14th July 2024

Systemic Disorders and the Kidney

Diabetic nephropathy

Background

Diabetes is the commonest cause of chronic kidney disease (CKD) and end stage renal failure (ESRF) in the world with diabetic nephropathy increasing both morbidity and mortality in diabetic patients. Peak incidence of nephropathy is between 10 and 20 years after diagnosis and patients with type 1 diabetes are more likely to follow a predictable decline toward ESRF than type 2 diabetes; perhaps due to higher mortality associated with cardiovascular events in type 2 patients.

Multiple mechanisms are involved in the development of diabetic nephropathy. These include persistent hyperglycaemia, increased oxidative stress and initial hyperfiltration leading to micro-endovascular damage and glomerular sclerosis.  The development of secondary hypertension further worsens the picture.

Diagnosis and classification

As a common complication of diabetes, patients should be screened for renal disease at least once a year. A renal blood panel should be measured with an eGFR of <60ml/min/1.73m2 or a creatinine increase of >20% when compared with previous prompting further investigation. A measurement of proteinuria using a first pass spot urinary albumin:creatinine ratio (ACR) should be undertaken in all patients – a measurement of >3 mg/mmol on two or more occasions should be regarded as clinically important proteinuria.  As in those without diabetes, renal ultrasound may be indicated in cases of accelerated progression of disease and/or red flag features, e.g. persistent haematuria.

A five point staging system is used to classify the severity of diabetic nephropathy (see table below).

Patients are classically asymptomatic in the earlier stages of nephropathy.  Peripheral oedema, difficult to control hypertension and constitutional symptoms such as fatigue, itch and nausea becoming particularly prevalent from stage III to IV onwards.

Management

A persistent reduction in eGFR (<60 for 90 days or more) or elevation in ACR (>3 for 90 days or more) should prompt pharmacological management. An angiotensin converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) should be offered to those with an ACR of >3 mg/mmol and titrated to the highest dose tolerated. All anti-hypertensives have a role but ACEIs and ARBs are most effective in reducing intraglomerular pressure and albuminuria.

Hyperglycaemia and hypertension should be addressed as per NICE targets and those with stage III disease or more should be offered atorvastatin 20mg.  Patients should be advised to stop smoking and encouraged to lose excess body weight.

References

• National Institute for Health and Care Excellence. Chronic kidney disease: assessment and management. London: NICE; 2021. (NICE Guideline No. 203.)  Available from: https://www.nice.org.uk/guidance/ng203
• Barratt J, Topham P, Carr S, Arici M. Oxford Desk Reference Nephrology 2ⁿᵈ ed. Oxford: Oxford University Press; 2021 Jul
• Kidney international supplements. KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney international supplements; 2013. Available from: https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf
• National Institute for Health and Care Excellence. Type 2 Diabetes in Adults: management. London: NICE; 2022. (NICE Guideline No. 28) Available from: https://www.nice.org.uk/guidance/ng28/chapter/Recommendations#reviewing-drug-treatments

Renal vasculitis

Background

Vasculitis is the presence of inflammatory leucocytes in vessel walls, often with fibrinoid necrosis. It occurs as either a primary autoimmune disorder or as a secondary manifestation of an underlying disease process. Systemic vasculitis is characterised by widespread organ involvement and is classified depending on the size of the blood vessel(s) involved. It is usually divided into large, medium and small vessel subtypes. Small vessel vasculitides have a particular propensity for affecting renal vasculature through their ability to cause focal necrotising glomerulonephritis.  This is with or without immune complex deposition (i.e. “immune” vs “pauci-immune”).

ANCA-associated small vessel vasculitides

Granulomatosis with polyangiitis (GPA), previously Wegener’s disease, is an autoimmune inflammatory process affecting the upper respiratory tract (epistaxis, sinusitis, nasal crusting), lungs (dyspnoea, haemoptysis) and kidneys (haematuria).  cANCA is positive in >90%, with the remainder mostly pANCA associated. A negative ANCA does not exclude vasculitis.  Rapidly progressive glomerulonephritis occurs, with urinalysis containing blood, protein and casts. The biopsy will show granulomas and epithelial crescents in Bowman’s capsule. Aggressive immunosuppression is needed to control renal involvement – cyclophosphamide (plus adjuvant steroid) should be offered to promote remission. Rituximab and/or plasma exchange may be required in relapsing or refractory cases.

Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) is often characterised by asthma, peripheral blood eosinophilia of >10%, sinusitis and mononeuritis multiplex. Involvement of the renal system is a feature of the “third-stage”, much rarer than in GPA and is a poor prognostic sign. Rapidly progressive glomerulonephritis is uncommon but may comprise a nephritic syndrome (hypertension, haematuria). 60% of patients are pANCA positive. High dose steroids alone are favoured in management, though additional immunosuppression with cyclophosphamide, azathioprine or IVIG may be required.

