Who to screen for chronic kidney disease Screening the general population for CKD is not ju sti \201 ed. However, targeted investigation of groups at high-risk of CKD does allow the majority of cases to be identi \201 ed at an early stage and enables timely therapeutic in tervention. The following groups should be tested for CKD: \200 \200 \200 Progression of CKD CKD is a potentially progressive disease. Experimental studies and obser vational data in humans suggest that CKD may progress as a result of both: \200 ongoing i njury from the primary renal insult; \200 a maladaptive response that is initiated within the kidney following a renal injury. patients with hypertension; patients with diabetes (types 1 and 2); patients with cardiovas cular disease (ischemic heart dis- ease, chronic heart failure, peripheral vascular disease and cerebral vascular disease); anyone found to have hematuria or proteinuria on an incide ntal medical examination; patients receiving drugs known to be potentially nephro- toxic (N SAIDs for example); patients known to have structural renal tract disease, renal calculi or prostatic hypertrophy; people with a family history of stage 5 CKD or heredi- tary kidney disease. Once a critical reduction in renal mass has occurred it appears that CKD progresses inexora bly even if the initiat- ing insult has resolved. This has led to the concept that a \200 \230maladaptive \200\231 response occurs within the kidney which in turn leads to further d amage (Fig. 11.1.2). There is a large body of experimental work which has examined potentia l maladaptive responses. Suggested mechanisms include: Hemodynamic factors: \200 \200 Further investigations Further investigations should initially be directed at identi- fying the underlying cause of CKD. This may require several different biochemical and immu- nolo gical tests as well as some radiological interventions. A renal USS is not justi \201 ed i n all patients with CKD but should be undertaken in anyone with: \200 \200 \200 \200 \200 systemic hypertension; intraglomerular hypertension. Nonhemodynamic factors: \200 \200 \200 \200 \200 \200 proteinuria; hyperlipidemia; glomerular hypertrophy; mesangial cell activation and prolifer ation; biologically active in \201 ltrating cells; production of prosclerotic cytokines an d growth factors. CKD stage 4 or 5; visible or invisible hematuria; symptoms of renal tract obstruction; rapi dly declining GFR; family history of polycystic kidney disease; The extent to which any of these factors contributes to the progression of CKD in humans is unknown. Observational studies suggest that whereas some patients with CKD experience a li near and predictable decline in renal function with time, others (possibly the majority) ma y have extended periods during which their renal func- tion is completely stable but which are punctuated by sud- den and stepwise decrements in renal function. Longitudinal studies suggest that renal function declines with age. Whether this is part of the natural aging pr ocess (and therefore should be considered normal) or a patho- logical condition remains con troversial. Such studies have generally included those at risk of CKD (diabetes, hyper- ten sion) and therefore the findings of an age-related decline in renal function may re \202 e ct unrecognized CKD in an aging population with comorbidity. Studies of people without como rbidities generally support the view that renal function declines only very slowly with age and that In patients with unexplained CKD and a normal renal tract, renal biopsy may be required. Th ese investigations are discussed in detail elsewhere in this book in the relevant chapters. Patients with CKD should also be investigated for complications of CKD, principally anemia and renal bone disease. Epidemiological data suggest that the prevalence of CKD- associate d complications increases sharply once GFR declines to <45 mL/min/1.73 m2. Therefore such p atients should have the following measured: \200 hemoglobin to identify anemia \200\223 other causes of non- CKD-related anemia should also be considered and excluded where necessary; calcium, phosphate and alkaline phosphatase; K. HARRIS 394 Renal injury Repair Decreased nephron number Phenotypic changes in intrinsic glomerular cells Glomerular hypertension Macrophage recruitment Systemic hypertension Release of cytokines and growth factors Proteinuria Glomerular hypertrophy Hyperlipidemia Increased ECM production Glomerulosclerosis CHRONIC KIDNEY DISEASE Fig. 11.1.2 Potential \200\230maladaptive \200\231 responses which contribute to progressi on in CKD. \200 \200 diabetes; smoking; Afro-Caribbean or South East Asian. GFR can remain normal into the 9th decade of life. Hence age alone is not a justi \201 cat ion for dismissing the \201 nding of CKD as unimportant. The K/DOQI classi \201 