Medullary sponge kidney A common, benign condition characterized by diffuse medullary cyst for- mation. It is a developmental, rather than a genetic, anomaly. Clinically, there is no family history, and patients are usually identi \201 ed either inci- dentally or when inv estigated for UTI or stones (see Table 7.7). Impaired calcium handling in the collecting du cts predisposes to formation of calcium-containing stones (often in cysts). Consider the di agnosis in young patients presenting with calcium stones. Haematuria (microscopic or gross) and recurrent UTIs may also complicate the disorder. Diagnosis is made on imaging; traditi onally IVU (typical \200\230 calyceal brush \200\231 ), now CT. Renal impairment is very rare, and management should be directed at infection and prevention of stone formation. Medullary cystic kidney disease Autosomal dominant inheritance, presenting in early adultho od with pro- gressive renal impairment. The affected genes MCKD-1 and \200\223 2 encode ke y signaling proteins in the renal cilia. Small cysts (1 \200\223 10mm) form at the cortico medullary junction, with associated tubulointerstitial in \202 ammation and scarring (glom eruli are unaffected). Affected individuals have a positive family history and present with nocturia, polydipsia, and polyuria (impaired concentrating ability). Urine dipstick is usu ally bland and BP often normal (there may be relative salt loss) (see Table 7.7). Investiga tion shows small to normal-sized kidneys on USS. CT may demonstrate the cystic change. Impa ired urate excretion and hyperuricaemia ( 9 gout) may occur. Renal function usually decline s to ESRD by age 60. No speci \201 c therapy available. Correction of salt and water deple tion may be necessary. Table 7.7 Sponge or cystic kidney disease? Medullary sponge kidney Medullary cystic kidney disease Age Any 20 \200\223 30 years CKD and ESRD \200\223 ++ (ESRD age <60) Salt-losing state \200\223 ++ Calcium stones ++ \200\223 UTI + \200\223 +ve family history \200\223 + CHAPTER 7 Diseases of the kidney 600 Tuberous sclerosis A multisystem disease associated with the growth of hamartomatous lesion s in multiple organs. Caused by mutations in the TSC1 (9q34) and TCS2 (16p13) tumor suppres sor genes. TSC2 (more common) lies adja- cent to PKD-1 , suggesting a role for PKD-1 in the development of cystic disease in some patients with tuberous sclerosis. Predominantly a ne uro- logical (presenting with epilepsy and developmental delay) and skin (e.g. facial angio \201 broma, shagreen patches, ungula \201 bromata) disease, but there are a number of c haracteristic renal features. \200 Angiomyolipomata: these benign hamartomas are present in 7 80% from early childhood. They can be a cause of signi \201 cant bleeding (requiring embolization) and ocassionally obstruction. Cystic disease: 7 20% patients have simple cysts, while 7 5% have polycystic disease that may be associated with progression to ESRD. Renal cell carcinoma: <1%. Suspect if angiomyolipoma changes appearance during surveillance. Management: Monitor BP, SCr, and eGFR (particularly if polycystic disease). \200 Renal USS annually 9 CT, as necessary. Angiomyolipomata have a characteristically high fat content. Refer to a specialist unit. Bardet \200\223Biedl syndrome AR inheritance ( 7 1 in 140,000) but genetically heterogeneou s, with muta- tions in at least 12 BBS loci described. Presents in childhood with short sta ture, weight gain, polydactyly, progressive visual loss, hypogonadism, i BP, CKD, and genit al abnormalities in \231\200 . Diabetes mellitus may occur later. Renal abnormalities in > 90%: fetal lobulation, calyceal cysts and club- bing, cystic dysplasia, and VUR. Progressiv e CKD in a minority. Lawrence Moon is similar, with additional spinocerebellar degeneration Other syndromes For renal disease associated with other syndromes, see Table 7.8. OTHER CYSTIC KIDNEY DISEASES 601 Table 7.8 Renal disease associated with syndromes Associations and renal anomalies Renal anomaly Clinical \201 ndings VATER and VACTERL 40% unilateral agenesis, others varied Vertebral defects, anal atresia, tracheoesophageal \201 stula with oesophageal atresia, a nd radial dysplasia (VATER) with cardiac malformations and limb anomalies (VACTERL) CHARGE Dysplasia Coloboma, heart defects, atresia (choanal), retarded growth and development, genital and ea r anomalies COACH Cystic dysplasia Cerebellar vermis hypo/aplasia, oligophrenia, ataxia, coloboma, and hepatic \201 brosis Chromosomal abnormalities Trisomies and deletions Variable and common Variable Turner and Noonan Variable structural anomalies Short stature, webbed neck, heart defects Supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenosis, el \201 n face, mental and statural de \201 ciency, characteristic dental malformation Infantile hypercalcaemia with nephrocalcinosis, renal