Microscopic polyangiitis is a further cause of acute renal-pulmonary syndrome. Lung involvement is rare, though it can be dramatic, in contrast to renal involvement, which can occur at any point in the disease course and is seen in around 80% of patients. Constitutional, gastrointestinal and skin symptoms are also common. Crescentic glomerulonephritis is seen on renal biopsy.  Treatment is similar to other ANCA mediated vasculitis.

Immune complex small vessel vasculitides

Cryoglobulinaemic vasculitis, Henoch-Schonlein purpura (IgA vasculitis) and anti-GBM disease fall under this umbrella.

Medium and large vessel vasculitides

With the exception of polyarteritis nodosa (PAN), medium and large vessel vasculitides do not generally give rise to glomerulonephritis.  Extra-cranial vascular involvement occurs in approximately 15% of patients with giant cell arteritis, but renal involvement is rare, and renovascular hypertension is uncommon.

In Takayasu arteritis (TA), stenosis of the main renal artery and/or its major branches can lead to renovascular hypertension.  This can be difficult to detect if there is co-existing subclavian stenosis, falsely lowering brachial blood pressure measurements.  TA is distinguished from fibromuscular dysplasia by presence of constitutional symptoms and elevated CRP and ESR. Most patients will have normal renal function and non-significant proteinuria/haematuria. Mild diffuse mesangial proliferative glomerulonephritis is very rarely seen in TA.

In contrast, renal involvement is common in polyarteritis nodosa, with more than two thirds of patients developing haematuria, proteinuria, hypertension and progressive renal dysfunction.  Vasculitis of the renal and interlobar arteries can cause micro-aneurysms, infarction and haematoma formation.

Diagnosis and Management

If the clinical situation allows, renal imaging followed by biopsy is the gold standard method for diagnosing renal involvement in vasculitis.

A positive ELISA PR3/MPO autoantibody screen, in combination with clinical suspicion and signs, such as haematuria and acute kidney injury (AKI), is highly sensitive for ANCA associated renal disease. It must be noted that false positive ANCA screens are seen in many other inflammatory conditions, such as lupus nephritis or chronic infections.

Magnetic resonance angiography of the kidneys is sensitive for detection of microaneurysms in PAN.  In addition, testing and treatment for hepatitis B positive patients with PAN should not be forgotten.

The standard regimes for inducing remission are high dose glucocorticoids in combination with either pulsed cyclophosphamide or rituximab. Plasma exchange may be considered on an individual basis in refractory disease. Following successful induction of remission, steroid sparing agents such as azathioprine can be added as maintenance therapy.

Renin-angiotensin systemic blockade is suggested in the first instance for IgA vasculitis with the addition of corticosteroids in the case of persistent proteinuria.

Unfortunately, despite best efforts and interventions, a number of patients will progress to end stage renal disease requiring haemodialysis/transplant.

References

• Maritati F, Iannuzzella F, Pavia MP, Pasquali S, Vaglio A. Kidney involvement in medium- and large-vessel vasculitis. J Nephrol. 2016 Aug;29(4):495-505. doi: 10.1007/s40620-016-0303-8. Epub 2016 Apr 20. PMID: 27098921.
• John R, Herzenberg AM. Vasculitis affecting the kidney. Semin Diagn Pathol. 2009 May;26(2):89-102. doi: 10.1053/j.semdp.2009.08.001. PMID: 19891303.
• Chung SA, Seo P. Microscopic polyangiitis. Rheum Dis Clin North Am. 2010 Aug;36(3):545-58. doi: 10.1016/j.rdc.2010.04.003. Epub 2010 Jun 11. PMID: 20688249; PMCID: PMC2917831.
• Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016 Sep;75(9):1583-94. doi: 10.1136/annrheumdis-2016-209133. Epub 2016 Jun 23. Erratum in: Ann Rheum Dis. 2017 Aug;76(8):1480. PMID: 27338776.
• National Institute for Health and Care Excellence. Rituximab in combination with glucocorticoids for treating anti-neutrophil cytoplasmic antibody-associated vasculitis. London; NICE;  2014. (NICE Guideline, TAG 308.) Available from: https://www.nice.org.uk/guidance/ta308

Lupus Nephritis

Background

Lupus nephritis is a severe manifestation seen in over 50% of patients with systemic lupus erythematosus (SLE) and is the main contributor to morbidity and mortality through its propensity to cause end-stage renal disease. The 2019 ACR and EULR classification criteria for SLE includes various features of renal involvement as its most heavily weighted diagnostic domain, in addition to a positive ANA titre of >1:80. The pathogenesis of lupus nephritis is complex with abnormalities in T-cell, B-cell and complement cascade pathways, but ultimately it is characterised by immune complex deposition in the glomeruli and inflammation throughout the kidneys.