cation d e \201 nes CKD at a given point in time. Clinically it is more useful to understand how CK D is progressing with time in order to focus efforts on those in whom a rate of decline of GFR would lead either to com- plications of CKD or to the need for RRT within their lifetim es This requires repeated measurement of renal function and for the results to be interpret ed in the clinical context of the individual patient. For example, young patients with CKD 4 progressing at a slow rate may be at greater risk of requiring RRT within their lifetimes than eld- erly patients with CKD 2 progressing at the same or an even faster rate. What co nstitutes progression of CKD is controversial. NICE has recently suggested that progression of CKD should be de \201 ned as a decline in GFR of: \200 Assessment of proteinuria Either urinary protein or albumin excretion must be quan- ti \201 ed in patients with CKD. The level that constitutes \200\230signi \201 cant proteinu ria \200\231 and hence would trigger further intervention is debated but typically guidelin es suggest a total protein excretion of 1 g/24 h (equivalent to a PCR of 100 mg/mmol or ACR of 70 mg/ mmol) in non diabetic CKD, although NICE has recently proposed a lower protein e xcretion threshold of 0.5 g/24 h. In diabetics, microalbuminuria (ACR \211 2.5 mg/mmol in men and ACR \211 3.5 mg/mmol in women) is an indication for the use of ACEIs or ARBs. Treatment The speci \201 c goals of treatment in CKD should be to: \200 >5 mL/min/1.73 m2 within 1 year minimize the risk of any additional renal injury (in par- ticular nephrotoxic drugs should be avoided); reduce the risk of death from CVD; reduce the rate of progression; manage the complications of CKD. or \200 \200 \200 >10 mL/min/1.73 m2 within 5 years in the absence of other causes of an alternative acute de terioration in renal function. Progression of CKD is more likely when the following risk factors are present: \200 \200 \200 Cardiovascular disease It is important to remember that at any stage of CKD the risk of pre mature cardiovascular death is far greater than the risk of progression. cardiovascular disease; proteinuria; hypertension; CHAPTER 11.1 Assessment of chronic kidney disease 395 For patients with CKD 3, the 5 year risk of progressing to require RRT has been estimated t o be only 1% compared to a 25% risk of dying. Many of the primary and secondary prevention studies in CVD excluded patients with CKD so the evidence base is generally poor. However, the principles of prevention and management of CVD in people with early CKD should not be d ifferent from those employed in people without CKD and should include where appropriate: \200 \200 \200 \200 Table 11.1.3 Key educational messages for patients and healthcare professionals for the man agement of CVD and CKD Stop smoking Lifestyle advice Exercise Weight management Healthy diet Avoid nephrotoxic agents (e.g. NSAIDs) Review medications lifestyle measures; blood pressure control; lipid lowering; antiplatelet agents. According to best practice guidelines Treat diabetes (if present) According to best practice guidelines Suggest patients buy their own BP meter Threshold for treatment is 140/90 mmHg Target BP is: Treat hypertension In more advanced CKD the underlying vascular pathology includes arterial medial calci \201 cation as well as athero- sclerosis. This may not respond to the modi \201 cation of trad itional risk factors (one prospective randomized trial in diabetic HD patients failed to sh ow any survival benefit from statins). In advanced CKD cardiovascular death is associated w ith abnormalities in markers of bone and mineral metabolism. Although there is speculation of a potential bene \201 t from treatments aimed at normalizng these abnormalities, there are no interventional studies available to demonstrate an improved clinical outcome from su ch intervention. 130/80 mmHg 125/75 mmHg if PCR >100 mg/mmol ACEIs or ARBs are \201 rst-line agents in pro teinuric CKD According to best practice guidelines for primary and secondary prevention Treat hyperlipidemia For secondary prevention Antiplatelet agents (aspirin) According to local guidelines (for example annual in \202 uenza and pneumococcal vaccinati ons) Vaccinations Reducing the rate of progression Treatments which are important in preventing CVD have many similarities with those that should be used in pre- venting progression of CKD, and can be used to provide a straightforward health educational message to patients (Table 11.1.3). I n general there is also considerable overlap in manage- ment protocols for CKD, diabetes an d CVD, and given that these commonly coexist in the same patient there is a strong argument for managing such patients as part of a chronic \200\230vascular risk \200\231 management program. For patients these messages should be