agenesis, pelvic kidney, renal artery stenosis, hypertension Williams (microdeletion chromosome 7) Varied Hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and out \202 ow tract defects of the heart DiGeorge (microdeletion chromosome 22) Single gene defects Meckel \200\223Gruber (AR) Cystic dysplasia Encephalocele, hepatic ductal dysplasia and cysts and polydactyly Cystic dysplasia Severely constricted thoracic cage and respiratory insuf \201 ciency, cysts in the liver a nd pancreas, retinal degeneration, short limbs, abnormal pelvis Jeune (asphyxiating thoracic dystrophy) (AR) Joubert (AR) Cystic dysplasia Cerebellar vermis hypoplasia, dysregulation of breathing pattern and eye movement, developm ental delay, retinal dystrophy Senior \200\223L ken (AR) Renal dysplasia or nephronophthisis Mutations in genes causing nephronophthisis may also cause retinitis pigmentosa or retinal aplasia, consistent with Leber amaurosis. (Continued) CHAPTER 7 Diseases of the kidney 602 Table 7.8 (Continued) Associations and renal anomalies Renal anomaly Clinical \201 ndings Bardet \200\223Biedl (AR) Abnormal calyces (on Retinal dystrophy, polydactyly, mental retardation and obesity IVP), renal dysplasia Lawrence \200\223Moon (AR) Renal dysplasia Similar to Bardet \200\223Biedl, with spino- cerebellar degeneration Ear pits, hearing loss, branchial cysts Branchio-oto- renal (AD) History of Potter \200\231s syn- drome, agenesis, and dysplasia Nail \200\223patella (AD) Congenital NS or glomerulonephritis Dysplasia of the nails and absent or hypoplastic patellae Neuro \201 - bromatosis (AD) Arterial stenosis and hypertension Neuro \201 bromas, pigmented patches Renal cysts or hypoplasia Overexpression causes renal cysts and tumors; underexpression causes renal hypoplasia. Colo boma Renal coloboma syndrome (PAX2 mutations) (see, Online Mendelian Inheritance in Man (OMIM), M www.ncbi.nlm.nih.gov). 603 Chapter 8 The kidney in systemic disease Polyarteritis nodosa 652 Churg \200\223 Strauss syndrome 654 Anti-GBM (Goodpasture \200 \231 s) Diabetic nephropathy 604 Diabetic nephropathy: progression 606 Diabetic nephropathy: pathol ogy 608 Diabetic nephropathy: disease 656 Lupus nephritis 658 Lupus nephritis: initial treatment 660 Lupus nephritis: further treatme nt 662 prevention, screening, and assessment 610 Diabetic nephropathy: management 612 Diabetic nep hropathy: management 2 616 Antiphospholipid syndrome (APS) 664 Systemic sclerosis 666 Rheumatoid arthritis 668 Sarcoidosis 670 Fabry \200\231 s disease 6 72 HIV and renal disease 674 HIV and renal disease: Other diabetes-related urinary tract disorders 618 Plasma cell dyscrasias 620 Myeloma: cast nephropathy 622 Monoclonal Ig deposition HIVAN 676 disease 626 HIV and renal disease: other Renal amyloid: AL amyloid 628 Renal amyloid: AA lesions 678 Hepatitis B 680 HBV-related renal disease 682 HBV and ESRD 684 Hepatitis C-rela ted renal amyloidosis 630 Renal amyloid: other forms 632 Cryoglobulinaemia 634 Sickle cell nephropathy 636 The kidney in systemic disease 686 HCV-related disease: management 688 HCV and ESRD 690 The kidney in infective endocarditis 6 92 Renal tuberculosis 696 Renal tuberculosis: TB-TIN and TB in patients with ESRD 698 vasculitis 638 ANCA-associated vasculitis 640 ANCA-associated vasculitis: investigations 642 ANCA-associated vasculitis: treatment 644 ANCA-associated vasculitis: monitoring response and predicting relapse 646 Schistosomiasis 700 Malaria 702 Henoch \200\223 Sch nlein purpura 650 CHAPTER 8 The kidney in systemic disease 604 Diabetic nephropathy Introduction Diabetic nephropathy (DN) is one of the most signi \201 cant complications of diabetes mellitus. It is the leading cause of CKD (and ESRD) in the w estern world, and its incidence is rising in developing countries. This increase has been d riven by the increased incidence of T2DM, improved life expec- tancy for these patients and better access to ESRD care. DN, therefore, consumes a very signi \201 cant amount of heal thcare resource. The topics on b pp. 604 \200\223619 are among the most important in this b ook. 2 There is very good evidence that the quality of diabetes care has a sig- ni \201 ca nt impact on the natural history of DN, with early treatment delaying or preventing onset. De \201 nitions \200 The earliest evidence of diabetic renal disease is the appearance o f microalbuminuria, i.e. low, but abnormal, amounts of albuminuria ( \211 30mg/day) ( b p . 