Version May 2024
INTRODUCTION — Although the glomeruli are normal on light microscopy in minimal change disease (MCD) at the time of presentation, many adults and children have a modest reduction (averaging 30 percent) in glomerular filtration rate (GFR), as evidenced by a moderate elevation in the plasma creatinine concentration [1-6]. This relatively common change is mediated at least in part by the reversible podocyte foot process fusion, which is apparent by electron microscopy, and which is characteristic of the disease [7-11]. In addition to this modest reduction in GFR, some patients with MCD develop acute kidney injury (AKI), which is often severe and may require dialysis [12-15]. In most cases, AKI is due to acute tubular necrosis.
The pathophysiology, etiology, clinical manifestations, and treatment of GFR reduction in patients with MCD are discussed in this topic. The pathophysiology and treatment of edema in such patients, as well as treatment of MCD in children and adults, are presented elsewhere:
●(See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)
●(See "Treatment of idiopathic nephrotic syndrome in children".)
●(See "Minimal change disease: Treatment in adults".)
PATHOPHYSIOLOGY — Many patients with MCD and nephrotic syndrome have a modest reduction in glomerular filtration rate (GFR) of approximately 30 percent [1-6]. Studies of children with this disorder show a close correlation of the GFR with both the reduced filtration fraction and the decreased serum albumin concentration that are proportional to the severity of the nephrotic state [6-8,10]. The driving force for glomerular filtration is the difference in hydrostatic pressure and oncotic pressure across the glomerular capillary. In severe nephrotic syndrome with MCD, oncotic pressure is greatly reduced due to leakage of albumin into the Bowman's space, which could lead to a drop in ultrafiltration across the glomerular basement membrane [16]. Filtrate that has passed through the glomerular basement membrane enters the urinary space via the slit pores between the adjacent foot processes. Foot process fusion decreases the filtration slit frequency, thereby increasing the average path length for filtration [7,8,10]. The capacity of the glomerular basement membrane to bar the egress of serum albumin into Bowman's space is altered, causing massive proteinuria, while foot process fusion reduces the glomerular capillary wall permeability to water and small solutes, decreasing hydraulic permeability and explaining the reduction in the GFR.
Low effective arterial blood volume is not the cause of reduced GFR in most patients with MCD. Although patients with MCD have a low plasma oncotic pressure, the "underfill" hypothesis that was thought to explain the reduction in GFR and the intense renal sodium reabsorption is no longer accepted [17-34]. Rather, in this particular edematous state, an increase in the interstitial pressure is accompanied by an increase of the lymph flow to the circulation that maintains a normal blood volume [15]. These changes in kidney function regress with treatment-induced remission of proteinuria. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)
In some patients with MCD (usually adults), an acute onset of a severe decline in GFR is seen, possibly requiring dialysis. As noted below, hypertension and older age are risk factors for AKI in patients with MCD. In several studies, for example, kidney biopsies performed in patients with MCD and AKI revealed vascular lesions of arterial and arteriolar sclerosis, which are commonly found in hypertensives [13,35]. These lesions of the renal vessels contribute to reduced blood flow to the glomeruli [36], which diminish in number with aging [37]. In addition, tubulointerstitial lesions are common with hypertensive nephrosclerosis [36]. Underlying vascular disease and tubulointerstitial lesions may be an important precursor to the development of AKI in patients with MCD.
EPIDEMIOLOGY, ETIOLOGY, AND CLINICAL MANIFESTATIONS — Many adults and children with MCD have a modest, persistent reduction in glomerular filtration rate (GFR), as evidenced by a moderate elevation in the plasma creatinine concentration. However, despite normal glomeruli by light microscopy, some patients with MCD develop AKI, which is often severe and may require dialysis.
The simultaneous presence of AKI and nephrotic syndrome should raise suspicion for MCD, particularly among older adults. In one large series, for example, 5 of 20 patients biopsied because of AKI and nephrotic syndrome had a diagnosis of MCD; two had pauci-immune glomerulonephritis, and no other etiology of nephrotic syndrome accounted for more than one case [38]. The likelihood of MCD is even higher in nephrotic patients with acute tubular necrosis as the cause of AKI (15 of 19 in one study) [39].
Acute kidney injury in adults with minimal change disease — AKI has been reported in approximately 25 to 35 percent of adults with MCD and is frequently present at the time the nephrotic syndrome is diagnosed [12,14,40,41]. Patients with MCD who develop AKI are more likely than those who do not develop AKI to be older, male, hypertensive, and to have more severe nephrotic syndrome [15,42]. As an example, in one retrospective review of 95 adults with MCD from the United States [14], AKI occurred in 24 patients (25 percent). In 17 patients, it was concurrent with the initial presentation of MCD, and in seven patients, it occurred during a relapse of MCD. Patients with AKI were older (54 versus 42 years) and were more likely to be male (63 versus 33 percent) and hypertensive (69 versus 37 percent). In addition, proteinuria was higher among those with AKI (13 versus 9 g/day). In another series of 125 adults and adolescents (age >16 years) from the Netherlands, AKI was observed in 50 patients (40 percent) [42]. Median time to recovery of kidney function was six weeks. Nine patients required hemodialysis; eight recovered kidney function, and one died from infectious complications while on dialysis.