supported by infor- mation lea \202 ets and there sh ould ideally be a dedicated educational program about CKD. Treatments that may be effective in delaying progression include: \200 \200 \200 treatment of hypertension; inhibition of the renin angiotensin system; dietary protein rest riction; Treatment of systemic hypertension in CKD can effectively reduce the rate of progression. T he ideal target blood pressure is debated but suggested targets are: \200 \200 Treat the primary disease Where possible, treatment aimed at the underlying pri- mary disea se should be instituted to minimize any subse- quent or ongoing damage to the kidney. Many renal diseases have no speci \201 c treatments, but exam- ples include: \200 130/80 mmHg for patients without proteinuria; 125/75 mmHg for those with proteinuria. ACEIs and ARBs reduce the rate of progression of CKD in diabetic nephropathy and proteinuri c CKD of any cause over and above what might have been expected from blood pressure control alone. Their mechanism of action may include reducing intraglomerular hypertension and pro - teinuria. ACEIs and ARBs are being used in combination in patients with proteinuric CKD t o attempt to augment any antiproteinuric effect. There is some evidence to support this app roach but the risk of side-effects (especially hyperka- lemia) may be greater, requiring mo re intense monitoring. The effect of low protein diets on the progression of CKD has been e xtensively studied with variable results. Such diets are dif \201 cult to maintain and if not properly monitored are associated with the risk of protein-calorie malnutrition which c arries a poor prognosis in patients starting RRT. With the bene \201 ts obtained from lowe r BP targets and the use of ACEIs and ARBs, many nephrologists no longer routinely prescrib e such diets for patients with CKD, although their use may be justi \201 ed in a highly mo tivated optimal control of the blood sugar in diabetics has been shown to delay the onset of CKD an d delay any subse- quent progression that might otherwise have occurred; immunosuppression has been shown to delay progres- sion of a small number of immunologically mediated renal d iseases; prevention of urinary tract sepsis in children with re \202 ux nephropathy. Treat factors involved in any maladaptive renal response Treatments aimed at minimizing ong oing renal damage from any maladaptive response that has occurred should be considered. Suc h treatments are nonspeci \201 c but have proved highly effective in reducing the rate of progression in a number of controlled clinical trials. K. HARRIS 396 patient with advanced CKD, as long as they are supervised by a dietician. There is some evi dence that statins can reduce the level of proteinuria in patients with proteinuric CKD, bu t their effect on progression is unknown. However, it is important to stress that such guidelines pro- vide an idealized overview of the optimal long-term man- agement of a population with CKD. They were not designed to repl ace a careful clinical risk assessment of an individual patient, nor the development of an appropriate ongoing management plan for that patient. Managing the complications of CKD Treatments for speci \201 c CKD-associated complications (anemia, bone disease) are dealed with in other chapters of this book. Referral to specialist care The majority of patients with CKD do not need follow- up by a r enal specialist and can be appropriately managed by generalists in primary care according t o locally agreed principles and guidelines (see Fig. 11.1.3 for a typical example). Referra l to a specialist may add value in the following settings. Follow-up CKD is a potentially progressive disease associated with a number of signi \201 cant complications and accelerated CVD. It is thus essential that any patient with CKD is m onitored both for evidence of progression and for the development of complications. The fre quency with which monitoring is required and the type of monitoring needed is dependent on: \200 \200 \200 To establish a diagnosis and agree a management plan in a patient with suspected CKD of any stage This will include the identi \201 cation and advice on control of risk factors for progression of CKD. The majority of such patients do not need long-term spe- cialist follow -up as the plan can frequently be implemented and the patient followed in primary care. Any circumstances where by re-referral would be appro- priate should be made explicit. stage of CKD; rate of progression; any risk factors for CVD or progression of CKD. Thus it is important that patients receive an individualized plan for follow-up which is ap propriate to their needs. Patients at high risk of progression (those with proteinuria or d if \201 cult-to-control hypertension and those who have already demonstrated they are prog ressing) generally