60). \200 Patients with microalbuminuria are often said to have \200\230 incipient \200\231 nephropathy. DN ( \200\230 overt \200\231 nephropathy) describes a clinical syndrome characterized by: \200 Persistent albuminuria (>300mg/day) on at least two occasions, 3 months apart. i BP. \200 Progressive d GFR. 2 As well as a hallmark of DN, incipient and overt nephropathy are important markers of i CV morbidity and mortality in both T1DM and T2DM. They warrant a ggressive intervention to improve all CV risk factors (e.g. LDL cholesterol, BP, smoking ce ssation, exercise, etc.). Epidemiology \200 7 20 \200\223 30% of patients with diabetes mellitus develop DN. \200 7 15% of ESRD in the UK is s to DN and is much higher elsewhere ( 7 40% in the US). >90% of these individuals will have T2DM. Incidence and natural history depend on ethnicity, e.g. Pima Indians ( b p. 8) have a 40% i ncidence of ESRD 10 years after developing microalbuminuria. Patients who have no proteinuria after 25 years of diabetes have only a very small risk of developing DN. DIABETIC NEPHROPATHY 605 T1DM \200 Microalbuminuria will develop in 20 \200\223 30% of patients after 15 years. \200 i BP often appears at the same time as microalbuminuria. \200 Without treatment, 7 80% will increase their urinary albumin excretion at a rate of 7 10 \200\223 20% per year, with overt nephropathy developing over 10 \200\223 15 years. Overt DN rarely develops within 10 years of diagnosis of T1DM. \200 Without treatment, ov ert DN will lead to a progressive fall in GFR over time. The rate is highly variable between individuals (2 \200\223 20mL/min/ year). 50% of those with overt DN will develop ESRD within 10 years (>75% within 20 years). Patients who progress from no microalbuminuria to microalbuminuria or from microalbuminuria to overt albuminuria are likely to have higher HbA1C and BP values . The overall long-term prevalence of ESRD in T1DM has recently fallen to <10%, having previously been higher. T2DM \200 7 3% of patients will have overt DN at the time of diagnosis of T2DM (diabetes may have been present for some time prior to discovery). Proteinuria is less speci \201 c for DN in T2DM. \200 Without treatment, 20 \200\223 40 % of those with microalbuminuria will progress to overt DN. In the UKPDS study, annual risk for progression from no microalbuminuria l microalbuminuria was 2.0%; from microalbuminuria l macroalbuminuria 2.8%, and from macroalbuminuria l i SCr or ESRD 2.3%. The rate of decline of GFR is variable but less predictable than for T1DM (T2DM = older patients with associated CV disease). \200 After 20 years of overt DN, 7 20% will have progressed to ESRD. These numbers are hugely signi \201 cant because of the higher prevalence of T2DM. 2 The greater risk of death from associated CV disease in T2DM prevents many with earlier nephropathy from progressing to ESRD. CHAPTER 8 The kidney in systemic disease 606 Diabetic nephropathy: progression Natural history The evolution of DN can be described in s tages (see Table 8.1). This applies to both T1DM and T2DM, although the latter is much less predictable. Table 8.1 Stages of DN Stage Duration Clinical and pathological correlation Hyper \201 ltration with renal hypertrophy and i GFR 1 At diagnosis 2 <5 years Early histological changes though clinically silent 3 5 \200\223 15 years Microalbuminuria. BP now starts to rise 4 15 \200\223 25 years Overt diabetic nephropathy with declining GFR 5 >25 years Advanced CKD/ESRD 3 Mortality risk increases at each stage. In the UKPDS, annual mortality risks were 1.4% (no microalbuminuria); 3.0%, (microalbuminur ia); 4.6% (macroalbuminuria); and 19.2%, (CKD and ESRD). Risk of death was higher than the risk for progression to the next phase once microalbuminuria present. Happily, more recent studies, e.g. IDNT and RENAAL, have challenged these data in an era of better diabetes care, demonstrating what improved care m ay achieve. Nonetheless, CV mortality in T2DM remains a signi \201 cant public health issue. See Box 8.1. Intensive monitoring and treatment in \202 uence natural history, preventing incipient, an d progression to overt, nephropathy. \200 The DCCT trial randomized >1,400 non-hypertensi ve type 1 diabetics to either intensive or conventional insulin therapy. During a mean 6.5 years \200\231 follow-up, HbA1C levels were signi \201 cantly lower in the intensive group, with a reduction in microalbuminuria. The bene \201 ts of good glycaemic control for preventing progression in T2DM were clearly demonstrated in the UKPDS study. DIABETIC NEPHROPATHY: PROGRESSION 607 3 Box 8.1 Diabetic nephropathy and risk of death \200 T2DM is associated with substantial ly increased risk of premature death \200\224 a risk that is primarily focused on those wi th nephropathy. 10-year mortality data in 7 15,000 subjects in the 3rd US National Health and Nutrition Exa mination Survey (NHANES III) revealed: \200 Reference group (subjects without diabetes or kidney disease), 10-year cumulative all-cause mortality of 7.7%. For T2DM without kidney disease, this rises to 11.5%. For T2DM with kidney disease, this rises to an astonishing 31.1%, representing an absolute risk difference with the reference group of 23.4% (adjusted for demographics, smoking, and BP)! Development and progression The following are important risk factors for the development an d pro- gression of DN in both T1DM and T2DM: \200 Poor glycaemic control. \200 Onset of T1DM before age 20. \200 i BP: 30% have i BP at diagnosis of T2DM. \200 70% have i BP at diagnosis of DN. Smoking. \200 \231\202 gender. \200 Ethnicity (Indo-Asians, African Americans, Pima In dians in the US). \200 Familial tendency. \200 Socio-economic factors, esp. poverty. 