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Published ahead of print on April 26, 2006
Clin J Am Soc Nephrol 1: 616-622, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01271005
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In-Depth Reviews

Spectrum of Renal Diseases Associated with Extreme Forms of Insulin Resistance

Carla Musso*, Edward Javor*, Elaine Cochran*, James E Balow{dagger}, and Phillip Gorden*

* Clinical Endocrinology Branch and {dagger} Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Address correspondence to: Dr. Phillip Gorden, CEB/NIDDK/NIH, 9000 Rockville Pike, CRC Room 6-5952, Bethesda, MD 20892-1770. Phone: 301-402-7340; Fax: 301-435-5873; E-mail: PhillipG{at}intra.niddk.nih.gov


   Abstract
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 Abstract
Introduction
 Other Specific Forms of...
 Discussion
 Conclusion
 References
 
Diabetic nephropathy is the leading cause of ESRD in the United States. Why the pathogenic mechanisms lead to nephropathy in certain patients with type 1 and 2 diabetes and spare others is unclear, but it is clear that hyperglycemia and glomerular hyperfiltration are important factors. In patients with syndromes of extreme insulin resistance, proteinuric forms of renal disease are common, but it is surprising to find that the renal pathology usually is not diabetic nephropathy. For instance, in the lipodystrophy syndromes, membranoproliferative glomerulonephritis type 1 and type 2, focal segmental glomerulosclerosis, and also diabetic nephropathy are seen. In the syndromes of autoantibodies to the insulin receptor, the various forms of lupus glomerulonephritis are seen. Even in patients with type 2 diabetes, the renal pathology may not be diabetic nephropathy. Therefore, in patients with syndromic forms of insulin resistance and type 2 diabetes, renal biopsy has an important role in defining the pathology that leads to proteinuric nephropathy and in formulating a therapeutic approach. It is the purpose of this article to review these unusual aspects of proteinuric nephropathy in patients with diabetes.


   Introduction
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 Abstract
 Introduction
Other Specific Forms of...
 Discussion
 Conclusion
 References
 
Nephropathy that is associated with type 1 and type 2 diabetes represents the leading cause of ESRD (1,2). Because the intensity and the duration of hyperglycemia are the primary known pathogenic factors in diabetic nephropathy (DN), it might be expected that the syndromic forms of diabetes under American Diabetes Association classification of "other specific forms of diabetes" would be highly susceptible to DN (3) (Table 1). This is especially true because these patients are characterized by extreme forms of insulin resistance and may have severe hyperglycemia for long periods of time. Surprising, classic DN is uncommon; however, these patients have a variety of renal diseases, and it is the purpose of this review to discuss the various renal pathologies that are seen in patients with extreme forms of insulin resistance (4–7).


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  		Table 1. Etiologic classification of diabetesa

 

   Other Specific Forms of Diabetes
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 Other Specific Forms of...
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The category of "other specific forms of diabetes" represents <10% of all cases of diabetes, but essentially all of the known causes of diabetes are represented in this group. The focus of this review is on syndromic forms of insulin resistance that are associated with renal diseases. These include the lipodystrophies, autoantibodies to insulin receptor, and syndromes that are associated with insulin receptor mutation (Table 1). The general characteristics of these syndromes are listed in Table 2. In addition, other secondary forms of diabetes, such as Cushing syndrome and acromegaly, are rarely associated with renal diseases such as DN (8,9). Although the phenotype and etiologic basis for these various syndromes are different, they all manifest hyperglycemia and in general glomerular hyperfiltration.