Lupus nephritis has an affinity for young adults, particularly those of Asian and African American origin.  It is 12 times more likely to affect females than males.  Patients may present with a variety of symptoms depending on the class of disease.

Diagnosis and Classification

Any sign of renal involvement, e.g. reproducible proteinuria, haematuria or urinary casts should prompt referral for renal biopsy.  The majority of patients with SLE will demonstrate histological evidence of lupus nephritis on renal biopsy (even in the absence of symptoms). A biopsy is required for diagnosis with changes in the glomerulus allowing for classification into the stages below:

Class IV disease (diffuse proliferative glomerulonephritis) is the commonest and severest form of lupus nephritis. The renal biopsy will typically demonstrate glomeruli with endothelial and mesangial cellular proliferation.  If severe, a ‘wire-loop’ appearance and thickening of the capillary walls secondary to immune complex deposition may be seen (also noted on electron microscopy examination).

Management

Without intervention, lupus nephritis will likely approach end stage renal disease.  Early recognition of disease and prompt induction of aggressive immunosuppression with corticosteroids is key to improving outcomes. Considering the chronicity of SLE, the dosage should be limited to prevent long term side-effects, and osteoporosis prophylaxis should be offered.  Immunosuppressants such as Cyclophosphamide and Azathioprine have a major role in maintaining remission. Co-existent hypertension should be treated.

References

• Kimmel P, Rosenberg M.  Chronic Renal Disease. 2ⁿᵈ ed. Massachusetts. Academic Press; Aug 2020
• Whittall Garcia LP, Gladman DD, Urowitz M, Touma Z, Su J, Johnson SR. New EULAR/ACR 2019 SLE Classification Criteria: defining ominosity in SLE. Ann Rheum Dis. 2021 Jan 15:annrheumdis-2020-218670. doi: 10.1136/annrheumdis-2020-218670. Epub ahead of print. PMID: 33452003
• Tamirou F, Houssiau FA. Management of Lupus Nephritis. J Clin Med. 2021 Feb 9;10(4):670. doi: 10.3390/jcm10040670. PMID: 33572385; PMCID: PMC7916202

Multiple Myeloma & Renal Disease

Background

Renal failure is present in around 40% of patients at the time of diagnosis of multiple myeloma, with approximately an additional 20% developing it later in the course of the disease.  It is a serious complication associated with a higher rate of mortality in multiple myeloma and may occur both acutely and chronically. Proteinuria and a raised blood creatinine are the most commonly noted features, though occasionally nephrotic syndrome is seen.

Pathophysiology

There are myriad mechanisms by which renal damage may occur. The most common is cast nephropathy, where excess urinary free IgG light chains aggregate with Tamm-Horsfall proteins in the distal tubules leading to local atrophy and fibrosis.  In addition, hypercalcaemia secondary to increased bone resorption increases the incidence of nephrocalcinosis. Another mechanism includes immunoglobulin and free light chain deposition (and/or amyloid proteins) which may have direct toxic effects or contribute to glomerular damage.

It should be remembered that a number of additional factors may be present that could exacerbate renal failure in myeloma patients:

• volume depletion
• NSAIDs for pain control
• chemotherapy agents
• bisphosphonate use

Diagnosis

Although readily suspected in patients with known multiple myeloma, monoclonal-gammopathy associated with nephropathy should be included in the differential diagnosis of any patient presenting with renal failure.  The diagnosis can only be made definitively with a kidney biopsy but is often simply established by a raised creatinine, reduced creatinine clearance and identifying the presence of a monoclonal protein in the urine as well as ruling out other causes. Light chain casts will have an eosinophilic appearance on haematoxylin and eosin stain and a pale pink appearance on periodic acid-Schiff staining.

Treatment

Initially, treatment should be centred on correcting volume depletion and electrolyte imbalances if present. Nephrotoxic agents should be withheld, particularly loop diuretics as they may precipitate cast formation. NICE recommends commencing a Bortezomib and Dexamethasone combination regimen for those with untreated newly diagnosed renal failure caused by multiple myeloma.

Ultimately, the treatment of myeloma related nephropathy hinges on the reduction of the paraprotein burden by chemotherapy.  In extreme circumstances, there may be a role for plasma exchange.