Most patients presenting with AKI in the setting of MCD have substantial proteinuria, hypoalbuminemia, and edema. In a large series of 75 adults with MCD who developed AKI, the mean urine protein excretion was 12 g/day and the serum albumin was 1.9 g/dL (19 g/L) [12]. Approximately one-half of patients had hypertension at the time of presentation, and 84 percent had massive edema. All cases of AKI occurred within three months of the time that the nephrotic syndrome was diagnosed (mean of 29 days). AKI was severe; most patients were oliguric at presentation, and approximately 20 percent required dialysis or died from intercurrent complications.
The usual etiologies of AKI in adults with MCD are as follows:
●Acute tubular necrosis – Most reported patients appear to have tubular changes that are similar to those in postischemic acute tubular necrosis [12-14,35,40]. In the study of 75 adults with MCD and AKI mentioned above, acute tubular necrosis was the cause of AKI in 65 percent of patients [12]. By contrast, tubular injury is not seen in kidney biopsies of patients with MCD who maintain relatively normal kidney function. These observations suggest that transient ischemia may occur early in the course of the disease. In one study of 53 patients with MCD, one-half had AKI [41]. Among those with AKI, immunostaining for endothelin-1 (ET-1) revealed strongly positive staining on tubules, whose cells were flattened or necrotic. This raised the hypothesis that in some patients with MCD, a surge of ET-1 secretion induces vasoconstriction and ischemia at the onset of proteinuria [15]. Older patients who develop this complication also tend to have underlying arteriolar nephrosclerosis, which might predispose to decreased nephron perfusion [12,35].
●Nonsteroidal antiinflammatory drugs (NSAIDs) – NSAIDs can diminish kidney function by decreasing the formation of vasodilator prostaglandins, thereby inducing renal vasoconstriction; this may induce ischemic tubular injury [43]. NSAIDs may also cause MCD as a toxic effect of therapy [44-48]. The latter complication is most often seen with fenoprofen and is typically accompanied by an acute interstitial nephritis that is responsible for the kidney failure [49]. (See "NSAIDs: Acute kidney injury".)
Although most common with NSAIDs, the combination of acute interstitial nephritis and MCD can also be induced by other drugs. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)
●Contrast-induced nephropathy – Nephrotic patients, particularly those with diabetes mellitus, are especially prone to AKI following iodinated contrast media-enhanced radiographic procedures. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast-associated acute kidney injury related to angiography".)
●Excessive diuresis – Natriuresis induced by loop diuretics can lead to plasma volume depletion and a decline in kidney function. This problem is most likely to occur in patients with a plasma albumin concentration of 1.5 g/dL (15 g/L) or less [50]. In most patients, however, the hypoalbuminemia is less severe. In addition, edema and renal sodium retention in MCD are primarily due to a direct effect of glomerular albumin leak on the renal tubules, rather than a decrease in plasma oncotic pressure and, consequently, reduced effective arterial blood volume [18,19,28-33]. Thus, such patients are generally at low risk of hypovolemia following fluid removal with diuretics [17,26]. (See "Pathophysiology and treatment of edema in adults with the nephrotic syndrome".)
●Increased urine viscosity – In nephrotic patients with oliguria and an unusually high degree of proteinuria, urine viscosity may contribute to impair kidney function. This is illustrated by a case in which a patient with AKI voided small amounts of gel-like urine with >120 g/L of albumin [51]. Kidney function recovered with a glucocorticoid-induced remission of proteinuria.
Acute kidney injury in children with minimal change disease — AKI is much less frequent in children with MCD as compared with adults. In one study of 1006 children with idiopathic nephrotic syndrome, the nine-year incidence of AKI was 0.8 percent [52]. As noted above, approximately 25 to 35 percent of adults with MCD develop AKI. (See 'Acute kidney injury in adults with minimal change disease' above.)
Conversely, AKI is common when children with MCD are hospitalized for complications of nephrotic syndrome, such as infection or thrombosis. As an example, in a multicenter study of 336 children with nephrotic syndrome, 197 developed AKI (59 percent) [53]. Common causes of AKI in these children include hypovolemia (due to diarrhea, vomiting, or excessive diuresis), infection (typically, pneumonia or peritonitis), nephrotoxic medications (such as NSAIDs), and the effects of drugs such as calcineurin inhibitors and angiotensin-converting enzyme (ACE) inhibitors [53-62].