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  		Table 2. Syndromic forms of IRa

 
Lipodystrophies
The lipodystrophies are a group of disorders that are characterized by variable decrements in adipose tissue. The degree of adipocyte loss may be complete (generalized) or partial and may result from one of several genetic mutations or from an acquired cause. Patients who are severely affected by lipodystrophy are unable to store fat normally and are deficient in adipokines or hormones that are made by fat cells. This leads to severe hypertriglyceridemia and increased fat storage in ectopic locations such as skeletal muscle and liver. This is associated with extreme insulin resistance, diabetes, and nonalcoholic fatty liver disease. Furthermore, we have found that these patients have a high prevalence of proteinuria. The only previous renal abnormality to be emphasized in patients with partial lipodystrophy was hypocomplementemic membranoproliferative glomerulonephritis, usually type 2, dense deposit disease (10). We find that in addition, patients with generalized lipodystrophy have a high prevalence of proteinuric renal disease that may take several forms; despite that these patients should have the same risk for DN as every other patient with long-standing diabetes, DN is not the most frequent lesion seen (11).

Generalized Lipodystrophy.  Patients with generalized lipodystrophy have essentially no adipose tissue and, therefore, have the most severe dyslipidemia, insulin resistance, and diabetes among patients with lipodystrophies (12). Two genetic abnormalities have been elucidated, but it is unclear how the genetic defect leads to lipodystrophy, and there is no known link of the genetic mutations to nephropathy (reviewed in detail in [12]). In the course of evaluating patients with both congenital generalized lipodystrophy (CGL) and acquired generalized lipodystrophy (AGL), we were struck by the frequency and the severity of proteinuria that we observed in these patients. Eighty-six percent had elevated urinary albumin (>30 mg/24 h), the majority (59%) of whom had macroalbuminuria (>300 mg/24 h), and five (17%) patients had nephrotic-range proteinuria (>3500 mg/24 h; Figure 1a). Another notable finding was the consistency (90%) and the degree of creatinine clearance elevation (Figure 1b), which we presume reflect marked hyperfiltration from their long-standing diabetes (11).


Figure 1
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  		Figure 1. Baseline albumin excretions (a) and creatinine clearances (b) of all patients who had generalized lipodystrophy and were evaluated. The dashed lines correspond to abnormal thresholds as indicated.

 
Renal pathology showed a surprisingly rare occurrence of DN (Figure 2 a) at autopsy in one case. Renal biopsy of six patients with the most severe proteinuria demonstrated focal segmental glomerulosclerosis (FSGS) in four patients (three CGL, one AGL; Figure 2b) and membranoproliferative glomerulonephritis (MPGN) type 1 in two patients with AGL (Figure 2, c and d) (11). One patient with MPGN had low C3 complement and elevated C3 nephritic factor (C3NeF), and the other did not. Biopsies of other patients with generalized lipodystrophy have demonstrated primarily FSGS (13–15).


Figure 2
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  		Figure 2. Spectrum of glomerular diseases in patients with insulin-resistant diabetes and lipodystrophies. (a) Nodular diabetic glomerulosclerosis (Kimmelstein-Wilson disease; periodic acid-Schiff stain). (b) Focal segmental glomerulosclerosis with hyalinosis; glomerulus shows two segmental areas of dense segmental sclerosis (*) along with hyaline deposits (arrows; hematoxylin and eosin stain). (c) Membranoproliferative glomerulonephritis (MPGN); glomerulus has a lobular appearance with marked mesangial matrix expansion and hypercellularity, which compromise capillary lumens (hematoxylin and eosin stain). Characteristic "splitting" or double-contour appearance of the glomerular capillary wall in MPGN (periodic acid methenamine silver stain). (d) Ultrastructure of type 1 MPGN showing a typical glomerular capillary loop with subendothelial electron-dense deposits (green arrows); extension of mesangial matrix beneath the endothelium creates by light microscopy a double-contour appearance of capillary loops with stains that accentuate the glomerular basement membranes (electron micrograph courtesy of Dr. Sharda Sabnis, Nephrology Section, Armed Forces Institute of Pathology, Washington, DC). (e) Ultrastructure of type 2 MPGN or dense-deposit disease illustrating the common form of MPGN in patients with acquired lipodystrophy; the dense deposits are associated with linear staining with antiserum to complement 3 but not Ig, indicating that the material is not typical immune complexes (electron micrograph courtesy of Dr. Sharda Sabnis).