2 Once established the most important factors fueling progression are: \200 BP. \200 Glyc aemic control. \200 Degree of proteinuria. CHAPTER 8 The kidney in systemic disease 608 Diabetic nephropathy: pathology Introduction The pathogenesis of DN is multifaceted, with s everal mechanisms contrib- uting to the renal injury and development of the characteristic histological changes. Histology \200 Ultimately, renal hypertrophy, hyper \201 ltration (initially with i GFR to above normal), and intrarenal hypertension cause mesangial expansion, glomerulosclerosis, a nd tubulointerstitial \201 brosis. The cardinal histological features are: Mesangial expansion ( l intercapillary, or Kimmelstiel \200\223 Wilson, nodule formation, often with capillary lumen encroachment). Glomerular and tubular basement membrane thickening. \200 Nodular glomerulosclerosis. Vascular changes are also usually present: Vessel changes from i BP. \200 Arteriosclerosis. \200 Afferent and efferent arteriolar hyalinosis. Tubular atrophy and interstitial \201 brosis appear as DN (and 6 CKD) progress. Immunostaining may demonstrate non-speci \201 c linear staining for IgG in glomerular and tubular basement membranes and Bowman \200\231 s capsule. Arteriolar damage, interstitial \201 brosis, and s FSGS may be the dominant lesions in older T2DM patients (often with less proteinuria and more vascular dise ase clinically). Pathophysiology Hyperglycaemia \200 The magnitude of hyperglycaemia correlates with the f unctional and structural changes of DN. \200 Long-term studies in T1DM (DCCT) and T2DM (UKPDS) have dem onstrated that blood glucose concentration is related to the development of microalbuminuri a and progression to overt DN. \200 Time-averaged HbA1c and BP correlate with loss of ren al function. Hyperglycaemia: Stimulates mesangial cell matrix production and cell growth, leading to early glomerular enlargement. Causes to advanced glycation end-product (AGE) formation: \210\222 AGEs result from non-enzymatic reaction between glucose and proteins. \210\222 They normally undergo renal excretion and accumulate as DN progresses, particular ly in the circulation and the kidneys. \210\222 AGEs: (i) impair function of glycated proteins; (ii) cause abnormal cell-to-cell interactions through cross-link formation; (iii) bind endogenous rece ptors for AGEs (RAGE), with deleterious consequences. Causes i oxidative stress. DIABETIC NEPHROPATHY: PATHOLOGY 609 Leads to activity of protein kinase C and hexosamine pathways (both l i production of vario us pro \201 brotic cytokines, including TGF- B ). Increases expression of glomerular TGF- B (and other mitogens) l cellular hypertrophy, i co llagen synthesis, and i matrix deposition. Promotes l i VEGF expression, possibly via the adenosine A 2B receptor ( l endothelial inju ry, vascular change, and podocytopathy). Glomerular haemodynamics \200 Glomerular hypertension and hyper \201 ltration occur earl y. A GFR of 25 \200\223 50% above normal is observed in 50% of patients with T1DM of 5 years \200\231 duration. Hyper \201 ltration appears to be caused by mediators involved in RAS, nitric oxide, and cyclo-oxygenase pathways. Endothelin -1 is a potent vasoconstrictor, the levels of which are increased in both plasma and renal tissue of diabetic subjects. The expression of receptors ET-A and ET-B is also i ncreased. ET-1 function is receptor-dependent (ET-A l smooth muscle vasoconstriction and gl omerulosclerosis; ET-B l vasodilation). Systemic i BP also drives glomerular i BP. \200 Haemodynamic disturbance l arteriolar and glomerular sclerosis. Podocyte function and proteinuria \200 Podocyte function is abnormal, with reduced expres sion of nephrin and altered glomerular permeability. Proteinuria further promotes tubular injury and interstitial \201 brosis. Renin \200\223angiotensin system \200 Local renal RAS activation l cell growth and matrix accumulation. \200 Angiotensin II generates reactive oxidative species and NADPH oxidase in vascular smooth muscle and the kidney. These may explain some of the additional bene \201 t of RAS inhibition beyond BP control. Genetics \200 A poorly understood genetic predisposition appears to operate. \200 DN is more common in Northern Europe and the USA. \200 Certain ethnic groups are affected more than others, e.g. Indo-Asians in the UK, African Americans, Pima Indians (astonishingly, b y