Changes in glomerular permeability may underlie AKI in some children. In one study of 11 children with MCD and oliguric AKI [63], for example, measured renal plasma flow at presentation was normal, and neither renal plasma flow nor filtration fraction improved after volume expansion with 20 percent albumin. This indicated that decreased renal perfusion was not contributing to the reduction in GFR. Rather, these findings are consistent with a principal role for reduced glomerular capillary loops permeability due to foot process fusion in the pathogenesis of the reduced GFR [7-11].
Acute kidney injury in other forms of nephrotic syndrome — AKI is unusual in other pure nephrotic states (ie, patients with a normal or near-normal urine sediment) such as diabetic nephropathy and amyloidosis.
There are, however, two major settings in which AKI can occur in pure nephrotic syndrome:
●In patients with the collapsing form of focal segmental glomerulosclerosis in which renal insufficiency is due both to glomerular and concurrent tubular injury. This disorder is often associated with HIV infection but may occur in the absence of this infection. (See "HIV-associated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)
●In some patients treated with NSAIDs [64]. These drugs reduce the GFR and may induce an acute kidney functional impairment that is reversible after stopping the medication. Conversely, NSAIDs may cause an acute allergic interstitial nephritis, which regresses slowly following treatment with glucocorticoids, although patients with interstitial nephritis do not have a normal urine sediment. (See "NSAIDs: Acute kidney injury".)
Other, less common causes of AKI in conjunction with nephrotic syndrome include the following:
●Allergic reactions to drugs that are commonly used in treatment of nephrotic syndrome (such as furosemide, thiazide diuretics, or warfarin) may occasionally produce AKI due to a hypersensitivity interstitial nephritis. Skin rash and eosinophilia may accompany these reactions. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)
●AKI due to crescentic glomerulonephritis has rarely been described in patients with membranous nephropathy (MN). In this setting, the urinalysis reveals an active sediment (red cells and granular and cellular casts) rather than a bland urine sediment as seen in most patients with AKI associated with nephrotic syndrome. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)
●Renal vein thrombosis is also a rare cause of AKI in the nephrotic syndrome. However, most patients with this complication have relatively stable kidney function; an elevation in the plasma creatinine concentration primarily occurs in the exceptional patient with acute bilateral renal vein thrombosis that produces renal infarction and flank pain before the development of a collateral venous circulation relieves the intrarenal venous pressure. (See "Renal vein thrombosis in adults".)
EVALUATION AND DIAGNOSIS — The evaluation of patients with nephrotic syndrome who develop AKI depends in part upon whether or not the cause of the nephrotic syndrome is already known:
●If the cause of nephrotic syndrome is not already known, then a kidney biopsy is typically performed to identify the etiology of both the nephrotic syndrome and the AKI.
●If the cause of nephrotic syndrome is already known (eg, in a patient with an established diagnosis of MCD), the initial evaluation is similar to that in patients without nephrotic syndrome. (See "Evaluation of acute kidney injury among hospitalized adult patients", section on 'Evaluation' and "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Evaluation' and "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults", section on 'Evaluation and diagnosis'.)
If the evaluation of AKI reveals prerenal azotemia, acute tubular necrosis, or obstructive uropathy, a kidney biopsy is not usually needed. Other patients typically undergo kidney biopsy to determine the etiology of AKI.
TREATMENT AND PROGNOSIS
AKI in patients with minimal change disease
Treatment — Therapy of AKI is aimed at inducing a remission of the nephrotic syndrome, eliminating factors that could potentially be contributing to the renal impairment, and treating the complications of AKI.
Therapy to induce remission in patients with MCD is discussed elsewhere. (See "Minimal change disease: Treatment in adults" and "Treatment of idiopathic nephrotic syndrome in children".)
Factors that could contribute to AKI in patients with MCD, such as infection, should be treated appropriately. Nephrotoxic medications (such as nonsteroidal antiinflammatory drugs [NSAIDs]) or drugs that could contribute to functional azotemia (such as angiotensin-converting enzyme [ACE] inhibitors) should be discontinued. In addition, volume replacement is appropriate in patients who have developed a decline in kidney function that is temporally related to diuretic-induced fluid removal. However, infusing albumin is not useful, as it is rapidly wasted in the urine and does not improve kidney function [65].
Prognosis — A majority of patients with MCD eventually go into remission, with disappearance of proteinuria, when receiving immunosuppressive therapy [1,2,42,66]; approximately two-thirds of such patients with AKI recover to normal or near-normal kidney function within an average of seven weeks. However, short-term dialysis may be required in selected cases [12,13]. Patients who suffer an episode of AKI compared with those without such an event have significantly higher serum creatinine levels over the long term [35,67].