 
We have treated these patients with recombinant methionyl human leptin primarily for their metabolic disease, which has ameliorated their dyslipidemia, insulin resistance, and liver disease (7). We concurrently observed a significant decrease in proteinuria and normalization of creatinine clearance in the majority of patients who were treated with leptin (Figure 3). Although proteinuria is markedly reduced in these patients, most also receive either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In general, these patients were not hypertensive and did not require therapy for BP regulation.


Figure 3
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  		Figure 3. Urine protein excretions in conjunction with median creatinine clearance of patients who were treated with recombinant leptin for up to 54 mo. The clustered lines correspond to individual urine protein excretions over time. The bold line corresponds to median creatinine clearance over time. The reduction in urine protein excretions in these patients was significant (P = 0.005 by ANOVA). For details see reference (11).

 
One patient with CGL and ESRD as a result of unspecified glomerular disease underwent a successful renal transplant and has had preservation of the renal graft and good metabolic control during a 4-yr follow-up period and is the subject of a separate report (16). Two additional patients are on chronic dialysis for ESRD; one patient has FSGS, and the other has MPGN.

Partial Lipodystrophy.  Patients with acquired partial lipodystrophy (APL), also known as Barraquer-Simons syndrome, characteristically lose adipose tissue from their face, neck, upper extremities, thorax, and upper abdomen (10). Patients often have compensatory hypertrophy of their lower extremity adipose tissue and typically have normal serum lipids and glucose. Although the cause is unknown, this disorder often is associated with low C3 and elevated C3NeF, the latter of which has been implicated as a possible cause for the lipodystrophy (17,18). C3NeF, an IgG autoantibody, dysregulates the alternative pathway, contributing to the consumption of C3, and may also lead to adipocyte lysis (19).

The predominant renal lesion that is associated with APL is MPGN type 2 (dense deposit disease; Figure 2e), also associated with low C3 and elevated C3NeF (10). The prevalence of MPGN in patients with APL is estimated at 22%. The pathogenesis is unclear, but, again, both hypocomplementemia and C3NeF have been suspected as contributing factors (10,19).

MPGN type 2 also was identified in one patient with Dunnigan’s partial lipodystrophy, which is characterized by adipocyte loss in the arms, legs, and trunk, with resultant hypertriglyceridemia, insulin resistance, and diabetes (Table 3) (20). This patient did not have low C3 or C3NeF present. Of the six patients with Dunnigan’s partial lipodystrophy we have studied, five had normal urine microalbumin excretions and one had macroalbuminuria (1.2 g/24 h) in association with chronic renal insufficiency (creatinine 1.6 mg/dl, creatinine clearance 71 ml/min), hypertension, and diabetes (unpublished observation, April 2006). Renal biopsy has not been performed.


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  		Table 3. Type of lipodystrophya

 
Other Forms of Lipodystrophy.  There are yet other forms of partial lipodystrophies of genetic and acquired causes that have not been associated with renal pathologies other than those previously mentioned. This includes dermatomyositis, HIV lipodystrophy associated with highly active antiretroviral therapy, and mandibuloacral dysplasia (Table 3).

Autoantibodies to the Insulin Receptor
Patients who have autoantibodies to the insulin receptor represent a general classification of diseases that are associated with autoantibodies to cell surface proteins such polypeptide hormone receptors. This class of disease includes Graves diseases with autoantibodies to the thyroid-stimulating hormone receptor, myasthenia gravis with autoantibodies to the acetylcholine receptor, and a number of other diseases of either hormone receptor or other cell surface proteins. It is interesting that the syndrome of autoantibodies to the insulin receptor is unique in its association with renal disease.