age 20, 7 50% of Pima Indians with diabetes will have developed DN, and 15% will have pro gressed to ESRD). DN is more likely in relatives of diabetic patients with nephropathy. \200 It is unclear why new cases of DN are rare after 15 years of diabetes. CHAPTER 8 The kidney in systemic disease 610 Diabetic nephropathy: prevention, screening, and assessment Primary prevention \200 Impro ve glycaemic control: Aim HbA1C <7%. \200 2 Clinical trials (e.g. DCCT and UKPDS) have consistently demonstrated the bene \201 ts of intensive blood glucose control for primary prevention of DN. Target BP <130/80mmHg. \200 Stop smoking. Encourage weight loss and exercise. \200 X Th e role of RAS blockade with ACE-I or ARB for prevention of microalbuminuria is controversial. \200 Several studies (e.g. DIRECT-Renal, BENEDICT, and ROADMAP) have attempted to address this issue. Some evidence of bene \201 t for prevention of microalbuminuria in high-risk T2DM with concomitant i BP, but the cumulative \201 ndings fail to support \200\230 pre-emptive \200\231 RAS blockade. Screening \200 Early detection affords the opportunity to delay or prevent progressive CKD and 6 ESRD. Annual screening by uACR should be performed (preferably an early morning sample, no UTI, s table glucose control) (see Table 8.2). \200 Start after 5 years of T1DM and at the time of diagnosis of T2DM. Table 8.2 uACR in diabetic nephrology uACR (mmol/mg) 24h albuminuria <2.5 <30mg/day 2.5 \200\223 30 30 \200\223 300mg/day (microalbuminuria) >30 Overt proteinuria Diagnosis A clinical diagnosis is usually possible. \200 T1DM: Proteinuria, retinopathy, DM of >10 years \200\231 duration. T2DM: Retinopathy often not present, duration of DM frequently uncertain. Non-speci \201 c renal damage (e.g. arteriolar damage, interstitial \201 brosis, and s FSGS) is a differential diagnosis of DN in T2DM and may be indistingui shable in terms of clinical presentation. Management is essentially identical, however. DN: PREVENTION, SCREENING, AND ASSESSMENT 611 Role of the renal biopsy in DN A renal biopsy is rarely required to establish the diagnosis of DN but might be considered in certain circumstances: \200 No diabetic retinopathy: Particularly in T1DM (retinopathy is observed in 85 \200\223 99% of patients with established nephropathy). 7 30% of those without retinopathy will have an alternative lesion at biopsy (membranous GN, IgA nephropathy, etc.). T2DM patients have DN without retinopathy more commonly. \200 Note: this implies proper o phthalmic assessment, not just brief fundoscopy. Dysmorphic red cells, red cell casts, or macroscopic haematuria: \200 Microscopic haematu ria, usually + to ++ only, is seen in 7 60% patients with DN. However, it will usually requ ire independent investigation ( b p. 22). Rapid onset, rapidly increasing, or massive proteinuria. \200 Conversely, a lack of prote inuria may cast doubt on the diagnosis and make histology desirable, e.g. possible drug-ind uced TIN ( b p. 580). Also consider renovascular disease in this situation ( b p. 586). Rapidly deteriorating GFR despite good BP and glycaemic control. \200 Symptoms or signs s uggestive of a multisystem disorder, e.g. vasculitis, connective tissue disorder, hepatitis C, HIV. Further investigation and assessment \200 Urinalysis (? haematuria); quantify proteinuria ( b p. 21). \200 SCr, eGFR, U&E, serum albumin, HbA1C, lipid pro \201 le. \200 Consid er serum and urine protein electrophoresis in older patients. \200 Check visual acuity, f undoscopy, and arrange ophthalmology review, if not already under follow-up. Check BP. \200 Examine for other evidence of vascular disease (bruits, peripheral pulses, etc.). Assess for peripheral neuropathy. \200 ECG. \200 Consider USS kidneys, esp. if microsco pic haematuria (kidneys are often normal-sized in DN despite d GFR). CHAPTER 8 The kidney in systemic disease 612 Diabetic nephropathy: management Introduction Treatment goals: prevention of (i) progressio n from microalbuminuria (incipient DN) to macroalbuminuria (overt DN); (ii) progressive dec line in renal function in patients with macroalbuminuria; and (iii) CV events. Glycaemic control X Unlike prevention, the effects of strict glycaemic control on progres- sion from micro- to macroalbuminuria, as well as bene \201 ts for preservation of renal fu nction, are more controversial. The ADVANCE and ACCORD studies have suggested that inten- sive treatment of hyperglycemia i n T2DM does not necessarily lead to an acceptable risk/bene \201 t ratio. Participants had strong CV risk pro- \201 les (including prior events) and were at high risk of future ev ents. Microvascular end points, including renal outcomes, were improved in both studies. Ho wever, primary CV outcomes were not improved by intensive glycaemic therapy and, in ACCORD, intensive treatment was associated with a 22% increase