Mazzucco G, Bertani T, Fortunata M, Bernardi M, Leutner M, Boldorini R, Monga G Different patterns of renal damage in type 2 diabetes mellitus A multicentric study on 393 biopsies. American Journal of Kidney Diseases 39 713-720, 2002 3. Parving HH, Gall MA, Skott P, Jorgensen HE, Lokkegaard H, Jorgensen F, Nielson B, Larsen S Prevalence and causes of albuminuria in non-insulin-dependent...
Influence Of Gfr On Albuminuria
Hyperfiltration, defined as a GFR above the range observed in age matched non-diabetic subjects gt 135 ml min 1.73 m2 in young subjects occurs in approximately 20 of normo- and microalbuminuria patients with type 1 diabetes 37, 38 and 0-20 of patients with type 2 diabetes 39, 40 depending on the reference range used. Hyperfiltration occurs less commonly in some ethnic groups compared with others 40 . The increase in GFR usually starts at the stage of normoalbuminuria but may continue for...
REFERENCES Ciq
1. Stalder G, Schmid R. 1959. Severe functional disorders of glomerular capillaries and renal hemodynamics in treated diabetes mellitus during childhood. Ann Paediatr, 193 129-138. 2. Ditzel J, Junker K. 1972. Abnormal glomerular filtration rate, renal plasma flow and renal protein excretion in recent and short-term diabetes. Br Med J, 2 13-19. 3. Mogensen CE, Andersen MJF. 1973. Increased kidney size and glomerular filtration rate in early juvenile diabetes. Diabetes, 22 706-712. 4. Berkman J,...
Classification Of Proteinuria
Measurement of urinary albumin creatinine ratio is most commonly used for diagnosing and tracking urine albumin excretion. Although collection of a 24hour urine sample might be desirable, the use of an early-morning first voided sample is common practice. Early-morning urine is more concentrated, which facilitates detection of albumin. Inclusion of the urinary creatinine factor adjusts for variation in urine volume. Use of the urinary albumin creatinine ratio has been made increasingly feasible...
The Use Of Antihypertensive Agents In Normotensive Dm With Microalbuminuria
The possibility that early therapy will postpone or retard progression of renal injury in diabetes has led to the use of antihypertensive agents in normotensive subjects. UAE has been shown to be reduced in a group of normotensive DM2 patients with microalbuminuria treated with captopril over a period of 6 months, whereas the untreated group had no change in albuminuria 50 . In the Melbourne study 43 there was no change in albuminuria after 12 months treatment with either nifedipine or...
REFERENCES Dlr
1. Zierler KL. Theory of the use of arteriovenous concentration differences for measuring metabolism in steady and non-steady states. J Clin Invest. 1961 40 2111-2125. 2. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron A. Obesity insulin resistance is associated with endothelial dysfunction. Implication for the syndrome of insulin resistance. J Clin Invest. 1996 97 2061-2610. 3. Gros R, Borkowski KR, Feldman RD. Human insulin-mediated enhancement of vascular beta-adrenergic...
Historical Perspective
1982-84 Three studies in patients with type 1 diabetes demonstrate that microalbuminuria predicts the subsequent development of macroalbuminuria overt diabetic nephropathy . This leads to the concept of microalbuminuria as a surrogate for diabetic nephropathy. Macroalbuminuria also becomes a surrogate for assessment of the onset of a decline in glomerular filtration rate. Despite early evidence that microalbuminuria predicts cardiovascular death to a greater extent than renal disease in type 2...
PATHOGENESIS Pathogenesis in general
UTIs almost exclusively result from the ascending route. Bacteria colonizing the perineum and vagina can enter the bladder and further ascend to the kidneys. The most important defense mechanisms of the host, are the urine flow from the kidneys to the bladder and the intermittent voiding, resulting in complete emptying of the bladder. Patients with urinary obstruction, stasis and reflux have more difficulty in clearing bacteria and these conditions also seem to predispose to the development of...
Autoregulation Of The Normal Kidney
Regulation of renal haemodynamics is a vital component in the overall control of renal function 23 . The ability of the kidney to maintain constancy of renal Mogensen CE ed. THE KIDNEY AND HYPERTENSION IN DIABETES MELLITUS. Copyright 2004 by Martin Dunitz, a member of the Taylor amp Francis Group, plc. All rights reserved. function GFR over a wide range of renal perfusion pressures is termed autoregulation 24 figure 1. Experimental studies suggests that autoregulation of GFR is due to...