References

• National Institute for Health and Care Excellence. Myeloma: Diagnosis and Management. London: NICE; 2016 Feb. (NICE Guideline No. 35.) Available from: www.nice.org.uk/guidance/ng35
• Dimopoulos MA, Sonneveld P, Leung N, Merlini G, Ludwig H, Kastritis E, Goldschmidt H, Joshua D, Orlowski RZ, Powles R, Vesole DH, Garderet L, Einsele H, Palumbo A, Cavo M, Richardson PG, Moreau P, San Miguel J, Rajkumar SV, Durie BG, Terpos E. International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. J Clin Oncol. 2016 May 1;34(13):1544-57. doi: 10.1200/JCO.2015.65.0044. Epub 2016 Mar 14. PMID: 26976420
• Korbet SM, Schwartz MM. Multiple Myeloma. Journal of the American Society of Nephrology. 2006 Sept; 17(9): 2533 – 2545
• Sive J, Cuthill K, Hunter H, Kazmi M, Pratt G, Smith D; British Society of Haematology. Guidelines on the diagnosis, investigation and initial treatment of myeloma: a British Society for Haematology/UK Myeloma Forum Guideline. Br J Haematol. 2021 Apr;193(2):245-268. doi: 10.1111/bjh.17410. Epub 2021 Mar 21. PMID: 33748957
• Kostopoulou M, Fanouriakis A, Cheema K, Boletis J, Bertsias G, Jayne D, Boumpas DT. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations. RMD Open. 2020 Jul;6(2):e001263. doi: 10.1136/rmdopen-2020-001263. PMID: 32699043; PMCID: PMC7425195

Renovascular disease

Background

Disease of the renal arteries is an increasingly common cause of renal impairment and renal hypertension, particularly in the Western world. Reduced renal perfusion results in the upregulation of the renin-angiotensin-aldosterone system, contributing to hypertension.

There are two main types of renovascular disease:

• Atherosclerosis related renal artery stenosis (most common; 90%)
• Fibromuscular dysplasia (9%)

More rarely, renal artery dissection or embolism may give rise to the same clinical picture.  Moderate renal artery stenosis may be asymptomatic, but hypertension will eventually develop as the condition progresses.

Atherosclerosis related renal artery stenosis

This is predominantly seen in older patients who are also likely to have systemic atherosclerosis.  Patients are likely to have other associated risk factors such as hypertension, diabetes mellitus, ischaemic heart disease, a smoking history or peripheral vascular disease.  Similar to other forms of atherosclerotic disease, mild to moderate stenosis may present with little or no symptoms. In contrast, more severe disease may present with flash pulmonary oedema, hypertension and/or decline in renal function.

Fibromuscular dysplasia

Fibromuscular dysplasia (FMD) is an idiopathic, non-inflammatory, non-atherosclerotic disease affecting the fibrous layers of the arterial walls. FMD has the propensity to affect any vascular bed but medium sized renal and cerebral arteries are the most commonly affected. Multifocal FMD causes a ‘string of bead’ appearance on magnetic resonance angiography or computed tomographic angiography, which corresponds to areas of vascular stenosis alongside areas of ‘bulging.’  A typical patient is a female between the ages of 16 and 50 with early onset or unexplained hypertension. Other symptoms depend on the distribution of vascular beds involved, for example, pulsatile tinnitus or chest pain.

Investigations & diagnosis

Serum electrolytes will be normal or appropriately deranged due to the degree of renal insufficiency. Urinalysis is generally bland; heavy proteinuria, blood or white cells should raise suspicion for an alternative diagnosis.  Screening for causes of secondary hypertension should be undertaken.

Urinary tract ultrasound is an inexpensive and non-invasive imaging technique and so should be used as a starting point.  CT angiography or MR angiography are acceptable detailed imaging modalities but if they are inconclusive and clinical suspicion remains high, catheter angiography may be considered.

Treatment

Both atherosclerosis related renal artery stenosis and fibromuscular dysplasia can be complex to treat. Multiple medications may need to be commenced to control hypertension.  Home blood pressure monitoring and referral to a specialist ‘hypertension’ clinic for monitoring of end organ damage is advised.  Revascularisation techniques such as balloon angioplasty and stent placement may be considered in cases of younger patients to reduce medication burden or in those with ‘difficult to treat’ disease.  Atherosclerotic disease has a particularly high risk of restenosis with angioplasty alone (around 90%); introduction of endovascular stenting has reduced this risk to around 20%.

References

• Herrmann SM, Textor SC. Renovascular Hypertension. Endocrinol Metab Clin North Am. 2019 Dec;48(4):765-778. doi: 10.1016/j.ecl.2019.08.007. Epub 2019 Sep 19. PMID: 31655775; PMCID: PMC7184322
• Faconti L, Morselli F, Sinha M, Chrysochou C, Chowienczyk PJ; British and Irish Hypertension Society. Fibromuscular dysplasia and hypertension-a statement on behalf of the British and Irish Hypertension Society. J Hum Hypertens. 2021 Nov;35(11):1051-1053. doi: 10.1038/s41371-020-00456-6. Epub 2020 Dec 1. PMID: 33262434
• Nair R, Vaqar S. Renovascular Hypertension. 2021 Nov 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31869068