These patients typically present with extreme insulin resistance and poorly controlled diabetes but may present with hypoglycemia. Features of hyperandrogenism and polycystic ovarian syndrome also are common (Table 2). They usually have an underlying collagen vascular disease such as systemic lupus erythematosus. More than 50% of these patients have clinical proteinuria, and the most common pathology seen is consistent with one of the forms of lupus nephritis (Figure 4) (4,6,21,22). Whereas the intensity of hyperglycemia is usually extreme, the duration of the hyperglycemia is variable, and this perhaps is the reason that DN is not seen in this group of patients.


Figure 4
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  		Figure 4. Spectrum of lupus nephritis in patients with insulin-resistant diabetes as a result of autoantibodies to insulin receptors. (a) Mesangial lupus nephritis (class II): The glomerulus shows increased mesangial cells and matrix but minimal compromise of capillary loop patency (periodic acid-Schiff stain). (b) Proliferative lupus nephritis (class III or IV): There is global but irregular increase of endocapillary cells and mesangial matrix, the combination of which substantively reduces the circulatory space of the glomerular tuft; capillary walls are irregularly thickened (Masson trichrome stain). (c) Membranous lupus nephropathy (class V): The glomerular tuft cellularity is essentially normal; capillary loops are characteristically prominent and have a stiff appearance; capillary wall thickening is mild and irregular, indicating stage 1 membranous nephropathy (Masson trichrome stain). (d) Ultrastructure of subendothelial immune complex deposits (green arrows) typically seen in class III or IV proliferative lupus nephritis; endothelial cells contain tubuloreticular structures (pink arrow), which are characteristic of lupus nephritis (electron micrograph courtesy of Dr. Sharda Sabnis). (e) Ultrastructure of subepithelial (epimembranous) deposits (green arrows) typically seen in class V lupus membranous nephropathy (electron micrograph courtesy of Dr. Sharda Sabnis).

 
Therapy is directed at the underlying process, which most commonly is lupus and requires a form of immunosuppression (4). Another therapy that has been used in this syndrome is Rituximab (a monoclonal anti-CD20 antibody), which showed a striking amelioration of the insulin-resistant diabetes in two patients (23,24). Therefore, the diabetic syndrome may spontaneously remit independent of the nephropathy or may remit in the context of the therapeutic regimen for the renal disease. It is important to consider both of these issues independently (4,6).

Mutation of the Insulin Receptor
Syndromes that are associated with mutations of the insulin receptor all are characterized by extreme insulin resistance, acanthosis nigricans, and hyperandrogenism but have no autoimmune features that are seen in autoantibody syndrome. These patients are rare but have a high incidence of diabetic complications. This includes DN. This is not surprising, because these patients have extreme hyperglycemia over a protracted period of time (5). In type 1 and type 2 diabetes, retinopathy may be concordant or discordant with nephropathy. Similarly, in the insulin receptor mutation syndrome, we have studied two sisters who are homogeneous for the same mutation in the insulin receptor; one patient died from DN, and the other has no evidence of nephropathy but is blind from retinopathy (5). There are even more rare case reports of extreme insulin resistance as a result of mutations in downstream substrates of the insulin receptor but no known association with renal diseases (25).


   Discussion
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 Abstract
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 Other Specific Forms of...
 Discussion
Conclusion
 References
 
DN is a clinical syndrome that is characterized by proteinuria, arterial BP elevation, decline in GFR, and high risk for cardiovascular disease. This complication develops in approximately 20 to 40% of patients with type 1 diabetes, between 10 to 15 yr after the onset of hyperglycemia, and at least to this extent in Pima Indians with insulin resistance and type 2 diabetes (1,26,27). Although the incidence of nephropathy may be somewhat lower in type 2 diabetes, these patients constitute the majority of individuals with diabetes. Collectively, all forms of diabetes are the leading cause of ESRD in the United States.