require more frequent monitoring than those without such risk factors. M any health economies have devised guidelines to aid health professionals in their ongoing m onitoring and assessment of patients with CKD. In order to improve their day-to-day utility , such guidelines have often been summa- rized into simple \202 ow charts, e.g. Fig. 11.1 .3. The treatment of complex kidney disease Specialist expertise and the required monitoring wi ll not be available in primary care. For instance, this would include the treatment and ong oing monitoring of complex glomerular disease. To allow timely planning for RRT This will be necessary for all patients progressing to ESR D despite optimal treatment, since this has been shown to improve patient outcomes. Full Biochemical Profile: \200 U+E \200\231s \200 Bicarbonaia \200 Albumin \200 Cal cium and Phasphate Allcaline Phasphatase \200 Fastin glucouse \200 Lipid profile CKD 1, 2 & 3 Medicine management FBC + Full biochemical profile* PCR >100 mg/mmol Microscopic Haematuria +ve or \210\222ve PCR <45 mg/mmol PCR 45-100 mg/mmol CKD 4 Medicine management - no NSAIDs. Discuss with or refer to nephrologist Consider glomerulonephritis especially if symptoms/signs suggestive of systemic disease or PCR >45 Microscopic Haematuria \210\222ve Microscopic Haematuria +ve* if clinically indicated. (See box overleaf). Follow urology guideline Microscopic haemaburia defined by 2 positive fast results in a 2 month period Discuss with or refer to nephrologist see Referral Guidelines Information DIAGNOSIS NO DIAGNOSIS CKD 5 Perform renal ultrasound only if history suggestive of urological disease of if +ve FH of p olycystic kidney disease Urgent referral to nephrologist if clinically appropriate. DIAGNOSIS Fall in eGFR >15ml in 12 months or 5ml/year over 3 years \200 PCR >100 \200 Fall in eGF R of >15% after starting ACEi or ARB Manage in Primary Care \200 Patient Information leaflets and advice including lifestyle Annual eGFR and PCR information, stopping smoking, exercise, weight management CKD 1 & 2 Treat hypertension according to guidelines: Threshold for Rx 140/90 - Target 130/80 (125/75 if PCR >100 mg/mmol) - ACEi or ARB as first line agents - Suggest patient buys own BP meter Fall in eGFR >5mls in 12 months \200 PCR >100 \200 Fall in eGFR or >15% after starting ACEi or ARB Treat hyperlipidaemia according to guidelines \200 Aspirin if indicated \200 Influenza/ pneumocoocal vaccination \200 Review medications, Avoid NSAIDs. 6/12 eGFR and PCR CKD 3 Fig. 11.1.3 Principles for the assessment, management and referral of adults with CKD. (Red rawn from the East Midlands Renal Network, http://www.emrn.org.uk/.) CHAPTER 11.1 Assessment of chronic kidney disease 397 In some cases specialist advice can appropriately be obtained using a \200\230virtual cons ultation \200\231 (letter or telephone discussion) without he need for the patient to visit the hospital. Ideally specialist nephrology services should support primary care by provid ing 24 h telephone access to quali- \201 ed advice. Based on the principles outlined abov e, NICE has recently suggested that the following groups of patients may bene \201 t from specialist advice. In the UK a Gold Standards Supportive Care Register has been developed on which a number of patients with CKD should be included in order to allow them to receive the most appropriat e supportive care. Inclusion on the register should be considered if any of the following a pply: \200 \200 those with CKD 5 or frail individuals with CKD 4; those thought by the care team to be in t he last year of life; those choosing conservative treatment (no RRT) or those discontinuing dialysis or opting not to restart dial- ysis if their transplant is failing; those with di f \201 cult physical symptoms (e.g. anorexia, nausea, pruritus, reduced function status, i ntractable \202 uid overload) or psychological symptoms despite opti- mal therapy. Group 1 Those in whom it is likely to be useful to establish a diagno- sis and in whom spec ialist treatment and monitoring may be required: \200 proteinuria \211 1 g/24 h unless e xplained by diabetes (PCR \211 100 mg/mmol or ACR \211 70 mg/mmol); \200 proteinuria \211 0.5 g/24 h and hematuria (PCR \211 50 mg/mmol or ACR \211 30 mg/mmol); \200 suspe cted rare or genetic causes of CKD; \200 suspected renal artery stenosis (suggested by a fall in Further reading Royal College of Physicians and the Renal Association. Chronic Kidney Disea se in Adults: UK Guidelines for Identification, Management and Referral. 