Unveiling the Silent Threat: A Case Study of Kidney Dysfunction with Normal Range Proteinuria

Introduction

Commonly, kidney diseases are found with proteinuria, which serves as a common marker of kidney damage resulting from glomerular or tubulointerstitial injury. Not all kidney dysfunction is coupled with increased protein excretion. A lesser-known condition, defined by kidney impairment with normal range proteinuria is commonly neglected and underperceived in nephrology. In clinical practice, such cases pose a special challenge for diagnosing and treatment, often necessitating renal biopsies to diagnose the underlying pathology.

The case study attempts to explore renal histopathology in a patient population at three teaching hospitals located in Southern China, Shenzhen, who presented with kidney dysfunction and normal urinary protein excretion by undertaking a systematic retrospective review to unearth the findings related to an underrecognized condition, whereby its importance and considerations for patient management can be brought into relevance.

Study Overview

Study Design and Population

A retrospective study was conducted at three major university teaching hospitals in Shenzhen, China from 2014 to 2024. The criteria for selection included patients with a range of unexplained renal insufficiency but normal range proteinuria as defined by a 24-hour urinary protein excretion of less than 150 mg or a spot urinary protein-to-creatinine ratio (PCR) below 150 mg/g. Of this group, 53 patients (2.2%) met the requirements mentioned above and went on to be studied further.

Patients with undetermined or uncertain kidney dysfunction were included in the study. The mean age of the selected patients was 47.3 ± 14.3 years, and there were 40 males and 13 females. The selected patients had a mean estimated glomerular filtration rate of 46.6 ± 16.8 mL/min per 1.73 m², confirming them to be moderately to severely mentally impaired.

Objectives

The primary aim of the study was to determine the underlying histopathological diagnoses in patients with renal dysfunction but without overt proteinuria. Secondary objectives included comparing clinical characteristics across histopathological groups and evaluating the utility of renal biopsy in guiding treatment decisions and predicting patient outcomes.

Histopathological Findings

Renal biopsies were performed on all 53 patients, and three primary categories of kidney disease were identified: glomerular disease (GD), tubulointerstitial disease (TID), and small vascular disease (SVD). The following are the histopathological findings:

Glomerular Disease (GD): The most common pathology, glomerular disease was found in 23 patients (43.4%). Glomerular diseases are typically associated with proteinuria, but in this cohort, the absence of significant protein excretion raised the question of atypical disease progression. Histologically, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and IgA nephropathy were the most frequent diagnoses. Patients with glomerular disease had a moderate reduction in eGFR, with a relatively stable renal function during the follow-up.

Tubulointerstitial Disease (TID): Nineteen patients (35.8%) were diagnosed with tubulointerstitial disease. Patients in this group exhibited the lowest mean eGFR and had the highest numerical 24-hour urinary protein excretion, although still within normal limits. TID is known for its association with drug toxicity, infections, and autoimmune disorders, with chronic tubulointerstitial nephritis being a frequent finding in this study. Interestingly, the incidence of acute kidney injury (AKI) was significantly higher in the TID group, often associated with systemic conditions like Sjögren’s syndrome or nephrotoxic agents.

Small Vascular Disease (SVD): The remaining 11 patients (20.8%) were diagnosed with small vascular disease. This group included patients with hypertensive nephrosclerosis and thrombotic microangiopathy. The SVD group had the highest prevalence of underlying hypertension, suggesting that long-standing uncontrolled blood pressure played a critical role in the pathogenesis of kidney dysfunction in these patients. Unlike glomerular or tubulointerstitial diseases, SVD typically presents with minimal proteinuria but is associated with progressive renal impairment.

Clinical Characteristics and Outcomes

The TID cases showed the greatest decrease in renal function, with a mean eGFR most significantly decreased compared with those who had glomerular or small vascular diseases. Moreover, the development of acute kidney injury was considerably more common among the TID group and, quite often, had to be treated as an emergency lest the kidney damage worsen.

Interestingly, patients with TID had a greater range of variation in 24-hour urinary protein excretion despite having proteinuria within the normal range. This is evidence of subtle and progressive tubular injury. Symptoms of the patients were often vague, such as fatigue, polyuria, and nocturia, presenting very commonly in chronic kidney disease, yet not very specific for tubular damage.

The small vascular disease group, even though they had the highest fraction of underlying hypertension, did show very stable renal function compared with the TID group. Patients with SVD were more likely to be on long-term antihypertensive therapy, so this might have played a role in reducing the progression of renal dysfunction.

Renal biopsies in all groups gave insights into the underlying pathology and helped inform the choice of treatment. Immunotherapy is also normally chosen in the management of glomerular diseases, especially FSGS or IgA nephropathy patients. Management of tubulointerstitial disease requires a multidisciplinary strategy with close monitoring of nephrotoxic medications and systemic causes of interstitial inflammation. Strict blood pressure control and vascular protection were, therefore the cornerstones of therapy for patients with small-vessel disease.

Discussion

Kidney dysfunction with normal-range proteinuria presents a unique diagnostic challenge, often being underdiagnosed due to the lack of overt proteinuria, which is a common trigger for further nephrological evaluation. This case study highlights the importance of considering renal biopsy even without significant proteinuria to determine the underlying pathology and guide treatment decisions.

The study underscores that glomerular, tubulointerstitial, and small vascular diseases can all present with minimal proteinuria, yet lead to varying degrees of renal dysfunction. In particular, the high prevalence of glomerular disease among patients with normal proteinuria challenges the conventional association of proteinuria with glomerular pathology. Moreover, the finding that tubulointerstitial disease patients had the most severe decline in renal function suggests that tubular damage may progress insidiously, without the classical warning sign of proteinuria.

Renal biopsies proved to be an invaluable diagnostic tool in this study, providing the necessary insights to tailor treatment strategies to the specific pathology. In addition, biopsies helped predict patient outcomes, particularly in cases where the risk of progression to end-stage renal disease (ESRD) was high.

Conclusion

This retrospective study highlights the diverse histopathological findings in patients with renal dysfunction and normal-range proteinuria. Glomerular, tubulointerstitial, and small vascular diseases were the most common diagnoses, presenting distinct clinical characteristics and implications for patient management.

The findings underscore the importance of renal biopsy in patients with unexplained renal insufficiency, even in the absence of proteinuria, to uncover the underlying pathology and inform therapeutic decisions. Clinicians should maintain a high index of suspicion for glomerular and tubulointerstitial diseases in such patients, as early diagnosis and appropriate management may prevent further deterioration of renal function.

References

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5. Chertow, G.M., et al., Acute kidney injury and the role of tubulointerstitial diseases. Journal of the American Society of Nephrology, 2020.

6. Tan, J.C., et al., Kidney biopsy findings in unexplained renal insufficiency with normal range proteinuria. Clinical Nephrology, 2022.