in all-cause mortality. So, more ag gres- sive glycaemic management in higher risk T2DM patients (usually later in the course o f their disease) delivered only a weak protective effect with respect to CV outcomes. KDOQI practice guidelines recommend maintaining HbA1c at <7%. However, some authorities sug gest a target between 7 \200\2238% in patients with longstanding disease who are at higher CV risk. See b p. 894 for the use of hypoglycaemic drugs in CKD ( (cid:2) met- formin!). Patients wi th T2DM and DN often require conversion to insulin. Blood pressure \200 i BP is proportional to i albumin excretion. \200 Numerous studies have demonstrated that treatment of BP, irrespective of the agent(s) used, has a bene \201 cial effect on albuminuria. RAS blockade with ACE-I or ARBs confers an additional \200\230 renoprotective \200\231 be ne \201 t, independent of BP reduction. \200 ACE-I or ARBs reduce the risk of progressio n of microalbuminuria to macroalbuminuria (by 60 \200\223 70%), reduce macroalbuminuria, a nd reduce the rate of decline in GFR. 2 ACE-I or ARBs should also be used in normotensive patients with micro- or macroalbuminuria. Strict adherence to evidence would generally see ACE-I used in T1DM and ARBs in T2DM. However, most clinicians are pragmatic and principally guided by tol erability. ACE-I also demonstrably reduce the risk of MI, CVA, and CV death (by 7 25% at 2 years). This might be true for ARBs as well. \200 Allow \211 25% change in SCr and eGFR. Greater increases may indicate the presence of renal artery stenosis (a >70% renal artery stenosis is present in 7 15% of individuals with T2DM and i BP). \200 Monitor K + after 1 week and then monthly for \201 rst 2 \200\223 3 months. Offer dietary advice if K + elevated b p. 259 ( 9 loop diuretic, e.g. furosemide 40 \200\223 80mg od). DIABETIC NEPHROPATHY: MANAGEMENT 613 A low-salt diet ( b p. 259) enhances the renoprotective effects of ARBs in T2DM. Furthermor e, lower urinary Na + excretion, re \202 ecting lower intake, is associated with fewer CV events. Target BP: Uncertain. In the UKPDS, a 12% risk reduction in diabetic complications was found with each 10mmHg drop in SBP, with lowest risk at 120mmHg. KDIGO recommend a BP target of <130/80mmHg if >30mg/24h proteinuria. UK Renal Association (and NICE) also recommend <130/80mmHg. \200 Recent guidelines for hy pertension from non-nephrological bodies, e.g. ESH-ESC (2013), have suggested the evidence for a target of <130/80mmHg is not particularly robust and suggested a target SBP of <140mm Hg for most hypertensive groups, including diabetics. \200 Many nephrologists will aim <1 25/75mmHg if proteinuria >1g/24h. \200 Add further therapy in a stepwise manner, selectin g drugs according to the comorbidity pro \201 le of the individual patient. \200 Diuretics may enhance the an ti-proteinuric effects of RAS inhibition. \200 Furthermore, volume overload is often an i mportant driver of i BP in DN with renal impairment. Thiazides may be suitable initially, but loop diuretics are preferred as GFR deteriorates (<40mL/min). B -blockers if arrhythmias, CCF, coronary artery disease. \200 Evidence favors non-dihydr opyridine calcium channel blockers (e.g. diltiazem) over dihydropyridine (e.g. amlodipine), but clinician preference and patie nt tolerability means this is often overlooked. Proteinuria \200 Proteinuria is itself an important treatment target. Aim <0.5g/24h (uACR <30mg/mmol or uPCR < 50mg/mmol), as BP allows. ACE-I or ARBs should be used in normotensive patients with proteinuria (micro- or macroalbuminuria). CHAPTER 8 The kidney in systemic disease 614 Box 8.2 ACE-I and ARB combination therapy X There is no evidence to support combination ACE -I and ARB therapy. \200 The ONTARGET study randomized >25,000 patients with either CV di sease or DM + microvascular disease to an ACE-I, ARB, or combination therapy. \200 No dif ferences were seen in p outcome (composite of CV morbidity and mortality). There were differences in s outcomes: K + (>5.5 mmol/L) and renal failure were signi \201 cantly higher for combined therapy. Subsequent post hoc analysis found doubling of SCr, need for acute dialysis, and death more frequently in the combined therapy group. Limitations: only 38% of subjects had DM, and only 13% microalbuminuria. A recent meta-analysis examined 33 randomized trials involving >68,000 patients. 