2006 (http://www.r enal.org/CKDguide/ full/UKCKDfull.pdf). GFR of >25% on initiating ACEI or ARB); NICE. Chronic Kidney Disease. National clinical guideline for the management of adults with chronic kidney disease in primary and secondary care (draft for consultation 2008). (http: //www.nice. org.uk/guidance/index.jsp?action=folder&o=39905). hypertension that remains poorly controlled despite the use of at least four antihypertensi ve drugs at therapeutic doses. UK Department of Health. The National Service Framework for Renal Services. Part one: Dialy sis and Transplantation; 2004. (http://www.dh.gov.uk/en/Publicationsandstatistics/Publicati ons/P ublicationsPolicyAndGuidance/DH_4070359). Group2 Those at high risk of needing RRT in the near future: \200 patients with CKD 4 and 5; \200 patients with a rapidly declining eGFR (>5 mL/min/1.73 m2 in \211 1 year) (>10 mL/min/1.73 m2 over \211 5 years). UK Department of Health: The National Service Framework for Renal Services Part Two: Chroni c Kidney Disease, Acute Renal Failure and End of Life Care; 2005. (http://www.dh.gov.uk/en/ Publ icationsandstatistics/Publications/PublicationsPolicyAndGuidance /DH_4101902). \200 The importance of referral to allow timely planning and preparation for RRT (including pre- emptive transplanta- tion) is well-accepted and was highlighted in the standards laid out i n Part 1 of the National Service Framework for Renal Services. Late referral of patients wi th advanced CKD is known to be associated with increased morbidity and mortality, increased length of hospital stay, and increased costs. The lack of time to prepare patients referre d late for dialy- sis, particularly the establishment of permanent vascular access for hemo dialysis, appears to be the dominant factor in the adverse outcomes, but untreated anemia, bone dis- ease, hypertension and acidosis may also contribute. Internet resources East Midlands Renal Network: http://www.emrn.org.uk European Best Practice Group Guidelines of the ERA- EDTA: http://www .ndt-educational.org/ National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI): http://www.kidney.org/professionals/kdoqi/ index.cfm National Institute for Health and Clin ical Excellence: Palliative and supportive care It is now recognized that not all patients with advanced CKD will necessarily bene \201 t from RRT, especially when quality-of-life issues are conside red. Active conservative management of advanced CKD may allow the patient to maintain a goo d quality of life for sev- eral months, which may be preferable to multiple admis- sions to hospital as part of establishing RRT. Some patients already on RRT but who develop intoler able symptoms from worsening comorbidities may also wish to withdraw from RRT. End-of-life care is now recognized as part of the much wider area of (noncancer-related) palliative car e and sup- portive care for people living, sometimes for years, with life-threatening condi tions including CKD. It is an active treatment option and requires multidiscipli- nary and multiagency input to be successful. http://www.nice.org.uk UK Renal Association: http://www.renal.org/ UK Renal Registry: http://www.renalreg.com/ See also CKD in the elderly, p. 468 Dialysis strategies, p. 480 Hematological disorders in CKD, p. 426 Skeletal disorders in CKD, p. 432 Vascular access, p. 488 D. TETA 398 Endocrine disorders in chronic kidney disease Introduction Chronic kidney disease (CKD), including end-stage renal disease (ESRD), has ma jor effects on the endocrine system. The failing kidney is associated with alterations of t he pro- duction, transportation, metabolism, elimination and protein binding of hormones. T his may result in increased (most commonly seen in CKD), unchanged or decreased circulat- i ng hormone levels as summarized in Table 11.2.1. In addi- tion, there may be decreased sens itivity to hormones, as a result of an altered target response (e.g. insulin). Therefore, t he \201 nal effect of a particular hormone on its target may not necessarily re \202 ect its circulating level. decreased levels due to a reset in the feedback loop to a lower TSH level for a given level of thyroid hormone); absence of the usual nocturnal TSH surge; blunted TSH response to thy rotropin-releasing hor mone (TRH) administration (corrected by recombinant EPO); TSH admini stration results in an increase in T3, but in a blunted response in T4 (not corrected by re combinant EPO). \200 Signi \201 cance of thyroid axis abnormalities in CKD Despite these biochemical abnormalit ies, clinical thyroid disease is not common in CKD and ESRD. Levels of T4 and T3 may be low without clinical hypothy- roidism. Despite the described biochemical abnormalities the TSH concentration in plasma remains a good indicator of hypo- and hyperthyroidism in CKD. Abno rmal thyroid function tests normalize after successful kidney transplantation. Mechanisms of endocrine dysfunction in CKD Increased circulating hormone levels This may re sult from a number of processes. Decreased GFR resulting in impaired renal clearance: \200 \200 \200 \200 \200 prolactin; insulin; glucagons; calcitonin; leptin. Growth