Summary

Nephrotic syndrome is a common clinical problem frequently encountered by primary care physicians. The clinical syndrome is a consequence of various renal diseases. While minimal change disease is the common cause of the syndrome in children; membranous nephropathy and focal segmental glomerulosclerosis are the common causes in adults. Drugs or systemic diseases leading to this clinical condition are not infrequent. Rapid diagnosis with renal pathology can be useful in delivering appropriate management to patients by physicians, and hence preventing the progression to advanced renal impairment. The exclusion of underlying malignancies in the elderly presenting with nephrotic syndrome is also important especially when related to membranous nephropathy. The prevention of relapse and maintenance of the disease in remission is still a challenge to clinicians.

摘要

腎病綜合症是基層醫生常見的臨床疾病，可以由多種的不同腎病形成。兒童最常見的成因是最小變化腎病。成人最常見的成因則是膜性腎病及焦點節裂性 腎小球血管硬化。藥物及系統性疾病引起亦非罕見。快捷的腎臟組織病理診斷能幫助醫生做適當的治療，從而防止病情的惡化成腎衰竭，年邁的病人特別膜性腎病者，則需要留意有沒有潛在的惡性疾病。如何防止復發和維持緩解期依然及臨床醫生時的批核。

---

Introduction

Nephrotic syndrome was originally described by Schreiner¹ as a clinical condition with multiple causes and characterised by the insidious onset of heavy proteinuria, usually greater than 3.5g/d in adult, accompanied by a low level of plasma albumin, usually below 30g/L. Patients with nephrotic syndrome also have variable combinations of various degrees of oedema, hypertension, hyperlipidaemia, and lipiduria. The clinical syndrome is a consequence of continued heavy protein loss in urine. However, clinicians should not be bounded by the arbitrary value of 3.5g/d to divide nephrotic from non-nephrotic proteinuria. The absolute rate of protein excretion whether or not it is greater than 3.5g/d has little diagnostic significance although such heavy proteinuria usually indicates glomerulopathy of some kind rather than tubulointerstitial or vascular disease of the kidney. However, protein excretion above 10g/d, is more commonly seen in focal and segmental glomerular sclerosis (FSGS), mesangiocapillary glomerulonephritis (MCGN), membranous glomerulopathy (MGN), and amyloidosis of the kidney.

The nephrotic syndrome can be caused by various primary glomerular diseases in which minimal-change disease, FSGS, MGN, and MCGN are the most common. The syndrome can also be associated with glomerular disease arising as a complication of other diseases such as infections (infective endocarditis, tuberculosis, hepatitis B, hepatitis C), neoplastic diseases (solid tumours, leukaemia and lymphoma), systemic diseases (diabetes mellitus, graves disease, hypothyroidism, systemic lupus erythematosus, rheumatoid arthritis). The clinical syndrome is also associated with a lengthy list of aetiological events. Some of the commonly seen examples are medications (Non-steroidal anti-inflammatory drugs, NSAIDs, lithium, captopril, heroin), allergens (bee sting, pollens), vaccines (diphtheria, pertussis, tetanus toxoid).

In Hong Kong, minimal-change disease, IgA nephropathy and membranous nephropathy comprised respectively 41%, 16% and 13% of primary glomerular diseases in children. Minimal-change disease is the most common cause and accounts for 61% of children with nephrotic syndrome.² While primary IgA nephropathy is the most common glomerulonephritis in adults and only 15% of these patients have nephrotic syndrome.³

Clinical manifestation of the nephrotic syndrome

The nephrotic syndrome is associated with a variety of renal and extrarenal manifestations. Heavy proteinuria, hypoalbuminaemia, dependent oedema, hyperlipidaemia, and hypertension are common findings. Decreased glomerular filtration rate (GFR) with raised serum creatinine and advanced renal failure complicating nephrotic syndrome is not infrequent.

Proteinuria

Proteinuria in glomerular diseases is due to the increased permeability of the glomerular basement membrane (GBM) to large molecules such as albumin. There are two major factors limiting the filtration of albumin and other large molecules.