1 \200 Dual blockade was not associated with d mortality. \200 It was associated with an 18% decrease in CCF-related admissions (many studies included patients with cardiac failure). Importantly, it was associated with a 55% increased risk of i K + , a 66% increased risk of d BP, and 41% increased risk of renal failure. The VA NEPHRON-D study of losartan with or without lisinopril in T2DM with overt nephropath y (uACR> 300mg/g and eGFR 30 \200\22390mL/min) was stopped early (median 2.2 years follow-u p) because of safety concerns involving hyperkalaemia and AKI. This was despite a non-signi \201 cant trend toward bene \201 t with respect to the primary and secondary end points (relating to progression of renal disease or death). However, there was no demonstrable dif ference in CV events. Overall conclusions, as the evidence currently stands: Combination therapy with an ACE-I and ARB should be avoided. \200 Maximizing the dose of either an ACE-I or an ARB is the best current strategy. 1 Makani H, et al. (2013). Ef \201 cacy and safety of dual blockade of the renin-angiotens in system: meta-analysis of randomized trials. BMJ , 346 , f360. DIABETIC NEPHROPATHY: MANAGEMENT 615 CHAPTER 8 The kidney in systemic disease 616 Diabetic nephropathy: management 2 Additional RAS blockade \200 There has been much inter est in combination therapy for RAS inhibition in DN. \200 For ACE-I + ARB therapy, see Box 8.2, b p. 614. \200 Aldosterone has been associated with progression of renal disease through increased \201 brosis and proteinuria. Plasma aldosterone often decreases with ACE-I or ARB therapy, but levels eventually return to baseline in many ( 7 40%) \200\224 a phenomenon termed \200\230 aldosterone escape \200\231 . The addition of the aldosterone antagonist spironolactone to a regimen including an ACE-I o r ARB has an anti-proteinuric (and variable BP) effect in both T1DM and T2DM. No studies have shown long-term bene \201 t for other endpoints. \200 (cid:2) There is a signi \201 cant risk of i K + , particularly in patients with d GFR, and this often limits the utility of spironolactone in practice. Combination therapy with a direct renin inhibitor has also been studied, with initial studies suggesting a BP-independent anti-proteinuric effect in T 2DM. However, the ALTITUDE study (aliskirin + ACE-I/ARB in T2DM) was stopped early because of ad verse events in the combination therapy group (renal failure, i K+, d BP, CV events). Other interventions \200 Treat dyslipidaemia: Aim fasting LDL <3.0mmol/L. Statins are usually necessary (and demonstrably reduce cardiac events in diabetic patients). X Statins may reduce proteinuria and preserve GFR in overt DN. \200 The role of aspirin a nd other antiplatelet agents for primary prevention of CV events in patients with DN is uncertain. However, if no contraindication, low-dose as pirin (75mg od) is often recommended. Smoking cessation. \200 Modest dietary protein restriction (0.8g/kg per day, b p. 208) ma y slow decline in GFR. X Some advocate a more stringent restriction to 0.6g/kg/day in selecte d patients. DIABETIC NEPHROPATHY: MANAGEMENT 2 617 Novel treatments for DN Better understanding of DN has informed novel therapeutic strategie s, particularly with respect to the downstream effects of hyperglycaemia (AGE formation, pr otein kinase C activity, production of pro- \201 brotic intermediates, endothelin activity , and in \202 ammatory pathways). Some show promise in both experimental models and clinic al trials. In all cases, larger studies will be necessary to determine if short-term improv e- ments (e.g. reduction in albuminuria) translate to overall improvements in DN outcomes. Pyridoxamine. Is a member of the vitamin B6 family that inhibits AGE formation. It reduces mesangial expansion, decreases albuminuria, and slows SCr rise in animal models. Clinical s tudies suggest promise for early intervention in DN. Experimental agents that prevent AGE cross-linkage or inhibit AGE and AGE receptor (RAGE) interaction are also under development. Ruboxistaurin. Is a selective protein kinase C inhibitor that reduces albuminuria (albeit w ith no signi \201 cant difference for other renal outcomes) in T2DM DN. Pirfenidone. Is an anti \201 brotic (via d TGF- B production) and a free radical scavenger under investigati on in several clinical contexts, including DN. It reduces mesangial expansion and collagen gene expression in animals. Clinical trials suggest it may improve GFR but not albuminuria. Tranilast is another anti \201 brotic agent that has shown bene \201 cial effects in ani mal models and clinical trials. Doxycycline may also have anti \201 brotic properties and has been shown to reduce proteinuria. Sulodexide. A glycosaminoglycan, inhibits TGF- B prod uction and causes dose-dependent reductions in albuminuria (persistent after discontinuatio n). Early clinical trials vs placebo have been disappointing. Avosentan. Is an ET-1 receptor antagonist that reduces urinary albumin excretion at the exp ense of increased CV events (CCF and volume overload). Atrasentan also reduces albuminuria and is more selective for the ET-A receptor. It is associated with peripheral oedema but is less likely to cause frank volume overload. Further trials are awaited. The transcription factor nuclear factor erythroid-related factor 2 (Nrf2) is involved in nu merous anti-in \202 ammatory and antioxidant path- ways. Nrf2 knockout mice suffer worse n ephropathy in experimental diabetes. Bardoxolone methyl , a synthetic triterpenoid, induces Nrf2 and improves GFR (but with no change in albuminuria). Unfortunately, the internationa l BEACON trial was stopped early, following excess adverse events in the treatment arm. Diabetic mice lacking vitamin D receptors demonstrate RAS upregu- lation, glomerulosclerosi s, and increased urinary albumin losses. The administration of an active vitamin D analog p aricalcitol has been shown to signi \201 cantly ameliorate this albuminuria. CHAPTER 8 The kidney in systemic disease 618 Other diabetes-related urinary tract disorders Papillary necrosis ( b p. 585) Occurs in 7 1 :20 with diabetic nephropathy. May be asymptomatic but can present as pain (recurrent renal colic) or infection. Haematuria, modest proteinuria (<2g/24h), and sterile pyuria are comm on. Renovascular disease ( b p. 586) Suspect if dif \201 cult to control BP, \202 uid re tention, or >20% rise in SCr (or fall in eGFR), following an ACE-I or ARB. Neurogenic bladder (diabetic cystopathy) A degree of bladder dysfunction is present in 7 40 % of patients with long-standing diabetes. It results from peripheral and autonomic neuropa - thy (characterized by segmental demyelination with impaired conduction). The \201 rst m anifestation is usually loss of sensation of bladder \201 lling, with subsequent progress ive loss of motor function. Incomplete emptying leads to a large-volume bladder, with a sig ni \201 cant post-micturition volume and urinary stasis. Recurrent UTIs and urinary incont inence are common. Investigation: MSU for M,C+S. USS bladder pre- and post-void. Ask the patient to complete a bladder diary. Urodynamic \201 ndings include decreased bladder sensation, impaired detr usor contractility, and eventual detrusor are \202 exia. Detrusor hyperre \202 exia is al so recognized. Screen for other manifestations of autonomic dysfunction, e.g. postural HR a nd BP. Exclude signi \201 cant prostatic disease. Interventions include regular voiding in the absence of urge (e.g. every 2h), anti-incontin ence aids to absorb urine losses and protect skin integ- rity, assisted voiding (e.g. supra pubic manual pressure), drugs (e.g. the parasympathomimetic agent bethanechol) (bene \201 ts inconsistent), inter- mittent self-catheterization, (also d bladder volume and may help partial recovery of detrusor function), long-term catheterization, urinary diver- sion, and treatment of associated infection. Urinary tract infection ( b p. 706) \231\200 with diab etes have twice the incidence of UTI, compared to those with- out diabetes. Diabetes is als o a risk factor for UTIs in \231\202 . There is also a higher incidence of pyelonephritis and renal abscess formation. 90% of cases of emphysematous pyelonephritis ( b p. 711) occur in patients with diabetes. Contrast induced-AKI ( b p. 148) Patients with diabetes, probab ly as a result of intrarenal microvascular disease, are more susceptible to CI-AKI. OTHER DIABETES-RELATED URINARY TRACT DISORDERS 619 Considerations in ESRD from diabetic nephropathy 2 Patients with T1DM (and selected patient s with T2DM) should be considered for combined kidney/pancreas transplantation ( b p. 446). Diabetic patients often need to initiate dialysis at an earlier stage than patients with ES RD from another cause, e.g. eGFR in the 10 \200\223 15mL/min range, as they are often more symptomatic, tolerate volume overload less well, and have a heightened propensity to hyper kalaemia. Survival and causes of death in diabetic patients on dialysis Diabetic patients with ESRD h ave a 5-year survival rate of 7 30% (com- pared with 7 60% in those without diabetes). This is largely a conse- quence of their comorbidity, particularly CV disease. A higher inciden ce of withdrawal from dialysis treatment is also reported. Dialysis modality: peritoneal dialysis vs haemodialysis No clear difference in outcome betw een PD and HD has been observed. USRDS data and Canadian studies have offered con \202 ict ing results (potentially explained by different patient demographics and comorbidi- ties). Overall, there is a suggestion that older diabetic patients survive longer on HD, and young er patients longer on PD. Renal transplantation in diabetics Renal transplantation is safe and effective. In appropri ately selected patients, it can offer improved survival and rehabilitation, compared to dia lysis. Studies have shown similar 1- and 5-year graft survival in dia- betic and non-diabet ic patients undergoing transplantation when data are censored for patients dying with a fun ctioning graft. Living donor graft survival is superior to deceased donor grafts (80% vs 64 % 5-year graft survival). CHAPTER 8 The kidney in systemic disease 620