In large series of patients with MCD, for example, 75 developed AKI, four of whom required hemodialysis for a period that ranged from 5 to 24 weeks [12]. Overall, the time between onset of AKI and recovery was 47 days (range of 3 to 180 days). At more than four years of follow-up, the mean serum creatinine in these 75 patients with an episode of AKI was significantly higher compared with patients who had MCD but no AKI.
Chronic kidney disease is a rare event [12-14,67] that occurs most often in patients with focal segmental glomerulosclerosis, either as the primary disease (segmental sclerotic lesions can easily be missed on percutaneous kidney biopsy) or as a consequence of the tubular epithelial cell injury in initial MCD [68]. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)
Some patients with MCD develop AKI that is irreversible [14,67]. One study reported five such cases in adults aged 44 to 74 years [67]. Prior kidney disease or occlusion of major renal vasculature was not present. These patients continued to excrete large amounts of protein (9 to 15 g/day) despite a low glomerular filtration rate (GFR) and severe oliguria. One patient died after five months without recovering kidney function. Four patients required hemodialysis for a period of 12 to 58 months.
The overall impression is that recovery of kidney function was achieved in approximately two-thirds of the cases within an average of seven weeks, but with wide variations in this length of time. Fourteen patients died of various complications, and some remained indefinitely on dialysis. These patients who did not recover were older and more hypertensive than those who recovered.
AKI in patients with other forms of nephrotic syndrome — The treatment of AKI in patients with other forms of nephrotic syndrome depends upon the etiology of the AKI:
●Collapsing focal segmental glomerulosclerosis (see "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Treatment' and "HIV-associated nephropathy (HIVAN)", section on 'Treatment')
●NSAIDs (see "NSAIDs: Acute kidney injury", section on 'Treatment')
●Allergic interstitial nephritis (see "Treatment of acute interstitial nephritis")
●Crescentic glomerulonephritis (see "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Treatment')
●Renal vein thrombosis (see "Renal vein thrombosis in adults", section on 'Treatment')
SUMMARY AND RECOMMENDATIONS
●Overview – Many adults and children with minimal change disease (MCD) and nephrotic syndrome have a modest reduction in glomerular filtration rate (GFR) of approximately 30 percent, as evidenced by a moderate elevation in the plasma creatinine concentration. This relatively common change is mediated at least in part by the reversible podocyte foot process fusion. In addition to this modest reduction in GFR, some patients with MCD develop acute kidney injury (AKI), which is often severe and may require dialysis. (See 'Pathophysiology' above.)
●AKI in adults with MCD – Most adults presenting with AKI in the setting of MCD have substantial proteinuria, hypoalbuminemia, and edema. The usual etiologies of AKI include acute tubular necrosis, nonsteroidal antiinflammatory drugs (NSAIDs), contrast-induced nephropathy, and excessive diuresis (most often in patients with a plasma albumin concentration ≤1.5 g/dL [15 g/L]). (See 'Acute kidney injury in adults with minimal change disease' above.)
●AKI in children with MCD – AKI is much less frequent in children with MCD as compared with adults but is common when children with MCD are hospitalized for complications of nephrotic syndrome, such as infection or thrombosis. Common causes of AKI in these children include hypovolemia (due to diarrhea, vomiting, or excessive diuresis), infection (typically pneumonia or peritonitis), nephrotoxic medications (such as NSAIDs), and the effects of drugs such as calcineurin inhibitors and angiotensin-converting enzyme (ACE) inhibitors. (See 'Acute kidney injury in children with minimal change disease' above.)
●AKI in other forms of nephrotic syndrome – AKI is unusual in other pure nephrotic states although it may be seen in patients with the collapsing form of focal segmental glomerulosclerosis, patients treated with NSAIDs, patients who have an allergic interstitial nephritis induced by medications used to treat nephrotic syndrome (such as furosemide), patients with crescentic transformation of membranous nephropathy, and patients who develop renal vein thrombosis as a complication of nephrotic syndrome. (See 'AKI in patients with other forms of nephrotic syndrome' above.)
●Evaluation – The evaluation of patients with nephrotic syndrome who develop AKI depends in part upon whether or not the cause of the nephrotic syndrome is already known (see 'Evaluation and diagnosis' above):
•If the cause of nephrotic syndrome is not already known, then a kidney biopsy is typically performed to identify the etiology of both the nephrotic syndrome and the AKI.
•If the cause of nephrotic syndrome is already known, the initial evaluation is similar to that in patients without nephrotic syndrome.
●Treatment – Therapy of AKI in patients with MCD is aimed at inducing a remission of the nephrotic syndrome, eliminating factors that could potentially be contributing to the kidney function impairment (eg, nephrotoxic medications, infection), and treating the complications of AKI. (See 'Treatment' above.)
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