1. The GBM is size-selective. The amount of molecule filtered reduces progressively while the size of the molecule increases.
2. The GBM is charge-selective. Neutral and cationic compounds are more readily filtered comparing with anionic compounds of the same molecular size. Proteinuria can be the result of enlargement of the size and/or damage of the charge barriers of GBM.^4,5 Membranous nephropathy is an example of the possible existence of large "pores" within the GBM.⁵ While proteinuria in minimal change disease is due to impairment of the charge barrier.⁶ The degree of proteinuria is also influenced by the glomerular filtration rate (GFR) and the plasma albumin concentration, in addition to the increment in glomerular permeability. Therefore, a decline in the GFR with progressive disease or marked hypoalbuminaemia can lead to a reduction in protein excretion, occasionally below the nephrotic levels.

Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to be effective in the reduction of proteinuria in patients with nephrotic syndrome.^7,8 ACEIs are also effective in lowering proteinuria in steroid-resistant nephrotic syndrome.^9,10 The degree of hypoalbuminaemia and hypercholesterolaemia also improved with the decrease in proteinuria. Angiotensin II type I receptor antagonist (AT II) has also been studied and has been found to have a comparable antiproteinuric ability as an ACEI in nephrotic syndrome.¹¹

Patients have been advised to take ACEI and a low protein diet to reduce urinary protein excretion. The combination of both has an additive antiproteinuric effect.¹² High protein intake increases the degree of proteinuria in nephrotic syndrome. However, the degree of proteinuria has been found to be similar when patients taking an ACEI with a high protein diet (1.6g/kg/day) are compared to those taking a low protein diet alone (0.8g/kg/day). The former group of patients taking higher protein diet subsequently had significantly higher total serum protein and albumin. Protein metabolism in nephrotic patients seems can be maintained with a high protein diet and an ACEI better than with a low protein diet alone.¹³

Hypoalbuminaemia

Various degree of hypoalbuminaemia are present in patients with nephrotic syndrome. The liver normally has the capacity to increase albumin synthesis to a degree that usually exceeds the urinary loss. However, the usual adaptive hepatic response to protein losses does not seem to be present in nephrotic patients.¹⁴ The mechanism by which hypoalbuminaemia occurs is incompletely understood.

Oedema in nephrotic syndrome

Two major factors have been suggested in the development of oedema in nephrotic patients.

1. Sodium retention directly induced by the renal disease, and
2. arterial underfilling due to the low plasma oncotic pressure leads to plasma volume depletion.^15,16

The more important factor leading to the development of oedema is sodium retention. Continued sodium retention is due primarily to the renal disease.¹⁷ The mechanism of sodium retention is the increased sodium reabsorption in the collecting tubules secondary to the increased resistance to atrial natriuretic peptide¹⁵ and the increased activity of the Na-K-ATPase pump in the cortical collecting tubule.¹⁸ It is important to emphasise that hypoalbuminaemia alone is not the major factor leading to the development of oedema as evidenced by previous studies in patients.¹⁹ There is, however, a subset of nephrotic patients having more severe hypoalbuminaemia with a plasma albumin concentration usually well below 20gm/l. These patients behave as if they are arterial underfilled having increased secretion of the hypovolaemic hormones leading to fluid retention.¹⁵

Arterial hypovolaemia is uncommon in most patients with the nephrotic syndrome. It has important implications for diuretic treatment since the excess fluid can usually be removed without inducing plasma volume depletion. Loop diuretics are potent drugs leading to natriuresis and diuresis in normal subjects. However, relative resistance to diuretics is generally found in nephrotic patients. Two factors are thought to be involved. Commonly used diuretics are highly protein bound. The degree of protein binding is reduced in hypoalbuminaemic patients and therefore there is reduced delivery to the kidney.²⁰ The second factor is diuretic entering the tubular lumen can be bound by filtered albumin and become inactivated.²¹ The clinical implication is that the diuretic dosage has to be increased to achieve adequate diuresis. Some patients with severe hypoalbuminaemia may be even more resistant. In this situation, diuretics can be added to salt-poor albumin to increase sodium excretion and diuresis.²² However, this additive diuresis effect may not be achievable in some patients, probably limited by the furosemide-albumin binding in the renal tubule.^23,24

Hyperlipidaemia

Disrupted lipid metabolism is common in patients with nephrotic syndrome. Marked elevations of plasma cholesterol, triglyceride, and lipoprotein(a) frequently occur.^25-27 Total HDL-cholesterol levels are frequently normal or reduced. The cardioprotective HDL₂ fraction is also frequently reduced.²⁸ Two abnormalities have been noted and may account for the changes.