REFERENCES Ijc
1. R ssing P, Hougaard P, Borch-Johnsen K, Parving HH. Predictors of mortality in insulin dependent diabetes 10 year observational follow up study. BMJ 1996 313 779-784. 2. Parving HH, Osterby R, Anderson PW, Hsueh W. Diabetic nephropathy. In Brenner BM ed . The kidney. 5th ed. W.B.Saunders Philadelphia 1996 pp 1864-1892. 3. Feldt-Rasmussen B. Increased transcapillary escape rate of albumin in type 1 insulin-dependent diabetic patients with microalbuminuria. Diabetologia 1986 29 282-286. 4....
Effect Of Pregnancy On The Subsequent Progression Of Diabetic Nephropathy
For years, there has been concern that the hyperfiltration, hypertension, or heavy proteinuria of pregnancy might damage glomeruli, tubules, and interstitium and accelerate the postpartum progression of DN to end-stage renal disease. In a pooled series of 195 women experiencing pregnancies with DN and having renal function assessed 1-10 years afterwards, 23 were in renal failure and 5.6 had died table 4 . Not surprisingly, the frequency of progression to renal failure after pregnancy was 49 in...
DIABETIC GLOMERULOPATHY The diffuse lesion
This consists of a uniform widening of the mesangial regions figure 1 . It is particularly well exhibited in sections stained by periodic acid-Schiff PAS or by silver methenamine that display structures often described as finger-like radiations from the glomerular hilum. Fig. 1. Diabetic glomerulopathy, diffuse type. There is a slight increase of PAS-positive material in all mesangial regions, radiating from the vascular pole upper right . PAS-haematoxylin.
Possibilities For Interventions
An obvious goal for therapeutic intervention is to optimize glycemic control in order to decrease the risk of late complications. Such therapy will tend to reduce hyperfiltration as discussed above. However, since the pathogenetic basis for the association between glomerular hyperfiltration and later nephropathy is still not clarified, non-glycemic therapy against glomerular hyperfiltration is not presently indicated. It seems rational though, not to prescribe higher protein content in diabetic...
Hyperglycemia And Proteinuria
The onset of microalbuminuria in patients with type 2 diabetes may be transient and related to increases in glomerular filtration rate in association with hyperglycemia. Albuminuria has been shown to decrease with decreases in glucose levels in patients with newly diagnosed type 1 or type 2 diabetes 4547 . However, other researchers reported no decline in albumin excretion with control of hyperglycemia in patients with newly diagnosed type 2 diabetes 48 . The United Kingdom Prospective Diabetes...
Results From Clinical Trials
The safety and vascular effects of LY333531 were evaluated in a one month clinical study on 29 patients with type 1 or 2 diabetes of less than 10 years, with no or minimal retinopathy. This double-blind, placebo-controlled randomized trial showed significant improvement in retinal blood flow and mean circulation time with no change in glycemic indices 84 . Results of the clinical trial of LY333531 in diabetic neuropathy have also been reported recently. A 1-year double-blind, randomized,...
Impaired Autoregulation Of Gfr In Patients With Diabetic Nephropathy
Animal studies have demonstrated impaired renal autoregulation in models of glomerulosclerosis 81 , glomerulonephritis 74 , nephrosclerosis 82,83 and nephrosis 84,85 . In humans Parving et al 68 demonstrated a wide variation in response to clonidine induced acute BP reduction ranging from normal to severely impaired GFR autoregulation in long-term Type 1 diabetic patients with nephropathy. A similar clonidine induced reduction in MABP had no impact on autoregulation in short-term...
Prevalence Of Impaired Gfr During Microalbuminuria In Type And Type Diabetes
Assessments of GFR in patients with microalbuminuria can be performed either cross-sectionally or longitudinally. The former yields data on prevalence and is heavily influenced by age, whereas the latter yields data on rate of GFR decline which is strongly influenced by blood pressure especially in type 2 diabetes. It follows that cross-sectional studies would be expected to show a higher prevalence of impaired GFR in elderly subjects with type 2 diabetes than in younger patients with type 1...