hormone Plasma GH levels are increased because of: \200 \200 increased secretion; impaired clearance. Increased secretion: \200 parathyroid hormone (PTH). Sensitivity to GH is decreased. Insulin-like growth factor-1 (IGF-1) levels are normal. Accumulation of inactive metabolites which may crossre- act with a de \201 ned hormonal as say, thus arti \201 cially increas- ing the measured circulating level: \200 \200 \200 Signi \201 cance of growth hormone abnormalities in CKD Children Growth retardation despit e elevated GH and normal IGF-1. Other factors may contribute to growth retardation in this setting including: \200 \200 \200 \200 PTH; calcitonin; prolactin. Decreased sensitivity to hormones Altered target response: \200 \200 \200 \200 \200 protein wasting; metabolic acidosis; hyperparathyroidism; recurrent infections. insulin; growth hormone; PTH; erythropoietin; 1,25-(OH)2 vitamin D3. Recombinant human growth hormone (rHGH) can restore growth velocity and increases muscle ma ss without affect- ing epiphyseal closure and glucose tolerance. Decreased circulating hormone levels Decreased secretion by the diseased kidney: \200 \200 Adults The role of GH in general adult health remains unclear and therefore it has proved d if \201 cult to determine the clinical consequences of GH dysregulation in CKD and ESRD. P reliminary results of small clinical trials have shown that rHGH may be useful in improving muscle wasting, a com- mon feature in patients on hemodialysis. Further data are awaited f rom large randomized controlled clinical trials. 1,25-(OH)2 vitamin D3; erythropoietin. Decreased secretion by other endocrine glands: \200 \200 \200 testosterone; estrogen; progesterone. Thyroid hormones A number of abnormalities in thyroid hormones have been described in CKD a nd ESRD. Total and free thyroxine (T4) concentrations are either decreased or normal. Total and free triiodothyronine (T3) concentrations are decreased. There are subtle abnormalitie s in the hypothalamic \200\223hypo- physeal axis including: \200 Prolactin Basal levels of prolactin are increased up to six times nor- mal in patients with CKD. Increased prolactin in CKD is due to a decrease in prolac- tin inhibitory factor (PIF ), which in turn is the consequence of a decrease in dopaminergic activity. Signi \201 cance of increased prolactin levels in CKD Hyperprolactinemia may be associated with: \200 \200 \200 amenorrhea; impotence; gynecomastia. normal thyroid-stimulating hormone (TSH) despite low thyroid hormone levels (inappropriate TSH response to CHAPTER 11.2 Endocrine disorders in chronic kidney disease 399 Table 11.2.1 Changes in hormone concentrations in CKD set point of the axis and decreased oral absorption of dexamathasone. Signi \201 cance of glucocorticoid abnormalities in CKD Despite these biochemical abnormal ities, clinical abnor- malities of glucocorticoid function are not common in CKD and ESRD. The cortisol response to major stress such as surgery is preserved. Hormonal system Changes in CKD Hypothalamo-pituitary axis Growth hormone \206\221 Prolactin \206\221 Thyroid axis Free T3 \206\223 Free T4 normal or \206\223 Mineralocorticoids Renin production is low in CKD due to the loss of renal tissue and volum e expansion. Aldosterone levels may be low, normal or elevated. Because of low renin levels , hyperkalemia may be the major stimulus for aldosterone secretion in CKD. TSH normal Gonads Testosterone \206\223 Estrogen normal or \206\223 Progesterone \206\223 LH normal or \206\221 Signi \201 cance of mineralocorticoid abnormalities in CKD Elevated levels of aldosterone in CKD are associated with: \200 \200 \200 FSH normal stimulation of colonic loss of potassium; increase in blood pressure; stimulation of mesang ial and vascular collagen synthesis. Elevated levels of aldosterone in CKD may play a role in the progression of CKD. Diagnosis of hyperaldosteronism in CKD is difficult because of t he changes in renin and aldosterone that occur with renal failure. Adrenal vein blood sampl ing and adrenal imaging studies may be required to con \201 rm a diagnosis. Pancreas Insulin \206\221 Glucagon \206\221 Adrenal glands Aldosterone normal or \206\223 or \206\221 Cortisol normal or \206\221 ACTH normal or \206\221 Catecholamines normal or \206\221 Kidneys Erythropoetin \206\223 Renin \206\223 1,25-(OH)2 vitamin D3 \206\223 Catecholamines Catecholamine levels are increased due to: \200 \200 decreased degradation; decreased neuronal reuptake. Antidopaminergic medications may aggravate hyperprol- actinemia in CKD, and should be avoid ed where possible. These include: \200 \200 \200 \200 Signi \201 cance of catecholamine abnormalities in CKD Increased cathecholamine levels in CKD may contribute to the sympathetic overactivity seen in these patients. The diagnosis of a pheochromocytoma should be made using total