1. Enhanced hepatic synthesis of lipoproteins containing cholesterol and apoprotein B is responsible for the elevation of plasma lipid levels. The reduction in plasma oncotic pressure is inversely related to the severity of hyperlipidaemia in patients with nephrotic syndrome.^25,29
2. Decreased clearance of very low-density lipoproteins (VLDL). The metabolic breakdown of VLDL to intermediate-density lipoproteins (IDL) and then to low-density lipoproteins (LDL) by lipoprotein lipases is slower in the nephrotic syndrome.^25,30

Hypercholesterolaemia is well known to be a major risk factor in the pathogenesis of coronary artery disease. Lowering cholesterol levels can decrease the incidence of coronary events by preventing progression and inducing regression of atherosclerotic lesions.³¹ It seems likely that patients with long-standing nephrotic syndrome and hyperlipidaemia are at increased risk for atherosclerotic disease, especially when other cardiovascular risk factors are present.²⁶ Patients with nephrotic syndrome have been reported to have higher relative risks than normal controls for myocardial infarction (5.5) and coronary death (2.8).³²

The optimal treatment for nephrotic hyperlipidaemia is uncertain. Hyperlipidaemia in the early stage of nephrotic syndrome may not require intervention especially when patients show rapid response with reducing proteinuria to treatment of the disease. However, intervention to lower hyperlipidaemia needs to be considered in those patients with persistent nephrotic and severe dyslipidaemic state. Dietary modification may be of some help. The use of a vegetarian soy diet that is rich in monounsaturated and polyunsaturated fatty acids and low in protein may produce a 25-30% reduction in lipid levels.³³ Antihyperlipidaemic agents can also be considered. However, their effects are variable. The most commonly used agents are fibric acid derivatives, bile acid sequestrants and HMG-CoA reductase inhibitors. Clofibrate and gemfibrozil are fibric acid derivatives that can lower the total cholesterol level by 10-30% and triglyceride level by 50% but are associated with an increased risk of myopathy.³⁴ Bile acid sequestrants (colestipol and cholestyramine) in a dose of 15 to 25gm/day can lower the total cholesterol level by up to 30% when given alone³⁵ and can give an additive effect when used with an HMG-CoA reductase inhibitor.³⁶ The gastrointestinal side effects of these agents often limit the compliance. HMG Co-A reductase inhibitors generally produce few side effects and can lower the plasma cholesterol and triglyceride concentration by 25-45%.^36,37 The concern with HMG Co-A reductase inhibitors is the development of the potentially life-threatening side effect of myositis leading to rhabdomyolysis and myoglobinuric acute renal failure. This complication is infrequent with monotherapy (occurring in 0.1-0.2% of cases),³⁸ but it can occur in as many as 5% of patients when taking with gemfibrozil and 30% of patients with cyclosporine.^39,40 There should be, therefore, extreme caution when using a HMG Co-A reductase inhibitor together with these agents. Preliminary observations have suggested that less proteinuria may be associated with a 10-15% reduction in the plasma levels of total and LDL cholesterol. Antihypertensive agents with antiproteinuric effects may be beneficial as an adjunctive form of hypolipidaemic therapy.⁴¹

Miscellaneous findings in the nephrotic syndrome

The incidence of arterial and venous throm-boembolism is increased (10-40% of patients) in patients with nephrotic syndrome. Deep vein and renal vein thrombosis are most common.⁴² Renal vein thrombosis may be unilateral or bilateral and often has an insidious onset and produces no symptoms referable to the kidney. Thrombotic events are occasionally diagnosed when a patient presents with acute loin pain and increasing proteinuria, or, pulmonary embolism.⁴² Renal vein thrombosis can occur with any cause of the nephrotic syndrome, but it seems to be more common in membranous nephropathy. Doppler ultrasonography may provide an accurate and non-invasive screening method for renal vein thrombosis. The standard diagnostic method is renal venography. Treatment of renal vein thrombosis consists of anticoagulation with heparin and then warfarin. Warfarin should continue for as long as the patient remains nephrotic. Surgical thrombectomy should be considered when there is bilateral renal vein thrombosis and renal failure that does not respond to anticoagulation.

The erythrocyte sedimentation rate (ESR) is elevated in almost all patients with the nephrotic syndrome. When elevation is extreme, to above 100mm/h, concomitant disorders such as infection, metastatic cancer, or collagen vascular disease should be considered.⁴³ When there is elevation in ESR associated with membranous nephropathy, an evaluation of the patient for an underlying malignancy is important especially when there is unexplained weight loss, haeme-positive stools, or anaemia.