Vegf 1
This growth factor is implicated in the microvascular complications of diabetes, especially retinopathy, but its role in nephropathy remains speculative. VEGF, also known as vascular permeability factor VPF , is a homodimeric glycoprotein that exists in at least five different isoforms that are produced by differential exon splicing 144 . Smaller isoforms are freely soluble and larger isoforms are locally bound to extracellular matrix 145 . Virtually all cell types produce VEGF an increase in...
Renal Autoregulation In Patients With Diabetes
In the first human study of renal autoregulation Parving et al. 68 studied Type 1 diabetic patients with and without diabetic nephropathy. They found no significant change in GFR during acute lowering of BP with clonidine in patients without clinical signs of microangiopathy. The patients had mean blood glucose less than 13 mmol l during the investigation 68 . In the first study of Type 2 diabetic patients with and without diabetic nephropathy 69 no significant change in GFR during acute...
Alternative Views And Future Directions
Current guidelines for the general care of patients with diabetes emphasize lower than usual blood pressure goals typically 130 80 mm Hg , smoking cessation, and the best possible glycemic control 7 . Hence, within the armamentarium for treating early renal disease, the finding of microalbuminuria leads only to the addition of an ACEI or ARB to the recommended regimen. Other issues such as low protein diets, phosphate control, and anemia management are in the province of more established renal...
Which Agent To Use
A large body of evidence has been collected as to the beneficial effects of various antihypertensive agents in DM1 and DM2 patients with abnormal albuminuria 4, 6, 37, 53, 107, 108 . It has been postulated that ACEI and ARB may possess beneficial effects over and above simple blood pressure control, although till recently most studies have involved small numbers of subjects and thereby introduced a potential Type II statistical error. Several meta-analyses of trials involving patients with...
Introduction 1
The term microalbuminuria was first coined in 1969 by Keen et al in Guy's Hospital Reports 1 . They described raised urinary albumin excretion rate AER in patients with type 2 diabetes. The authors noted that the AER correlated with the systolic blood pressure and made the prescient speculation that the results of hypertension and hyperglycaemia combine to increase the degree of albuminuria. In 1974 Parving et al described that microalbuminuria was also present in non-diabetic populations with...
Overnight Albumin Excretion Rate And Blood Glucose Control
Several previous reports have suggested a relationship between poor blood glucose control and increased urinary albumin excretion 39,41,42,43 . In our study 14 we found that only females with microalbuminuria had significantly elevated HbA1c values compared with diabetic patients with normoalbuminuria. Blood glucose control tends to be poorer during puberty, particularly in girls, which may be explained by changes in hormonal and or lifestyle factors 44,45,46,47,48 . In recent studies 49,50,102...
Overnight Albumin Excretion Rate And Arterial Blood Pressure
The normal range for diastolic blood pressure in diabetic boys Figure 3 and girls Figure 4 aged 8 to 18 years with normoalbuminuria was determined in a study of the relationship between blood pressure and urinary albumin excretion in young Danish Type 1 diabetic patients 69 . Figures 3 and 4 also include data from patients diagnosed with micro- and macroalbuminuria 69 . Ten out of 16 boys with microalbuminuria had diastolic blood pressure above the upper quartile while eight out of 14 girls...
The Central Role Of The Heparan Sulfate Proteoglycan And The Steno Hypothesis
It has been suggested that the first change in the extracellular matrix in diabetes might be an undersulphation of HS- proteoglycans PGs 10 , followed by an absolute decrease of HS 11 . These alterations in HS-PG metabolism have been identified as the possible molecular basis for the abnormal permselectivity of glomerular and extrarenal capillaries in diabetes mellitus. HS-PGs consist of a central core protein to which HS-GAG side chains are linked. These HS-GAG side chains are formed by...
REFERENCES Sol
1 Deckert T, Poulsen JE Diabetic nephropathy fault or destiny Diabetologia 21 178-183, 1981. 2 Moloney A, Tunbridge WMG, Ireland JT, Watkins PJ Mortality from diabetic nephropathy in the United Kingdom. Diabetologia 25 26-30, 1983. 3 Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR The changing natural history of nephropathy in type I diabetes. Am J Med 78 785-794, 1985. 4 Seaquist ER, Goetz FC, Povey S Diabetic nephropathy an hypothesis regarding genetic susceptibility for the...