At least two general mechanisms are involved in the development of DN; the first mechanism is glucose levels per se and intracellular hyperglycemia in cells with no barriers to glucose uptake such as mesangial cells. These cells may be injured by oxidative stress, advanced glycation end products, and others factors that can be ameliorated by reducing blood glucose and intracellular glucose concentration (28). This mechanism is strongly supported by several recent clinical trials. The Diabetes Control and Complications Trial (DCCT) showed that combined, intensive therapy reduced the occurrence of microalbuminuria by 39% and that of albuminuria by 54% (29). The United Kingdom Prospective Diabetes Study (UKPDS) of patients with type 2 diabetes found that fewer patients who were treated with intensive versus conventional therapy had progression of microalbuminuria (27 versus 39%) and proteinuria (7 versus 13%) over 15 yr of follow-up (30). The second important mechanism seems to be hyperfiltration and alteration of the renal microcirculation. This hypothesis clearly is supported by amelioration of disease progression by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (31–35).

All these factors are present in our patients with syndromic insulin resistance, and they are susceptible to DN. It is paradoxic, therefore, that the predominant renal diseases that are seen in these patients are not DN but other nephropathies, such as FSGS and MPGN (Table 4). These nephropathies frequently are seen as secondary conditions to other systemic diseases such as vital hepatitis and even morbid obesity (36).


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  		Table 4. Summary of renal diseases in syndromic forms of IRa

 
Nephropathies are common in three different syndromic forms of diabetes. In the patients with autoantibodies to the insulin receptor, hyperglycemia, and proteinuria, it is not surprising that the predominant renal lesion is a variety of lupus nephritis because lupus is a common background condition. In patients with mutations in the insulin receptor, there is long-term and intense exposure to hyperglycemia, and these patients predominantly have DN either concordant or discordant with retinopathy.

The most surprising group are patients with the various forms of lipodystrophy, in whom long-standing hyperglycemia and proteinuria are common. In these patients, renal biopsy is important because the nature of the proteinuric nephropathy is not predictable. Although extreme hypertriglyceridemia is common in these patients, we have not been able to associate this with the renal diseases (37).

Leptin is a newly recognized adipose-derived hormone that has a major effect to decrease hyperglycemia, hyperlipidemia, and hepatic steatosis (38). Furthermore, it has a significant effect to decrease both hyperfiltration and proteinuria (11). Whether this will have an effect on the course of renal disease that is seen in these patients is unclear.

From a diagnostic perspective, several generalizations seem warranted. In type 1 diabetes and certain groups with type 2 diabetes, such as Pima Indians, the occurrence of hyperglycemia and proteinuria usually represent DN. This is bolstered by the presence of retinopathy and longer duration of hyperglycemia. In type 2 diabetes, the issue may be more complex, and renal biopsy may be the only way to distinguish the nature of the renal disease in patients with hyperglycemia and proteinuria that is similar to our syndromic patients. This is well established in a recent Japanese study in which other forms of nephropathy were seen on renal biopsy in addition to or instead of DN (39). Although short duration of diabetes (<5 yr) or absence of diabetic retinopathy favors a diagnosis other than DN, this is complicated by the lack of information on the onset of hyperglycemia in patients with type 2 diabetes and the known discordance with retinopathy.

There are case reports of apparent histologic DN in the absence of diagnosed diabetes, but this is uncommon and the metabolic state may fluctuate with changes in diet, weight, and other influences. Therefore, in general, hyperglycemia is a necessary but insufficient factor in the pathogenesis of DN. Although the intensity and the duration of hyperglycemia are major pathogenic factors, only approximately 30% of patients with type 1 diabetes develop DN; even in a very high prevalence groups of type 2 diabetes, such as Pima Indians, this also is the case. Therefore, other unknown factors that may be environmental or genetic are involved (40).


   Conclusion
Top
 Abstract
 Introduction
 Other Specific Forms of...
 Discussion
 Conclusion
References
 
Proteinuric renal diseases are common in patients with syndromic forms of extreme insulin-resistant diabetes and lipodystrophy; the pathologic lesion usually is not DN but other, secondary forms of renal diseases that are seen associated with other systemic diseases.


   Acknowledgments
 
This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.


   References
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