Proteins other than albumin are also lost in the urine in the nephrotic syndrome. The urinary loss of protein leading to significant clinical disease is uncommon but has been observed in some patients. This results in the loss of vitamin D with impaired calcium absorption, osteomalacia, and secondary hyperparathyroidism.⁴⁴ An increased incidence of infection is noted and perhaps is due to loss of IgG and factors B and D. Refractory iron-deficiency anaemia due to loss of transferrin in urine has also been seen.⁴⁵

The development of acute renal failure complicating the nephrotic syndrome is uncommon. However, progressing to chronic renal impairment is possible. Therefore, it is important to make an accurate diagnosis to guide appropriate treatment. A percutaneous renal biopsy, in addition to blood and urinary tests, is usually required to establish the exact diagnosis especially in adults. The histopathology can also help to identify the degree of active and chronic changes to guide the prognosis and therapy.^46,47

Future aspects of treatment of nephrotic syndrome

Newer therapeutic approaches have been sought in the fields of immunosuppressive drugs used in organ transplantation including cyclosporin, tacrolimus, and mycophenolate mofetil.

Cyclosporine A has been used empirically for more than twelve years in the treatment of idiopathic nephrotic syndrome, in both children and adults. Cyclosporine diminishes or abolishes proteinuria by two differing mechanisms. The first is its immunosuppressive action, which is presumably directed toward secretion of a glomerular permeability factor. The second appears to be a non-immunologic effect on glomerular permselectivity, explaining reduced proteinuria in various aetiologies of nephrotic syndrome with no immunologic background. The success rate for inducing remission of idiopathic nephrotic syndrome is highest in steroid-dependent forms, essentially observed in minimal change disease where complete remission is achieved in 75% of cases. It is lowest in steroid-resistant idiopathic nephrotic syndrome, especially when accompanied with lesions of focal segmental glomerulosclerosis, with a success rate in the order of 20% complete remission and 25% partial remission. Therefore, the main advantage of cyclosporine is the corticosteroid-sparing effect in the treatment of idiopathic nephrotic syndrome.⁴⁸ However, long-term treatment with clyclosporine requires monitoring of renal damage with interstitial fibrosis even though renal function tests are apparently stable. Tacrolimus and mycophenolate mofetil have been shown to be effective in some cases in the reduction of proteinuria and inducing remission of relapsing nephrotic syndrome.^49,50 However, the number of patients in these studies was small and further studies are required to verify their effects as a standard treatment of nephrotic syndrome in the future.

NSAIDs and clyclooxygenase II inhibitors (COX II) have been used in the treatment of nephrotic syndrome to reduce proteinuria. However, these drugs have many renal side effects limiting their usage.⁵¹

Conclusion

The nephrotic syndrome, can occur in glomerular diseases, diabetes mellitus, amyloidosis, and various aetiological factors. It is still a challenge to clinicians in both diagnosis and management. Rapid and efficient diagnosis of diseases presenting as acute glomeru-lonephritis and/or nephrotic syndrome by renal biopsy is critcal for early and appropriate therapy aimed at preservation of renal function. Progressive renal damage to end stage renal failure may result if the underlying disease is not promptly treated accordingly. Provisional clinical estimation of the underlying pathological diagnosis has been shown to be frequently incorrect both in children and adults.² Renal biopsy in adults, and in carefully selected paediatric patients, is a useful diagnostic procedure.

Management of nephrotic syndrome is also a challenge to clinicians because of the resilience to currently available treatments and frequent relapse of the nephrotic state. Many patients become steroid-dependent. The side effects of corticosteriods are always troublesome and can be serious especially in children. Newer immunosuppressive drugs may be useful in reducing the dosage of steroid and hence its side effects. However, the long-term effectiveness in terms of renal protection, and the potential renal toxicity of the immunosuppressive agents has yet to be determined.

Key messages

1. Management of nephrotic syndrome is a clinical challenge.
2. Angiotensin-converting enzyme inhibitors (ACEIs) can reduce the degree of proteinuria.
3. The role of lipid-lowering agents in the acute phase of hyperlipidaemia in nephrotic syndrome is unclear.
4. Immunosuppressive agents can be useful in reducing the degree of corticosteroid-dependence in some cases.

---

---

References