and free plasma metanephrines, as urinary ex cretion will be reduced or absent in CKD and ESRD. A-methyldopa; neuroleptics; metoclopramide; cimetidine. Treatment of hyperprolactinemia Bromocriptine reduces prolactin levels but may not cor- rec t symptoms of hyperprolactinemia. Side-effects (nausea and vomiting) are common in CKD and limit its use. Recombinant human EPO treatment may normalize prol- actin levels and improve impotence in men and menstrual irregularities in women. Insulin and carbohydrate metabolism Abnormalities of carbohydrate metabolism in CKD include : \200 \200 \200 insulin resistance (IR); circulating inhibitors of insulin action; decreased islet cell ins ulin secretion. Adrenal hormones Glucocorticoids Adrenocorticotropic hormone (ACTH) is either normal or ele vated. Basal cortisol levels are normal. The circadian rhythm of cortisol secretion is unal tered. Responses of the glucocorticotropic axis in CKD: \200 Peripheral IR is the consequence of a blunted response to a normal insulin level in plasma. Insulin resistance has been described in patients with preserved renal function and CKD. A s GFR decreases, IR is accompanied by an accumulation of circulating inhibitors of insulin action and a decrease in islet cell insulin release. corticotropin-releasing hormone (CRH) induces a normal or blunted ACTH response; standard A CTH stimulation test for diagnosing hypoad- renalism is not affected; insulin-induced hypog lycemia fails to raise plasma cortisol; dexamethasone suppression test to assess hyperadren al- ism is blunted; a high dose of oral (8 mg) or IV (1 mg) dexamethasone is necessary to s uppress the gland because of an altered Mechanism of insulin resistance in CKD This has not been fully elucidated. It is thought to be due to postreceptor abnormalities induced by several factors: \200 \200 \200 \200 \200 accumulation of uremic toxins; metabolic acidosis; lack of vitamin D; proin \202 ammatory cytokines; D. TETA 400 other potential contributors such as uric acid, pseudou- ridine, advanced glycation end-pro ducts. Factors other than renal function modulate the hyperlep- tinemia and hyperadiponectinemia a ssociated with CKD and include: \200 fat mass; \200 in \202 ammation; \200 hyperinsu linemia; \200 acidosis. Signi \201 cance of insulin resistance in CKD Insulin resistance is associated with the de velopment of endothelial dysfunction, an early step in the pathogenesis of atherosclerosis. The presence of IR correlates with cardiovascular mortal- ity in nondiabetic dialysis pati ents. Insulin resistance contributes to muscle catabolism in dia- lysed patients. Insulin r esistance may also contribute to the progression of CKD via deleterious renal hemodynamic e ffects. The accumulation of adipokines in CKD may directly con- tribute to the development of CKD a nd associated compli- cations: \200 hyperleptinemia may contribute to protein-energy wast- ing observed in patients with ESRD; hyperleptinemia may worsen the sympathetic overactiv- ity seen in CKD and ESRD; hyperleptin emia promotes hypertension. Assessment of insulin resistance Insulin resistance is assessed by the HOMA-IR (homeosta- s is model assessment of insulin resistance). HOMA-IR calculation: insulin concentration ( U /ml) \227 fasting glucose (mmol/L) The role of hyperadiponectinemia in CKD and its compli- cations is unclear and is awaiting further investigation. Further reading Axelsson J, Stenvinkel P. Role of fat mass and adipokines in chronic 22.5 kidney disease. Curr Opin Nephrol Hypertens 2008; 17: 25 \200\22331. Impact of dialysis technique on insulin resistance Hemodialysis and peritoneal dialysis onl y partially correct the IR seen in patients with CKD. PD is associated with higher insuline mia than HD and a more severe IR due to the result of the glucose load absorbed from glucos e-based dialysis \202 uids. The use of icodextrin and aminoacids as glucose-free peri- to neal dialysis \202 uids reduces IR. Carrero JJ, Qureshi AR, Axelsson J, et al. Clinical and biochemical implications of low thy roid hormone levels (total and free forms) in euthyroid patients with chronic kidney diseas e. J Intern Med 2007; 262: 690 \200\223701. Feldt-Rasmussen B, Lange M, Sulowicz W, et al.; APCD Study Group. Growth hormone treatment during hemodialysis in a random- ized trial improves nutrition, quality of life, and cardio vascular risk. J Am Soc Nephrol 2007; 18: 2161 \200\2232171. Ritz E. Metabolic syndrome and kidney disease. Blood Purif 2008; 26: 59 \200\22362. Drugs known to improve insulin resistance \200 \200 \200 \200 Seikaly MG, Salhab N, Warady BA, Stablein D. Use of rhGH in chil- dren with chronic kidney disease: lessons from NAPRTCS. Pediatr Nephrol 2007; 22: 1195 \200\223204. ACEIs. ARBs. 25-(OH) vitamin D3. Thiazolidinediones. Internet resources Insulin Resistance and Pre-Diabetes: Adipokines Adipokines are a group of hormones and cytokines secreted by adipocytes. The mos t important adipokines identi \201 ed to date are lep- tin and adiponectin. The known biol ogical actions of leptin include: \200 \200 \200 \200 http://diabetes.niddk.nih.gov/dm/pubs/insulin- resistance/ International Committee for Insu lin Resistance (ICIR): http://www.insulinresistance.us/about.php Growth hormone for children with chronic kidney d isease (The Cochrane Collaboration): anorexia; increased energy expenditure; proin \202 ammatory effects; proatherogenic effect s. http://www.cochrane.org/reviews/en/ab003264. html Adipocytye.co.uk, a website devoted to th e adipocyte and adipokines: The known biological actions of adiponectin include: \200 \200 \200 http://adipocyte.co.uk/Adiposetissuepeptides. htm a potent insulin-sensitizing effect; antiatherogenic effects; anti-in \202 ammatory effect s. See also Sexual disorders in CKD, p. 402 Hypertension in CKD, p. 406 Cardiovascular risk factors in CKD, p. 412 CKD in diabetic patients, p. 472 Adipokines in CKD and ESRD There is marked hyperleptinemia (5 \200\2237 times normal in ESR D: PD > HD). There is moderate hyperadiponectinemia ( 2-fold increase in ESRD). This page intentionally left blank D. TETA 402 Sexual disorders in chronic kidney disease Introduction Sexual dysfunction is a common problem in patients with chronic kidney disease (CKD) both in males and in females. The pathophysiology of these disorders is primarily or ganic in origin. Many factors contribute including: \200 \200 \200 \200 \200 \200 In nonresponders, vacuum erector devices or penile implants may be used. Psychological inte rventions may also be useful. An approach to sexual dysfunction in the male patient is summ arized in Fig. 11.3.1. hormone abnormalities; peripheral vascular disease; peripheral neuropathy; autonomic dysfun ction; drug therapy; psychological factors associated with CKD and its treat- ment. Sexual dysfunction in females Clinical features include: \200 \200 \200 \200 \200 loss of libido; irregularity of menstrual cycle; amenorrhea; anovulation; sterility. Sexual dysfunction in males Clinical features include: \200 \200 \200 \200 \200 <10% of women with ESRD on dialysis have regular menses. loss of libido; impotence; testicular atrophy; gynecomastia; infertility. Hormone abnormalities Estradiol levels are normal to low. Estrone levels are normal to low. Progesterone levels are normal to low. Testosterone levels are normal to low. FSH is norma l. LH is mildly elevated. Increased LH:FSH ratio similar to that seen in prepuberty. Impair ed positive hypothalamic feedback in response to estrogens. No mid-cycle surge of LH and FS H, resulting in no ovulation. Hormonal abnormalities Testosterone is decreased, indicating peripheral testicular failure. Luteinizing hormone (LH) is increased. Follicle-stimulating hormone (FSH) is increased. Re sponse to LH-releasing hormone (LHRH) is unpredict- able (blunted, normal or exaggerated), indicating central hypothalamic abnormalities. Hyperprolactinemia and hyperparathyroidism m ay also contribute (see below). Treatment of sexual dysfunction Much less is known about the factors contributing to sex- u al dysfunction in women with CKD and therefore treat- ments are lacking. There is some evid ence in the non-CKD population that sildena \201 l may be useful for the treatment of fema le sexual dysfunction although there is no evidence in the CKD population. There may be a r ole for psychological interventions in some women. Factors involved in the pathogenesis of impotence Gonadal dysfunction: \200 \200 decreased production of testosterone; hypothalamic \200\223pituitary function; \200 \200 \200 \200 blunted increase in serum LH levels; decreased amplitude of LH secretory burst; variable in crease in serum FSH levels; increased prolactin levels. Psychological factors related to CK D. Zinc de \201 ciency. Medications. Anemia. Secondary hyperparathyroidism. Impaired arter ial in \202 ow and venous drainage of the penis. Autonomic neuropathy. Pregnancy in CKD Female patients with ESRD on dialysis may occasionally become pregnant. Re sidual renal function may improve the likelihood of preg- nancy. Daily dialysis may improve both the likelihood of pregnancy and the maternal and fetal outcomes once pregnancy has oc curred. Impact of renal transplantation Rapidly restores fertility in pre-menopausal women. Ovulati on usually starts within a month of transplantation. Stable graft function, adequate contro l of blood pressure and minimal immunosuppression are advised before con- ception is consid ered, i.e. a waiting time of 2 years after transplantation is usual. Data on the effective ness of contraceptive agents in this setting are lacking. An approach to sexual dysfunction in the female patient is summarized in Fig. 11.3.2.